Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

109. Lymphomas

Alexandre Chan and Gary C. Yee


KEY CONCEPTS

 Images Patients with Hodgkin lymphoma present with a painless, rubbery lymph node, which most commonly resides in the neck (cervical or supraclavicular nodes).

 Images Patients with early stage Hodgkin lymphoma should be treated with combination chemotherapy with or without involved-field radiation.

 Images Combination chemotherapy with doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) is the primary treatment for patients with advanced-stage Hodgkin lymphoma. Patients with advanced unfavorable disease may be treated with more aggressive regimens that have greater activity, but are associated with a higher risk of secondary malignancies.

 Images Some patients with Hodgkin lymphoma will be refractory to initial therapy or will have a recurrence following a complete remission. Response to salvage therapy depends on the extent and site of recurrence, previous therapy, and duration of initial remission. High-dose chemotherapy and autologous hematopoietic stem cell transplantation should be considered in patients with refractory or relapsed disease.

 Images The current classification system for non-Hodgkin lymphoma is the World Health Organization classification system, which is based on the principle that non-Hodgkin lymphomas can be classified into specific disease entities, defined by a combination of morphology, immunophenotype, genetic features, and clinical features.

 Images As compared with Hodgkin lymphoma, the clinical presentation of non-Hodgkin lymphoma is more variable because of disease heterogeneity and more frequent extranodal involvement.

 Images The Ann Arbor staging system correlates poorly with prognosis in non-Hodgkin lymphoma because the disease does not spread through contiguous lymph nodes and often involves extranodal sites.

 Images Several prognostic models have been developed to estimate prognosis in patients with non-Hodgkin lymphoma. The International Prognostic Index (IPI) score is a well-established model for patients with aggressive non-Hodgkin lymphoma. The Follicular Lymphoma International Prognostic Index (FLIPI) is a similar model used for patients with follicular and other indolent lymphomas.

 Images The clinical behavior and degree of aggressiveness can be used to categorize non-Hodgkin lymphoma into indolent and aggressive lymphomas. Patients with an indolent lymphoma usually have a relatively long survival, with or without aggressive chemotherapy. Although these lymphomas respond to a wide range of therapeutic approaches, few if any of these patients are cured of their disease. In contrast, aggressive lymphomas are rapidly growing tumors and patients have a short survival if appropriate therapy is not initiated. Most patients with aggressive lymphomas respond to intensive chemotherapy and many are cured of their disease.

 Images Patients with localized follicular lymphoma can be cured with radiation therapy alone. Advanced follicular lymphoma is not curable, and there are many treatment options, including watchful waiting, extended-field radiation therapy, single-agent alkylating agents, anthracycline-containing combination chemotherapy, purine analogs, interferon-α, anti-CD20 monoclonal antibodies, and high-dose chemotherapy with hematopoietic stem cell transplantation.

 Images Patients with localized aggressive lymphomas can be cured with several cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine [Oncovin], prednisone) chemotherapy and involved-field irradiation. Patients with bulky stage II, stage III, or stage IV aggressive lymphomas can be cured of their disease with R-CHOP chemotherapy.

 Images Conventional-dose salvage therapy can induce responses in patients with aggressive lymphomas who relapse, but long-term survival and cure is uncommon. Some patients with aggressive lymphoma who relapse and respond to salvage therapy can be cured with high-dose chemotherapy and autologous hematopoietic stem cell transplantation.


Lymphomas are a heterogeneous group of malignancies that arise from malignant transformation of immune cells that reside predominantly in lymphoid tissues. They most commonly present as a solid tumor, but can sometimes present as circulating tumor cells in peripheral blood. The differing histology of lymphoma cells has led to classification of Hodgkin lymphoma (Reed–Sternberg cells) or non-Hodgkin lymphoma (B- or T-cell lymphocyte markers). Non-Hodgkin lymphomas (NHLs) are further classified into distinct clinical entities, which are defined by a combination of morphology, immunophenotype, genetic features, and clinical features. Chemotherapy is the mainstay of treatment in patients with lymphoma, especially those with widespread disease. Overall cure rates are high for many subtypes of lymphomas, even when patients present with advanced disease.

HODGKIN LYMPHOMA

Hodgkin lymphoma is a form of lymphoma, named after Thomas Hodgkin, who first described seven cases of a mysterious disease of the lymph system more than 150 years ago. Hodgkin lymphoma is fatal in more than 90% of the patients who are untreated for 2 to 3 years, and the cause is still unknown. The prognosis with treatment is generally good, but is not well predicted by stage alone. The International Prognostic Index (IPI) score was created to better predict an individual’s risk of recurrence, which in turn influences treatment decisions. Patients with Hodgkin lymphoma can be categorized into four prognostic groups: early favorable disease, early unfavorable disease, advanced favorable disease, and advanced unfavorable disease. These groups are defined by patient age, gender, tumor size and spread (tumor stage), presence or absence of systemic symptoms, and laboratory test results. When appropriate therapy is given, more than 75% of all newly diagnosed Hodgkin lymphoma patients can be cured. However, the success of treatment has not been without cost. The treatment programs are intense, technically demanding, and associated with considerable acute toxicity and long-term complications. The long-term effects, particularly secondary malignancies, account for a higher cumulative mortality than Hodgkin lymphoma 15 to 20 years after treatment. Long-term toxicities with standard chemotherapy regimens have been more fully documented in recent years and are shaping future therapies.13

Epidemiology and Etiology

Hodgkin lymphoma represents less than 1% of all known cancers in the United States. It is estimated that 9,290 new cases of Hodgkin lymphoma will be diagnosed in the United States in 2013, and there will be 1,180 deaths associated with Hodgkin lymphoma during this same period.4 This disease occurs slightly more frequently in males than in females. Once thought to be a disease of the young, it is now recognized that Hodgkin lymphoma exhibits bimodal distribution in industrialized countries. The first peak occurs in the third decade of life, with a small peak occurring after age 50.1,3 The 5-year overall survival for all stages of Hodgkin lymphoma is about 85%.5 Death rates as a consequence of recurrent Hodgkin lymphoma are less than those from other causes 15 years after treatment.6

The etiology of Hodgkin lymphoma is currently unknown, but laboratory and epidemiologic evidence support infectious exposure as a potential cause.7,8 Studies suggest an increased risk of Hodgkin lymphoma in patients who have been infected with the Epstein-Barr’s virus (EBV); and many patients experience EBV activation even before the onset of Hodgkin lymphoma. EBV is found in about 40% of all classical Hodgkin lymphoma cases, and it is frequently observed in cases of mixed cellularity and lymphocyte-depleted Hodgkin lymphoma.9 Reed–Sternberg cells (large, bilobate, multinuclear cells), the malignant cells in Hodgkin lymphoma, are linked to EBV. Immunosuppressed individuals are also at much higher risk to develop Hodgkin lymphoma. Such individuals include patients with congenital immunosuppression, solid-organ transplantation recipients, and human immunodeficiency virus (HIV)-infected patients. Although the risk of developing Hodgkin lymphoma is about sevenfold greater in patients with HIV, the level of CD4 may vary depending on the subtype of Hodgkin lymphoma.7

Genetic factors are also associated with an increased risk of Hodgkin lymphoma. The strongest evidence suggesting that genes are important in the etiology of Hodgkin lymphoma comes from identical twin studies, which show that the unaffected identical twin has almost a 100-fold increase in risk.10

Pathophysiology

Hodgkin lymphoma is a clonal malignant lymphoid disease of transformed lymphocytes. The malignant cell in Hodgkin lymphoma is known as the Reed–Sternberg cell named after Drs. Dorothy Reed and Carl Sternberg, who were credited with the first definitive microscopic description of Hodgkin lymphoma.1,11 Procedures to isolate and analyze Reed–Sternberg cells remain a challenge to scientists, due to the relatively small percentage (1% to 2%) of Reed–Sternberg cells that are found in the Hodgkin lymphoma mass.9 Fortunately, new laboratory techniques have led to significant progress in identifying the origin of the Reed–Sternberg cell. Single-cell polymerase chain reaction and DNA microarray analyses indicate that nearly all classic Hodgkin lymphoma cases and all nodular lymphocyte-predominant Hodgkin lymphomas have immunoglobulin gene rearrangements, which indicates a germinal center or postgerminal center B-cell origin.9,12 Interestingly, nearly all Reed–Sternberg cells fail to express B-cell specific cell surface proteins.

B-cell transcriptional processes are disrupted during malignant transformation, which prevents B-cell surface marker expression and production of immunoglobulin messenger ribonucleic acid. The normal cellular consequence of failure to express immunoglobulin is apoptosis, but because of alterations in the normal apoptotic pathways, cell survival and proliferation are favored. Reed–Sternberg cells overexpress nuclear factor-κ B, which is associated with cell proliferation and antiapoptotic signals. Infections with viral and bacterial pathogens upregulate nuclear factor-κ B and consequently are hypothesized to be involved with the etiology of Hodgkin lymphoma.1,9,12 This hypothesis is supported by the presence of EBV in many Hodgkin lymphoma tumors, but it is important to note that not all tumors are associated with EBV. Another signaling pathway, Janus kinase–signal transduction and transcription (JAK–STAT), has also been found to be active in Hodgkin lymphoma.1,9 As molecular techniques continue to improve, our understanding of the pathophysiology of Hodgkin lymphoma will also improve.

The histopathologic classification of Hodgkin lymphoma has undergone numerous changes over the past three decades. The current classification system is the 2008 World Health Organization (WHO) classification (see Table 109-1).13 This classification divides Hodgkin lymphoma into two major groups: classical Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma, which constitute about 95% and 5% of cases, respectively. Classic Hodgkin lymphoma is further divided into four subtypes: nodular sclerosis, mixed cellularity, lymphocyte-depletion, and lymphocyte-rich. The subtypes in these classifications are based on characteristics of the Reed–Sternberg cell, the surrounding cells, and the connective tissue. Nodular sclerosis has features that make it distinct from the other three subtypes, which represent a continuum of background cellularity, with lymphocyte-predominance being the most cellular and lymphocyte-depletion being the least cellular. Nodular lymphocyte-predominant Hodgkin lymphoma is separated because of its distinct immunophenotype: CD15, CD20+, CD30, and CD45+ (the opposite of classical Hodgkin lymphoma). With the introduction of extensive staging, sophisticated radiotherapy, and effective combination chemotherapy, the prognostic value of these subtypes is becoming less clear. The true value of understanding these subtypes is likely tied to the pathogenesis of the disease and its potential prevention in the future.

TABLE 109-1 WHO Classification of the Mature B-Cell, T-Cell, and NK-Cell Neoplasms (2008)

Images

Clinical Presentation

Images Most patients with Hodgkin lymphoma present with a painless, rubbery, enlarged lymph node in the supradiaphragmatic area and commonly have mediastinal nodal involvement.14 Hodgkin lymphoma is occasionally diagnosed in an asymptomatic patient who has a mediastinal mass found with chest radiography or another imaging procedure. Asymptomatic adenopathy of the inguinal and axillary regions may be present at diagnosis but is less common (Fig. 109-1).1,14 Patients can also present with constitutional symptoms (B symptoms) before the discovery of lymph node enlargement, and these symptoms include fever, drenching night sweats, and weight loss. At diagnosis, these symptoms may appear in about 25% of all patients and up to 50% of patients with advanced disease. Patients may also experience other nonspecific symptoms including pruritus, fatigue, and development of pain after alcohol consumption at sites where nodes are involved.3 Extranodal manifestations, such as bowel and hepatic involvements, are much less common in Hodgkin lymphoma than NHL.1

Images

FIGURE 109-1 Areas of lymph nodes used in the staging of Hodgkin and non-Hodgkin lymphoma. Each rectangle corresponds to a nodal area.

Diagnosis, Staging, and Prognostic Factors

Diagnostic and staging procedures are based on recommendations made at the Ann Arbor and Cotswolds conferences and new scientific advances, as described in the National Comprehensive Cancer Network (NCCN) guidelines.15The diagnosis and pathologic classification of Hodgkin lymphoma can only be made by review of a biopsy (preferably an excisional biopsy) of the enlarged node by an expert hematopathologist.

In addition to a careful physical examination and routine laboratory tests, chest radiography and computed tomography (CT) scans of the chest, abdomen, and pelvis are routinely performed. Furthermore, positron emission tomography (PET) plays an important role in the initial staging of Hodgkin lymphoma, as it has shown high sensitivity and specificity in the staging of the disease.16 The use of integrated PET-CT has further improved the staging of Hodgkin lymphoma given that it can provide more sensitive and specific imaging as compared with each imaging alone. The NCCN guideline recommends either an integrated PET-CT scan (preferred) or a PET scan with diagnostic CT for initial staging.15 Bone marrow biopsy is also recommended in patients with advanced-stage disease.

Staging can be based on clinical or pathologic findings. The clinical stage is based on all noninvasive procedures (history, physical examination, laboratory tests, and radiologic findings), whereas the pathologic stage is based on the biopsy findings of strategic sites (muscle, bone, skin, spleen, and abdominal nodes) with an invasive procedure such as a laparoscopy or laparotomy. Patients with extranodal disease (muscle, skin, bone, or Waldeyer ring) contiguous to involved nodes are classified with the subscript “E” in the Cotswolds staging system.15 As a result of improved imaging techniques, pathologic workup and staging that can be associated with toxicity is rarely performed.


CLINICAL PRESENTATION Hodgkin Lymphoma

General

    • Most patients with Hodgkin lymphoma may have lymph node in the supradiaphragmatic and mediastinal areas.

Symptoms

    • About 25% of all patients present with fever, night sweats, and weight loss (i.e., B symptoms), and up to 50% of patients with advanced disease.

    • Fatigue, malaise, and pruritus.

Signs

    • Enlarged lymph node, which may present as painless and rubbery.

Laboratory Tests

    • A complete blood count, tests of renal and liver function, and serum electrolytes should be obtained.

    • Lactate dehydrogenase levels may be useful as prognostic factors and for monitoring response to therapy.

Other Diagnostic Tests

    • Varies depending on sites of involvement.

The Ann Arbor staging classification, which was developed at the 1970 Ann Arbor conference, has proven to be a good workable scheme. At the Cotswolds meeting in 1989, the Ann Arbor classification was modified to account for new diagnostic techniques (e.g., CT and magnetic resonance imaging), and the understanding that prognosis is associated with the bulk of the disease and the number of involved nodal sites (see Table 109-2).3 After careful staging, about one-half of patients have localized disease (stages I, II, and IIE) and the remainder have advanced disease (stage III or IV). About 10% to 15% present with metastatic disease (stage IV). It is important to note that Hodgkin lymphoma appears to follow a predictable pattern of nodal spread that is not seen with the NHLs.14,15

TABLE 109-2 The Ann Arbor Staging Classification of Hodgkin Lymphoma

Images

Patient prognosis is predominately driven by age and tumor stage. Patients older than ages 65 to 70 have a lower cure rate than younger patients. The difference in cure rates may be related to the frequent presence of comorbid diseases and decreased organ function in older patients, which impairs their ability to tolerate intensive chemotherapy.17 Stage is the other dominant factor in predicting survival; patients with limited-stage disease (stages I to II) have a 90% to 95% cure rate, while those with advanced disease (stages III to IV) have only a 60% to 80% cure rate.3,15

Seven adverse prognostic factors with similar impact on survival (each factor reduced survival by 7% to 8% per year) have been identified through an international collaborative effort. These factors can be combined to generate an International Prognostic Score (IPS) that can be used to predict progression-free and overall survival (see Table 109-3).18

TABLE 109-3 The International Prognostic Factors Project Score for Advanced Hodgkin Lymphoma

Images

TREATMENT

Hodgkin Lymphoma

Desired Outcomes

The current goal in the treatment of Hodgkin lymphoma is to maximize curability while minimizing short- and long-term treatment-related complications. According to the Surveillance, Epidemiology, and End Results (SEER) database, the 5-year age-adjusted relative survival is greater than 80%.5 Therefore, the treatment goal of all stages of Hodgkin lymphoma should be cure.

General Approach to Treatment

Although multiple treatment modalities are used to treat Hodgkin lymphoma, surgery has a limited therapeutic role regardless of stage. It is, however, important for diagnosis (excisional biopsy), and on certain occasions, such as placement of a central line.

Combination chemotherapy is the primary treatment modality for most patients with Hodgkin lymphoma. In general, patients with early stage Hodgkin lymphoma are treated with combination chemotherapy and radiation, whereas patients with advanced-stage disease are treated with combination chemotherapy with or without radiation therapy. For patients with refractory or recurrent disease, salvage therapy consists of multiagent chemotherapy with or without high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT), which can be curative.1,3,19

Radiation is often an integral part of the treatment plan. Selected patients with early stage disease (usually nodular lymphocyte-predominant histology) can receive radiation as the only treatment modality, whereas most patients will receive chemotherapy and radiation. Although radiation is a local therapy, many patients with advanced disease will also receive radiation therapy to residual or bulky disease sites after chemotherapy. The major concern with radiation therapy is its long-term effects, such as cardiovascular disease and secondary malignancies, which commonly occur in the lung, breast, gastrointestinal tract, and connective tissue.20 To avoid these toxicities, several studies have been completed and others are ongoing to determine the optimal extent (radiation field) and dose of radiation.21,22 Radiation to a single field that contains Hodgkin lymphoma is called involved-field radiation; radiation to the involved field and a second uninvolved area is termed extended-field radiation or subtotal nodal irradiation; and radiation of all areas is called total nodal irradiation. When given with chemotherapy, involved-field radiation is usually used to avoid the increased toxicity associated with extended-field radiation.21 The following sections review treatment of early stage favorable disease, early stage unfavorable disease, advanced-stage favorable disease, advanced-stage unfavorable disease, and salvage therapy.

Treatment of Early Stage Favorable Disease

Patients with early stage favorable disease have stage IA or IIA disease and no adverse risk factors (extranodal disease, bulky disease, three or more sites of nodal involvement, or an erythrocyte sedimentation rate of ≥50 mm/h [≥13.9 μm/s]). In the past, extended-field radiation was considered to be the treatment of choice for stages IA and IIA disease. Although most patients were cured of their disease, it is associated with long-term toxicities due to large radiation fields, such as heart disease, pulmonary dysfunction, and secondary malignancies.3,20,23

In an effort to avoid the long-term effects of extended-field radiation and improve treatment results, several studies have evaluated a combined modality approach that involves the use of short-duration chemotherapy and involved-field radiation. Based on favorable results of these studies, most patients with early stage favorable disease are no longer treated with radiation alone.

