Nuclear Oncology, 1 Ed.

CHAPTER 21

LYMPHOMA AND LEUKEMIA

Jasna Mihailovic • Stanley J. Goldsmith

LYMPHOMA

INTRODUCTION

Lymphoma is a malignancy of the lymphatic system. The patient may be asymptomatic and comes to diagnosis as an incidental finding on a physical examination or conventional imaging performed for other reasons. It may present as a solid tumor, such as an enlarged lymph node or as extranodal lymphoma involving organs, either as isolated organ involvement or as disseminated disease.1 Lymphoma is the fifth most common malignancy in the United States and represents 5.3% of all malignancies (excluding simple basal cell and squamous cell skin cancers) and 56% of all blood malignancies.2,3

TABLE 21.1

WHO 2008: THE MATURE B-CELL NEOPLASMS

In general, the lymphomas are divided into two groups: Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL). Thomas Hodgkin, in 1832, was the first to describe the form of lymphoma that bears his name, Hodgkin lymphoma or HD.1 Since then, other forms of lymphoma have been described and grouped under several proposed classifications. These include the Working Formulation Classification,4 the Karl Lennert Classification,5 and the Revised European-American Classification (REAL).6 The most recent classification is the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues which was published in 2008 (Table 21.1).7 The Ann Arbor staging system was developed in 1971 to describe the extent of disease based on the number of involved sites, disease location, and presence or absence of clinical symptoms. Initially developed for HD, it has since been adapted to stage NHL into one of four stages (Table 21.2).8,9

HODGKIN DISEASE

Hodgkin lymphoma represents 10% to 15% of all lymphomas and is divided into two main groups: Classic HD accounting for 95% of HD patients and nodular lymphocyte predominant HD for the remaining 5% of cases. Classic HD is classified into subgroups: nodular sclerosis which accounts for 75% of patients, 20% of mixed cellularity, lymphocyte rich and lymphocyte depletion types, the remaining 5%.10 Cervical lymph nodes are the most common involved site in 60% to 80%. Extranodal involvement is rare in HD and is caused mainly by direct spread of disease. Hematogenous spread occurs in the minority of cases (10% to 15%) and usually carries a poor prognosis. The overall cure rate is over 80% whereas the recurrence rate is between 10% and 40%. The prognosis is directly related to the stage of disease and the presence of systemic symptoms.1 In 1998, a prognostic score index was created for advanced HD, the International Prognostic Score (IPS). According to the IPS, there are seven adverse prognostic factors at presentation: a serum albumin level <4 g/dL, a hemoglobin level <10.5 g/dL, male gender, age ≥45 years, stage IV disease by Ann Arbor Classification, leukocytosis (a white cell count ≥15,000/mm3), and lymphocytopenia (a lymphocyte count <600/mm3, a count <8% of the white cell count, or both). About 85% of patients initially present with stage I or II disease.11

TABLE 21.2

ANN ARBOR STAGING SYSTEM FOR HODGKIN DISEASE

NON-HODGKIN LYMPHOMA

NHL accounts for about 85% of lymphomas. The clinical behavior includes indolent and aggressive types. Aggressive lymphomas account for about 60% of NHL whereas indolent lymphomas represent the remaining 40%.10 Diffuse large B-cell lymphoma (DLBCL) is the most common histologic diagnosis among the aggressive lymphomas, accounting for about 30% of all lymphomas. Localized aggressive lymphomas are usually treated with combination chemotherapy combined with radiation therapy; about 85% of these patients are cured.1 Follicular lymphoma (FL) is the most common indolent lymphoma, accounting for 22% of NHLs worldwide and at least 30% of the NHLs diagnosed in the United States. The predominant presentation for FL is painless multiple site lymphadenopathy. In extranodal NHLs, liver and bone marrow (BM) are commonly involved.12

Patients with FL have a 5% to 7% annual rate of histologic transformation to DLBCL. Chronic lymphocytic leukemia may also undergo transformation to diffuse large-cell lymphoma (DLCL). Transformation usually carries a poor prognosis. DLBCL can present with either nodal or extranodal disease or both. At presentation, more than half of the patients will have some site of extranodal involvement. The gastrointestinal tract and the BM are usual sites of extranodal involvement, each involving about 15% to 20% of patients.12

