Bethesda Handbook of Clinical Oncology, 2nd Edition

Hematologic Malignancies

28

Non-Hodgkin Lymphoma

Martin E. Gutierrez*

Richard F. Little

Wyndham H. Wilson

*Medical Oncology clinical Research Unit, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

The non-Hodgkin lymphomas (NHLs) are a group of entities that vary in clinical behavior and morphologic appearance. The various types of NHLs are thought to represent neoplastic lymphoid cells that are arrested at different stages of normal differentiation. On the basis of their natural history, NHLs can be clinically classified as indolent, aggressive, or highly aggressive.

EPIDEMIOLOGY

Over the last 20 years, the incidence of NHL has been steadily increasing at approximately 4% per year, which represents 55,000 new cases annually. Mortality has shown similar increases. Approximately one third of the increase has been attributed to a combination of improved diagnosis and immunosuppressive therapy, and to the AIDS epidemic. A slight decrease in the incidence of AIDS-related NHL (ARL) has been noted since 1996, but the incidence in other groups of other NHLs has continued to increase.

PATHOPHYSIOLOGY

Cytogenetics, gene rearrangement, and oncoproteins are important molecular markers of the histologic subtype, histogenesis, and mechanisms of lymphomagenesis. Tumor clonality may be assessed by immunoglobulin (Ig) gene rearrangement in B cells and by T-cell–receptor (TCR) rearrangement in T cells. Cytogenetics and/or oncogene rearrangement by polymerase chain reaction (PCR) may also be useful to assess clonality. However, the absence of evidence for clonality does not exclude the presence of a malignant lymphoid process, whereas the presence of its evidence does not necessarily confirm a malignant lymphoid process (see Tables 28.1 and 28.2).

TABLE 28.1. Molecular Characteristics of B-cell Lymphomas

Histology

Cytogenetics

Oncogene/protein

Ig gene rearrangements

 

Heavy

κ λ

 

CLL, chronic lymphocytic leukemia; SLL, small lymphocytic lymphoma.
Trisomy 12 is seen in 30% of cases and abnormalities in 13q are present in 25% of patients.
t(14;18) is present in 75% to 95% of FCC NHL.
Cytogenetic abnormalities have been seen in extranodal MZ NHL.
Bcl-2 rearrangements up to 30% and Bcl-6 up to 45% of cases of DLBCL.

 

CLL/SLLa

Trisomy 12; deletions + of 13q14 and 11q22–23

+

+

 

Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia

t(9;14)

PAX-5 gene

+

+

 

Follicular center cell

t(14;18)

Bcl-2

+

 

   Grade I/II/IIIab

 

Marginal zonec

Trisomy 3

+

 

t(11;18)

 

Mantle cell lymphoma

t(11;14)

Bcl–1/Cyclin D1

+

 

Diffuse large B-celld

t(14;18); 3q27; 17p

Bcl-2; Bcl-6; p53

+

+

 

Primary mediastinal large cell

Gains 9p

REL gene; MAL gene overexpression

+

+

 

Lymphoblastic lymphoma/leukemia

t(9;22)

BCR/ABL

+

±

 

t(12;21)

TEL/AML1

 

t(1;19)

PBX/E2A

 

Burkitt lymphoma

t(8;14)(q24;q32)

c-myc

+

+

 

t(2;8)(11p; q24)

+

 

t(8;22)(q24;q11)

 

TABLE 28.2. Molecular Characteristics of T-cell Lymphomas

Histology

Cytogenetics

Oncoprotein

TCR gene rearrangements

TCR, T-cell–receptor; CLL, chronic lymphocytic leukemia; PLL, prolymphocytic leukemia; ATLL, adult T-cell lymphoma/leukemia; EBV, Epstein–Barr virus; ALCL, anaplastic large-cell lymphoma.
TCR gene rearrangement is present in 75% and IgH in 10%.
TCR gene rearrangement in 60% +.
Alk: ALK gene.

T-CLL/T-PLL

Inv14(q11;q32), + Trisomy 8q

Bcl-3

+

Mycosis fungoides

+

Peripheral T-cell lymphoma unspecified

±

Angioimmunoblastic T-cell lymphomaa

Trisomy 3 or 5, EBV +

+

ATLL

HTLV-1 integration +

+

Enteropathy T cell

–EBV–

β+

Hepatosplenic γ/δ

δγ+

Systemic ALCLb,c

t(2;5)

Alk+

+

Precursor T-lymphoblastic

Variable

Tcl-4

Variable

   Lymphoma/leukemia

t(7;9)

A major known risk factor for NHL appears to be an abnormality in immune function (either immunodeficiency or dysregulation), as seen in human immunodeficiency virus (HIV) infection, iatrogenic immune suppression, congenital immune deficiencies (i.e., Wiskott-Aldrich syndrome and X-linked lymphoproliferative disorder), and autoimmune diseases. Infectious agents have also been implicated as risk factors; Epstein–Barr virus (EBV) is associated with African Burkitt lymphoma and AIDS-related diffuse large B-cell lymphomas (DLBCLs); Kaposi sarcoma–associated herpesvirus (KSHV, also known as human herpesvirus-8 or

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HHV-8) is etiologically linked to primary effusion lymphomas and multicentric Castleman disease; and human retroviruses such as human T-cell lymphoma virus 1 (HTLV-1) are the etiologies of adult T-cell leukemia/lymphoma. Infectious agents have also been implicated through stimulating B-cell clones, such as hepatitis C virus and splenic marginal zone (MZ) lymphoma, Helicobacter pylori and gastric MZ lymphomas, and possibly, Chlamydia and ocular MZ lymphomas. Environmental and occupational exposures, especially organic compounds (organophosphate insecticides), have been etiologically linked to lymphoma.