Clinical trials comparing radiation alone to radiation plus chemotherapy show lower relapse rates in patients treated with combined modality therapy (radiation and chemotherapy), but no change in overall survival because of the availability of effective salvage therapy.22 Current trials focus on questions such as the optimal number of chemotherapy cycles, the volume of radiation that must be used to obtain optimal patient outcomes, and the role of PET scanning to individualize therapy. Emerging data also suggest that as few as two cycles of chemotherapy followed by involved-field radiation is sufficient in favorable, early stage disease patients. Different combination chemotherapy regimens have been used in these studies, and no one regimen is clearly superior to another.2123

The current NCCN guidelines recommend that patients with early stage favorable disease be treated with two cycles of the Stanford V regimen (doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone) or four cycles of the ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine) regimen, followed by consolidative involved-field radiation.24 With this approach, 5-year progression-free and overall survival rates of >90% can be achieved.

Investigators are now focusing on novel strategies to minimize the long-term toxicities of Hodgkin lymphoma treatment, particularly among those patients who have good treatment prognosis. One recently published study compared the efficacy of two versus four cycles of ABVD and involved-field radiation in early stage favorable disease Hodgkin lymphoma patients. It was shown that treatment with two cycles was as effective and less toxic than four cycles of chemotherapy followed radiation therapy at 5 years.25 Such encouraging data would need to be confirmed with longer followup of the treatment.

Nodular lymphocyte-predominant Hodgkin lymphoma has been described as more indolent in nature, and better prognosis can be achieved when compared with classic Hodgkin lymphoma. The use of radiation alone for nodular lymphocyte-predominant Hodgkin lymphoma patients who choose to omit chemotherapy, or who cannot tolerate chemotherapy, does not appear to adversely affect survival.15 The disadvantage of radiation therapy alone as compared with combination chemotherapy and radiation is the higher relapse rate. Patients who relapse after radiation alone (20% to 25%) can be successfully salvaged with chemotherapy. If the decision is made to use radiation alone, extended-field radiation appears to be superior to involved-field radiation.26 It is shown that more extensive radiation reduces the risk of treatment failure at 10 years (31% vs. 43%), although it does not improve overall survival. However, the risk of long-term complications (such as secondary malignancies) is increased with the use of extended-field radiotherapy when compared with less extensive radiation fields.20

Treatment of Early Stage Unfavorable Disease

Patients with early stage disease who have certain features associated with a poor prognosis (B symptoms, extranodal disease, bulky disease, three or more sites of nodal involvement, or an erythrocyte sedimentation rate >50 mm/h [≥13.9 μm/s]) are defined as having unfavorable disease. Different groups or clinical trials have different definitions for unfavorable disease.22 Current guidelines recommend combined modality therapy (combination chemotherapy and involved-field radiation) to reduce the relapse rate and avoid the toxicity associated with extended-field radiation.15

Images Although randomized trials show that combined modality therapy reduces the relapse rate in patients with early stage unfavorable disease, questions concerning the appropriate radiation volume, most effective chemotherapy regimen, and number of chemotherapy cycles remain.22 A number of studies have compared extended-field radiation to involved-field radiation. In one large trial conducted by the German Hodgkin Study Group (GHSG), patients with early stage unfavorable Hodgkin lymphoma treated with chemotherapy and involved-field radiation had similar freedom from treatment failure and overall survival as those treated with the same chemotherapy regimen and extended-field radiation.27 Because toxicity was greater with extended-field radiation, the accepted standard is chemotherapy and involved-field radiation.

Different chemotherapy regimens and number of chemotherapy cycles were also compared in clinical trials. Mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) was one of the first highly effective regimens introduced to treat Hodgkin lymphoma. MOPP or MOPP-like regimens were then given alternately or hybridized with a combination of ABVD. In advanced disease, ABVD was found to be less toxic than alternating MOPP/ABVD, and both were found to be superior to MOPP alone. Consequently, ABVD has now become the standard regimen used to treat patients with early stage unfavorable disease. It has established effectiveness in patients with advanced-stage disease and a favorable toxicity (both acute and chronic) profile.

Despite excellent results from treatment with ABVD and radiation, about 5% of patients do not respond to initial treatment and another 15% of patients will relapse following an initial response. Several studies have evaluated more aggressive regimens or more cycles of therapy. However, none of these regimens has proven to be more effective than ABVD, and each is associated with more toxicity. The current NCCN guideline lists the Stanford V regimen as an acceptable option, which also uses more drugs than the ABVD regimen.15

In summary, most patients with early stage disease will be treated with two to four cycles of ABVD chemotherapy and involved-field radiation. The number of cycles administered is based on the classification of favorable versus unfavorable disease. For patients who have unfavorable disease with bulky disease, ABVD followed by involved-field radiation. If patients attain complete remission after four cycles by restaging, they can be treated with involved-field radiation alone or two additional cycles of ABVD (total of six) followed by involved-field radiation. For patients who have unfavorable yet nonbulky disease, observation without involved-field radiation can be a treatment option after six cycles of ABVD.15 Current trials are evaluating the use of PET scans as biomarkers to individualize therapy and minimize the amount of therapy necessary for cure.16

Treatment of Advanced-Stage Disease

Advanced-stage disease consists of stages III and IV disease. In some studies, stage IIB with a large mediastinal mass or extranodal disease is also considered advanced-stage disease (Table 109-2). By definition, patients with stages III and IV disease have tumors on both sides of the diaphragm, which almost always precludes the use of radiation alone as a therapeutic modality. Intensive combination chemotherapy is the mainstay of treatment, although some patients will benefit from radiation following chemotherapy. The prognosis of advanced-stage disease is excellent with 5-year overall survival rates ranging from less than 56% to 90%. Prognostic factors have been identified and standardized to provide a more accurate individual prognosis (Table 109-3).18

Patients with advanced-stage Hodgkin lymphoma can be classified into two groups based on the number of prognostic factors present from the IPI (Table 109-3). Advanced-stage patients with three or fewer poor prognostic factors are considered to have favorable disease and an about 60% likelihood of being failure-free at 5 years with traditional combination chemotherapy. Advanced-stage patients with four or more poor prognostic factors are considered to have unfavorable disease and a less than 50% likelihood of being failure-free at 5 years with traditional combination chemotherapy. Because of the high treatment failure rate, the therapeutic goal for this group of high-risk patients is to improve antitumor control.

Combination Chemotherapy

One of the initial combination chemotherapy regimens introduced in the early 1960s that was shown to cure advanced Hodgkin lymphoma was the MOPP regimen (Table 109-4). MOPP chemotherapy was a mainstay of treatment for patients with stages III and IV advanced Hodgkin lymphoma.

TABLE 109-4 Combination Chemotherapy Regimens for Hodgkin Lymphoma

Images

Images The development of ABVD by Bonnadonna et al. at the Milan Cancer Institute about a decade later represents the next important step in the evolution of therapy for Hodgkin lymphoma (Table 109-4).28ABVD was initially shown to be effective in treating MOPP failures and was later compared directly to MOPP in advanced disease, where it produced an 82% complete response rate, as compared to a 67% complete response rate with MOPP. Improved failure-free survival was demonstrated with ABVD, but no significant differences in 5-year overall survival were noted.29 Because ABVD was less toxic and provided similar or better outcomes than MOPP, it eventually replaced MOPP as the standard regimen for advanced-stage Hodgkin lymphoma.

In the early 1980s, the Goldie–Coldman hypothesis proposed that chemotherapy resistance was related to spontaneous mutation rates and the development of resistant clones. To test that hypothesis, researchers designed several clinical trials to evaluate the efficacy of alternating non–cross-resistant drug combinations in patients with Hodgkin lymphoma.30 The initial approach adopted by investigators was to alternate or combine the MOPP and ABVD regimens. When MOPP and ABVD (or doxorubicin [Adriamycin], bleomycin, vinblastine [ABV]) are combined in a monthly cycle, it is referred to as a hybrid regimen. Besides a potential benefit in efficacy, another potential benefit of alternating or hybrid regimens is the decreased risk of long-term toxicities. In the alternating MOPP/ABVD regimen, the cumulative doses of procarbazine and mechlorethamine are reduced by 50%, and the cumulative doxorubicin dose is reduced by 50%. In the hybrid regimen, the cumulative doxorubicin dose is reduced by 33%, and the cumulative bleomycin dose is reduced by 50%.

Several clinical trials have been performed to evaluate the efficacy of alternating or hybrid MOPP/ABVD regimens. The results of these trials show that alternating and hybrid regimens are superior to MOPP but not to ABVD.30Another approach evaluated by researchers was the administration of sequential cycles of MOPP and ABVD (MOPP → ABVD). Results of an intergroup trial showed sequential MOPP and ABVD to be inferior to the MOPP/ABV hybrid regimen in terms of response and survival.31 In another randomized comparison trial of the MOPP/ABV hybrid regimen and ABVD, the complete remission rate, failure-free survival, and overall survival were similar between the two regimens.32 The latter trial was closed prematurely because of an increased number of treatment-related deaths and secondary malignancies in the patients who received the MOPP/ABV hybrid regimen.

More aggressive regimens such as Stanford V and bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone (BEACOPP) have been evaluated as alternatives to MOPP or ABVD.19 The Stanford V regimen generated considerable interest because of the results of phase II trials.23,33 Stanford V, ABVD, and a MOPP/ABV hybrid-like regimen (mechlorethamine, vincristine, procarbazine, prednisone, epidoxorubicin, bleomycin, vinblastine, lomustine, doxorubicin, and vindesine [MOPPEBVCAD]) were compared in a randomized trial to determine the best regimen to support a reduced radiotherapy program.34 Five-year failure-free and progression-free survival were significantly worse for the Stanford V regimen as compared to the other two regimens. However, no significant differences in projected 5-year progression-free and overall survival were observed between Stanford V and ABVD in a recently published randomized trial of patients with advanced Hodgkin lymphoma.35 The investigators speculated that differences in the application of radiotherapy may explain the divergent results in the two randomized trials. More pulmonary toxicity occurred in the ABVD group, but other toxicities occurred more frequently in the Stanford V group.

The GHSG developed the BEACOPP regimens based on principles of dose density, dose intensity, and mathematical modeling. BEACOPP uses similar drugs as in the cyclophosphamide, vincristine, procarbazine, and prednisone (COPP)/ABVD regimen, but rearranges the drugs in a shorter 3-week cycle. Several different versions of BEACOPP have been developed: standard-dose BEACOPP, escalated-dose BEACOPP, and dose-dense BEACOPP (BEACOPP-14).36 Granulocyte colony-stimulating factor support is required for the escalated-dose BEACOPP and BEACOPP-14 regimens.

Several randomized trials have compared BEACOPP to other regimens.3,19 The GHSG conducted a randomized comparison of eight cycles of COPP/ABVD (alternating), BEACOPP, or an escalated-dose BEACOPP regimen in 1,201 patients with advanced Hodgkin lymphoma.37 Most patients had advanced favorable disease, and all patients received radiation to sites of bulky or residual disease after chemotherapy. Escalated-dose BEACOPP appears to be the most active regimen in this study with 10-year freedom from treatment failure at 82% and overall survival at 86%, but this regimen also appeared to be more toxic.38 Despite filgrastim support, 90% of patients in the escalated-dose BEACOPP group had grade IV leukopenia, as compared with 19% in patients in the COPP/ABVD arm and 37% in the standard-dose BEACOPP arm. The higher rate of acute toxicity did not translate into a higher risk of treatment-related fatalities (<2% for all three regimens). The risk of toxic deaths due to sepsis or acute cardiac events was higher in elderly patients receiving BEACOPP.39 Furthermore, the higher rate of leukemia in patients receiving escalated-dose BEACOPP (2.5% at 5 years followup, and 3% at 10 years followup) as compared with those in the COPP/ABVD arm (0.4%) are of concern. In another study, 370 patients with advanced Hodgkin lymphoma were randomized to receive six cycles of ABVD, six cycles of CEC (cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epirubicin, vincristine, procarbazine, vinblastine, bleomycin), or four cycles of escalated-dose BEACOPP with two cycles of standard-dose BEACOPP.40 BEACOPP was superior to ABVD for 5-year failure-free survival (78% vs. 65%, P = 0.036) and progression-free survival (81% vs. 68%, P = 0.038), but 5-year overall survival was not significantly different between ABVD and BEACOPP. It appears that BEACOPP may be superior to ABVD in patients with high-risk advanced Hodgkin lymphoma (IPS ≥3). Higher rates of neutropenia and severe infections were observed with BEACOPP as compared with ABVD.

Finally, GHSG has conducted several trials to evaluate the optimal number and intensity of BEACOPP. In the HD12 study, eight cycles of escalated-dose BEACOPP were compared to four cycles of escalated-dose and four cycles of standard-dose BEACOPP (4 + 4 BEACOPP regimen) with or without radiation therapy. Freedom-from-treatment failure, progression-free survival, and overall survival were not different between the two treatment arms.41Although the 4 + 4 BEACOPP regimen resulted in less acute hematologic toxicities during cycles five to six, this difference did not translate into a lower risk of treatment-related mortality. In the recently published HD15 noninferiority trial, eight cycles of escalated-dose BEACOPP was compared with six cycles of escalated-dose BEACOPP and eight cycles of BEACOPP-14.42 Freedom-from-treatment failure and overall survival were significantly better in the patients treated with six cycles of escalated-dose BEACOPP as compared with those treated with eight cycles of escalated-dose BEACOPP. No significant differences were observed between the eight cycles of escalated-dose BEACOPP versus BEACOPP-14. The risk of treatment-related mortality and secondary malignancies was also lower in patients treated with six cycles of escalated-dose BEACOPP. Of interest was the use of PET-guided radiotherapy in all of the treatment arms.


Clinical Controversy…

Some clinicians believe that escalated-dose BEACOPP is superior to ABVD in the treatment of patients with advanced-stage Hodgkin lymphoma. Escalated-dose BEACOPP has been shown to be superior to COPP/ABVD, which is similar to MOPP/ABVD. Other experts believe that ABVD is still the treatment of choice because escalated-dose BEACOPP has not been tested directly against it. They also express concern over the long-term toxicity with escalated-dose BEACOPP.

The results of these studies suggest that escalated-dose BEACOPP is superior to ABVD in the treatment of advanced Hodgkin lymphoma, but at the cost of more treatment-related toxicity. Some experts recommend that these more intensive regimens should only be considered in patients with high-risk disease because of the potentially higher risk of secondary malignancies. The NCCN guideline suggests that patients attaining a complete remission after four cycles of escalated-dose BEACOPP can be followed up with standard-dose BEACOPP and radiation therapy.15

Risk-Adapted Therapy

Patients with advanced-stage Hodgkin lymphoma can be classified into two groups based on the IPS (Table 109-3). Advanced-stage patients with three or fewer poor prognostic factors are considered to have favorable disease and an about 60% likelihood of being failure-free at 5 years with traditional combination chemotherapy.18 Advanced-stage patients with four or more poor prognostic factors are considered to have unfavorable disease and a less than 50% likelihood of being failure-free at 5 years with traditional combination chemotherapy. Because of the high treatment failure rate, the therapeutic goal for high-risk patients is to improve antitumor control.

One recently published study has reported the feasibility of a risk-adapted treatment approach based on the IPS, with the goal of reducing cumulative doses of chemotherapy in patients with low-risk Hodgkin lymphoma.43 Low-risk patients with early unfavorable disease and standard-risk patients with IPS of <3 were treated with two cycles of standard-dose BEACOPP, and high-risk patients with an IPS ≥3 were treated with two cycles of escalated-dose BEACOPP. After an interim gallium or PET/CT scan, patients with positive disease were given escalated-dose BEACOPP, while patients who had negative disease were given standard-dose BEACOPP. For all patients, the complete remission rate, 5-year event-free survival, and overall survival were 97%, 85%, and 90%, respectively. Although this was not a randomized study, the results support the use of a risk-adapted treatment modality in the treatment of advanced-stage Hodgkin lymphoma.

In summary, the NCCN guidelines suggest that ABVD or Stanford V should be considered for primary treatment for patients with advanced disease. Escalated-dose BEACOPP should be considered for patients with unfavorable disease because of increased efficacy. It is recommended that patients in advanced-stage disease with an IPS <4 should be treated with ABVD because of less acute toxicity, the absence of sterility, and a low risk of secondary acute myeloid leukemia/myelodysplastic syndrome.15

Radiation

The role of low-dose consolidative radiation when added to chemotherapy for the treatment of advanced-stage Hodgkin lymphoma is controversial.19,23 The rationale for its use is based on the radiosensitivity of Hodgkin lymphoma, a 20% to 40% relapse rate, and the tendency of Hodgkin lymphoma to relapse at sites of initial involvement.44 Many clinical trials have been conducted to evaluate the benefit of additional radiation in patients who have a complete response to combination chemotherapy. The results of these studies are inconsistent, and a meta-analysis of 14 randomized trials showed a modest improvement in disease control at 10 years, but no difference in overall survival.45 In one study, patients with advanced disease were randomized to receive either involved-field radiation after MOPP/ABV hybrid chemotherapy or no further therapy. Eight-year event-free survival reported for patients achieving a complete response randomized to receive radiation, no radiation, and a group of partial responders who received radiation were 73%, 77% and 76%, respectively. These results suggest that radiation provides no benefit for patients who achieve a complete remission with chemotherapy. Furthermore, radiation was also associated with a higher risk of secondary cancers (12.9% vs. 5.6% in the radiation and no radiation arms, respectively). It does, however, show a significant role for consolidative radiation in patients who have a partial response after chemotherapy.46

Summary

In summary, the standard treatment of advanced-stage favorable Hodgkin lymphoma is six to eight cycles of ABVD chemotherapy. Escalated-dose BEACOPP should be considered for patients with unfavorable disease. This risk-adapted approach should result in 70% to >90% of patients achieving a complete remission and 60% to 80% of patients being cured of their disease. No further treatment is needed for patients attaining a complete remission. Patients achieving a partial remission should receive consolidative radiation to residual sites of disease.

Treatment of Refractory or Relapsed Disease

Images The goal of salvage therapy is cure regardless of the site(s) of recurrence or primary therapy. With the increasing use of chemotherapy with or without radiation, regardless of disease extent, the rate of primary refractory disease is decreasing. Patients who do not achieve a complete remission with the initial regimen are considered to have primary refractory disease. These patients have a poor prognosis when treated with salvage chemotherapy, and therefore should be offered autologous HSCT as a treatment option.47,48

Patients who relapse after an initial complete response can be treated with the same regimen, a different potentially non–cross-resistant regimen, radiation, or high-dose chemotherapy and autologous HSCT (often preceded by conventional-dose chemotherapy). There are no data available from randomized trials comparing the cytoreductive regimens that are used before transplantation. However, as most patients are now treated with ABVD, doxorubicin should be avoided in salvage chemotherapy regimens if the cumulative dose has reached >400 mg/m2, particularly in those patients who have received mediastinal radiotherapy because they are at much higher risk of cardiotoxicity.