In 1993, The International non-Hodgkin Lymphoma Prognostic Factors Project established the International Prognostic Index (IPI) to predict prognosis for patients with aggressive NHL. It was also used to determine the best treatment based on a risk profile. The IPI summarizes different factors at the time of diagnosis and has become an established parameter for risk stratification and determination of patient’s outcome. It includes the presence or absence of five adverse prognostic factors:

• Age ≥60 years

• Ann Arbor tumor stage III or IV

• >1 site of extranodal involvement

• Performance status 2 (ECOG) or Karnofsky ≥70

• Elevated serum lactate dehydrogenase level

In addition, there is a follicular lymphoma-specific IPI (FLIPI) score which replaces performance status with hemoglobin level and the number of extranodal sites with the number of nodal sites (more than four).12,13

IMAGING

Conventional Imaging

Correct pretreatment staging determines the extent and spread of disease and is important in the selection of therapy. The clinical stage, as well as the histologic tumor type, determines the prognosis of lymphoma. Moreover, the clinical stage provides a basis to select the patient’s treatment course. The Ann Arbor staging system was established to divide patients into two groups: Those who might be candidates for radiation therapy and others who should receive systemic treatment. Initially, it was based on physical examination and BM evaluation.14 For many decades, staging of lymphoma also included patients’ history, laboratory analyses, and ultrasound (US). Recently, computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine procedures, particularly 18F-FDG PET/CT have been used to stage and restage lymphoma patients. Since the introduction of these methods, the use of US is limited mostly for US-guided biopsy of focal lesions.15 Before the era of these modern diagnostic imaging tools, laparotomy and lymphangiography were performed to detect lymph node involvement and complete staging of lymphoma.16

For many years, CT was the main imaging tool for detection, staging, and follow up of lymphoma patients. CT has high sensitivity and specificity in pretreatment staging but low specificity in the evaluation of response to treatment. The assessment of lymphoma by CT relies on size-related criteria. Nevertheless, lymphoma may appear with lymph node involvement without enlargement of the lymph nodes. Thus, involved lymph nodes may be missed on CT although images with good resolution will identify an increased number of lymph nodes.1720 CT is also a good method to image lymphoma organ involvement in extranodal NHL.2123

The role of MRI in the evaluation of lymphoma is also based on nodal size and has similar accuracy to CT. Decreased signal on T2-weighted images is specific for benign lymph nodes enabling MRI to differentiate them from nodal tumor involvement in which the signal is not decreased. In case of micrometastases, the MRI is not specific.24 Performance of whole-body MRI including diffusion-weighted imaging (DWI) in the staging of newly diagnosed lymphoma has been recently described as a promising tool.25 Gu et al.26 stated that DWI enhanced lesion conspicuity and improved diagnostic accuracy for lymphomas. More recently, Kwee et al.27 proposed that MRI can be limited to a head/neck and trunk imaging only instead of conventional whole-body imaging for lymphoma staging. MRI is the most sensitive diagnostic imaging tool for the detection of BM involvement.2232

Radionuclide Imaging

Gallium-67, Thallium-201, and 99mTc-sestamibi

In the past, the radionuclides Gallium-67 (67Ga), Thallium-201 (201Tl) and 99mTc-sestamibi (99mTc-MIBI) have been used as tracers to image lymphoma. Both 201Tl and 99mTc-MIBI are widely used for myocardial perfusion but can be used for tumor detection and assessment of tumor viability.3335 For many years, 67Ga citrate was probably the most widely used radionuclide for the assessment of the extent of both HL and NHL involvement. It was specifically useful to detect the extent of disease in HD and high-grade NHL. 67Ga citrate is not sufficiently sensitive to detect lymph node involvement in low-grade NHL. 67Ga was particularly useful to detect the treatment response of the high-grade tumors, HD, and NHL. 67Ga had some additional limitations such as nonspecific localization in inflammatory or infectious lesions.36 Compared to 67Ga, 201Tl has greater tumor avidity in low-grade lymphoma involvement. In the assessment of the presence of disease and of site localization in patients with low-grade lymphoma, 201Tl had a sensitivity of 100% compared to 67Ga with only 56% patient sensitivity and 32% site sensitivity.37 There are several reports combining 201Tl and 67Ga scintigraphy to increase overall sensitivity.38,39 99mTc-MIBI has a slightly lower sensitivity and specificity than 201Tl to assess lymphoma: 71% and 76%, respectively.40 Several studies report on the role of 99mTc-MIBI to assess response and effectiveness of chemotherapy protocols based on the association between 99mTc-MIBI and multidrug resistance.4145