Staging for Non-Hodgkin Lymphoma

  • Staging evaluation of NHL should include history and physical examination and clinical laboratory assessment of organ function. In addition, viral serology for HIV (in aggressive NHL), HTLV-1, and hepatitis B and C viruses needs to be considered if indicated by risk or by lymphoma subtype.
  • Routine blood tests including lactate dehydrogenase (LDH) should be performed.
  • T-cell subset analysis (e.g., CD4 cell count) should be done if the patient is HIV positive.
  • In young men with an isolated mediastinal mass, where the differential diagnosis includes mediastinal germ cell tumor, determination of serum α-fetoprotein or β-human chorionic gonadotropin can be useful.
  • Radiologic evaluation should include chest x-ray and computerized tomographic scans of chest, abdomen, and pelvis. Positron emission tomography (PET) scans are useful for identifying sites of disease and for assessing responses. Gallium scans, although used in the past, are less sensitive and less specific than PET.

Staging Procedures:

  • Bone marrow (BM) biopsy
  • Lumbar puncture with cytology in patients at risk for central nervous system (CNS) disease—DLBCL with elevated LDH level and more than one extranodal site and/or aggressive lymphoma in the BM. All Burkitt lymphoma and AIDS-related lymphoma (ARL) cases should be assessed.

Definitions:

  • B symptoms: unexplained weight loss of more than 10% of body weight over the previous 6 months, fever, and “drenching” night sweats
  • X: bulky disease (10 cm maximal dimension)
  • E: extranodal disease
  • Single E site is sufficiently limited in extent/location that it can be subjected to definitive treatment with radiation.

Diagnostic Confirmation by Tissue Biopsy:

Sufficient material is critical to conduct the studies that ensure accurate diagnosis. Needle biopsies generally yield inadequate tissue for these studies and should be avoided for use in primary diagnosis. Important studies for diagnostic confirmation often include assessment of clonality, immunophenotyping, cytogenetic analysis, and molecular studies. Oncogene rearrangement and/or overexpression of oncoproteins can be diagnostically useful:

  • t(8;14) or MYC in Burkitt lymphoma
  • t(14;18) or bcl-2 in follicular lymphoma
  • t(2;5) or anaplastic lymphoma kinase (ALK) in anaplastic large-cell lymphoma
  • t(11;14) or bcl-1 in mantle cell lymphoma

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  • Trisomy 3 or trisomy 18 (marginal zone lymphoma)
  • Some tumors (e.g., T-cell–rich B-cell lymphoma or lymphomatoid granulomatosis) have an excess of reactive T cells that may obscure the minority of diagnostic malignant B cells if inadequate tissue is obtained.

The Ann Arbor/American Joint Commission for Cancer (AJCC) and Cotswolds staging systems are applicable to all histologies except lymphoblastic and mycosis fungoídes (MF) (see Table 28.3).

TABLE 28.3. Staging System in Non-Hodgkin Lymphomas

Stage

Ann Arbor/AJCC and Cotswolds

St. Jude lymphoblastic NHL

Mycosis fungoides

I

Single node region or lymphoid structure or single extranodal site mediastinum or abdomen

Single tumor (extranodal) or single anatomic area (nodal), excluding

Confined to the skin

II

Two or more nodes on same side of diaphragm or single nodal site with extranodal extension

Single tumor (extranodal) with regional node involvement

·         Primary gastrointestinal tract tumor (usually ileocecal) ± mesenteric nodes

Clinically positive nodes

III

Nodal regions or lymphoid structures on both sides of the diaphragm

Node regions or lymphoid structure on both sides of the diaphragm

·         All primary intrathoracic tumor (i.e., mediastinal, pleural, and thymic)

·         All extensible primary intraabdominal disease; unresectable

·         All primary paraspinal or epidural tumors regardless of other sites

Histologically proven nodes

IV

Bone marrow or liver or extranodal site(s) beyond those designated as “E”

Any of the above with initial CNS or BM involvement

Visceral disease

Restaging for Response Evaluation

  • On completion of therapy, staging studies should be repeated. Restaging is also recommended after the first four cycles (all tests with abnormal results should be repeated). Disease progression or inadequate response implies extremely poor prognosis. If residual masses are present after systemic chemotherapy, a PET scan may help distinguish active disease from residual scar. If residual masses are unclear on imaging, evaluation biopsy may be required.
  • Response to therapy may be slower in indolent lymphomas than in aggressive and highly aggressive lymphomas. Restaging can be performed less frequently in these cases.

Prognostic Features

  • The disease-related prognostic features include histologic type and tumor histogenesis. Indolent lymphomas are rarely curable, but often have a prolonged natural history. DLBCL

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is potentially curative, with outcome depending on histogenesis: a better prognosis is associated with a germinal center B cell (GCB) gene expression pattern, and a worse prognosis is associated with a non-GCB gene expression pattern.

  • Adverse clinical characteristics such as tumor bulk, advanced stage, many extranodal sites, and high tumor proliferation (MIB-1 and LDH) may be overcome with infusional regimens such as dose-adjusted EPOCH (doxorubicin, etoposide, vincristine, cyclophosphamide, and prednisone). Bcl-2expression has been associated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) failure but may be partially overcome with rituximab.
  • Prognostic assessment and modeling: The International Prognostic Index (IPI) was initially developed for aggressive NHL, but it has been applied to other NHL subtypes also.
  • One point is assigned for each of the following:
  • Individuals older than 60 years
  • Eastern Cooperative Oncology Group (ECOG) performance status more than one
  • LDH level greater than normal
  • More than one extranodal site
  • Ann Arbor stage III or IV disease
  • Age-adjusted International Index for patients younger than 60 years.

CLASSIFICATION OF NON-HODGKIN LYMPHOMAS

The World Health Organization (WHO) classification is the currently accepted system and incorporates immunophenotypic, molecular, and clinical elements to distinguish NHL subtypes (see Tables 28.4 and 28.5). NHLs are broadly classified as B-cell lymphomas or T-cell lymphomas depending on the lymphocyte lineage giving rise to the tumor.