The response to salvage therapy depends on the extent and site of recurrence, previous therapy, and duration of initial remission. Patients who relapse after radiation therapy alone have a good chance of being cured with combination chemotherapy, although fewer patients are being treated with radiation alone. High response rates (60% to 87%) have been observed with salvage chemotherapy regimens.49 Other patient groups who have a favorable prognosis following salvage therapy include patients who experience a local recurrence in a nonirradiated location and those who relapse more than 1 year after completion of their initial chemotherapy. Patients who experience late relapses can be cured with retreatment with the same chemotherapy regimen, treatment with a different, potentially non–cross-resistant regimen, or high-dose chemotherapy and autologous HSCT.

Patients who have an early relapse (<1 year after treatment) generally respond poorly to standard-dose salvage chemotherapy. High-dose chemotherapy and autologous HSCT is more effective, but also produces a higher risk of treatment-related mortality. Therefore, the choice of salvage treatment should consider the patient’s tolerance for a particular set of chemotherapeutic agents and treatment approach (standard-dose chemotherapy vs. high-dose chemotherapy and autologous HSCT).47

High-dose therapy should be considered in patients who relapse within 12 months of initial remission and in those who are refractory to first-line chemotherapy.47 Although no single preparative regimen has been shown to be superior to another, most regimens do not include total-body irradiation because of its potential pulmonary toxicity. Most patients are already at higher risk for pulmonary toxicity because of previous exposure to one or more of the following: bleomycin, thoracic radiation, and nitrosoureas. Long-term effects of high-dose chemotherapy and autologous HSCT were elucidated in a recent study. Among 218 Hodgkin lymphoma patients who were treated with high-dose chemotherapy and autologous HSCT, 70% survived over 2 years. A total of 15 patients were diagnosed with a second malignancy and the median time from autologous HSCT to secondary malignancy diagnosis was 9 years. The risk of secondary malignancy is possibly caused by high-dose etoposide in the rescue regimen, as well as those patients who were initially treated with MOPP chemotherapy.50

Brentuximab vedotin is an antibody-drug conjugate (ADC) comprising an anti-CD30 antibody conjugated by a protease cleavable linker to a potent antimicrotubule agent, monomethyl auristatin E (MMAE). After binding of the ADC to CD30 on the cell surface, the ADC-CD30 complex is internalized. This leads to the release of MMAE via proteolytic cleavage in the lysosomal compartment. Tubulin binding by MMAE disrupts the microtubule network, which can lead to apoptotic death of the cancer cells.51 In a pivotal multicenter phase II study of 102 patients with relapsed or refractory Hodgkin lymphoma after HSCT, objective responses and complete remissions was observed in 75% and 34% patients, after a median followup of 9 months. Common toxicities associated with brentuximab vedotin include neuropathy, neutropenia, nausea, and fatigue.52 Based on these results, the FDA recently approved brentuximab vedotin (Adcetris®) for the treatment of patients with Hodgkin lymphoma after failure of HSCT or in patients who have failed at least two prior chemotherapy regimens and are not candidates for HSCT.

Long-Term Complications

A variety of acute and chronic toxicities may occur as a result of treatment for Hodgkin lymphoma. Long-term complications of radiation therapy, chemotherapy, and combined modality therapy have become more evident as the curability and long-term survival of Hodgkin lymphoma patients has improved.13,20 Gonadal dysfunction (including sterility and hypothyroidism), secondary malignancies, and cardiopulmonary diseases have become important considerations in the treatment of this malignancy. Almost all men and up to 50% of premenopausal women treated with six cycles of regimens containing alkylating agents become sterile. This appears to be a dose-related phenomenon. For men, even a single dose of nitrogen mustard or chlorambucil can cause sterility, so if fertility is a major concern, ABVD may be the best alternative.50

The risk of secondary malignancies is increased about threefold in long-term survivors of Hodgkin lymphoma. The risk of developing leukemia carries the highest increase in risk and is seen with radiotherapy, chemotherapy, and chemoradiotherapy. Solid tumors, including breast cancers, gastrointestinal cancers, and lung cancers are also likely to develop more than 10 years after the completion of treatment.5355 A recently published British cohort study suggested that unlike radiotherapy, which may increase the occurrence of cancer at almost all anatomic sites, chemotherapy is associated with an increased risk of leukemia, NHL, and lung cancer.55 However, studies that evaluate the risk of secondary malignancies (and other complications) must be interpreted cautiously because many factors probably contribute to the development of secondary malignancies.56 In addition, much of the long-term complication data are derived from patients who were treated with older regimens and extensive field radiotherapy, which are no longer commonly used in clinical practice. Furthermore, as minimal data are currently available on the appropriate followup duration and procedures to monitor for long-term effects, many of the recommendations in the NCCN guideline are based on clinical practice. Monitoring and followup should be personalized and patient-specific, after assessing a patient’s risks for long-term complications.15

NON-HODGKIN LYMPHOMA

The NHLs are a heterogeneous group of lymphoproliferative disorders that affect individuals from early childhood to late adulthood. Advances in molecular biology techniques and our understanding of the human immune system have led to major progress in understanding the pathogenesis and treatment of the lymphomas. NHLs are classified into distinct clinical entities that are defined by a combination of morphology, immunophenotype, genetic features, and clinical features. These differences influence the natural history, and approach and response to treatment. The use of extensive combination chemotherapeutic regimens shows dramatic improvement in survival and cure in patients with a disease that was once considered incurable. The 5-year survival rate for patients with NHL has increased from 48% to 71% over the past 25 years, and the mortality rate actually declined from 1997 to 2004.4,5 Further improvement in survival is anticipated with the continued expansion of our therapeutic armamentarium, including high-dose chemotherapy and biologic therapy.

Epidemiology and Etiology

NHL is the fifth most common cause of newly diagnosed cancer in the United States and accounts for about 4% of all cancers. An estimated 69,740 new cases will be diagnosed in 2013, and it is estimated that 19,020 people will die from NHL during this same period.4 Although the average age of patients at the time of diagnosis is about 67 years, NHL can occur at any age. The incidence rate generally increases with age, and is higher in men than in women and in whites than in blacks.5 The age-adjusted incidence rate of NHL increased by more than 80% in the United States since the early 1970s, from about 11 cases per 100,000 in 1975 to about 20 cases per 100,000 in 2003 and 2004.5The incidence of NHL increased by 3% to 4% from 1975 to 1991, but appears to have stabilized since reaching its peak in 1994. The increased incidence of NHL over the past three decades is second only to melanoma and has been referred to as an epidemic of NHL. Although the increase has been noted particularly among the elderly and patients with acquired immune deficiency syndrome (AIDS), much of it cannot be explained by known risk factors.

The etiology of NHL is unknown, although several genetic diseases, environmental agents, and infectious agents are associated with the development of NHL.7,57 An increased incidence of NHL is seen in many congenital and acquired immunodeficiency states, supporting the role of immune dysregulation in the etiology of NHL.57 Patients with congenital immunodeficiency disorders such as Wiskott-Aldrich’s syndrome and ataxia telangiectasia, acquired immunodeficiency disorders such as AIDS, and those receiving chronic pharmacologic immunosuppression in the setting of solid-organ transplantation are predisposed to the development of NHL. Autoimmune diseases (Hashimoto’s thyroiditis, Sjögren’s syndrome) cause chronic inflammation in the mucosa-associated lymphoid tissue (MALT), which predisposes patients to subsequent lymphoid malignancies. Other autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, are also associated with the development of NHL, but the use of immunosuppressive agents in these diseases makes the pathologic cause less clear.

Certain infections are associated with the development of lymphoma.7 EBV was discovered in cell lines from tumors of patients with African (endemic) Burkitt lymphoma, and EBV DNA is associated with nearly all cases of endemic Burkitt lymphoma. However, EBV is associated with sporadic Burkitt lymphoma in 15% to 85% of cases. EBV is also associated with posttransplant lymphoproliferative disorders and some lymphomas in patients with AIDS or congenital immunodeficiencies. The human T-cell lymphotropic virus type 1 was the first human retrovirus associated with a malignancy. Infection with human T-cell lymphotropic virus type 1, especially in early childhood, is strongly associated with an aggressive form of T-cell lymphoma, known as adult T-cell leukemia/lymphoma. Human T-cell lymphotropic virus type 1 is endemic in parts of southern Japan, Africa, South America, and the Caribbean. In endemic areas, more than 50% of all NHL cases are adult T-cell leukemia/lymphoma. A third virus associated with NHL is human herpes virus 8 (also referred as Kaposi sarcoma–associated herpesvirus [KSHV]). This virus was originally isolated from Kaposi sarcoma lesions in AIDS patients. Gastric infection with Helicobacter pylori, a gram-negative bacteria that leads to chronic gastritis, is associated with gastric MALT lymphomas. Finally, hepatitis C virus has been associated with splenic and nodal marginal zone lymphomas.

A number of physical agents are also associated with the development of NHL.57 Exposure to herbicides, particularly phenoxyl herbicides, is associated with the development of NHL. These observations may explain why certain occupations, such as farmers, forestry workers, and agricultural workers, are associated with a higher risk of NHL. Exposure to lawn-care pesticides is also increasing in the general population. A higher risk of NHL is also associated with exposure to other chemical solvents and dyes, exposure to radiation from nuclear explosions, and high intake of meats and dietary fats. Smoking or alcohol consumption is not strongly associated with an increased risk of NHL.

Molecular Abnormalities

Chromosomal translocations have become a hallmark of many lymphoid malignancies.58,59 The presence of these specific translocations can be helpful in the diagnosis and classification of lymphoid malignancies. The mechanisms leading to the translocations are unknown, but they usually involve the antigen receptor loci. In contrast to most myeloid and some lymphoid leukemias, NHLs usually place a structurally intact cellular protooncogene under the regulatory influence of highly expressed immunoglobulin or T-cell receptor genes, leading to effects on cell growth, cellular differentiation, or apoptosis. The most common chromosomal translocations involve t(8;14), t(14;18), and t(11;14); each translocation involves the immunoglobulin heavy-chain gene locus on chromosome 14 at 14q32. The translocation t(8;14) that involves c-MYC, a well-characterized oncogene clearly associated with malignancy, is implicated in nearly all cases of Burkitt lymphoma. The translocation t(14;18) that involves BCL-2, one of several putative B-cell lymphoma–associated oncogenes, is found in about 90% of cases of follicular B-cell lymphomas. The translocation t(11;14) that involves BCL-1 is found in about 70% of patients with mantle cell lymphoma. Another putative B-cell lymphoma–associated oncogene, BCL-6, is found in about one-third of diffuse large B-cell lymphomas.

Although mutations in the p53 tumor suppressor gene have been recognized in many human neoplasms, such mutations have not been consistently found in patients with lymphoma, which suggests that it may occur late in malignant evolution.

Because of their role in the pathogenesis of lymphoma, oncogenes are attractive molecular targets for the development of new and novel therapies.60

Pathology and Classification

NHLs are neoplasms derived from the monoclonal proliferation of malignant B or T lymphocytes and their precursors. About 85% to 90% of NHLs in the United States are of B-cell origin.57 Proliferation of malignant cells results in the replacement of the normal cells and architecture of lymph nodes or bone marrow with a relatively uniform population of lymphoid cells. The classification of NHLs has evolved over the past five decades, as advances in immunology and genetics have allowed scientists to recognize a number of previously unrecognized subtypes of NHLs (Table 109-5).61,62 The current classification schemes characterize the NHLs according to the cell of origin (B cell vs. T cell), clinical features, and morphologic features. Additional immunohistochemical markers, cytogenetic features, and genotypic characteristics may help to further classify NHL into subtypes.

TABLE 109-5 Evolution in the Classification of Non-Hodgkin Lymphomas

Images

Morphology

The macroscopic and microscopic appearance of the involved tissue remains one of the most important factors in the diagnosis and classification of NHLs.61,62 In the 1950s, Rappaport et al. proposed a morphologic classification of malignant lymphomas based on two features: that the malignant cell would disrupt the nodal architecture in a nodular or diffuse manner, and that lymphomas of histiocytic origin existed. The Rappaport classification gained rapid acceptance in the United States because of its precision, simplicity, and prognostic significance. Application of the system divided NHLs into those with large (i.e., incorrectly called “histiocytes”) or small cells, with or without a nodular (i.e., follicular) growth pattern.

Immunology

In the 1970s, it became apparent that NHLs were tumors of the immune system and were derived from B or T lymphocytes. With the availability of techniques using antibodies to antigens on the surface of lymphoid cells (i.e., immunophenotype) and cytochemical assays, expert pathologists independently developed new classification schemes for NHL in the 1970s and 1980s.61,62 The Kiel classification was based primarily on the work of Lennert in Germany and became widely used in Europe. In North America, the Lukes and Collins classification scheme was used briefly, but was soon superseded by the Working Formulation. Like the Rappaport classification, divisions within the Working Formulation were based largely on cell size (large [histiocytic] vs. small [lymphocytic]), cell shape (round vs. not round), and growth pattern (follicular [nodular] vs. diffuse). Both the Kiel and Working Formulation classification schemes considered the histologic grade of the tumor, but only the Working Formulation considered actual survival curves of patients with the various subtypes of NHL. Low-grade indicated longer median survival (i.e., indolent) whereas intermediate-grade and high-grade indicated shorter median survival (i.e., aggressive). In the 1980s and early 1990s, the Working Formulation became the most widely used classification scheme in North America. It was based on the premise that NHL was a single disease with a range of histologic grades and clinical aggressiveness.

New Disease Entities

In the 1980s and early 1990s, rapid advances in immunology and genetics allowed scientists to recognize a number of previously unrecognized subtypes of NHLs. Cytogenetic and molecular genetic analyses identified the presence of many chromosomal translocations, oncogenes, and their gene products in patients with NHL (see Molecular Abnormalities later in this chapter). In addition, diseases that would have been lumped together as low-grade or intermediate/high grade in the Working Formulation showed marked differences in survival, which prompted scientists to reevaluate lymphoma classification schemes.

Information from these studies allowed scientists to further classify B-cell lymphomas as malignant expansions of cells from the germinal center, mantle zone, or marginal zone of normal lymph nodes.61,63Germinal centers are complex structures that form in the spleen and lymph nodes in response to antigenic challenge. In addition to B cells, germinal centers contain antigen-presenting cells and helper T cells that cooperate in mediating the B-cell changes that result in a more potent secondary immune response. Malignant transformation often occurs or is initiated in germinal center B cells. Follicular, Burkitt, and most large cell lymphomas are believed to be tumors of germinal center B cells. Three histologically distinct microenvironments have been described within the germinal center: a mantle zone surrounding interior, dark, and light zones. The mantle zone contains small resting B cells that have not been exposed to antigens (naïve). Tumors of cells from the mantle zone are usually clinically indolent and histologically low grade. Antigen-triggered activation of the densely packed B cells of the dark zone causes cells to proliferate and subjects genomic DNA to somatic hypermutation. Surviving clones from within the dark zone then enter the light zone where proliferation slows and affinity selection occurs. During affinity selection, only cells with surface immunoglobulin receptors with high affinity for the antigen survive. Antigen-specific B cells generated in the germinal center reaction leave the follicle and reappear in the outer mantle zone, to form a marginal zone. Marginal zones are particularly prominent in mesenteric lymph nodes, Peyer’s patches, and the spleen. These postgerminal center B cells include memory B cells of the marginal zone and plasma cells. Marginal cell B-cell lymphomas tend to be indolent and may be either extranodal or nodal; extranodal marginal cell B-cell lymphomas are also referred to as MALT lymphomas.

T-cell lymphomas can be classified on the basis of antigen expression as either precursor (thymic) or mature (peripheral) in origin. These classifications clinically translate to precursor lymphoblastic lymphomas or to a heterogeneous group of peripheral T-cell lymphomas. Tumors of natural killer or natural killer-like T cells are uncommon.

The International Lymphoma Study Group, an informal group of 19 hematopathologists from the United States, Europe, and Asia, adopted a new approach to lymphoma classification in 1993. Because it represented a revision of current or prior European and American lymphoma classifications, it was called the Revised European-American Classification of Lymphoid Neoplasms (REAL). The REAL classification system is based on the principle that a classification is a list of “real” disease entities, which are defined by a combination of morphology, immunophenotype, genetic features, and clinical features.61,62 The relative importance of each of these criteria for both definition and diagnosis differs among different diseases. Morphology is always important, and some diseases are primarily defined by morphology alone (e.g., follicular lymphoma), although immunophenotype can be helpful in difficult cases. Some diseases have a specific immunophenotype (e.g., mantle cell lymphoma, small lymphocytic lymphoma) that is virtually diagnostic of that disease. A specific genetic abnormality is important in some lymphomas—t(11;14) in mantle cell lymphoma, t(8;14) in Burkitt lymphoma, and t(14;18) in follicular lymphoma—whereas other lymphomas lack specific genetic abnormalities (e.g., MALT lymphoma, diffuse large B-cell lymphoma). Finally, other lymphomas consider clinical features (e.g., extranodal vs. nodal presentation in marginal zone lymphoma and peripheral T-cell lymphoma).

Since 1995, members of the European and American Hematopathology societies have worked to develop a new WHO classification of hematologic malignancies. The final classification was published in 2001 and revised in 2008.13,61,62 The WHO classification uses an updated version of the REAL classification and expands the principles of the REAL classification to the classification of myeloid and lymphoid malignancies.

Images The 2008 WHO classification categorizes lymphoid malignancies into two major categories: B-cell lymphomas and T-cell (and natural killer cell) lymphomas (Table 109-1).13,61,62 B-cell lymphomas represent about 85% to 90% of all NHLs. Lymphomas within each category can be divided into malignancies of precursor or mature cells. Hodgkin lymphoma and multiple myeloma are now recognized as mature B-cell neoplasms. The WHO classification uses the term grade to refer to histologic parameters such as cell and nuclear size, density of chromatin, and proliferation fraction, and the term aggressiveness to denote clinical behavior of a tumor. This classification scheme includes both lymphomas and lymphoid leukemias because there is no distinction between the solid and circulating forms of these diseases. The WHO classification includes several previously unrecognized types of lymphomas, and new entities not specifically recognized in the Working Formulation account for about 20% to 25% of the cases.