TABLE 21.3

FDG UPTAKE IN LYMPHOMA

111In-DTPA-Pentetreotide (Octreoscan)

Somatostatin receptor imaging (SRI) with 111In-pentetreotide has also been used to image lymphoma since lymphocytes and some of the tumors derived from lymphocytes express somatostatin receptors, predominantly subtype 2. Since the expression of specific receptor subtypes varies in lymphomas, SRI is not a reliable method to determine the extent of disease in general but it is quite sensitive to detect high-grade lymphoma including Hodgkin lymphoma. The sensitivity of 111In-SRI in HD is 70% to 90%; 98% in supradiaphragmatic lesions and 67% in infradiaphragmatic lesions versus a sensitivity in low-grade NHLs of 62% for supradiaphragmatic; and 44% for infradiaphragmatic disease.4651

18F-Fluorodeoxyglucose PET and PET/CT

By the end of 1990s, imaging with fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) based on imaging of tumor metabolic activity, opened a new era in diagnosis and management of neoplasms in general. It was recognized quite early that NHL and HD were readily identified by 18F-FDG. Furthermore, 18F-FDG PET, even prior to the introduction of PET/CT was being used not only to evaluate the extent of disease but also in patient surveillance following treatment since it was observed that in responsive patients, the previously identified lesion failed to accumulate the tracer. It soon became apparent that the accumulation of 18F-FDG varied among the different histologic lymphoma types depending on the proliferative activity52; some, the higher-grade lymphomas and Hodgkin lymphoma, were highly 18F-FDG-avid tumors53–55 whereas others, the low-grade lymphomas such as FL, had low 18F-avidity (Table 21.3).56 Nevertheless, the low-grade lymphomas, for which 67Ga scintigraphy was not considered useful, could frequently be identified with 18F-FDG PET imaging.57

Staging

A comparison between several diagnostic imaging methods in the initial staging of lymphoma is shown in Table 21.418F-FDG PET shows higher sensitivity than CT and other conventional staging methods but not at the expense of the specificity. 18F-FDG PET shows high sensitivity (90% and 98%) in staging of patients with NHL and HD as well as high-negative predictive value of 97.4%.58,59 Several studies show higher sensitivity for 18F-FDG PET than for CT60–65 and other conventional diagnostic imaging procedures.6669 In a study by Hoh et al.65 that evaluated 18F-FDG PET-based staging results compared to the patient’s clinical stage based on conventional imaging tools (CT, MRI scans, and 67Ga scans), staging by 18F-FDG PET was superior to conventional methods with a sensitivity of 94% versus 83% for other methods.69 Bangerter et al.70 reported 18F-FDG PET had a sensitivity of 96% with a specificity of 94%. 18F-FDG PET accuracy was similar or better than CT in determination of hilar and mediastinal involvement. Although Jerusalem et al.71 detected more lymph nodes by 18F-FDG PET than by CT and concluded that 18F-FDG PET is sensitive for the staging of aggressive NHLs and resulted in fewer staging changes. Although most of the studies show a high level of concordance between 18F-FDG PET and CT, PET/CT as a hybrid imaging system shows the best results.7274 Thus, Fueger et al.72 showed that 18F-FDG PET/CT detected more extranodal lesions than either CT or 18F-FDG PET and concluded that 18F-FDG PET/CT is more accurate than either 18F-FDG PET or CT alone for staging and restaging of patients with indolent NHL.