  • B lymphocytes give rise to B-cell NHL; this accounts for 88% of NHLs.
  • T lymphocytes give rise to T-cell NHL; this accounts for 12% of NHLs.

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  • Expression (or lack thereof) of cell surface antigens and immunoglobulin proteins depends on the type of lymphocyte and its stage of differentiation. Thus, analysis of these proteins in tumor cells is diagnostically useful and may help determine tumor histogenesis.

TABLE 28.4. B-cell Immunophenotype

Histology

SIg

CIg

CD

5

10

11

15

23

30

34

43

45

CLL, chronic lymphocytic leukemia; SLL, small lymphocytic lymphoma; FCC, follicular center cell.
Positive B-cell–associated antigens: CD19, CD20, CD22, and CD79.
SIg+: IgM±, IgD > IgG > IgA.
SIg M > IgG >IgA and IgD; CIg+ in 40%.
SIgM+ usually IgD+, κ > λ and CD11c.
IgM > IgG >IgA and IgD; CIg+ in 40%.
TdT+, HLA – Dr+ and CD20–/+.

CLL/SLLa

±

±

+

±

 

+

 

 

+

 

Lymphoplasmacytoid lymphomaa

+

+

±

 

 

 

±

 

FCC grade I/II/IIIa,b

+

±

 

±

 

 

 

Marginal zonea,c

+

+

±

 

 

 

±

 

Mantle cell lymphomaa,d

+

+

±

 

 

 

+

 

Diffuse large B-Cella

±

±

±

±

 

 

 

 

 

±

Primary mediastinal large B-cella,e

±

±

 

±

 

 

±

Precursor B lymphoblastic Lymphoma /leukemiaa,f

±

 

±

 

 

 

 

±

 

 

Burkitt lymphomaa

+

 

+

 

 

 

 

 

 

TABLE 28.5. T-cell Immunophenotype

Histology

CD

1a

2

3

4

5

7

8

25

56

TdT

CLL, chronic lymphocytic leukemia; PLL, prolymphocytic leukemia; ALCL, anaplastic large-cell lymphoma.
T-CLL: 60% are CD4+ and 21% CD4+8+; rare cases are CD4-8+ and CD25-.
Peripheral T-cell are most commonly CD4 > CD8. It can be CD 4-8-; CD45RA may be + and CD45RA -.
Intestinal T cell is CD103+.
ALCL are CD30+, CD45±, EMA+ and CD15+.

T-CLL /T-PLLa

 

+

+

+

+

+

+

 

 

Mycosis fungoides

 

+

+

+

+

–/+

 

 

Peripheral T-cell lymphoma unspecifiedb

 

±

±

+

±

–/+

±

 

 

 

Angioimmunoblastic lymphoma

 

+

+

+

+

 

 

 

 

 

Enteropathy T cellc

 

 

+

 

+

±

 

 

 

Adult T-cell lymphoma/leukemia

 

+

+

+

+

+

 

 

Systemic ALCLd

 

 

–/+

 

 

 

 

±

 

 

Hepatosplenic γ/δ

 

 

+

 

 

 

+

 

Precursor T-lymphoblastic lymphoma/leukemia

±

±

+

+

±

+

+

 

 

+

There is an increasing appreciation of the relation between tumor histogenesis and clinical behavior, such as previously discussed with DLBCL. Patients with chronic lymphocytic leukemia/lymphoma (CLL) can be grouped according to whether the variable region of the Ig genes (IgVH) shows sequence homology to germline IgVH genes, or on the basis of evidence of somatic mutations. Prognosis is poorer in patients with unmutated IgVH genes (pregerminal center histogenic origin) than in patients with somatic mutations (germinal center B-cell histogenic origin).

The World Health Organization (WHO) recognizes three major categories of lymphoid neoplasms:

  1. B-cell neoplasms
  2. T- and NK-cell neoplasms
  3. Hodgkin lymphoma.

Both lymphomas and lymphoid leukemias are included in the WHO classification. Solid and leukemic phases are present in many lymphoid neoplasms. The WHO classification stratifies these neoplasms primarily according to lineage. A cell of origin is postulated for each neoplasm, and for many neoplasms, this cell of origin represents the stage of differentiation of the tumor cells in the tissues and may or may not reflect the stage of differentiation during which the initial transforming events occur, because it is not possible to know these events in many cases.

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Each histologic entity is grouped according to general clinical behavior as indolent, aggressive, or highly aggressive lymphomas for the sake of the reader. For further information about the WHO classification of tumors, see http://www.iarc.fr/who-bluebooks/.