The WHO classification has broad clinical implications. The WHO Clinical Advisory Committee has agreed that clinical groupings of lymphoid neoplasms into prognostic categories are neither necessary nor desirable because such arbitrary groupings are of no practical value and may be misleading.64

Clinical Presentation

Images Patients with NHL present with a wide variety of symptoms, depending on the site of involvement and whether tumor involvement is nodal or extranodal. Sites of involvement and dissemination of the malignant cells can sometimes be predicted based on the cell of origin and the tendency of tumors to frequently disseminate to areas where the normal counterparts of the lymphoma cells are located. For example, B-cell lymphomas involve areas of the lymphoid system normally populated by B-lymphocytes, such as lymph nodes, spleen, and bone marrow. T-cell lymphomas commonly disseminate to various extranodal sites, such as the skin and lungs.59

Most patients present with peripheral lymphadenopathy. The lymphadenopathy may be either localized or generalized, and the involved nodes are often painless, rubbery, and discrete, and usually located in the cervical and supraclavicular regions as in Hodgkin lymphoma (Fig. 109-1). Rapid and progressive lymphadenopathy is more characteristic of aggressive lymphomas. Waxing and waning of lymph nodes, including their complete disappearance and reappearance, is more characteristic of indolent lymphomas. Massive lymphadenopathy can sometimes lead to organ dysfunction. For example, patients with NHL may present with acute renal failure from retroperitoneal adenopathy causing ureteral obstruction or from metabolic abnormalities such as hyperuricemia with uric acid nephropathy.

About 40% of patients with NHL present with fever (temperature >38°C [100.4°F]), weight loss (unexplained weight loss of 10% of body weight over the past 6 months), or night sweats (drenching night sweats). If one or more of these symptoms is present, the patient is noted to have B symptoms, and a B is added to the stage of disease (discussed in the Diagnosis, Staging, and Prognostic Factors section under Hodgkin Lymphoma earlier in this chapter). B symptoms are more commonly observed in patients with aggressive NHLs.


CLINICAL PRESENTATION Non-Hodgkin Lymphoma

General

    • Patients with non-Hodgkin lymphoma present with a wide variety of symptoms, depending on the site of involvement and whether tumor involvement is nodal or extranodal.

Symptoms

    • About 40% of patients present with fever, night sweats, and weight loss (i.e., B symptoms).

    • Fatigue, malaise, and pruritus.

Signs

    • More than two-thirds of patients present with peripheral lymphadenopathy.

Laboratory Tests

    • A complete blood count, tests of renal and liver function, and serum electrolytes should be obtained.

    • Serum β2 -microglobulin and lactate dehydrogenase levels may be useful as prognostic factors and for monitoring response to therapy.

Other Diagnostic Tests

    • Varies depending on sites of involvement.

Patients with Hodgkin lymphoma rarely present with extranodal (i.e., extralymphatic) disease, but 10% to 35% of patients with NHL have primary extranodal disease at the time of diagnosis. The frequency of extranodal presentation varies dramatically among different subtypes. The most common extranodal sites are the gastrointestinal tract followed by the skin. The liver or spleen may be enlarged in patients with generalized adenopathy. Patients with mesenteric or gastrointestinal involvement may present with signs and symptoms of nausea, vomiting, obstruction, abdominal pain, a palpable abdominal mass, or gastrointestinal bleeding. Patients with bone marrow involvement may have symptoms related to anemia, neutropenia, or thrombocytopenia. Other sites of extranodal disease include the testes and bone. The incidence of solitary brain lymphoma is increasing, especially in patients with AIDS.

Diagnosis, Staging, and Prognostic Factors

As with Hodgkin lymphoma, the diagnosis of NHL must be established by pathologic review of tissue obtained by biopsy.59,65 The preferred procedure is an excisional biopsy, where the entire involved lymph node is removed for review by an experienced hematopathologist. This procedure should be done carefully to prevent distortional artifact of the architecture, which could lead to an inaccurate diagnosis. Needle biopsy of the node can sometimes provide adequate tissue for pathologic diagnosis, if an excisional biopsy cannot be performed. When adenopathy is not present, diagnosis may be established by biopsy of cutaneous lesions, bone marrow biopsy and aspiration in patients with unexplained myelosuppression, liver biopsy in patients with hepatomegaly or elevated liver function tests, or biopsy of involved extranodal organs, such as bone, Waldeyer’s ring, lung, and testis.

After the diagnosis is established, further workup is required to determine the extent of involvement.59,65 Clinical staging always begins with a thorough history and physical examination. Patients should be questioned about the presence or absence and extent of fever, night sweats, and weight loss. A detailed history of lymphadenopathy should also be obtained, including when and where the lymph nodes were first noted, and their rate of growth. A complete physical examination is performed to assess the extent of disease involvement, with special attention given to all nodal areas (Fig. 109-1). All patients should have a complete blood count, serum chemistries including liver and renal profiles, a chest radiograph, and bone marrow aspiration and biopsy. The likelihood of bone marrow involvement varies among the different histologic types of lymphoma (Table 109-6). Lumbar puncture to evaluate the cerebrospinal fluid is recommended in patients who have histologic types of lymphoma that often spread to the CNS.

TABLE 109-6 Clinical Characteristics of Patients with Common Types of Non-Hodgkin Lymphomas

Images

Imaging studies are usually important in the staging workup. CT scanning can identify both nodal and extranodal sites of disease, and has largely replaced lymphangiography for the evaluation of retroperitoneal lymphadenopathy. The abdominal and pelvic CT scan can identify mesenteric and retrocrural node involvement. CT scans can also detect tumor involvement of organs, including the kidneys, ovary, spleen, and liver. PET is currently not used routinely for staging of NHL.65,66 Magnetic resonance imaging is of limited usefulness in the staging of NHL. Gallium scans are sometimes used as part of the staging workup. Other tests, such as liver–spleen scan, bone scan, upper gastrointestinal series, and IV pyelogram, are sometimes useful in patients with organ symptomatology or serum chemistry abnormalities.

Although staging laparotomy was widely used in the late 1960s and 1970s as part of the staging workup in patients with lymphoma, it is rarely used today because of technical improvements in imaging studies and the morbidity and potential mortality associated with the procedure.

The Ann Arbor staging classification developed for the clinical staging of Hodgkin lymphoma is also used to stage patients with NHL (Table 109-2). After completion of the staging workup, most patients will be found to have advanced disease (stages III and IV). The frequency of localized disease at the time of diagnosis varies depending on the histologic type of lymphoma (Table 109-6). Stage is a more important prognostic factor in Hodgkin lymphoma than in NHL.

Images The Ann Arbor system emphasizes the distribution of nodal disease sites because Hodgkin lymphoma usually spreads through contiguous lymph nodes and does not involve extranodal sites. But NHL is a disease with tremendous heterogeneity that does not spread through contiguous lymph nodes and that often involves extranodal sites. As a result of these clinical differences between Hodgkin lymphoma and NHL, Ann Arbor stage correlates poorly with prognosis.

Images This lack of accuracy with the Ann Arbor staging system in NHL has led to several international projects to develop prognostic models for the most common types of NHLs—diffuse large B-cell lymphomas and follicular lymphomas. The International Non-Hodgkin Lymphoma Prognostic Factors Project was based on more than 2,000 patients with diffuse aggressive lymphomas treated with an anthracycline-containing combination chemotherapy regimen in the United States, Europe, and Canada.67 The Project identified five risk factors that correlated with low complete response rate to chemotherapy and poor survival: age >60 years, reduced performance status ≥2, abnormal serum lactate dehydrogenase (LDH) levels, two or more extranodal sites of disease, and advanced tumor stage (Ann Arbor stages III or IV) (Table 109-7). In patients ≤60 years old, three risk factors correlated with low complete response rate to chemotherapy and poor survival: reduced performance status, abnormal serum LDH levels, and Ann Arbor stage. It is unclear whether the effect of serum LDH level is related to a tumor or a host event. LDH likely measures cellular catabolism (the enzyme is released from injured cells), or the product of tumor burden and proliferation. Because each of the factors has about the same impact (e.g., relative risk) on prognosis, the number of adverse risk factors is summed to provide the IPI. Patients could, therefore, have a score of 0 to 5. For patients ≤60 years old, a simplified IPI score can be developed based on Ann Arbor stage, serum LDH level, and performance status.

TABLE 109-7 Risk Factors and Survival According to the International Non-Hodgkin Lymphoma Prognostic Factors Project

Images

As prognosis improves as a result of more effective therapy, it is important to reevaluate prognostic factors. The IPI was based on patients treated from 1982 to 1987 with anthracycline-based combination chemotherapy; none of the patients received rituximab. In a reexamination of the IPI in a cohort of patients treated with rituximab-containing chemotherapy, Sehn et al. found that the IPI remained predictive, but it only identified two, rather than four, risk groups.68 When the number of risk factors is redistributed, three risk groups are identified that correlate with prognosis. This revised IPI score may more accurately predict prognosis in patients treated with rituximab-containing combination chemotherapy, but needs to be validated in a larger group of patients.

Although the IPI is often used to predict prognosis in patients with other NHL subtypes, the IPI has several shortcomings when applied to patients with indolent lymphomas. Because only patients with diffuse aggressive lymphomas were used to develop the IPI system, some important prognostic factors may have been missed. Furthermore, the IPI system has limited discriminating power in follicular lymphoma because only about 10% of patients are categorized as high-risk in the IPI system. To address these concerns, an international cooperative study was designed to develop a prognostic model similar to the IPI in patients with follicular lymphoma. The results of that study, which was based on more than 4,000 patients with follicular lymphoma diagnosed between 1985 and 1992, were recently published.69 Five factors were identified that correlated with poor survival: age >60 years, advanced tumor stage (Ann Arbor stage III or IV), low hemoglobin level (<12 g/dL [7.45 mmol/L]), five or more nodal sites of disease (Fig. 109-1), and an abnormal serum LDH level. Analogous to the IPI, the number of adverse risk factors is summed to provide the Follicular Lymphoma International Prognostic Index (FLIPI). Three prognostic groups were identified: low-risk (0 to 1 factors), intermediate-risk (2 factors), and high-risk (≥3 factors). FLIPI appeared to have higher discriminating power among groups as compared with the IPI system. Table 109-8 shows the correlation between the FLIPI score and overall survival. The survival data from FLIPI, however, may not reflect current treatment results because none of the patients in the cohort used to derive the FLIPI were treated with rituximab. In an updated prognostic model (FLIPI-2) derived from patients with newly diagnosed follicular lymphoma treated with rituximab-containing chemoimmunotherapy regimens, age >60 years, low hemoglobin level (<12 g/dL [7.45 mmol/L]), longest diameter of the largest lymph node >6 cm, abnormal β2-microglobulin levels and bone marrow involvement were identified as adverse risk factors. FLIPI-2 was highly predictive of treatment outcomes and separated patients into three distinct risk groups: low-risk (0 factors), intermediate-risk (1 or 2 factors), and high-risk (≥3 factors). Three-year progression-free survival was 91%, 69%, and 51% and overall survival was 99%, 96%, and 84% in low-, intermediate-, and high-risk patients, respectively.70

TABLE 109-8 Risk Factors and Survival According to the Follicular Lymphoma International Prognostic Index

Images

Although IPI and FLIPI are clinically useful tools to estimate prognosis, the factors used to calculate these scores probably represent clinical surrogates for the biologic heterogeneity among NHLs and many researchers are interested in determining the prognostic importance of certain phenotypic and molecular characteristics of NHLs. For example, molecular markers of apoptosis, cell-cycle regulation, cell lineage, and cell proliferation are being evaluated as potentially clinically useful prognostic factors.71

Gene expression profiling with microarrays may also correlate with survival. Using gene expression profiling, investigators identified at least two molecularly distinct forms of diffuse large B-cell lymphomas based on gene expression patterns indicative of different stages of B-cell differentiation: germinal center B-cell–like (GCB) and activated B-cell–like (ABC).72 The GCB subtype of diffuse large B-cell lymphoma probably arises from normal germinal center B-cells while the ABC subtype may arise from postgerminal center B-cells. Many oncogenic pathways are different for the GCB and ABC subtypes, and these differences may lead to the development of targeted therapies for each subtype.63,71 Patients with the germinal center B-cell profile had significantly better overall survival independent of IPI score after treatment with cyclophosphamide, doxorubicin, vincristine (Oncovin®), prednisone (CHOP) or CHOP-like chemotherapy. In a recently published study of patients with diffuse large B-cell lymphoma treated with either CHOP or rituximab and CHOP (R-CHOP), Lenz et al. identified several gene expressions signatures that predicted survival in both CHOP and R-CHOP cohorts: GCB, stromal-1, and stromal-2.73 The GCB and stromal-1 signatures were associated with a favorable prognosis while the stromal-2 signature was associated with an unfavorable prognosis. The stromal-1 signature reflects extracellular matrix deposition and histiocytic infiltration whereas the stromal-2 signature reflects tumor blood vessel density. The authors speculated that diffuse large B-cell lymphomas that express the stromal-2 signature may respond to antiangiogenic agents.

Another recently identified molecular subtype is double-hit diffuse large B-cell lymphoma, defined as the existence of both MYC gene arrangement and t(14;18) BCL2 translocation.74 In one pathologic study that used immunohistochemical scoring, patients with high expression of both BCL2 and MYC protein had the worst prognosis. Double-hit NHL is associated with significantly lower complete response rate, shorter overall survival and shorter progression-free survival.75 NCCN guidelines suggest that patients with double-hit lymphoma usually have a very poor prognosis, with a median overall survival that is 4 to 6 months even with highly aggressive chemotherapy. It is highly recommended that these patients be enrolled in clinical trials.65

Two molecularly distinct profiles of follicular lymphoma also have been identified; the first included genes encoding for T-cell markers and genes highly expressed in macrophages, and the second included genes that are preferentially expressed in macrophages, dendritic cells, or both.76 Patients with the first molecular signature had a more favorable outcome than those with the second signature. These results suggest that molecular classification of tumors on the basis of gene expression may allow identification of clinically significant subtypes of cancer.

TREATMENT

Non-Hodgkin Lymphoma

Desired Outcomes

The primary goals in the treatment of NHL are to relieve symptoms, cure the patient of the disease whenever possible, and minimize the risk of serious toxicities. The treatment strategy depends on many factors, including the patient’s age, concomitant disease, disease type, stage of disease, site of disease, and patient preference.

General Approach

Images Historically, both the clinical behavior and degree of aggressiveness are often used to describe NHLs. Indolent lymphomas, which make up about 25% to 40% of all NHLs, are characterized by their slow-growth behavior. Patients with an indolent lymphoma usually have a relatively long survival (measured in years), with or without aggressive chemotherapy. Although these lymphomas respond to a wide range of therapeutic approaches, there is no convincing evidence of a survival plateau, which indicates that patients are rarely cured of their disease. In contrast, aggressive lymphomas, which make up about 60% to 75% of all NHLs, are characterized by rapid growth rate and short survival (measured in weeks to months), if appropriate therapy is not initiated. Despite their more aggressive nature, many patients with aggressive lymphomas who respond to chemotherapy can experience prolonged disease-free survival and some are cured of their disease. Therefore, the terminology for the NHLs represents a paradox, where “indolent” is bad and “aggressive” is good in terms of the likelihood for cure.

Therapeutic approaches to NHL include radiation therapy, chemotherapy, and biologic agents. The role of radiation therapy in the treatment of NHL differs from its role in the treatment of Hodgkin lymphoma. Although the disease responds to radiation therapy, only a small percentage of patients with NHL present with truly localized disease that can be treated with local or regional radiation therapy. Radiation therapy is used more commonly in advanced disease, primarily as a palliative measure to control local bulky disease.

Effective chemotherapy for NHL ranges from single-agent therapy in indolent lymphomas to aggressive, complex chemotherapy regimens in aggressive lymphomas. The most active agents used in the treatment of NHL include the alkylating agents (e.g., cyclophosphamide, chlorambucil), bleomycin, doxorubicin, purine analogs, etoposide, methotrexate, vincristine, and corticosteroids (e.g., prednisone, dexamethasone). The most aggressive chemotherapy approaches are dose-dense chemotherapy or high-dose chemotherapy followed by autologous or allogeneic HSCT.

B-cell lymphomas have served as a model for immunotherapy with monoclonal antibodies for more than 20 years, beginning with the successful use of custom-made monoclonal antibodies targeted against the idiotype present on the patient’s cancer cells.77,78 These encouraging results lead to the development of monoclonal antibodies against a more generic target, a molecule on the surface of B cells that would be present on tumor cells. One potential target, the CD20 molecule, is present only on cells in the B-lymphocyte lineage. It is expressed on the surface of both normal and malignant B cells, but not on other normal tissues. Rituximab (Rituxan®) is a chimeric monoclonal antibody directed at the CD20 molecule. Its antitumor activity is mediated through complement-dependent cytotoxicity, antibody-dependent cytotoxicity, and induction of apoptosis.78 With the availability of monoclonal antibodies and radioimmunoconjugates for the therapy of lymphoma, nearly all patients with NHL will receive one or more biologic agents during the course of their disease.

Objective response to therapy for NHL should be defined according to the International Workshop to Standardize Response Criteria for Non-Hodgkin Lymphoma, which was recently updated to incorporate the results of newer tests to monitor response such as PET, immunohistochemistry, and flow cytometry.66 The revised guidelines describe criteria for response (e.g., complete response, partial response, and stable disease) and survival (e.g., overall, disease-free, event-free, progression-free).

Appropriate therapy for NHL depends on the patient’s age, histologic type, stage of disease, site of disease, and presence of adverse prognostic factors (as measured by IPI or FLIPI score), and patient preferences. In general, treatment of lymphoma can be divided into limited disease and advanced disease. Limited disease includes those patients with localized disease (Ann Arbor stages I and II). Advanced disease is defined as all Ann Arbor stage III or IV patients, and also frequently includes Ann Arbor stage II patients with poor prognostic features (Tables 109-6 and 109-7).67,69

The following section discusses the clinical characteristics and therapy of the most common disease entities.

Indolent Lymphomas

Follicular Lymphomas

The combined group of follicular lymphomas makes up the second most common histologic type of NHL in the United States, comprising about 20% of all NHLs worldwide and up to 70% of indolent lymphomas reported in American and European clinical trials.79 The WHO classification includes criteria for grading follicular lymphoma based on the number of centroblasts per high-power field: grade 1 to 2 (0 to 15 centroblasts/high-power field) and grade 3 (>15 centroblasts/high-power field).13 The clinical behavior and treatment outcome of grades 1 and 2 follicular lymphoma are similar, and they are usually treated as indolent lymphomas. In contrast, grade 3 follicular lymphoma is synonymous with what is often referred to as follicular large cell lymphoma and is usually treated as an aggressive lymphoma.