As a consequence of these studies, 18F-FDG PET has become the standard imaging tool for the staging of lymphoma (Fig. 21.1). Most of the early literature analyzed studies using PET scanners, without attenuation correction and inaccurate anatomical localization of lesions. More recently, hybrid imaging utilizing PET/CT has been available and is a more powerful technique for the staging of lymphoma. PET/CT allows more accurate lesion localization than PET alone.73,7578 PET/CT performed even without intravenous contrast with low-dose CT (40 to 80 mAs) is more sensitive and specific than contrast-enhanced full-dose CT for evaluation of nodal and extranodal lymphomatous involvement.75,76

Detection of more extensive disease by PET changes staging. 18F-FDG PET makes possible detection of additional sites of lymphoma in up to 30% of patients. With this aim, a large number of studies have been focused on HD and aggressive NHL (Table 21.5).58,60,63,64,67,72–74,79–83 Some studies showed results that change stage; some reported 8%,58,60 some 15.5% to 18.2%63,79,80 of change; others reported higher values ranging between 20% and 29%;73,81,83,84 whereas very high changes in stage, between 40% and 47.7%, were observed in other studies.64,67,82 18F-FDG PET studies resulted more frequently in upstaging than in downstaging, influenced by its advantage to detect more sites of disease with greater sensitivity.58,63,64,72,73,79–81,83 There were only a few studies with discordant result.67,82 In comparison to PET and CT, PET/CT has advantage in initial staging. Thus, Fueger reported correct stage that was determined by PET/CT, PET, and CT in 76%, 62%, and 58%, respectively. PET/CT correctly upstaged 18% of patients compared to CT in 20% of patients compared to PET alone and PET/CT more accurately (4%) staged patients than PET.72

Since the therapeutic protocol selected depends on the extent of lymphoma involvement, changing the stage results in alteration of management. Usually, patients with early-stage (stage I or II) lymphoma are treated with involved field radiation therapy whereas chemotherapy is utilized in patients with a more advanced stage disease (stage III or IV). Armitage reported that up to one-third of patients with FL are diagnosed with stage I and II disease, whereas 70% to 90% of mucosa-associated lymphoid tissue (MALT) lymphomas are present initially with localized disease (stage IE to IIE).85 These patients undergo external beam radiation therapy, whereas higher stages usually require systemic therapy. If additional disease sites are detected, systemic therapy would be utilized.86

Extranodal Involvement

NHL may present with extra lymph node involvement with an incidence of 10% to 58%.8790 For the detection of extranodal lymphoma, 18F-FDG PET is superior to CT (Table 21.6).59,9194

TABLE 21.4

COMPARISON OF DIAGNOSTIC IMAGING PROCEDURES IN INITIAL STAGING

Moog reported histologic verification in 58 biopsies of patients with NHL or HD and obtained better results with 18F-FDG PET compared to CT; 98% accuracy for 18F-FDG PET and 78% for CT. 18F-FDG PET downstaged patients in 2.5% of the patients and upstaged in 12% of patients with extranodal NHL malignant lymphoma.95

The most common extranodal sites of involvement in NHL are the gastrointestinal tract and head and neck sites (Fig. 21.2). Gastrointestinal lymphoma occurs in 10% to 15% of NHL patients and 30% to 40% of patients with extranodal NHL.96 Physiologic uptake of 18F-FDG, however, may compromise the accuracy of 18F-FDG PET and results in false-positive and false-negative results.58 18F-FDG PET/CT and oral contrast reduce error. Oral contrast allows better delineation and separation between lymph nodes and bowel loops.97,98 Extranodal involvement of liver and spleen may present as diffuse involvement or as a mass. Liver involvement is present in 15% of NHL patients and 3% of HD patients at presentation whereas splenic involvement is present in 30% to 40% of NHL patients and 22% of patients with HD.58,98,99 Moog et al.58 showed that 18F-FDG PET was better than CT in detection of spleen, liver, and bone involvement that resulted in modified staging of patients.

MALT lymphoma mainly involves gastric mucosa and rarely skin, thyroid, breast, thymus, orbit, liver, kidney, prostate, urinary bladder, and gall bladder.96,100,101 Approximately 25% of patients have multiple sites of involvement including BM.102

FIGURE 21.1. 18F-FDG PET/CT in the staging of extent of disease in lymphoma. Coronal images: left to right: CT, 18F-FDG PET, PET/CT fusion images illustrating stage I, stage II, stage III, and stage IV involvement prior to treatment. Stage I, single lymph node involvement; stage II, multiple lymph node involvement in a single region; stage III, active disease above and below the diaphragm; stage IV, active disease involving organs. Although the larger masses are detectable on the CT images alone, the metabolic assessment demonstrating increased anaerobic metabolism is useful to identify small lymph nodes with lymphoma involvement as well as to provide a baseline for comparison with posttreatment imaging.