Indolent Lymphomas

B Cell

  • B-chronic lymphocytic leukemia/Small lymphocytic lymphoma(SLL): These diseases affect older patients (median age in the seventh decade) and involve the BM, peripheral blood (PB), lymph node (LN), liver, and spleen. SLL represents the nonleukemic equivalent of CLL. These diseases are incurable and have median survivals of approximately 10 years. They can transform to more aggressive prolymphocytic leukemia (PLL) or large B-cell NHL (Richter syndrome), which have median survivals of less than 1 year.
  • Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia:This lymphoma affects primarily older patients (median age in the seventh decade). The sites of involvement include BM, LN, and spleen; rarely, PB or extranodal sites are involved. Paraproteinemia with IgM and hyperviscosity symptoms may occur. When disseminated, this entity is incurable and has a median survival of approximately 8 to 10 years.
  • Follicular center cell (FCC) grades I, II, and IIIa:The median age occurrence of this lymphoma is in the sixth decade. It is the second most common subtype of NHL, comprising approximately 35% of lymphomas. FCC lymphomas are graded on the basis of the proportion of small and large cells. Grade I contains predominantly centrocytes (small B cells) and zero to five centroblasts (large B cells); grade II contains mixed centrocytes and 6 to 15 centroblasts; and grade IIIa contains centrocytes and more than 15 centroblasts per high power field (HPF). It commonly shows LN and BM involvement, splenomegaly, extranodal involvement, and a clinical leukemic phase. Advanced-stage disease is incurable in most patients and has a median survival of 8 to 10 years. Histologic transformation of this disease to an aggressive large B-cell lymphoma occurs in most patients, although it may not manifest clinically.
  • Marginal zone:There are two major clinical presentations of MZ: extranodal and nodal types. Extranodal types are associated with autoimmune diseases like Sjögren syndrome, Hashimoto thyroiditis, or H. pylori gastritis. Recent evidence indicates that proliferation may be antigen driven in some mucosa-associated lymphoid tissue (MALT) lymphomas such as H. pylori gastritis, and eradication of the antigen may result in tumor regression. Median age of occurrence of MZ lymphomas is in the seventh decade. These tumors are usually indolent but incurable and have a median survival of 10 years. Nodal types may represent the nodal dissemination of extranodal types of MZ. However, isolated nodal types occur, and are less indolent than the extranodal types.

T Cell

  • T-chronic lymphocytic leukemia/T-prolymphocytic leukemia:T-CLL/T-PLL comprise 1% of CLLs but up to 20% of PLLs. Patients often have high white blood cell (WBC) counts (e.g., >100,000 per mm3) and may have cutaneous or mucosal infiltrates. T cells are more aggressive than their B-cell counterparts and have a median survival of 8 years.
  • Mycosis fungoídes:MF is a cutaneous T-cell lymphoma that often has multiple cutaneous plaques, nodules, and/or generalized erythroderma. Nodal involvement and leukemic phases (Sézary syndrome) are late occurrences. Large-cell lymphoma may develop as a terminal event. The disease may be relatively indolent over prolonged periods and may have a median survival of 10.2 years, but in the group with poor prognosis (patients older than 65 years and stage IVB), the median survival is 1.1 years.

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Treatment Principles

Patients with early-stage FCC and MZ lymphomas may be potentially cured with radiation treatment. In stage I FCC lymphoma, radiation treatment (e.g., 30 to 50 Gy) has a disease-free survival of 54% to 88% at 10 years, although recent evidence suggests that radiation does not increase overall survival (OS) (see Fig. 28.1). In advanced-stage patients, the Stanford group showed no difference in survival between watching until medical symptoms required treatment (called “watch and wait”) and early intervention. On the basis of this approach, therapy is often not begun until symptoms or impending organ compromise occurs or until the lymphoma transforms to an aggressive subtype.

 

FIG. 28.1. Indolent non-Hodgkin lymphoma (NHL) approach.

Selection of treatment is based on the clinical situation. Generally, radiation may be used to palliate local disease, whereas cytotoxic or monoclonal antibody therapies may be used in disseminated disease. The choice of agents depends on the cell type (B versus T cell), histology, and treatment history (see Table 28.6). Standard chemotherapy is not usually curative.

TABLE 28.6. Indolent Lymphoma Treatment

 

Treatment description

Combination chemotherapy

CVP

Cyclophosphamide 400 mg/m2 PO daily for 5 d, d 1–5 (total dose/cycle = 2,000 mg/m2)
Vincristine 1.4 mg/m2 i.v. on d 1 (maximum dose/cycle = 2 mg; total dose/cycle = 1.4 mg/m2)
Prednisone 100 mg/m2 PO daily for 5 d, d 1–5 (total dose/cycle = 500 mg/m2)
• treatment is repeated every 21 d

Single agents

Fludarabine

Fludarabine 25 mg/m2/d i.v. for 5 d, d 1–5 (total dose/cycle = 125 mg/m2)
• treatment is repeated every 28 d

Rituximab

Rituximab 375 mg/m2 i.v. weekly (total dose/wk = 375 mg/m2)

Radiolabeled monoclonal antibody

Zevaline and Bexxar

Some of the treatment possibilities are oral chlorambucil, CVP (cyclophosphamide, vincristine, and prednisone), fludarabine, or rituximab (monoclonal anti-CD20 antibody). Rituximab, as a single agent in previously untreated follicular lymphoma, yields up to 75% response rates. Maintenance rituximab may prolong remission. At 3 years of median follow-up, the duration of remission is 23 months for maintenance rituximab versus 12 months for rituximab as a single agent, thereby favoring the rituximab maintenance group receiving 375 mg per m2 every 2 months for four doses after induction. As a single agent in previously treated follicular lymphoma, rituximab can yield responses in 50% to 60% of cases, with median response duration ranging from 6 to 16 months. Rituximab combinations, like rituximab with CHOP, induce complete responses in up to 95% of previously untreated follicular lymphomas, with the median response duration not being achieved until 50 months of follow-up. Rituximab combined with fludarabine yields results similar to the combination of CHOP and rituximab.