Follicular lymphomas tend to occur in older adults, with a slight female predominance (Table 109-6). Most patients have advanced disease at diagnosis, but about 25% to 33% of patients have localized disease (clinical stage I or II) at diagnosis.80 Extranodal disease, bulky disease, and B symptoms are uncommon features at diagnosis. Most patients with follicular lymphoma have the chromosomal translocation t(14;18) at the time of diagnosis.

The clinical course is generally indolent, with median survivals of 8 to 10 years. But the natural history of follicular lymphoma can be unpredictable. Spontaneous regression of objective disease has been noted in as many as 20% to 30% of patients.81 There is also a high conversion rate of follicular lymphoma to a more aggressive histology over time that steadily increases after diagnosis and reaches about 30% at 10 years.82 At autopsy, most patients with follicular lymphoma have some evidence of diffuse large B-cell lymphoma. Patients with transformed indolent lymphoma should be treated in the same way as patients with an aggressive lymphoma.

Most patients have dramatic responses to initial therapy, and their disease course is characterized by multiple relapses, with responses to salvage therapy becoming progressively shorter after every relapse, eventually leading to death from disease-related causes. This pattern of constant relapses over time without evidence of a survival plateau and the failure of randomized controlled trials to show a survival benefit with aggressive chemotherapy led to the conclusion that therapy does not prolong overall survival and patients are not cured of their disease. However, several recently published studies suggest that the use of biologic agents, particularly rituximab, has changed the natural history of the follicular lymphoma. In a study of patients enrolled in Southwest Oncology Group (SWOG) trials over a period of more than 20 years, patients treated with CHOP and a monoclonal antibody had a significantly longer 4-year overall survival than those treated with CHOP alone (91% vs. 69%).83 Similar results were reported in patients treated over a 30-year period at the M.D. Anderson Cancer Center.84 That study also showed an apparent plateau in the failure-free survival curve.

Certain subsets of patients with follicular lymphoma have a much better or worse prognosis. Some studies suggest that the natural history of follicular large cell lymphoma (i.e., grade 3 follicular lymphoma) is similar to that of other aggressive lymphomas and that treatment with intensive combination chemotherapy regimens may result in long-term disease-free survival, including a possible plateau in the survival curve.79 The recent development of the FLIPI prognostic model should help clinicians to identify patients in different prognostic groups based on disease characteristics at the time of diagnosis.69 Patients who are predicted to have a poor prognosis (i.e., high-risk) could then be offered aggressive or experimental therapy, whereas those who are predicted to have a good prognosis (i.e., low-risk) would be treated with standard therapy, avoiding unnecessary toxicity.

Treatment of Localized Disease (Stages I and II) Radiation therapy is the standard treatment for early stage follicular lymphoma. Involved-field, extended-field, and total nodal irradiation have been used. Carefully staged patients with either stage I or contiguous stage II disease treated with radiation therapy alone can achieve disease-free survival rates of 40% to 50% and overall survival rates of 60% to 70% at 10 years.79 Late relapses are uncommon; only 10% of patients who reached 10 years without relapse subsequently experienced a recurrence.

Chemotherapy is not usually given in most patients with localized follicular lymphoma, but it may be helpful in some patients with high-risk stage II disease (e.g., multiple sites of involvement or bulky disease).85

Images About 40% to 60% of patients with clinical stage I or II follicular lymphoma are cured of their disease with radiation therapy alone.65 Most centers use radiation at a dose of 30 to 40 Gy (3000 to 4000 rad) to either involved (i.e., local) or regional fields, which would consist of irradiation to the involved nodal region plus one additional uninvolved region on each side of the involved nodes. Extended-field irradiation is not usually used because of the absence of a survival benefit and possible increased risk of secondary malignancies. In addition, previous use of extended-field irradiation compromises the ability of that patient to receive subsequent chemotherapy. The current NCCN guidelines state that locoregional radiation therapy is preferred for most patients with early stage follicular lymphoma.65 Immunotherapy (i.e., rituximab) with or without chemotherapy or radiation therapy is also listed as an option (category 2B).

Treatment of Advanced Disease (Stages III and IV) Images The management of stages III and IV indolent lymphomas remains controversial because until recently, no therapeutic approaches had been shown to prolong overall survival despite the high complete remission rates to initial therapy. However, the results of recently published studies suggest that the initial use of biologic therapy such as rituximab is associated with longer overall survival.83,84More than 80% of patients with stage III or IV follicular lymphoma are alive at 5 years, and the median survival ranges between 7 and 10 years.

Therapeutic options for these patients are diverse and include watchful waiting, radiation therapy, single-agent chemotherapy, combination chemotherapy, biologic therapy, radioimmunotherapy, and combined-modality therapy.86Although complete remission can be achieved in 50% to 80% of patients with various treatments, the median time to relapse is usually only 18 to 36 months. About 20% of patients who have a complete response remain in remission for longer than 10 years. After relapse, patients are retreated, and high remission rates can be achieved. Unfortunately, response rates and duration of response both decrease with each retreatment.

Several different approaches can be used to treat follicular lymphoma. Carefully selected patients may receive no initial therapy followed by single-agent chemotherapy, rituximab, or radiation therapy when treatment is needed. Candidates for the conservative approach are usually older, asymptomatic, and have minimal tumor burden. Patients with symptoms, extensive extranodal involvement, bulky disease, cytopenia due to bone marrow involvement, or impaired end-organ function at the time of diagnosis are not candidates for conservative treatment. Alternatively, patients can be treated aggressively with combination chemotherapy, with or without rituximab, or radioimmunotherapy early in the disease course. Both conservative and aggressive approaches are listed as possible options in the current NCCN guidelines, but the guidelines recommend that initial therapy should include rituximab unless contraindicated.65 Patients who respond to induction therapy may receive maintenance therapy with single-agent rituximab.

A recently published observational study of 2,728 patients with newly diagnosed follicular lymphoma treated in the United States from March 2004 to March 2007 showed that about two-thirds of patients were treated with rituximab, either alone (14%) or combined with chemotherapy (52%).87 About 18% of patients were treated with observation.

At the time of relapse, many of the same treatment options are available, and the following factors must be considered: age, symptomatic status of the patient, tumor burden, rate of regrowth (based on previous assessment of active disease sites), presence or absence of characteristics suggesting transformation or biologic progression, prior therapy, degree and duration of response to prior therapy, availability of clinical trials, and patient preferences.65

Watch-and-Wait Because there are no convincing data that standard treatment approaches have improved survival, some clinicians have adopted a “watch-and-wait” approach for asymptomatic patients where therapy is delayed until the patient experiences systemic symptoms or disease progression such as rapidly progressive or bulky adenopathy, anemia, thrombocytopenia, or disease in threatening sites such as the orbit or spinal cord.86,88 The median time until treatment is required is 3 to 5 years, and about 20% of patients do not require therapy for up to 10 years. The 10-year survival is 73%, which is not significantly different from patients who received therapy at the time of diagnosis. In a randomized study of asymptomatic patients with indolent lymphomas (mostly follicular), patients who underwent watchful waiting had similar cause-specific and overall survival as compared with those who received immediate chlorambucil.88 With a median length of followup of 16 years, about 17% of patients who were randomized to the watchful waiting group died of other causes without receiving chemotherapy and an additional 9% are alive and have not yet had chemotherapy. As described above, patients with follicular lymphoma who are followed without therapy sometimes have spontaneous regressions that can be complete while the disease in other patients can convert to a more aggressive histology. If the watchful waiting approach is chosen, the patient should be evaluated at least every 2 months for the first year and quarterly thereafter, so that intervention can occur before serious problems occur.

Chemotherapy Oral alkylating agents, given either alone or combined with prednisone, have been the mainstay of treatment for follicular lymphoma. More intensive chemotherapy has not been shown to improve patient outcome. In a randomized trial of oral chlorambucil, oral cyclophosphamide, or cyclophosphamide, vincristine, and prednisone (CVP) in patients with indolent lymphoma, no significant difference in overall survival or freedom-from-relapse between the three groups was observed.81 The dosage of single-agent chlorambucil or cyclophosphamide is usually adjusted to maintain a platelet count above 100,000 cells/mm3 (100 × 109/L) and a white blood cell count above 3,000 cells/mm3 (3 × 109/L). Although single-agent alkylating agents have a high initial complete remission rate, the time required to achieve a complete response is slow (median time is 9 to 12 months). Complete responses occur more rapidly with combination chemotherapy, particularly with doxorubicin-containing regimens. Many clinicians will therefore give CHOP or CHOP-like chemotherapy when a rapid response is necessary. The development of the CHOP regimen is described in more detail in the Aggressive Lymphomas section later in this chapter. Table 109-9 shows the CHOP regimen that is widely used in the treatment of NHL. In those who achieve a complete response, the duration of response is relatively short (about 2.5 years). There is no benefit of maintenance therapy with chemotherapy. After the “best” response is achieved, many experts will discontinue therapy and observe.

TABLE 109-9 CHOP Regimen

Images

Both single-agent alkylating agents and CVP are well tolerated by most patients. The advantages of oral chlorambucil are no hair loss, little or no nausea, and minimal myelosuppression. Because of its mild side effect profile, oral chlorambucil is usually recommended for older patients who are minimally symptomatic or who have other comorbidities. There are some concerns with the risk of secondary acute leukemia in patients receiving continuous exposure to alkylating agents.

Anti-CD20 Monoclonal Antibodies The approval of rituximab is arguably the most important recent development in the treatment of NHL. Its initial approval in 1997 was based on an open-label multicenter study that enrolled 166 patients with relapsed or recurrent indolent lymphoma.89 Rituximab, given IV at a dose of 375 mg/m2 weekly for 4 weeks, resulted in an overall response of 48% (complete response: 6%, partial response: 42%). Median time to progression for responders was 13.2 months and median duration of response was 11.6 months. Other studies of single-agent rituximab in patients with relapsed or refractory indolent NHL have reported overall response rates of 40% to 60% and complete response rates of 5% to 10%.90

Based on the activity of rituximab in relapsed or refractory patients, it is currently being used as first-line therapy, either alone or in combination with chemotherapy.77,9092 When given as a single agent to patients with previously untreated indolent NHL, the overall response rate is 60% to 70% and the complete response rate is 20% to 30%. It is interesting to note that many of these patients remain in molecular remission (i.e., polymerase chain reaction–negative) at 12 months. Single-agent rituximab is listed as an acceptable option for first-line therapy of follicular lymphoma, particularly for patients who cannot tolerate more intensive chemotherapy regimens.65

The rationale for the use of rituximab in combination with conventional agents is based on clinical activity of both agents/regimens, non–cross-resistant mechanisms of action, nonoverlapping toxicities, and synergistic antitumor activity in vitro. Many clinical trials have evaluated the use of rituximab in combination with other chemotherapy agents. In a phase II trial of six courses of R-CHOP, the overall and complete response rate in 40 patients with previously untreated or relapsed indolent lymphoma was 95% and 55%, respectively.93 More than 70% of patients were progression-free after 4 years of followup. In an updated analysis, median time-to-progression was reached at 82 months.94 Based on these encouraging results, several randomized controlled trials have evaluated rituximab in combination with various chemotherapy regimens in first-line therapy for follicular or other indolent lymphomas.77,91In the R-CHOP versus CHOP trial, patients who were randomized to receive R-CHOP as initial therapy had significantly higher overall response rates (96% vs. 90%), reduced risk for treatment failure (relative risk 0.4), and longer time-to-treatment failure and overall survival.95 In another randomized trial of R-CHOP versus CHOP in relapsed or resistant follicular lymphoma, patients treated with R-CHOP had higher overall and complete response rates (85% vs. 72% and 30% vs. 16%, respectively) and lower risk of treatment failure (hazard ratio [HR] 0.65), but no significant difference in overall survival was observed.96 Similar results were reported when rituximab was added to other combination regimens.77,78 In a meta-analysis of all randomized controlled trials, patients with indolent lymphoma treated with rituximab and chemotherapy had a significantly higher overall response rate and reduced risk of treatment failure (HR 0.62) and death (HR 0.65).97 Rituximab is FDA-approved for first-line therapy for follicular lymphoma in combination with CVP chemotherapy. R-CHOP is listed as an acceptable option for first-line therapy of follicular lymphoma (category 1).65

Rituximab and CHOP chemotherapy can be combined in many different ways.98 In the R-CHOP regimen developed by Czuczman et al., two doses of rituximab are given before the start of CHOP therapy; two more doses are given in the middle of the six cycles of CHOP; and two additional doses are given at the end of CHOP therapy.93 However, in most NHL protocols and in clinical practice, rituximab is given on day 1 of CHOP chemotherapy.98 In some protocols, rituximab is given on the day before chemotherapy (i.e., day 0) or rituximab is given on day 1 and the other drugs are given on day 3.

In patients who respond to rituximab, either alone or combined with chemotherapy, maintenance therapy with single-agent rituximab is often given to prolong the duration of remission. Rituximab is FDA approved as single-agent maintenance therapy in patients achieving a complete or partial response following induction chemotherapy. The FDA approval was based on a randomized controlled trial in previously untreated patients with advanced-stage follicular lymphoma treated with maintenance rituximab after CVP chemotherapy.99 Three-year progression-free survival was significantly longer in the maintenance rituximab group as compared with the observation group (68% vs. 33%). However, it is important to note that only about 3% of patients with newly diagnosed follicular lymphoma are treated with chemotherapy alone in the United States.92 In another recently published randomized controlled trial, patients responding to first-line chemotherapy in combination with rituximab (such as R-CVP, R-CHOP or rituximab, fludarabine, cyclophosphamide, and mitoxantrone [R-FCM]) were randomized to receive rituximab maintenance (12 infusions of 375 mg/m2 given IV, once every 8 weeks) or no maintenance.100 After a median followup of 24 months, rituximab maintenance significantly improved progression-free survival compared to observation (75% vs. 58%). Interestingly, induction therapy with R-CHOP or R-FCM was associated with improved progression-free survival, which suggests that R-CVP was not beneficial in this study. Longer followup is needed to evaluate the effect of rituximab maintenance on overall survival.

The use of maintenance rituximab in newly diagnosed follicular lymphoma is controversial.101,102 Although it improves progression-free survival, no overall survival benefit has been observed. And maintenance rituximab is expensive and may be associated with adverse effects, including an increased risk of grades 3 or 4 infections. The NCCN guideline lists maintenance therapy with rituximab (one dose every 8 weeks for up to 2 years) as an option following first-line therapy for patients initially presenting with high tumor burden.65


Clinical Controversy…

Maintenance rituximab is often used in patients with indolent lymphoma who respond to induction chemoimmunotherapy. While maintenance rituximab has been shown to prolong overall survival in patients with refractory or relapsed disease, no consistent survival benefit has been observed in newly diagnosed patients. Various dosing schedules have been used.

Rituximab maintenance following second-line therapy has also been evaluated in patients with relapsed or refractory disease. Two randomized trials have demonstrated a progression-free survival advantage with rituximab maintenance over observation for patients treated with induction chemotherapy.103,104 In a recently published trial of patients with relapsed or resistant follicular lymphoma responding to CHOP or R-CHOP induction, maintenance rituximab significantly improved median progression-free survival as compared with observation alone (3.7 years vs. 1.3 years). The 5-year overall survival, however, was not significantly different between the study arms (74% vs. 64%).104 It is also important to note that patients who develop progression of disease during or within 6 months of first-line maintenance rituximab will likely experience little, if any, benefit from maintenance therapy in the second-line setting. The NCCN guideline recommends optional maintenance therapy with rituximab (one dose every 12 weeks for 2 years) for patients who are in remission after second-line therapy.65

Most of the adverse effects of rituximab are infusion-related, particularly after the first infusion, and consist of fever, chills, respiratory symptoms, fatigue, headache, pruritus, and angioedema.94 Premedication with oral acetaminophen 650 mg and diphenhydramine 50 mg is usually given 30 minutes before rituximab infusion. The package insert recommends a step-up infusion rate of rituximab to decrease the risk of infusion-related infusion. Duration of infusions, however, may take up to 5 hours. Studies have demonstrated that rapid infusion of rituximab (infused over 90 minutes) is feasible in patients who tolerate their first cycle of rituximab without increasing the risk of infusion-related reactions.105106 The FDA has approved rapid infusions of rituximab, but they are not recommended in patients with clinically significant cardiovascular disease and high circulating lymphocyte counts (greater than 5000 cells/mm3 [5 × 109/L]). Reactivation of hepatitis B has been reported in patients receiving chemotherapy, either alone or combined with rituximab.107 Hepatitis B testing is recommended in patients who are considering rituximab therapy.65

In addition to rituximab, other anti-CD20 antibodies are currently under research development.78 Ofatumumab, a fully human antibody against CD20, is currently approved for treatment of refractory chronic lymphocytic leukemia. It binds to two sites on the CD20 molecule, which brings the antibody closer to the cell membrane and increases complement-dependent cytotoxicity.108 Ofatumumab is being evaluated in randomized controlled trials against rituximab-based regimens for treatment of both indolent and aggressive lymphomas.

Bendamustine Bendamustine is an alkylating agent with structural similarities to both alkylating agents and purine analogs. The mechanism of action of bendamustine appears to be different from other alkylating agents and it does not show cross-resistance to other alkylating agents. When used as a single agent, bendamustine shows antitumor activity in relapsed or refractory indolent lymphomas. Overall and complete response rates of 70% to 80% and 30% to 35% have been reported, respectively, in phase II trials.109

The combination of bendamustine and rituximab (BR) has been shown to demonstrate better efficacy outcomes than R-CHOP in advanced follicular lymphoma. In a phase II trial, the overall and complete response rate to BR was 92% and 55%, respectively.110 In a randomized controlled trial of first-line therapies for advanced indolent NHL, patients who received BR had a higher complete response rate (40% vs. 30%) and longer median progression-free survival (55 vs. 35 mo) as compared with those who received R-CHOP.109 The BR regimen was tolerated better than R-CHOP. Based on these results, BR is listed as an acceptable option for first-line therapy of follicular lymphoma (category 2A).65

The combination of bendamustine, rituximab, and bortezomib (BVR) has also been evaluated in two recent studies in patients with relapsed or refractory follicular lymphoma. In both studies, overall response rate was high (>90%) with median progression-free survival ranging from 15 to 22 months.111,112 Serious adverse events were reported in 34% of patients; the most common grade 3 or 4 adverse events were myelosuppression, gastrointestinal side effects, fatigue, and peripheral neuropathy. The NCCN guideline lists BVR as an option for second-line therapy for follicular lymphoma.65

Purine Analogs Several studies report encouraging results with two adenosine analogs, fludarabine phosphate in previously untreated and relapsed advanced follicular lymphoma.87 The mechanism of action for both drugs is not well understood, but both agents accumulate in lymphocytes and are resistant to adenosine deaminase. In patients with relapsed or refractory indolent lymphoma, single-agent fludarabine has an overall response rate of almost 50% and a complete response rate of 10% to 15%. Response rates are higher in previously untreated patients, with overall and complete response rates of 70% and almost 40%, respectively. The median time to progression is less than 6 months for relapsed disease and more than 12 months for previously untreated patients. Although the response rates to 2-chlorodeoxyadenosine in previously untreated patients is similar to those with fludarabine, the duration of response appears to be shorter with 2-chlorodeoxyadenosine.