TABLE 21.5

FDG PET AND CHANGE IN STAGING

TABLE 21.6

DIAGNOSTIC IMAGING IN STAGING OF EXTRANODAL LYMPHOMA

Beal et al. reported PET/CT sensitivity of 81% in patients with MALT lymphoma.103 Primary bone lymphoma accounts for less than 5% of all primary bone tumors but 18F-FDG accumulates in primary bone tumors as well as in bone lymphomatous involvement.104 Differentiating between the two may be difficult and require clinical correlation.

The detection of BM involvement is important since it identifies high-risk patients and alters management. This is usually important in the early stage of disease. BM involvement occurs in 10% of newly diagnosed HD and 25% in newly diagnosed NHL and is an indicator of poor prognosis.91 This incidence rises to between 60% and 70% in low-grade NHL, mainly follicular, whereas it varies from 90% to 100% in mantle cell lymphoma. In aggressive NHL, BM involvement occurs in 25% to 40% of patients.105,106 MRI provides the best imaging of BM involvement with a low T1 and high short tau inversion recovery (STIR) signal. In patients with negative BM biopsies, MRI findings resulted with upstaging up to 33%. In low-grade NHL, there are some reports of false-negative results because of microscopic infiltration of BM. Inflammation and posttreatment changes may also compromise MRI results.1

The accuracy of 18F-FDG PET to detect BM involvement is as high as 93%107 with a reported sensitivity of 81% and a specificity of 100% with confirmation by BM biopsy.58 In another study, 18F-FDG PET accuracy of 95% was superior to CT as well as BM biopsy because of sampling error producing false negatives.108 Jerusalem et al. reported that 18F-FDG PET was not reliable for detection of BM involvement in low-grade NHL.109 In a meta-analysis that included 26 eligible reports of 18F-FDG PET for evaluation of BM infiltration in lymphoma staging, Pakos et al. came to a similar conclusion. There was better sensitivity of HD and aggressive NHL than in patients with less aggressive (low-grade) NHL consistent with the general observation if 18F-FDG uptake as a marker of vigorous glucose metabolism in high-grade, more aggressive lymphomas.110

Treatment with granulocyte colony-stimulating factors (G-CSF) appears as diffuse increases in BM uptake but this can usually be identified with clinical correlation although a degree of uncertainty remains (Fig. 21.3).111,112Lymphoma of the CNS accounts for 2% to 4% of extranodal sites of lymphoma and 1% to 4% of malignant tumors of the brain.96

Restaging

Aside from its role in initial staging, 18F-FDG PET is important in restaging after initial treatment with chemotherapy. There are several studies in restaging patients with NHL, HD, or both NHL and HD that show 18F-FDG PET superiority over CT (Table 21.7). Cashen et al.,113 Gigli et al.,114 and Bishu115 reported high negative predictive value (NPV) of PET for restaging whereas high specificity was reported by Bangerter, Gigli, and Bishu.59,114,115 In comparison with other imaging modalities, PET and PET/CT have significant advantages.67,80,116122

Zinzani et al. showed that 18F-FDG PET-positive findings after induction treatment were highly sensitive for residual disease whereas negative 18F-FDG PET at restaging was a strong indication of the absence of active lymphoma. They recommended histopathologic verification in patients with residual PET-positive findings.123 In fact, this observation has led to the recognition that 18F-FDG PET can identify transformation of low-grade lymphoma, such as FL, to a high-grade lymphoma. The generalization can be made that low-grade lymphoma will generally have a standardized uptake value (SUV) below 5 compared to high-grade lymphomas that generally will have SUVs of 8 or more. Although no single SUV level is diagnostic, finding of a site with a strikingly greater SUV has been found to indicate that the lymphoma has transformed to a high-grade lymphoma (Fig. 21.4).124