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  • Radioimmunotherapy for relapsed disease:Yttrium 90-ibritumomab tiuxetan (Zevalan) is FDA approved and is well tolerated. A randomized trial indicated a marginally statistically significant higher ORR and CR, but not response duration, for Zevalan than for rituximab alone in relapsed or refractory low-grade, follicular, or transformed B-cell NHL. Tositumomab and Iodine I 131 tositumomab (Bexxar) are also U.S. Food and Drug Administration (FDA)–approved for the treatment of CD20-positive, follicular lymphoma that is refractory to rituximab and that relapses following chemotherapy.
  • CLL/SLL:Fludarabine and rituximab, given concurrently or sequentially, increase response rates. Alemtuzumab is approved for fludarabine-refractory disease, with response rates of approximately 30%.
  • Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia:Initial therapy with rituximab has produced overall response rates of 30% to 60%. Other conventional therapies include alkylating agents (especially chlorambucil) with or without corticosteroids. Treatment with CHOP is sometimes used. Purine analogs such as fludarabine are also active. Response rates to first-line therapy range from 38% to 85%. Response rates to fludarabine in previously treated patients range from 30% to 50%.
  • In MF, a variety of active treatments are available for good-prognosis disease, but the extent to which outcomes are related to therapy or to the natural history of the disease is often not well documented. Reported treatments include low-dose oral methotrexate, topical bexarotene gel, topical gel formulation combining methotrexate and laurocapram, and topical nitrogen mustard. Combined modality therapy, including subcutaneous interferon-α and oral isotretinoin followed by total-skin electron beam therapy and long-term maintenance therapy with topical nitrogen mustard and interferon-α, has been reported as being useful. Extracorporeal photopheresis with or without other modalities has been reported.

Aggressive Non-Hodgkin Lymphomas

B Cell

  • Mantle cell lymphoma:This lymphoma occurs primarily in older patients (median age in the seventh decade), with a high male-to-female ratio. It often involves the spleen, BM, LN,

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and extranodal sites, particularly the gastrointestinal tract (lymphomatous polyposis) in up to 90% of cases. Unlike other aggressive lymphomas, it is incurable and has a short median survival of 3 to 5 years. The blastic variant is more aggressive than the other forms, with a propensity for CNS involvement and shorter survival.

  • FCC grade IIIb:Histologically, FCC grade IIIb lymphoma presents with sheets of centroblasts and no centrocytes. This entity is rare and is biologically similar to de novo DLBCL. It should be treated like DLBCL and appears to have a similar rate of cure.
  • DLBCL:This lymphoma constitutes up to 30% of adult lymphomas. As in other lymphomas, the median age is in the sixth decade. Patients frequently exhibit a rapidly enlarging mass or an acute onset of symptoms. Extranodal involvement is seen in 40% of cases. DLBC can be cured with combination chemotherapy and should be treated promptly and aggressively. The OS and progression-free survival (PFS) are approximately 50% and 32%, respectively, at 5 years.
  • Primary mediastinal (thymic) large cell lymphoma:This recently recognized subtype of DLBCL is believed to arise in thymic tissue and commonly forms a large anterior mediastinal mass. It occurs most commonly in young women in their third or fourth decade and may involve extranodal sites such as the kidney, lung, and liver. The OS and PFS are similar to other large B-cell lymphomas.
  • HIV-associated B-cell lymphomas:The incidence of lymphoma is 60 times higher than that expected among HIV-infected individuals. The median age of occurrence is in the fourth decade, compared with the sixth decade in patients with non–HIV-related lymphomas. Most patients have advanced-stage disease and often have extranodal involvement, including the gastrointestinal tract, BM, and CNS. CNS may be the only site involved, as in primary CNS lymphoma, or the lymphoma may form a part of systemic disease. Histologically, these lymphomas are aggressive B cells and are divided between the large B-cell (>70%) and Burkitt subtypes of lymphoma.

T Cell

  • Peripheral T-cell lymphomas (PTLs):These lymphomas are less common, comprising less than 15% of lymphomas in the developed countries, but have a higher incidence in other parts of the world. They are divided into specified and unspecified types. The unspecified PTLs are so named because they do not fit the requirements for the specified types and do not share a common biology or clinical behavior. Patients typically have generalized disease and may have pruritus and eosinophilia. PTLs frequently involve LN, skin (subcutis), liver, and spleen. In general, PTLs have an aggressive clinical course, although some may be relatively indolent. T-cell lymphomas have a lower rate of cure and higher rate of relapse than B-cell lymphomas, with an OS and failure-free survival (FFS) of 25% and 18%, respectively, at 5 years.
  • Intestinal T-cell lymphoma:Adult patients often have a history of gluten-sensitive enteropathy, or uncommonly, there may be no evidence of an underlying enteropathy. The geographic distribution of intestinal T-cell lymphomas is similar to that of intestinal enteropathies and hence is rare in western countries. Patients may have abdominal pain and jejunal perforation.
  • Angiocentric lymphoma:These lymphomas are seen most commonly in Asia, where they usually occur in the nasopharyngeal area with symptoms of obstruction and pain. Nasal angiocentric lymphoma, the most common type, is caused by T/natural killer cells that express Epstein–Barr antigens. Treatment for localized disease primarily involves radiation, and the role of chemotherapy is unclear. At relapse, and less commonly at presentation, the disease may disseminate to extranodal sites such as the lungs and skin.
  • Angioimmunoblastic T-cell lymphoma (AILT):This subtype of lymphoma was commonly known as angioimmunoblastic lymphadenopathy with dysproteinemia (AILD). It occurs in older patients who often have fever, rash, diffuse adenopathy, and polyclonal

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hypergammaglobulinemia. It was previously considered to be a reactive process but studies have demonstrated clonal T-cell rearrangements in most cases. The course is quite aggressive but very responsive to steroids and chemotherapy. Patients may develop opportunistic infections and secondary EBV lymphomas, and most patients die from the disease.