Combination regimens that include one of these purine analogs are also being investigated.87 Fludarabine and mitoxantrone (FN) and fludarabine, mitoxantrone, and dexamethasone (FND), given with or without rituximab, are examples of fludarabine-containing regimens that show encouraging results in patients with indolent lymphoma.

Purine analogs usually do not cause nausea and vomiting or hair loss, but they are associated with cumulative and prolonged myelosuppression and profound immunosuppression, which increases the risk of opportunistic infections, such as fungal infections, Pneumocystis jiroveci pneumonia, and viral infections. Because the use of fludarabine-based regimens may impair stem cell mobilization and collection, some experts avoid fludarabine-based regimens for patients who are potential candidates for autologous HSCT.

Radioimmunotherapy Two anti-CD20 radioimmunoconjugates—131I-tositumomab (Bexxar) and90Y-ibritumomab tiuxetan (Zevalin)—are currently available as treatment options for patients with indolent NHLs.113 Both131 I-tositumomab and90Y-ibritumomab tiuxetan are mouse antibodies linked to a radioisotope, either iodine-131 (131I) or yttrium-90 (90Y). Indolent lymphomas are known to be responsive to radiation therapy (i.e., radiosensitive), and the rationale of radioimmunotherapy is that the antibody will act as a guided missile to deliver its payload (i.e., radiation) to its target (i.e., lymphoma cells that express the CD20 antigen). The specificity of the monoclonal antibody allows delivery of the radiation selectively to the tumor (and adjacent normal tissues).

Radioimmunoconjugates have some advantages and disadvantages over unlabeled (“naked”) monoclonal antibodies such as rituximab. Tumor cell kill following rituximab depends on binding of the antibody to the tumor cell and the host immune system. Therefore, tumor cells that do not express the target antigen are not accessible to the antibody, or those that are resistant to immune-mediated attacks may escape treatment. Radioimmunoconjugates, because of their ability to deliver radiation over a distance from a source, can not only kill tumor cells that are in contact with the antibody, but also adjacent tumor cells which may not have been in contact with the antibody or may not express the target antigen. This effect is sometimes referred to as the relevant bystander or crossfire effect. However, one disadvantage of radioimmunotherapy is that it can also damage adjacent normal tissues, such as bone marrow cells.

Both131 I-tositumomab and90Y-ibritumomab tiuxetan have shown activity in relapsed and refractory patients with indolent or transformed lymphomas.113 In patients who respond to radioimmunotherapy, the duration of remission can be more than several years. Although radioimmunotherapy is usually reserved for second-line therapy of follicular lymphoma, some clinicians consider radioimmunotherapy earlier in the disease course, including for patients with previously untreated disease. In a phase II study, patients with previously untreated follicular lymphoma were treated with six cycles of CHOP chemotherapy followed 4 to 8 weeks later by131 I-tositumomab.114 The overall response rate to the entire treatment regimen was 91%, including 69% complete remissions, and the 5-year progression-free survival is estimated to be 67%. Similar results were reported in a phase II trial of131 I-tositumomab given without induction CHOP chemotherapy in previously untreated patients with advanced-stage follicular lymphoma.115 Durable responses have also been reported with131I-tositumomab and CVP.116

Radioimmunotherapy is generally well-tolerated. The major acute toxicities with both radioimmunoconjugates are infusion-related reactions and myelosuppression.131 I-tositumomab can also cause thyroid dysfunction. The primary concern with radioimmunotherapy is the development of treatment-related myelodysplastic syndrome or acute myelogenous leukemia.117

The decision to use radioimmunotherapy must be made carefully because of the complexity, risks, and costs of the treatment regimen. Because of safety concerns related to delivery of radiation to bone marrow, candidates for radioimmunotherapy usually have limited bone marrow involvement and adequate absolute neutrophil and platelet counts. Although medical oncologists usually select patients for therapy, the radioimmunotherapy regimen must be administered at a radiation oncology or nuclear medicine facility.

Hematopoietic Stem Cell Transplantation High-dose chemotherapy, followed by autologous or allogeneic HSCT, is another option for patients with relapsed follicular lymphoma.118,119 In patients who are transplanted at the time of initial treatment failure, 5-year event-free survival is about 40% to 50%. Although the rate of recurrence is lower after allogeneic HSCT as compared with autologous HSCT, that benefit is offset by increased treatment-related mortality after allogeneic HSCT. The presence of a survival plateau after allogeneic HSCT suggests that some patients may be cured of their disease.

A panel of follicular lymphoma experts recently published their recommendations, which was based on an evidence-based review.119 Their recommendations are: (1) autologous HSCT is recommended as salvage therapy based on pre-rituximab data, with a significant improvement in progression-free and overall survival; (2) autologous HSCT is not recommended as consolidation therapy after first-line chemotherapy for most patients because of no significant improvement in overall survival; (3) autologous HSCT is recommended for transformed follicular lymphoma patients; (4) reduced-intensity conditioning before allogeneic HSCT appears to be an acceptable alternative to myeloablative regimens; and (5) an human leukocyte antigen (HLA)-matched unrelated donor appears to be as effective as an HLA-matched related donor for reduced intensity conditioning allogeneic HSCT. There are insufficient data to make a recommendation on the use of autologous HSCT after rituximab-based salvage therapy.

Rituximab is being evaluated in the setting of autologous HSCT.120 It is given pretransplant as an in vivo purging agent prior to stem cell collection. In other studies, rituximab is given as post-transplant consolidation.

Aggressive Lymphomas

Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphomas (DLBCLs) are the most common lymphoma in the International NHL Classification Project, accounting for about 30% of all NHLs.121 DLBCLs are characterized by the presence of large cells, which are similar in size to or larger than tissue macrophages and usually more than twice the size of normal lymphocytes. The median age at the time of diagnosis is in the seventh decade, but DLBCL can affect individuals of all ages, from children to the elderly. Patients often present with a rapidly enlarging symptomatic mass, with B symptoms in about 30% to 40% of cases.121 About 30% to 40% of patients with DLBCL present with extranodal disease; common sites include the head and neck, gastrointestinal tract, skin, bone, testis, and CNS. DLBCL is the most common type of diffuse aggressive lymphomas, which are characterized by an aggressive clinical behavior that leads to death within weeks to months if the tumor is not treated. Diffuse aggressive lymphomas are also sensitive to many chemotherapeutic agents, and some patients treated with chemotherapy can be cured of their disease.

Several factors have been shown to correlate with response to chemotherapy and survival in patients with aggressive lymphoma.71 Because the IPI was originally developed based on patients with aggressive lymphoma, IPI score correlates with prognosis (Table 109-7).67 As described above, the revised IPI score may more accurately predict prognosis in patients receiving rituximab-containing combination chemotherapy.68

Therapy of DLBCL is based on the Ann Arbor stage, IPI (or revised IPI) score, and other prognostic factors.121 About one-half of patients present with localized (stage I or II) disease. However, many patients present with large bulky masses (i.e., larger than 10 cm), and patients with bulky stage II disease are treated with the same approach used for patients with advanced disease (stage III or IV).

Treatment of Localized Disease (Stages I and II) Before 1980, radiation therapy was the primary treatment for patients with localized DLBCL. Five-year disease-free survival with radiation therapy alone was about 50% and 20% in patients with stage I and stage II disease, respectively.121 Randomized trials in the 1980s showed that radiation therapy followed by chemotherapy resulted in significantly longer disease-free and overall survival as compared with radiation therapy alone. Other studies reported excellent results with a short course of chemotherapy (three cycles) followed by involved-field radiotherapy or six to eight cycles of CHOP chemotherapy, with or without consolidation radiotherapy. With either of these approaches, 5-year progression-free survival was >90% for patients with stage I disease and about 70% for patients with stage II disease.121

Because the more effective approach was not clear, the SWOG performed a randomized trial that compared three cycles of CHOP and involved-field radiotherapy or six cycles of CHOP in patients with stage I and nonbulky stage II aggressive lymphoma.65 Patients treated with three cycles of CHOP plus radiotherapy had significantly better 5-year progression-free (77% vs. 64%) and overall (82% vs. 72%) survival than did patients treated with CHOP alone. The incidence of life-threatening toxicity was higher in patients who received CHOP alone. But with longer followup, more patients who received abbreviated chemotherapy experienced late relapses and the differences in progression-free or overall survival were no longer significant between the two arms. Further subgroup analysis of that trial identified several prognostic factors that led to the development of the stage-modified IPI score. Four adverse risk factors comprise the score: nonbulky stage II disease (bulky stage II disease is considered advanced disease), age >60 years, elevated LDH levels, or performance status ≥2.

The stage-modified IPI score is often used to identify patients with localized aggressive NHL who may have a poor prognosis. Based on the results of this trial, the current standard for therapy of most patients with localized nonbulky aggressive lymphoma without any adverse risk factors is three to four cycles of R-CHOP followed by locoregional radiation therapy (30 to 40 Gy [3000 to 4000 rad]).121 Five-year median survival in this favorable group of patients exceeds 90%.

Five-year median survival is reduced to about 70% in patients with at least one adverse risk factor in the stage-modified IPI score. Patients in this high-risk subgroup may benefit from more aggressive chemotherapy (six cycles of R-CHOP) followed by locoregional radiation therapy.65

Treatment of Advanced Disease (Bulky Stage II, Stages III and IV) It has been known since the late 1970s that intensive combination chemotherapy can cure some patients with disseminated DLBCL.121Initial studies with cyclophosphamide, vincristine (Oncovin), and prednisone or prednisolone (COP; same as CVP) produced a plateau on the survival curve of just 10%, with a median survival of less than 1 year. Based on the activity of single-agent doxorubicin, McKelvey et al. developed the CHOP regimen (Table 109-9).122 A few years later, a SWOG study showed that CHOP was more active than COP, and CHOP chemotherapy rapidly became the treatment of choice for patients with aggressive lymphomas.123 Studies in larger numbers of patients showed that about 50% of patients had a complete remission to CHOP chemotherapy, and 50% to 75% of the patients who had a complete response (about one-third of all patients) experienced long-term disease-free survival and cure of their disease.

In an effort to improve these results, many investigators used several general approaches to develop second- and third-generation regimens in the 1980s.121 Results of phase II trials suggested that these second- and third-generation regimens were more active than CHOP, with slightly higher complete response rates and improved disease-free survival rates. However, they were also more difficult to administer, more toxic, and more expensive. Based on these results, many oncologists adopted one of these second- or third-generation combination regimens as their standard regimen for patients with advanced aggressive lymphomas.

Many randomized studies have compared different combination regimens in patients with aggressive lymphoma. Although the results of these studies show that no one regimen is clearly superior to another, they demonstrate the superiority of anthracycline-containing regimens over those that do not contain an anthracycline. In the largest and most widely quoted study, the SWOG initiated a randomized trial in 1986 that compared CHOP to three of the most commonly used third-generation regimens in nearly 900 patients with bulky stage II, stage III, or stage IV aggressive NHL. At the time of the initial publication (median followup: 35 months), no differences in disease-free and overall survival were observed between the four groups.124 Furthermore, no significant differences in disease-free or overall survival were observed in any subgroup of patients. But the risk of treatment-related mortality was higher in patients receiving one of the third-generation regimens. Extended followup of that trial shows that about 35% of patients who participated in that trial are probably cured of their disease, regardless of the initial combination chemotherapy regimen.125 Interestingly, the overall survival is about 10% higher than the disease-free survival, which probably reflects the effectiveness of salvage high-dose chemotherapy with autologous HSCT (see the Treatment of Refractory or Relapsed Disease section later in this chapter).

Based on the lack of survival benefit with the newer combination chemotherapy regimens, the less complicated and less expensive CHOP regimen was considered as the treatment of choice for most patients with DLBCL and other aggressive NHLs for many years. Even with CHOP chemotherapy, however, less than 50% of patients with DLBCL were cured of their disease and most patients who relapse after an initial response do so in the first two years. New treatment approaches were clearly needed.

Several studies attempted to improve treatment results by increasing chemotherapy dose (i.e., dose-intensity), shortening the interval between chemotherapy cycles (i.e., dose-density), or both. Because of the increased risk of severe neutropenia, these approaches require growth factor support. Although results of these studies have not consistently shown improved survival, encouraging results from several recently published studies suggest that these approaches be evaluated in future randomized trials.126,127

Based on the encouraging results of R-CHOP in indolent lymphomas, several studies evaluated this combination in aggressive lymphomas.91,125 The first randomized controlled trial that established the efficacy of R-CHOP in advanced-stage DLBCL showed that R-CHOP significantly increased complete response rates and overall survival in elderly (≥60 years old) patients as compared with CHOP alone (discussed in the Treatment of Elderly Patients with Advanced Disease section later in this chapter).128,129 Although the results of that study established R-CHOP as standard therapy in older patients, the role of R-CHOP in the treatment of younger patients was not clear. That issue was recently addressed in the MabThera International Trial, which enrolled younger (18 to 60 years old) patients with good-prognosis DLBCL.130 Patients randomized to receive rituximab plus CHOP-like chemotherapy had significantly higher complete response rates (86% vs. 68%) and longer 3-year event-free and overall survival (79% vs. 59% [HR 0.44] and 93% vs. 84% [HR 0.40], respectively). Furthermore, in a population-based study conducted in British Columbia, institution of a policy recommending R-CHOP for all patients with newly diagnosed advanced-stage DLBCL resulted in significant improvements in progression-free and overall survival.131 Based on these trial results, rituximab received FDA approval for first-line treatment in combination with CHOP or CHOP-like chemotherapy and R-CHOP is recommended for all patients with advanced-stage DLBCL in the current NCCN guideline.65

Treatment outcomes for high-risk patients according to the IPI (or revised IPI) score are unsatisfactory. High-risk groups generally include all patients older than 60 years and those with an IPI score of ≥3 (or an age-adjusted IPI score of ≥2). Because progression-free survival is only about 50% in these high-risk patients treated with R-CHOP,68,132 other more aggressive treatments, preferably as part of a clinical trial, should be considered in these patients. Examples of more aggressive approaches include dose-intense or dose-dense chemotherapy with growth factor support, usually combined with rituximab, or high-dose chemotherapy with autologous HSCT.121,133

One approach is to give high-dose chemotherapy with autologous HSCT as intensive consolidation in high-risk patients with DLBCL who achieve a remission with standard chemotherapy.121 Several randomized controlled trials have been conducted in patients with aggressive NHLs, and no consistent survival advantage has been reported. A recently published meta-analysis of all randomized controlled trials of autologous HSCT as intensive consolidation in aggressive NHL concluded that there was no evidence that autologous HSCT improved outcomes in good-risk patients.134 The evidence for high-risk patients was inconclusive.


Clinical Controversy…

Because of high relapse rate in patients who have a complete response to R-CHOP, some experts believe that high-dose chemotherapy with autologous HSCT should be considered as consolidation therapy in high-risk patients with aggressive NHLs who have a complete remission to R-CHOP chemotherapy. Other experts, however, believe that the evidence supporting high-dose chemotherapy with autologous HSCT in this setting is inconclusive and that autologous HSCT should be reserved for patients who relapse.

Images In summary, all patients with bulky stage II, stage III, or stage IV disease should be treated with R-CHOP or rituximab and CHOP-like chemotherapy until a complete response is achieved (usually four cycles).65 Clinicians are encouraged to adopt the revised response criteria proposed by the International Working Group.66 In patients who have a positive pretreatment PET scan, PET scanning can be useful in response assessment. A rapid response to chemotherapy (i.e., a complete response achieved in the first three treatment cycles) is associated with a more durable remission compared with patients requiring longer treatment cycles. Two or more cycles of chemotherapy should be given following attainment of a complete response (total of six to eight cycles). The use of long-term maintenance therapy following a complete response has not been shown to improve survival. Treatment outcomes for high-risk patients according to the IPI (or revised IPI) score are unsatisfactory and alternative treatment approaches, preferably as part of a clinical trial, should be considered in these patients.65 High-dose chemotherapy with autologous HSCT should be considered in high-risk patients who respond to standard chemotherapy and are candidates for autologous HSCT.

Treatment of Elderly Patients with Advanced Disease More than one-half of patients with NHL are older than 60 years of age at diagnosis, and about one-third are older than age 70 years. The International Non-Hodgkin Lymphoma Prognostic Factors Project showed that patients older than 60 years of age had a significantly lower complete response rate and overall survival.67 The reasons for the poorer outcome in elderly patients are not clear. Older patients do not tolerate intensive chemotherapy as well as younger patients, and some studies report that older patients have a higher risk of treatment-related mortality. As a result, many clinicians treat elderly patients with reduced dose or less-aggressive chemotherapy regimens. In general, these less-intensive regimens have used anthracyclines with less cardiotoxicity than doxorubicin, have substituted mitoxantrone for doxorubicin, or have used short-duration weekly therapy.121

Over the past few years, several nonrandomized and randomized trials have evaluated different treatment approaches in older patients with aggressive NHL.121 The results of these studies suggest that carefully selected elderly patients with good performance status and without significant comorbidities can tolerate aggressive anthracycline-containing regimens as well as younger patients. These patients should be treated initially with full-dose R-CHOP or similar regimens; dosages can be reduced later if severe toxicity occurs. Hematopoietic growth factors may allow elderly patients to maintain dose intensity.