In the posttreatment period, residual masses, mostly in the mediastinum, remain on CT findings in 50% to 64% of patients with HD, and in 20% to 60% of patients with NHL.124127 Residual masses on CT may represent fibrosis, necrosis, or active tumor. In 30% to 50% of residual masses in large-cell NHL patients, only 5% will have active lymphoma.127 In the past, 67Ga scintigraphy was widely performed for posttreatment evaluation of high-grade lymphoma and HD. 67Ga was useful to detect residual viable tumor since it differentiated between high-grade active tumor tissue and posttreatment fibrotic changes. Because of the low spatial resolution and bowel excretion of 67Ga, abdominal tumor sites were difficult to evaluate.128130 Although CT and MRI detect the size and exact anatomical location of the masses as well as morphologic changes, these techniques cannot reliably distinguish between residual active tumor and fibrotic tissue.131136 MRI provides better morphologic details but has a low sensitivity rate (45%).137,138

18F-FDG PET replaced 67Ga based on more accurate identification of abdominal residual masses and a shorter imaging protocol. In 1987, the ability of PET to differentiate between active lymphoma and fibrosis on the basis of increased glycolysis was described for the first time.139 18F-FDG PET has high specificity in the differentiation between active tissue versus necrosis and fibrosis.67,116,118–120,133,140,141 18F-FDG PET was found to play an important role in the posttreatment evaluation because of better evaluation of residual masses due to a positive predictive value of 100% versus 42% for CT.142

Cremerius evaluated the role of 18F-FDG PET in the evaluation of residual lymphoma versus posttherapy changes. In assessing residual lymphoma activity, 18F-FDG PET was more accurate than CT. 18F-FDG PET also showed higher specificity than CT, 92% and 17%, respectively. 18F-FDG PET correctly identified all biopsy-proven residual diseases in all patients.116 In 24 patients, 18F-FDG PET and CT were compared with respect to detecting viable tumor in residual masses. Sensitivity and specificity of PET were 87.5% and 94.4% versus 25% and 56% for CT. Persistent lymphoma disease still remains a diagnostic problem, particularly in HD.120

FIGURE 21.2. Extranodal organ involvement in lymphoma. A:18F-FDG PET maximal intensity projection (MIP) images (display of all acquired transaxial slices reconstructed in computer memory and displayed so as to appear as a volume display). Four different patients illustrating varied and extensive extranodal involvement—usually an ominous clinical finding. B: Transaxial projections, two different patients. Left to right: CT, transaxial PET, and fused image of CT corresponding to transaxial PET. Patient 1, large solitary focus in spleen; patient 2, multiple small foci of disease involvement in the spleen in addition to several foci in the hepatic parenchyma.

FIGURE 21.3. Differential diagnosis of bone marrow 18F-FDG activity. A: Lower extremity 18F-FDG MIP images of patient with extensive marrow involvement with hypermetabolic lymphoma cells. Although quite extensive, note patchy pattern. B: Whole-body MIP images of hyperplastic marrow secondary to granulocyte colony-stimulating factor (G-CSF) administration or bone marrow rebound following completion of chemotherapy (three different patients). Left to right: diffuse hyperplastic bone marrow activity, bone marrow hyperplasia, and activation of spleen (does not indicate splenic involvement with lymphoma; patient should be reimaged after marrow recovery); diffuse marrow hyperplasia with absent marrow in T11 and L5 vertebrae. This pattern is seen when there was prior vertebral involvement or other reasons for normal marrow replacement. It may be difficult to differentiate from diffuse, patchy bone marrow involvement. Differential diagnosis can be based on timing of imaging in relationship to G-CSF or suspension of chemotherapy.

Response to Treatment

In HD, more than 80% of patients are cured after the standard therapy regimen. Patients with aggressive NHL have a worse prognosis and outcome; after the first-line chemotherapy, 50% to 70% of patients achieve complete remission; one-third of patients are cured whereas 7% relapse annually.1 Identifying patients who will be cured by a specific therapeutic regimen early in the course of their therapy would be most valuable. Pretherapy ­clinical risk factors [International Prognostic Score (IPS) in advanced HD and International prognostic index (IPI) in aggressive NHL] have been developed and are useful but have limited accuracy.1,11–13,143 Posttreatment evaluation would divide treated patients into one of the two categories: responders and nonresponders.