  • Adult T-cell Lymphoma/Leukemia (ATLL):This lymphoma occurs mostly in HTLV-1–endemic regions such as Japan and the Caribbean basin. It is an aggressive T-cell lymphoma caused by HTLV-1 infection. The clinical presentation includes high WBC count, hypercalcemia, hepatosplenomegaly, and lytic bone lesions. Clinically, ATLL has been classified into four distinct clinical presentations called smoldering, chronic, lymphomatous, and acute, with clinical behaviors that range from indolent to highly aggressive.
  • Anaplastic large-cell lymphoma:There are two clinical entities of this lymphoma, systemic and primary cutaneous. The systemic form occurs in both children and adults and usually expresses ALK kinase, because of t(2;5). It has either a T-cell or null phenotype. True anaplastic large-cell lymphomas (ALCL) of B-cell phenotype are very rare and are biologically unrelated to T-cell ALCL. Systemic ALCL may involve lymph nodes or extranodal sites, including the skin, and 50% of the patients may have constitutional symptoms and advanced stages at presentation. It is highly responsive to chemotherapy and is curable, with an OS and FFS of 75% and 60%, respectively, at 7 years. The primary cutaneous form occurs mostly in adults and has isolated skin nodules. The clinical behavior is indolent, and the skin lesions may regress spontaneously. Systemic disease is uncommon and has a late occurrence. This entity appears to be incurable, and some cases appear to be within the spectrum of lymphomatoid papulosis type A.

Treatment Principles

Many subtypes of aggressive lymphomas are potentially curable with appropriate therapy. However, histologic subtype and prognostic factors influence their curative potentials. Among the various histologies, the aggressive B-cell lymphomas have a better PFS than T-cell lymphomas, with the exception of systemic anaplastic lymphoma, which is among the most curable subtypes. It is important to recognize that some T-cell subtypes, such as ATLL and primary cutaneous anaplastic lymphoma, have no curative potential and should be approached in a palliative mode. Other T-cell subtypes such as angioimmunoblastic lymphomas and PTL have low curative potential with conventional-dose treatment and should be considered for trials targeting high-risk patients. Prognostic factors are helpful in identifying patients at various risk levels for curative purposes. The International NHL Prognostic Factor Project evaluated 3,273 patients from 16 institutions to develop a validated prognostic model. The model, known as the IPI, identified five adverse prognostic factors, which, based on the number of factors, could stratify patients into low-, low-intermediate–, high-intermediate–, and high-risk groups (see Table 28.7). This model can be used to identify patients at high risk for failure who should be considered for more aggressive

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therapy, preferably in a clinical trial. A molecular model of outcome has been developed recently on the basis of cDNA microarrays and is independent of the IPI. Early and appropriate treatment will improve outcome in patients with curable lymphomas. Doxorubicin-containing combination chemotherapy should be used in patients with advanced-stage disease, the standard being cyclophosphamide, hydroxydaunomycin, vincristine (Oncovin), prednisone, and rituximab (CHOP-R). Recent evidence, however, suggests that dose-adjusted EPOCH-R, an infusional regimen with pharmacodynamic dosing, may be more effective than CHOP-R. These regimens will be compared in a phase III randomized study. Patients should be restaged after four and six cycles of treatment. Patients showing complete response (CR) or with stable minimal residual disease (i.e., unconfirmed CR) after four cycles usually receive two to four more cycles. However, patients with persistent disease after six cycles should receive salvage treatment. CHOP-R (see Table 28.8) was shown to produce 76% CRs in patients in all risk groups, with a 2-year event-free survival (EFS) and OS of 57% and 70%, respectively. The greatest benefit of rituximab appears to be in tumors with bcl-2 overexpression. Patients with early-stage disease (i.e., stage I and nonbulky stage II) may receive full-course CHOP-R or, alternatively, may receive limited chemotherapy followed by involved radiation therapy. With this approach, the 5-year estimates of OS and PFS are 82% and 77%, respectively.

TABLE 28.7. International Prognostic Index for Aggressive Diffuse Large B-cell Lymphomas

Risk category (International Prognostic Index)

Score

Patients in risk group (%)

Complete responses (%)

5-year disease-free survival (%)

5-year survival (%)

Low

0 or 1

35

87

70

73

Low-intermediate

2

27

67

50

51

High-intermediate

3

22

55

49

43

High

4 or 5

16

44

40

26

TABLE 28.8. Standard Therapy for Aggressive Non-Hodgkin Lymphoma

Combination chemotherapy

Treatment description

Reference

CHOP-R

Cyclophosphamide 750 mg/m2 i.v. d 1 (total dose/cycle = 750 mg/m2)

8

Doxorubicin 50 mg/m2 i.v. d 1 (total dose/cycle = 50 mg/m2)

Vincristine 1.4 mg/m2 i.v. d 1 (maximum dose/cycle = 2 mg; total dose/cycle = 1.4 mg/m2)

Prednisone 50 mg/m2/d PO for 5 d, d 1–5 (total dose/cycle = 250 mg/m2)

Rituximab 375 mg/m2 i.v. d 1

Treatment is repeated every 21 d

Salvage therapy: Patients with potentially curable lymphomas who are refractory or who have relapsed after standard treatment may still be cured with salvage approaches. High-dose therapy with autologous transplantation has been shown to be superior to conventional-dose salvage therapy with high-dose Ara-C and dexamethasone (DHAP) and is now a standard of care. The curative potential of transplantation, however, is influenced by multiple factors including disease responsiveness (i.e., sensitive versus resistant relapse), number of earlier regimens, and presence of bulky (>10 cm) disease. Depending on the study, the long-term survival of patients after autologous transplantation ranges from 20% to 50% depending on prognostic factors and length of follow-up. Patients at high risk for salvage failure should be considered for experimental approaches such as allogeneic transplantation. Patients who are not candidates for transplantation or those who have relapsed thereafter may be effectively palliated with single-agent or combination chemotherapy or radiation.

Chemotherapy regimens for NHL are listed in Table 28.9. The approach of aggressive NHL treatment is shown in Fig. 28.2.

 

FIG. 28.2. Algorithm for the treatment of aggressive non-Hodgkin lymphoma (NHL). NHL, non-Hodgkin lymphoma; CHOP-R, cyclophosphamide, hydroxydaunomycin, vincristine (Oncovin), prednisone, and rituximab; DA-EPOCH-R, dose-adjusted doxorubicin, etoposide, vincristine, cyclophosphamide, prednisone, and rituximab; HD CT, high dose chemotherapy; AuBMT, autologous bone marrow transplantation; DFS, disease-free survival.