The combination therapy, R-CHOP, has replaced CHOP as standard treatment for elderly patients with aggressive lymphoma, based on the results of the Groupe d’Etude des Lymphomes de l’Adulte (GELA) study.128,129 In that study of 399 elderly patients with DLBCL, patients who were randomized to receive R-CHOP had a significantly higher complete response rate (76% vs. 63%) and longer event-free and overall survival as compared with those who received CHOP. After 10 years of followup, progression-free survival was significantly longer among those who received R-CHOP than CHOP (36.5% vs. 20.1%).129 A higher risk of death or development of secondary cancer was not observed with the additional of rituximab to CHOP after 10 years of followup. In another randomized controlled trial conducted primarily in the United States (Eastern Cooperative Oncology Group 4494), elderly (≥60 years old) patients who received rituximab, either as induction or maintenance with CHOP chemotherapy, had significantly longer failure-free survival as compared with those not given rituximab during their treatment course.135 Maintenance therapy with single-agent rituximab did not provide any additional benefit in patients who received R-CHOP as induction therapy. It is important to note that rituximab is given differently in the two studies. In the GELA study, rituximab is given on day 1 (the same day that cyclophosphamide, doxorubicin, and vincristine are administered) with each cycle of CHOP chemotherapy.128,129 In the Eastern Cooperative Oncology Group 4494 study,135 R-CHOP was modeled after the regimen developed by Czuczman et al.: Two doses of rituximab are given before cycle 1, and one dose is given before cycles 3, 5, and 7 (if administered).93 In most NHL protocols and in clinical practice, rituximab is given on day 1 of CHOP chemotherapy.98

Dose-dense chemotherapy, where the interval between cycles is shortened from 3 weeks to 2 weeks has been evaluated. Before the rituximab era, patients who were randomized to receive biweekly CHOP (CHOP-14) had significantly longer 5-year event-free and overall survival than patients who received standard CHOP every 21 days (CHOP-21).136 All patients in the CHOP-14 group received prophylactic growth factors starting from day 4. Toxicity was similar between the two groups. In the next study, the same group of investigators evaluated the addition of rituximab (CHOP-14 vs. R-CHOP-14) and the number of treatment cycles (six vs. eight cycles).137 Patients who received rituximab did better than those who did not, and eight cycles were not better than six cycles. The addition of rituximab to the CHOP-14 regimen resulted in significantly longer 3-year event-free and overall survival (67% vs. 47% and 78% vs. 68%, respectively). Emerging data in the rituximab era, however, suggested that R-CHOP-21 remains the standard treatment regimen when compared against R-CHOP-14 for treatment of DLBCL. The NCCN guideline does not recommend dose-dense R-CHOP (R-CHOP-14) as first-line therapy for DLBCL.65

Treatment of Refractory or Relapsed Disease Although many patients with aggressive NHL experience long-term survival and cure with intensive chemotherapy, about 10% to 20% of patients fail to achieve a complete remission and, of those patients who do achieve a complete remission, about 20% to 30% subsequently relapse. Therefore, about 30% to 40% of all patients with aggressive NHL will require salvage therapy at some point during their disease course. Response to salvage therapy depends on the initial responsiveness of the tumor to chemotherapy. Patients who achieve an initial complete remission and then relapse generally have a better response to salvage therapy than those who are primarily or partially resistant to chemotherapy.

Many conventional-dose salvage chemotherapy regimens have been used in patients with relapsed or refractory NHL. Many patients who respond to salvage therapy (i.e., chemosensitive relapse) will then receive high-dose chemotherapy with autologous HSCT. In an effort to avoid cross-resistance, most salvage regimens incorporate drugs not used in the initial therapy. Some of the more commonly used salvage regimens include dexamethasone, cytarabine, cisplatin (DHAP), etoposide, methylprednisolone, cytarabine, cisplatin (ESHAP), and mesna, ifosfamide, mitoxantrone, etoposide (MINE), and no one regimen appears to be clearly superior to any other regimen.121Rituximab is sometimes added to these salvage regimens. With these salvage regimens, about 30% to 50% of patients achieve a complete response, with a median duration of remission of 1 to 2 years. Only about 5% to 10% of patients will have long-term disease-free survival.

Ifosfamide, carboplatin, and etoposide (ICE) chemotherapy is a newer regimen that has been used in patients with refractory disease. Some clinicians believe that ICE is better tolerated than older cisplatin-based regimens, particularly in older patients. The combination of ICE and rituximab (RICE) is currently being evaluated as a salvage regimen, and early results are encouraging.120 It is recommended, however, to exclude rituximab in second-line therapy if patient’s disease is refractory or if the duration of remission is less than 6 months. One recent study (CORAL study) has compared two salvage regimens (R-ICE and R-DHAP) that are used for treatment of patients with relapsed or refractory DLBCL, followed by autologous HSCT.138 No significant difference was detected between R-ICE and R-DHAP for 3-year event-free survival or overall survival. However, poor prognosis was observed among patients who have received prior rituximab treatment and if they have experienced early relapse (defined as less than 12 months after diagnosis). This suggests that new treatment strategies are needed in order to improve the response rates of salvage regimens.

Images To improve the cure rate, many studies have evaluated high-dose chemotherapy with autologous HSCT as intensive consolidation therapy in patients who respond to salvage therapy.139 In the PARMA study, 215 patients with relapsed aggressive NHL who had a response to DHAP salvage therapy were randomized to receive either high-dose chemotherapy or continued DHAP therapy.140 Patients who received high-dose chemotherapy had significantly longer 5-year disease-free survival (46% vs. 12%) and overall survival (53% vs. 32%) than those treated with conventional salvage therapy. Further analysis of that study showed that patients who relapsed within 12 months of their initial diagnosis were less likely to benefit from high-dose chemotherapy than patients who relapsed after 12 months. Based on a review of the available evidence, including the PARMA study, high-dose chemotherapy with autologous HSCT is considered to be the treatment of choice in younger patients with chemotherapy-sensitive relapse.65 High-dose chemotherapy with autologous HSCT is not recommended in patients with untested or chemotherapy-refractory relapse.

Rituximab is being evaluated in the setting of autologous HSCT. It can be given pretransplant as an in vivo purging agent prior to stem cell collection and as posttransplant consolidation.139

Other Aggressive Lymphomas

Mantle cell lymphoma (MCL) is one of the new disease entities that was previously unrecognized by other classification systems.141 This histologic type was found in 6% of cases in the International Lymphoma Classification Project.80 The chromosomal translocation t(11;14) occurs in most cases of MCL. MCL usually occurs in older adults, particularly in men, and most patients have advanced disease at the time of diagnosis (Table 109-6). Extranodal involvement is found in about 90% of cases. The course of the disease is moderately aggressive; the median overall survival is about 3 years, with no evidence of a survival plateau.

Patients with disseminated MCL are usually treated with the same intensive combination chemotherapy regimens that are used in diffuse aggressive lymphomas. One widely used combination regimen is cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with methotrexate and cytarabine (hyperCVAD) with or without rituximab. Overall response rates to these regimens is about 90%, with about two-thirds of patients achieving a complete response.141 Because MCL usually expresses CD20, rituximab, either alone or combined with CHOP and bendamustine, has been used with some success in patients with newly diagnosed and relapsed MCL.97,142 In a meta-analysis of randomized controlled trials, the addition of rituximab to combination chemotherapy was associated with improved overall survival (HR 0.60).97 Despite the high response rates, MCL is not considered curable with standard chemotherapy. Consequently, younger patients who have an initial response to chemotherapy often undergo autologous or allogeneic HSCT as consolidation therapy. The NCCN guideline recommends that patients with advanced-stage MCL be treated initially with rituximab and combination chemotherapy, followed by autologous HSCT as first-line consolidation therapy.65 Unfortunately, most patients with MCL eventually relapse and are treated with salvage therapy or enrolled in trials of investigational agents, some of which are aimed at molecular targets. Bortezomib (Velcade®) is currently approved for treatment of patients with MCL that has relapsed after at least one prior therapy based on the results of a phase II study that showed a 33% response rate.143 Ibrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor is currently investigated for treatment of relapsed or refractory MCL. In a Phase 2 study, ibrutinib had demonstrated a high response rate of 68%, with majority of the patients receiving three prior therapies.144

Non-Hodgkin Lymphoma in Acquired Immune Deficiency Syndrome

The risk of NHL for patients with AIDS is increased more than 100-fold as compared with the general population.145,146 AIDS-related lymphoma arises as a consequence of long-term stimulation and proliferation of B lymphocytes from HIV and the reactivation of prior EBV infection as a consequence of HIV-induced immunosuppression. AIDS-related lymphoma usually occurs late in the course of HIV infection and is the cause of death in about 15% of HIV-infected individuals. Although HIV infects T cells, more than 95% of AIDS-related lymphomas are B-cell neoplasms. Most cases of AIDS-related lymphomas are classified as Burkitt or DLBCL.

The clinical presentation is similar to that observed in other immunocompromised states. Most patients with AIDS-related lymphoma present with B symptoms and have advanced-stage (III or IV) disease at the time of diagnosis.145 Involvement of extranodal sites is common. The clinical course of AIDS-related lymphoma is usually aggressive and has improved with the availability of highly active antiretroviral therapy (HAART). Improved survival has been observed, primarily in patients with DLBCL. Patients with AIDS-related lymphoma treated with intensive therapy have a median survival that is similar to the survival of patients with HIV-negative NHLs.146 In the post-HAART era, many of the prognostic factors have also changed and only lymphoma-related factors such as the IPI remain as independent predictors of prognosis.

The treatment of patients with AIDS-associated lymphomas is difficult because the immunocompromised state of these patients increases their risk of significant toxicity as a consequence of myelosuppressive therapy. Except for primary CNS lymphoma, AIDS-related lymphoma is never considered truly localized and systemic chemotherapy is indicated. For patients with adequate immune function and without a history of an opportunistic infection, chemotherapy regimens similar to that used for aggressive lymphomas may be used.65 However, many patients with AIDS-related lymphoma were previously treated with less-intensive regimens because of the increased risk of treatment-related toxicity. In the post-HAART era, however, most clinicians believe that standard doses of chemotherapy can be safely administered to patients who achieve a virologic response to HAART.

The results of treatment with standard chemotherapy regimens have been disappointing, particularly in patients with Burkitt lymphoma. In patients with DLBCL, the complete response rate with combination chemotherapy is about 40% to 50%, with 5-year overall survival rates of about 20% to 30%. Newer approaches, such as the dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) regimen developed at the National Cancer Institute, appear promising. The role of rituximab in the treatment of AIDS-related DLBCL is not clear. In a randomized trial of CHOP versus R-CHOP, no significant differences in progression-free and overall survival were observed.147 However, 14% of patients treated with R-CHOP died of treatment-related infection as compared with only 2% of those in the CHOP group. NCCN guidelines suggest omission of rituximab in patients at high risk for serious infectious complications.65

The optimal timing for HAART is not clear in patients with AIDS-related lymphoma.145,146 If HAART is given concurrently with chemotherapy, patients should be monitored closely for possible pharmacokinetic interactions between HAART and chemotherapy. Some experts suggest that HAART should be withheld until the completion of chemotherapy to allow administration of full chemotherapy doses and to avoid the risk of pharmacokinetic interactions. Prophylactic antibiotics should be continued during chemotherapy and intrathecal chemotherapy should be administered to prevent CNS relapses.

PERSONALIZED PHARMACOTHERAPY

Molecular testing of the lymphoma cells at the time of diagnosis is an essential part of the diagnostic work-up. Molecular subtypes have been identified that predict for survival. For example, two molecular subtypes of DLBCL have been identified, and the ABC subtype appears to be less responsive to chemotherapy than the GCB subtype. Another molecular subtype associated with poor response is double-hit DLBCL, defined as the existence of both MYC gene arrangement and t(14;18) BCL2 translocation.

In addition to disease stage, several prognostic indices such as IPS, IPI and FLIPI are used clinically for predicting response to therapy and survival in individual patients. The results of these evaluations form the basis for risk-adapted therapy, where the intensity of the recommended therapy is tailored to the risk category of the patient. More intensive therapy is generally recommended for higher risk patients, particularly when long-term survival or cure is the treatment goal.

Age or comorbidities often limit the use of chemotherapy regimens. Patients with poor cardiac function may not be able to receive doxorubicin, an important component of combination regimens used to treat both Hodgkin lymphoma and NHL. Patients with preexisting diabetic neuropathy or who develop peripheral neuropathy during chemotherapy may not be able to receive all of their planned doses of vinca alkaloids, particularly vincristine. Most patients with NHL are elderly and these patients may not tolerate the toxicities of intensive chemotherapy regimens. Dosage adjustments or treatment delays may be required.

Interim PET scans are currently being investigated as a biomarker of early response in patients with advanced-stage Hodgkin lymphoma. If validated, PET scans may allow clinicians to decide which patients should receive treatment intensification and which patients should have their treatment discontinued.

EVALUATION OF THERAPEUTIC OUTCOMES

Hodgkin and NHLs tend to respond well to radiation, chemotherapy, and biologic therapy. The goal of therapy for patients with Hodgkin lymphoma and aggressive NHL is long-term survival and cure. The therapeutic goal in patients with indolent NHLs is less clear because of the indolent nature of the disease and the lack of convincing evidence showing that therapy prolongs survival. Therapeutic responses should be evaluated based on physical examination, radiologic evidence, PET/CT scanning, and other positive findings at baseline. Patients with Hodgkin lymphoma and aggressive NHLs are usually evaluated for response at the end of four cycles of therapy or at the end of treatment if fewer than four cycles of therapy are planned. If patients are treated with chemotherapy alone, two additional cycles of chemotherapy are given after the patient has achieved a complete remission. Recent studies have also shown that early interim PET scans may possess prognostic value in patients with advanced Hodgkin lymphoma. The rapidity of response to therapy in patients with indolent NHL depends on the choice of therapy. Responses occur slowly with therapy with oral alkylating agents, but occur much more rapidly with aggressive therapies such as combination chemotherapy with or without rituximab. If radiation alone is used, then a therapeutic evaluation should occur at the end of treatment.

ABBREVIATIONS

Images

Images

Images

REFERENCES

    1. Diehl V, Re D, Harris NL, Mauch PM. Hodgkin Lymphoma. In: DeVita VT, Jr., Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. Philadelphia, PA: Lippincott Williams & Wilkins, 2008:2167–2220.

    2. Townsend W, Linch D. Hodgkin’s lymphoma in adults. Lancet 2012;380:836–847.

    3. Horning SJ. Hodgkin’s lymphoma. In: Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds. Abeloff’s Clinical Oncology. 4th ed. New York, NY: Churchill Livingstone, 2008:2353–2370.

    4. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11–30.

    5. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2009. 2012, http://seer.cancer.gov/csr/1975_2009_pops09/.

    6. Ng AK, Bernardo MP, Weller E, et al. Long-term survival and competing causes of death in patients with early-stage Hodgkin’s disease treated at age 50 or younger. J Clin Oncol 2002;20:2101–2108.

    7. Ambinder RF. Infectious etiology of lymphoma. In: Armitage JO, Mauch PM, Harris NL, Coiffier B, Dalla-Favera R, eds. Non-Hodgkin Lymphoma. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:83–101.

    8. Hjalgrim H, Engels EA. Infectious aetiology of Hodgkin and non-Hodgkin lymphomas: A review of the epidemiological evidence. J Intern Med 2008;264:537–548.

    9. Küppers R. New insights in the biology of Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program 2012:328–334.

   10. Mack TM, Cozen W, Shibata DK, et al. Concordance for Hodgkin’s disease in identical twins suggesting genetic susceptibility to the young-adult form of the disease. N Engl J Med 1995;332:413–418.

   11. Jaffe ES, Harris NL, Stein H, Isaacson PG. Classification of lymphoid neoplasms: The microscope as a tool for disease discovery. Blood 2008;112:4384–4399.

   12. Papadaki T, Stamatopoulos K. Hodgkin disease immunopathogenesis: long-standing questions, recent answers, further directions. Trends Immunol 2003;24:508–511.

   13. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press, 2008.

   14. Mauch PM, Kalish LA, Kadin M, Coleman CN, Osteen R, Hellman S. Patterns of presentation of Hodgkin disease. Implications for etiology and pathogenesis. Cancer 1993;71:2062–2071.

   15. Oncology NCPGi. Hodgkin Disease/Lymphoma, version 2.2012. 2012, http://www.nccn.org.

   16. Connor JM. Positron emission tomography in the management of Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program 2011:317–322.

   17. Proctor SJ, Wilkinson J, Sieniawski M. Hodgkin lymphoma in the elderly: A clinical review of treatment and outcome, past, present and future. Crit Rev Oncol Hematol 2009;71:222–232.

   18. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med 1998;339:1506–1514.

   19. Advani R. Optimal therapy of advanced Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program 2011:310–316.

   20. Hodgson DC. Late effects in the era of modern therapy for Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program 2011:323–329.

   21. Meyer RM, Hoppe RT. Point/counterpoint: Early-stage Hodgkin lymphoma and the role of radiation therapy. Hematology Am Soc Hematol Educ Program 2012:313–321.

   22. Armitage JO. Early-stage Hodgkin lymphoma. N Engl J Med 2010;363:653–662.

   23. Evens AM, Hutchings M, Diehl V. Treatment of Hodgkin lymphoma: The past, present, and future. Nat Clin Pract Oncol 2008;5:543–556.

   24. Abuzetun JY, Loberiza F, Vose J, et al. The Stanford V regimen is effective in patients with good risk Hodgkin lymphoma but radiotherapy is a necessary component. Br J Haematol 2009;144:531–537.

   25. Engert A, Plutschow A, Eich HT, et al. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med 2010;363:640–652.

   26. Specht L, Gray RG, Clarke MJ, Peto R. Influence of more extensive radiotherapy and adjuvant chemotherapy on long-term outcome of early stage Hodgkin’s disease: A meta-analysis of 23 randomized trials involving 3,888 patients. International Hodgkin’s Disease Collaborative Group. J Clin Oncol 1998;16:830–843.

   27. Engert A, Schiller P, Josting A, et al. Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin’s lymphoma: Results of the HD8 trial of the German Hodgkin’s Lymphoma Study Group. J Clin Oncol 2003;21:3601–3608.

   28. Bonnadonna G, Zucali R, Monfardini S, De Lena M, Uslenghi C. Combination therapy of Hodgkin’s disease with Adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer 1975;36:252–259.

   29. Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 1992;327:1478–1484.

   30. Goldie JH, Coldman AJ, Gudauskas GA. Rationale for the use of alternating non-cross-resistant chemotherapy. Cancer Treat Rep 1982;66:439–449.

   31. Glick JH, Young ML, Harrington D, et al. MOPP/ABV hybrid chemotherapy for advanced Hodgkin’s disease significantly improves failure-free and overall survival: The 8-year results of the intergroup trial. J Clin Oncol 1998;16:19–26.

   32. Duggan DB, Petroni GR, Johnson JL, et al. Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin’s disease: Report of an intergroup trial. J Clin Oncol 2003;21:607–614.

   33. Horning SJ, Hoppe RT, Breslin S, Bartlett NL, Brown BW, Rosenberg SA. Stanford V and radiotherapy for locally extensive and advanced Hodgkin’s disease: Mature results of a prospective clinical trial. J Clin Oncol 2002;20:630–637.