TABLE 21.7

FDG PET AND PET/CT IN RESTAGING LYMPHOMA PATIENTS AFTER CHEMOTHERAPY

Previously, evaluation of treatment response using CT relied on tumor volume reduction. 67Ga scans were used to detect residual metabolic activity in high-grade disease and hence 67Ga scintigraphy was described as a very useful functional imaging method to monitor treatment response in these patients. Some authors used 67Ga to assess treatment response prior to completion of therapy, after one to two cycles as well as at midtreatment and found it to be a good predictor of outcome.144148 Since 18F-FDG PET assesses tumor viability, it can also be used as an indicator of the biologic changes after the initiation of therapy. 18F-FDG PET scans after several cycles of chemotherapy are more accurate than 67Ga scintigraphy to evaluate response to therapy. Zijlstra reported better positive and negative predictive values for 18F-FDG PET scans compared to 67Ga scintigraphy after two cycles of therapy.149 Others reported positive 18F-FDG PET scans after the third cycle of chemotherapy had a higher sensitivity for predicting the relapse compared to 67Ga scans.117

Several 18F-FDG PET studies have shown that demonstration of a metabolic response prior to completion of therapy for both HD and NHL patients is more meaningful than assessment following completion.10 Thus 18F-FDG PET images can predict long-term response, progression free survival (PFS), and overall survival (OS).

Some studies were performed on mixed patient populations including NHL and HD,66,113,114,117,118,149,150–156 others on NHL patients only,113,114,118,149,152,153,156,157 and others on classical HD.117,154

In 2002, Kostakoglu et al. found better correlation of PFS with 18F-FDG PET findings obtained after completion of the first chemotherapy cycle compared to 18F-FDG PET at completion of the treatment. 18F-FDG PET was performed at baseline, after one cycle and again after completion of chemotherapy in patients with aggressive NHL or HD. Patients with positive 18F-FDG PET scans after either one cycle or after completion of the therapy had a short PFS compared to those with negative PET scans, regardless of the immediate posttherapy clinical response. More significantly, there was a significant difference in PFS between positive and negative 18F-FDG PET scans obtained after one cycle and after completion of treatment (p < 0.001) (Fig. 21.5). A negative scan after one cycle was more predictive than a negative scan after the full course of therapy. This suggests that persistent tumor metabolic activity on 18F-FDG PET after one cycle of chemotherapy identifies patients who require a more intensive regimen. Patients with a positive 18F-FDG PET after one cycle had a high likelihood of relapse and a shorter interval until relapse than patients with negative 18F-FDG PET scans after one cycle of chemotherapy.150 It may be possible to alter the treatment to second-line chemotherapy and stem cell transplantation without completing the full course of initial regimen, or in case of repeated positive PET after two to three cycles and repeated tumor biopsy to change to alternative dose intense regimen. These investigators concluded that 18F-FDG PET after one cycle is more accurate to predict the outcome than after completion of chemotherapy.150,151 Subsequently, they confirmed their earlier findings and detected higher sensitivity, accuracy, and NPV after the first cycle (100%, 96%, and 100%), than at the end of treatment (79%, 92%, and 91%, respectively).151 In a multivariate analysis in aggressive NHLs, Spaepen et al. showed that 18F-FDG PET at midtreatment was a stronger predictor for PFS and overall survival than the IPI. Patient who had positive PET scan at midtreatment either rapidly relapsed after a temporarily achieved complete response (CR), never achieved CR, or progressed during the course of therapy. In contrast, almost all patients with negative midtreatment 18F-FDG PET scan achieved a durable CR; however, some patients, nevertheless, experience progression of disease.155 For patients without an early response, it may be appropriate to consider an alternative regimen.153At present, there is no evidence to support less than completion of a full course of their first-line treatment regimen in patients with negative 18F-FDG PET results after one cycle.

FIGURE 21.4. Transformation of lymphoma grade in a patient presenting with low-grade follicular lymphoma involving the parotid glands. Left to right: CT, 18F-FDG PET, and PET/CT fusion images. Toprow: Coronal sections. Image on far right is an MIP image demonstrating mildly increased 18F-FDG activity in bilateral parotid masses (A) and prominent hypermetabolic masses (B) in the abdominal periaortic lymph nodes. Middle row: Transaxial sections of mildly hypermetabolic parotid masses, SUVmax 1.8 to 2.9, which were the presenting symptom and finding. 18F-FDG PET characterization of these masses is typical of a low-grade lymphoma which was confirmed on biopsy. ­Bottom row: Transaxial images of periaortic lymph nodes which are markedly hypermetabolic, SUVmax 16 to 19.5. Biopsy demonstrated large B-cell lymphoma, a high-grade variant which would not have been detected or biopsied without the high SUV finding on the 18F-FDG PET/CT.