TABLE 28.9. Alternative or Salvage Regimens for Aggressive Non-Hodgkin Lymphoma

Combination chemotherapy

Treatment description

Reference

Etoposide, cyclophosphamide, and doxorubicin dosages may be increased by 20% from the previous cycle's dosage if there is no evidence of absolute neutropenia (ANC >500/mm3) or thrombocytopenia (platelet count >25,000/mm3).

EPOCH-R (dose adjusted)a

Rituximab 375 mg/m2 i.v. d 1 of each cycle prior to beginning infusions

9, 10

Etoposide 50 mg/m2/d by continuous i.v. infusion for 4 d, d 1–4 (total dose/cycle = 250 mg/m2)

Doxorubicin 10 mg/m2/d by continuous i.v. infusion for 4 d, d 1–4 (total dose/cycle = 40 mg/m2)

Vincristine 4 mg/m2/d by continuous i.v. infusion for 4 d, d 1–4 [total dose/cycle = 1.6 mg/m2 (no cap)]

Prednisone 60 mg/m2/dose PO every 12 h for 5 d, d 1–5 (total dose/cycle = 600 mg/m2)

Cyclophosphamide 750 mg/m2 i.v. d 5 (total dose/cycle = 750 mg/m2)

Filgrastim 5 µg/kg/d s.c. starting d 6; continues until ANC >5,000 cells/mm3

• treatment is dose adjusted on the basis of neutrophil nadirs and repeated every 21 d

CHOEP

CHOP with etoposide 100 mg/m2 i.v. d 1, 2, and 3

11

R-ICE

Rituximab 375 mg/m2 i.v. 48 h prior to cycle 1 and on d 1 of cycles one to three

12

Etoposide 100 mg/m2 i.v. d 3, 4, and 5

Carboplatin AUC 5: dose = 5 × (25 + creatinine clearance) capped at 800 mg i.v. on d 4

Ifosfamide 5,000 mg/m2 mixed with an equal amount of Mesna continuous i.v. for 24 h on d 4

DHAP

Cisplatin 100 mg/m2 by continuous i.v. infusion for 24 h on d 1 (total dose/cycle = 100 mg/m2)

13

Cytarabine 2,000 mg/m2/d i.v. over 3 h every 12 h for 2 doses on d 2 (total dose/cycle = 4,000 mg/m2)

Dexamethasone 40 mg/d PO or i.v. for 4 d, d 1–4 (total dose/cycle = 160 mg/m2)

• treatment is repeated every 21–28 d

ESHAP

Etoposide 40 mg/m2/d over 1 h i.v. for 4 d, d 1–4 (total dose/cycle = 160 mg/m2)

14

Methylprednisolone 250–500 mg/d i.v. for 5 d, d 1–5 (total dose/cycle = 1,250–2,500 mg)

Cytarabine 2,000 mg/m2 i.v. over 2 h on d 5 (total dose/cycle = 2,000 mg/m2)

Cisplatin 25 mg/m2/d by continuous i.v. infusion for 4 d, d 1–4 (total dose/cycle = 100 mg/m2)

• treatment is repeated every 21–28 d

ACVBP

Doxorubicin 75 mg/m2 i.v. d 1

15

Cyclophosphamide 1,200 mg/m2/dose i.v. d 1

Vindesine 2 mg/m2 i.v. d 1 and 5

Bleomycin 10 mg i.v. d 1 and 5

Prednisone 60 mg/m2/d PO d 1–5

Highly Aggressive NHL

B Cell

  • Precursor B lymphoblastic lymphoma/leukemiais mostly a disease found in children and presents as leukemia in 80% and as lymphoma in 20% of cases. Involvement of nodes, skin,

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bone and/or BM may be seen. Poor prognostic factors include translocations of t(1;19), t(9;22), and 11q13 abnormalities, and tumors that lack expression of CD10, CD34, and CD24. Patients with more than 50 chromosomes have a better prognosis. The EFS at 5 years is 85% and 64% for localized and advanced disease, respectively.

  • Burkitt lymphomaoccurs primarily in children, although occasional cases, which are often called Burkitt-like lymphoma, are seen in adults. Burkitt and Burkitt-like lymphomas are believed to be similar diseases, with the latter showing some “atypical” pathologic features. The disease was initially identified in equatorial Africa, where it was found to be associated with EBV and translocation of the c-myc oncogene, and is regarded as the endemic form of lymphoma. In the western countries, a sporadic “nonendemic” form, which is infrequently associated with EBV, occurs commonly, and Burkitt lymphoma often involves mesenteric LN and the distal ileum and cecum. Burkitt lymphoma is highly curable with aggressive chemotherapy, with PFS being more than 90% (see Tables 28.10 and 28.11).

TABLE 28.10. Adults and Children with Burkitt and Burkitt-like Non-Hodgkin Lymphoma have Similar Outcomes when Treated with Cyclophosphamide, Vincristine, Doxorubicin, High-dose Methotrexate/Ifosfamide, Etoposide, and High-dose Cytarabine (CODOX-M/IVAC) Regimen

Number

CR (%)

EFS at 2 yr (%)

Adapted from Magrath I, Adde M, Shad A, et al. Adults and children with small noncleaved cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol 1996;14(3):925–934, with permission.

Children: 21

   90

   85

Adults: 20

100

100

Total: 41

   95

   92

TABLE 28.11. Estimate of 1-year Event-free Survival for Subgroups of High-risk Patients Treated With Cyclophosphamide, Vincristine, Doxorubicin, High-dose Methotrexate/Ifosfamide, Etoposide, and High-dose Cytarabine (CODOX-M/IVAC) Regimen

Variable

n

1-yr EFS (%)

(95% CI)

Log-rank P value

From Mead GM, Sydes MR, Walewski J, et al. An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt's lymphoma: results of United Kingdom Lymphoma Group LY06 study. Ann Oncol 2002;13:1264–1274, with permission.