   34. Gobbi PG, Levis A, Chisesi T, et al. ABVD versus modified Stanford V versus MOPPEBVCAD with optional and limited radiotherapy in intermediate- and advanced-stage Hodgkin’s lymphoma: Final results of a multicenter randomized trial by the Intergruppo Italiano Linfomi. J Clin Oncol 2005;23:9198–9207.

   35. Hoskin PJ, Lowry L, Horwich A, et al. Randomized comparison of the Stanford V regimen and ABVD in the treatment of advanced Hodgkin’s Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244. J Clin Oncol 2009;27:5390–5396.

   36. Klimm B, Diehl V, Pfistner B, Engert A. Current treatment strategies of the German Hodgkin Study Group (GHSG). Eur J Haematol 2005 (suppl s66);75:125–134.

   37. Diehl V, Franklin J, Pfreundschuh M, et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med 2003;348:2386–2395.

   38. Engert A, Diehl V, Franklin J, Lohri A, Dorken B. Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin’s Lymphoma: 10 Years of follow-up of the GHSG HD9 study. J Clin Oncol 2009;27:4548–4554.

   39. Ballova V, Ruffer JU, Haverkamp H, et al. A prospectively randomized trial carried out by the German Hodgkin Study Group (GHSG) for elderly patients with advanced Hodgkin’s disease comparing BEACOPP baseline and COPP-ABVD (study HD9 elderly). Ann Oncol 2005;16:124–131.

   40. Federico M, Luminari S, Iannitto E, et al. ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin’s lymphoma: Results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. J Clin Oncol 2009;27:805–811.

   41. Borchmann P, Haverkamp H, Diehl V, et al. Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage Hodgkin’s lymphoma: Final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol 2011;29:4234–4242.

   42. Engert A, Haverkamp H, Kobe C, et al. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): A randomised, open-label, phase 3 non-inferiority trial. Lancet 2012;379:1791–1799.

   43. Dann EJ, Bar-Shalom R, Tamir A, et al. Risk-adapted BEACOPP regimen can reduce the cumulative dose of chemotherapy for standard and high-risk Hodgkin lymphoma with no impairment of outcome. Blood 2007;109:905–909.

   44. Prosnitz LR. Consolidation radiotherapy in the treatment of advanced Hodgkin’s disease: Is it dead? Int J Radiat Oncol Biol Phys 2003;56:605–608.

   45. Loeffler M, Brosteanu O, Hasenclever D, et al. Meta-analysis of chemotherapy versus combined modality treatment trials in Hodgkin’s disease. International Database on Hodgkin’s Disease Overview Study Group. J Clin Oncol 1998;16:818–829.

   46. Aleman BM, Raemaekers JM, Tomisic R, et al. Involved-field radiotherapy for patients in partial remission after chemotherapy for advanced Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys 2007;67:19–30.

   47. Brice P. Managing relapsed and refractory Hodgkin lymphoma. Br J Haematol 2008;141:3–13.

   48. Majhail NS, Weisdorf DJ, Defor TE, et al. Long-term results of autologous stem cell transplantation for primary refractory or relapsed Hodgkin’s lymphoma. Biol Blood Marrow Transplant 2006;12:1065–1072.

   49. Seyfarth B, Josting A, Dreyling M, Schmitz N. Relapse in common lymphoma subtypes: salvage treatment options for follicular lymphoma, diffuse large B-cell lymphoma and Hodgkin disease. Br J Haematol 2006;133:3–18.

   50. Kulkarni SS, Sastry PS, Saikia TK, et al. Gonadal function following ABVD therapy for Hodgkin’s disease. Am J Clin Oncol 1997;20:354–357.

   51. de Claro RA, McGinn KM, Kwitkowski VE, et al. U.S. Food and Drug Administration approval summary: Brentuximab vedotin for the treatment of relapsed Hodgkin lymphoma or relapsed systemic anaplastic large cell lymphoma. Clin Cancer Res 2012;18:5855–5859.

   52. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol 2012;30:2183–2189.

   53. Dores GM, Metayer C, Curtis RE, et al. Second malignant neoplasms among long-term survivors of Hodgkin’s disease: A population-based evaluation over 25 years. J Clin Oncol 2002;20:3484–3494.

   54. Franklin J, Pluetschow A, Paus M, et al. Second malignancy risk associated with treatment of Hodgkin’s lymphoma: Meta-analysis of the randomised trials. Ann Oncol 2006;17:1749–1760.

   55. Swerdlow AJ, Higgins CD, Smith P, et al. Second cancer risk after chemotherapy for Hodgkin’s lymphoma: A collaborative British cohort study. J Clin Oncol 2011;29:4096–4104.

   56. Travis LB. Evaluation of the risk of therapy-associated complications in survivors of Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program 2007:192–196.

   57. Wang SS, Hartge P. Epidemiology. In: Armitage JO, Mauch PM, Harris NL, Coiffier B, Dalla-Favera R, eds. Non-Hodgkin Lymphoma. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:64–82.

   58. Dalla-Favera R, Pasqualucci L. Molecular genetics of lymphoma. In: Armitage JO, Mauch PM, Harris NL, Coiffier B, Dalla-Favera R, eds. Non-Hodgkin Lymphoma. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:115–130.

   59. Wilson WH, Armitage JO. Non-Hodgkin’s lymphoma. In: Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds. Abeloff’s Clinical Oncology. 4th ed. New York, NY: Churchill Livingstone, 2008:2371–2404.

   60. Reeder CB, Ansell SM. Novel therapeutic agents for B-cell lymphoma: developing rational combinations. Blood 2011;117:1453–1462.

   61. Swerdlow S, Campo E, Harris NL, et al., eds. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid tissues. Lyon: IARC Press, 2008.

   62. Harris NL. History and classification of lymphoid malignancies. In: Armitage JO, Mauch PM, Harris NL, Coiffier B, Dalla-Favera R, eds. Non-Hodgkin Lymphoma. Philadelphia, PA: Lippincott Williams & Wilkins, 2010: xv–xxix.

   63. Lenz G, Staudt LM. Aggressive lymphomas. N Engl J Med 2010;362:1417–1429.

   64. Harris NL, Jaffe ES, Diebold J, et al. World Health Organization Classification of neoplastic diseases of the hematopoietic and lymphoid tissues: Report of the Clinical Advisory Committee meeting—Airlie House, Virginia, November 1997. J Clin Oncol 1999;17:3835–3849.

   65. Oncology NCPGi. Non-Hodgkin’s Lymphoma, version 1.2013. 2013, http://www.nccn.org.

   66. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579–586.

   67. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 1993;329:987–994.

   68. Sehn LH, Berry B, Chhanabhai M, et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 2007;109:1857–1861.

   69. Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood 2004;104:1258–1265.

   70. Federico M, Bellei M, Marcheselli L, et al. Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol 2009;27:4555–4562.

   71. Sehn LH. Paramount prognostic factors that guide therapeutic strategies in diffuse large B-cell lymphoma. Hematology Am Soc Hematol Educ Program 2012:402–409.

   72. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 2002;346:1937–1947.

   73. Lenz G, Wright G, Dave SS, et al. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 2008;359:2313–2323.

   74. Aukema SM, Siebert R, Schuuring E, et al. Double-hit B-cell lymphomas. Blood 2011;117:2319–2331.

   75. Green TM, Young KH, Visco C, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large b-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 2012;30:3460–3467.

   76. Dave SS, Wright G, Tan B, et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 2004;351:2159–2169.

   77. Cheson BD, Leonard JP. Monoclonal antibody therapy for B-cell non-Hodgkin’s lymphoma. N Engl J Med 2008;359:613–626.

   78. Maloney DG. Anti-CD20 antibody therapy for B-cell lymphomas. N Engl J Med 2012;366:2008–2016.

   79. Freedman AS, Friedberg JW, Mauch PM, Dalla-Favera R, Harris NL. Follicular lymphoma. In: Armitage JO, Mauch PM, Harris NL, Coiffier B, Dalla-Favera R, eds. Non-Hodgkin’s Lymphoma. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:266–283.

   80. The Non-Hodgkin’s Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. Blood 1997;89:3909–3918.

   81. Horning SJ. Natural history of and therapy for the indolent non-Hodgkin’s lymphomas. Semin Oncol 1993;20 (suppl 5):75–88.

   82. Bernstein SH, Burack WR. The incidence, natural history, biology, and treatment of transformed lymphoma. Hematology Am Soc Hematol Educ Program 2009:532–541.

   83. Fisher RI, LeBlanc M, Press OW, et al. New treatment options have changed the survival of patients with follicular lymphomas. J Clin Oncol 2005;23:8477–8452.

   84. Liu Q, Fayad L, Cabanillas F, et al. Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 Years of treatment experience at the University of Texas M.D. Anderson Cancer Center. J Clin Oncol 2006;24:1582–1589.

   85. Seymour JF, Pro B, Fuller LM, et al. Long-term follow-up of a prospective study of combined modality therapy for stage I–II indolent non-Hodgkin’s lymphoma. J Clin Oncol 2003;21:2115–2122.

   86. Gribben JG. How I treat indolent lymphoma. Blood 2007;109:4617–4626.

   87. Freedman AS, Friedberg JW. Approach to the diagnosis of non-Hodgkin’s lymphoma. In: Rose BD, ed. UpToDate. Waltham, MA, 2009.

   88. Ardeshna KM, Smith P, Norton A, et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin’s lymphoma: A randomised controlled trial. Lancet 2003;362:516–522.

   89. McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituxumab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 1998;16:2825–2833.

   90. Cohen Y, Solal-Celigny P, Polliack A. Rituximab therapy for follicular lymphoma: A comprehensive review of its efficacy as primary treatment, treatment for relapsed disease, re-treatment and maintenance. Haematologica 2003;88:811–823.

   91. Cvetkovic RS, Perry CM. Rituximab: A review of its use in non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Drugs 2006;66:791–820.

   92. Friedberg JW, Taylor MD, Cerhan JR, et al. Follicular lymphoma in the United States: First report of the National LymphoCare Study. J Clin Oncol 2009;27:1202–1208.

   93. Czuczman MS, Grillo-Lopez AJ, White CA, et al. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 1999;17:268–276.

   94. Czuczman MS, Weaver R, Alkuzweny B, Berlfein J, Grillo-Lopez AJ. Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin’s lymphoma treated with rituximab plus CHOP chemotherapy: 9-Year follow-up. J Clin Oncol 2004;22:4711–4716.

   95. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: Results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005;106:3725–3732.

   96. van Oers MHJ, Klasa R, Marcus RE, et al. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular lymphoma non-Hodgkin’s lymphoma in patients both with and without rituximab during induction: Results of a prospective randomized phase 3 intergroup trial. Blood 2006;108:3295–3301.

   97. Schulz H, Bohlius JF, Trelle S, et al. Immunochemotherapy with rituximab and overall survival in patients with indolent or mantle cell lymphoma: A systematic review and meta-analysis. J Natl Cancer Inst 2007;99:706–714.

   98. Ghielmini M. Multimodality therapies and optimal schedule of antibodies: Rituximab in lymphoma as an example. Hematology Am Soc Hematol Educ Program 2005:321–328.

   99. Hochster H, Weller E, Gascoyne RD, et al. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: Results of the randomized phase III ECOG1496 study J Clin Oncol 2009;27:1607–1614.

  100. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): A phase 3, randomised controlled trial. Lancet 2011;377:42–51.

  101. Cheson BD. Hematology: The case against rituximab maintenance. Nat Rev Clin Oncol 2009;6:622–624.

  102. Seymour JF. Follicular lymphoma: Maintenance therapy is (often) indicated. Nat Rev Clin Oncol 2009;6:624–626.

  103. Forstpointner R, Unterhalt M, Dreyling M, et al. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood 2006;108:4003–4008.

  104. van Oers MH, Van Glabbeke M, Giurgea L, et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin’s lymphoma: Long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol 2010;28:2853–2858.

  105. Al Zahrani A, Ibrahim N, Al Eid A. Rapid infusion rituximab changing practice for patient care. J Oncol Pharm Pract 2009;15:183–186.

  106. Chiang J, Chan A, Shih V, Hee SW, Tao M, Lim ST. A prospective study to evaluate the feasibility and economic benefits of rapid infusion rituximab at an Asian cancer center. Int J Hematol 2010;91:826–830.

  107. Yeo W, Chan TC, Leung NWY, et al. Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab. J Clin Oncol 2009;27:605–611.

  108. Beers SA, Chan CH, French RR, et al. CD20 as a target for therapeutic type I and II monoclonal antibodies. Semin Hematol 2010;47:107–114.

  109. Rummel MJ, Gregory SA. Bendamustine’s emerging role in the management of lymphoid malignancies. Semin Hematol 2011;48:S24–S36.

  110. Robinson KS, Williams ME, van der Jagt RH, et al. Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin’s lymphoma. J Clin Oncol 2008;26:4473–4479.

  111. Fowler N, Kahl BS, Lee P, et al. Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: the phase II VERTICAL study. J Clin Oncol 2011;29:3389–3395.

  112. Friedberg JW, Vose JM, Kelly JL, et al. The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma. Blood 2011;117:2807–2812.

  113. Goldsmith SJ. Radioimmunotherapy of lymphoma: Bexxar and Zevalin. Semin Nucl Med 2010;40:122–135.

  114. Press OW, Unger JM, Braziel RM, et al. Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non-Hodgkin’s lymphoma: Five-year follow-up of Southwest Oncology Group Protocol S9911. J Clin Oncol 2006;24:4143–4149.

  115. Kaminski MS, Tuck M, Estes J, et al.131 I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 2005;352:441–449.

  116. Link BK, Martin P, Kaminski MS, Goldsmith SJ, Coleman M, Leonard JP. Cyclophosphamide, vincristine, and prednisone followed by tositumomab and iodine-131-tositumomab in patients with untreated low-grade follicular lymphoma: Eight-year follow-up of a multicenter phase II study. J Clin Oncol 2010;28:3035–3041.

  117. Armitage JO, Carbone PP, Connors JM, Levine AM, Bennett JM, Kroll S. Treatment-related myelodysplasia and acute leukemia in non-Hodgkin’s lymphoma patients. J Clin Oncol 2003;21:897–906.

  118. van Besien KW. Allogeneic stem cell transplantation in follicular lymphoma: recent progress and controversy. Hematology Am Soc Hematol Educ Program 2009:610–618.

  119. Oliansky DM, Gordon LI, King J, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of follicular lymphoma: An evidence-based review. Biol Blood Marrow Transplant 2010;16:443–468.

  120. Gisselbrecht C. Use of rituximab in diffuse large B-cell lymphoma in the salvage setting. Br J Haematol 2008;143:607–621.

  121. Armitage JO, Mauch PM, Harris NL, Dalla-Favera R, Bierman PJ. Diffuse large B-cell lymphoma. In: Armitage JO, Mauch PM, Harris NL, Coiffier B, Dalla-Favera R, eds. Non-Hodgkin Lymphoma. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:304–326.

  122. McKelvey EM, Gottleib JA, Wilson HE, et al. Hydroxydaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma. Cancer 1976;38:1484–1493.

  123. Jones SE, Grozea PN, Metz EN, et al. Superiority of Adriamycin containing combination chemotherapy in the treatment of diffuse lymphoma: A Southwest Oncology Group study. Cancer 1979;43:417–425.

  124. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 1993;328:1002–1006.

  125. Fisher RI, Miller TP, O’Connor OA. Diffuse aggressive lymphoma. Hematology Am Soc Hematol Educ Program 2004:221–236.

  126. Blayney DW, LeBlanc ML, Grogan T, et al. Dose-intense chemotherapy every 2 weeks with dose-intense cyclophosphamide, doxorubicin, vincristine, and prednisone may improve survival in intermediate- and high-grade lymphoma: A phase II study of the Southwest Oncology Group (SWOG 9349). J Clin Oncol 2003;21:2466–2473.

  127. Coiffier B. Increasing chemotherapy intensity in aggressive lymphoma: A renewal? J Clin Oncol 2003;21:2457–2459.

  128. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235–242.

  129. Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: A study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood 2010;116:2040–2045.

  130. Pfreundschuh M, Trumper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large B-cell lymphoma: A randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006;7:379–391.

  131. Sehn LH, Donaldson J, Chhanabhai M, et al. Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol 2005;23:5027–5033.

  132. Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: A study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2005;23:4117–4126.

  133. Held G, Schubert J, Reiser M, Pfreundschuh M. Dose-intensified treatment of advanced-stage diffuse large B-cell lymphomas. Semin Hematol 2006;43:221–229.

  134. Greb A, Bohlius J, Trelle S, et al. High-dose chemotherapy with autologous stem cell support in first-line treatment of aggressive non-Hodgkin lymphoma—results of a comprehensive meta-analysis. Cancer Treat Rev 2007;33:338–346.

  135. Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 2006;24:3121–3127.

  136. Pfreundschuh M, Trumper L, Kloess M, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: Results of the NHL-B2 trial of the DSHNHL. Blood 2004;104:634–641.

  137. Pfreundschuh M, Schubert J, Ziepert M, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: A randomised controlled trial (RICOVER-60). Lancet Oncol 2008;9:105–116.

  138. Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 2010;28:4184–4190.

  139. Nademanee A, Forman SJ. Role of hematopoietic stem cell transplantation for advanced-stage diffuse large B-cell lymphoma. Semin Hematol 2006;43:240–250.

  140. Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 1995;333:1540–1545.

  141. Zain J, Bhagat G, O’Connor OA. Mantle cell lymphoma. In: Armitage JO, Mauch PM, Harris NL, Coiffier B, Dalla-Favera R, eds. Non-Hodgkin Lymphoma. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:284–303.

  142. Rummel MJ, Al-Batran SE, Kim SZ, et al. Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin’s lymphoma. J Clin Oncol 2005;23:3383–3389.

  143. Fisher RI, Bernstein SH, Kahl BS, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 2006;24:4867–4874.

  144. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle cell lymphoma. N Engl J Med 2013;369:507–516.

  145. Levine AM, Said JW. Management of acquired immunodeficiency syndrome-related lymphoma. In: Armitage JO, Mauch PM, Harris NL, Coiffier B, Dalla-Favera R, eds. Non-Hodgkin Lymphoma. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:507–526.

  146. Mounier N, Spina M, Gisselbrecht C. Modern management of non-Hodgkin’s lymphoma in HIV-infected patients. Br J Haematol 2007;136:685–698.

  147. Kaplan LD, Lee JY, Ambinder RF, et al. Rituximab does not improve clinical outcome in a randomized phase III trial of CHOP with or without rituximab in patients with HIV associated non-Hodgkin’s lymphoma: AIDS Malignancy Consortium trial 010. Blood 2005;106:1538–1543.