International Prognostic

   Index score

0–1

   6

83.3

(53.5–99.0)

2

19

63.2

(41.5–84.9)

3

14

57.1

(31.2–83.1)

0.8852

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T Cell

Precursor T-lymphoblastic lymphomas/leukemias are most common in young adult men in their third decade of life. In children, these cancers constitute 40% of all lymphomas and 15% of lymphoblastic leukemias. Patients often have a rapidly enlarging mediastinal mass, with or without peripheral LN involvement. The distinction between lymphoma and leukemia is based on the percentage involvement of the BM, with 25% to 30% defining the disease as a leukemia. The EFS at 5 years is 85% and 64% for localized and advanced disease, respectively.

Treatment Principles

The most highly aggressive lymphomas are curable by chemotherapy and should be treated expeditiously and with appropriate therapy. A number of aggressive regimens have shown equal results and are outlined in Tables 28.12, 28.13, and 28.14. The aggressive treatment of adults with Burkitt lymphoma has achieved results similar to those obtained in children and justifies the higher toxicity associated with these regimens. However, older patients often tolerate these aggressive regimens poorly.

TABLE 28.12. Hyper CVAD Alternating with High-dose Methotrexate and Ara-C

Cycle

Day

Drug

Dose

Route

Time

CNS prophylaxis: Methotrexate 12 mg intrathecal on d 2 and Ara-C 100 mg intrathecal on d 8 of each cycle for 16 intrathecal treatments in high-risk patients; four intrathecal treatments in low-risk patients.

Odd number cycles 1, 3, 5, and 7

1–3

Cyclophosphamide

300 mg/m2(total dose 1,800 mg/m2)

i.v.

Each dose given over 2 h every 12 h for six doses

1–3

Mesna

600 mg/m2

Continuous i.v.

Infused over 24 h daily for 3 d. Start 1 h before cyclophosphamide and continue for 12 h after last dose.

4

Doxorubicin

50 mg/m2

i.v.

Over 2 h

4 and 11

Vincristine

2 mg

i.v.

4–11 and 11–14

Dexamethasone

40 mg/d

PO or i.v.

DI–4 and 11–14

G-CSF

10 µg/kg

s.c.

Daily, starting 24 h after the last dose of doxorubicin, until granulocytes are >30,000/ìL or until d 21 (whichever comes first).

Even number cycles

1

Methotrexate

1 g/m2

Continuous i.v.

Infused over 24 h

2, 4, 6, and 8

Leucovorin

50 mg i.v. or PO is given

i.v. or PO

12 h after the completion of methotrexate, followed by 15 mg i.v. or PO every 6 h for eight doses. The methotrexate level is checked at 24 h and 48 h after the completion of the methotrexate infusion. If the level is >1 µM at 24 h or >0.1 µM at 48 h, the leucovorin dose is increased to 50 mg i.v. every 6 h until the level is <0.1 µM.

2–3

Ara-C,

3 g/m2

i.v.

Given over 2 h every 12 h for four doses

G-CSF

5 µg/kg,

s.c.

Begin after chemotherapy completion until the ANC is >30,000/ìL or until d 21 (whichever comes first). Then it is held for 1 d and the next cycle is started.

TABLE 28.13. Cyclophosphamide, Vincristine, Doxorubicin, High-dose Methotrexate (CODOX-M) Regimen

Day

Drug

Dose

Route

Time

MTX, methotrexate; G-CSF, granulocyte colony stimulating factor; AGC, absolute granulocyte count; ANC, absolute neutrophil count.
Next cycle should be started on the day the unsupported ANC is >1.0 × 109/L, and unsupported platelet >75 × 109/L.

1

Cyclophosphamide

800 mg/m2

i.v.

Vincristine

1.5 mg/m2 (max 2 mg)

i.v.

Doxorubicin

40 mg/m2

i.v.

Cytarabine

70 mg

Intrathecal

2–5

Cyclophosphamide

200 mg/m2

i.v.

Daily

3

Cytarabine

70 mg

Intrathecal

8

Vincristine

1.5 mg/m2 (max 2 mg)

i.v.

10

Methotrexate

1,200 mg/2

i.v.

Over 1 h

240 mg/m2

i.v.

Each h over 23 h

11

Leucovorin

192 mg/m2

i.v.

At h 36

12 mg/m2

i.v.

Every 6 h until MTX level <5 × 10–8M

13

G-CSF

5 µg/kg

s.c.

Daily until AGC > 109/L

15

Methotrexate

12 mg

Intrathecal

16

Leucovorin

15 mg

PO

24 h after intrathecal methotrexate

TABLE 28.14. Ifosfamide, etoposide, and high-dose cytarabine (IVAC) regimen

Day

Drug

Dose

Route

Time

MTX, methotrexate; G-CSF, granulocyte colony-stimulating factor; AGC, absolute granulocyte count.
Next cycle should start (CODOX-M) on the day the unsupported ANC is >1.0 × 109/L, and unsupported platelet is >75 ×109/L.

1–5

Etoposide

60 mg/m2

i.v.

Daily over 1 h

Ifosfamide

1,500 mg/m2

i.v.

Daily over 1 h

Mesna

360 mg/m2 (mixed with ifosfamide) followed by 360 mg/m2

i.v.

3 hourly (seven doses/24 h period)

1 and 2

Cytarabine

2 g/m2

i.v.

Over 3 h, 12 hourly (total of four doses)

5

Methotrexate

12 mg

Intrathecal

6

Leucovorin

15 mg

PO

24 h after intrathecal MTX

7

G-CSF

5 µg/kg

s.c.

Daily until AGC > 1.0 × 109/L

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