FIGURE 21.5. A: Pre- and Posttherapy 18F-FDG PET MIP images in a Hodgkin disease patient demonstrating complete metabolic response. No evidence of 18F-FDG + foci. B: Left, pretherapy 18F-FDG PET MIP image in patient with a diffuse large B-cell lymphoma (DLBCL), a high-grade lymphoma; right,18F-FDG PET MIP image after only three cycles of chemotherapy, approximately halfway through projected course of therapy. No evidence of 18F-FDG + foci, demonstrating prediction of a prolonged remission.

FIGURE 21.5. C: Coronal projections, CT, 18F-FDG PET, and PET/CT fusion in a patient with DLBCL at baseline (top row) and after the first cycle of CHOP chemotherapy (bottom row). All evidence of tumor hypermetabolism has resolved after a single cycle of therapy. The full course of therapy, nine cycles, was completed and at the time of imaging after 24 months, the patient continued to be free of symptoms or evidence of disease progression, confirming that it is possible to assess efficacy early in the course of therapy. DLCL, diffuse large-cell lymphoma; PFS, progression free survival.

Hutchings et al. investigated treatment response with 18F-FDG PET in patients with HD after two or three cycles and compared the findings with end-treatment 18F-FDG PET. After the completion of treatment, 18F-FDG PET did not add prognostic information to early interim PET results that was clearly positive or negative. Hutchings et al. conclude that interim 18F-FDG PET is a reliable tool for early prediction of a long-term remission and PFS. They found a highly significant relationship between early interim PET and PFS (p < 0.0001) and OS (p < 0.03). A positive interim 18F-FDG PET was highly predictive of early relapse in patients with advanced stage HL. All patients relapsed within 2 years.154

Mikhael et al. compared 18F-FDG PET and CT in posttreatment evaluation in aggressive NHLs. 18F-FDG PET was more accurate than CT in assessing remission status. The relapse rate was 100% for positive PET scans versus 14% for negative PET scans and 41% and 25% for positive and negative CT scans, respectively. They stated that compared to CT, 18F-FDG PET is a more accurate method of assessing remission and estimating posttreatment prognosis with positive and negative predictive accuracies of 100% and 82% for 18F-FDG PET versus 41% and 75% for CT, respectively. The prognostic value of interim 18F-FDG PET, after two to four cycles of chemotherapy was useful to predict treatment outcome. Positive predictive accuracy of interim PET is 88%, whereas the negative predictive value is 100% accurate.118

Altamirano reported that 18F-FDG PET had greater prognostic value than CT after the third cycle of chemotherapy and at regimen completion. 18F-FDG PET after three cycles was predictive of the outcome at 18 months in patients with intermediate and aggressive NHL and HD.66 Others also found that an 18F-FDG PET interim scan, was a good predictor of PFS in patients with aggressive NHLs and HD.118,154,155 Nevertheless, some studies did not confirm the value of interim 18F-FDG PET as a predictor of outcome.113,114 Given the large number of reports confirming the value of interim 18F-FDG PET assessment of lymphoma activity, it is difficult to understand these negative findings. Since many lymphoma chemotherapeutic protocols include corticosteroids which are known to interfere with glucose metabolism, it is possible that the negative correlation of these few studies is a consequence of an insufficient interval between steroid administration and 18F-FDG PET or PET/CT assessment.

Most 18F-FDG PET studies are evaluated, based on visual observer analysis. To categorize responders and nonresponders (based on 18F-FDG uptake: no 18F-FDG uptake or residual uptake), it is best to use the SUVs.156158 Itti et al. performed semiquantification of SUV values to improve the prognostic value of PET.156 Using 18F-FDG SUV, they reported reduced false-positive 18F-FDG PET results after the initial two cycles of chemotherapy. After four cycles of therapy, visual analysis was equal to SUV criteria.

Response Criteria

Assessment of the change in tumor burden is an important feature of the clinical evaluation of cancer therapeutics. Both tumor shrinkage (objective response) and time to the development of disease progression are important endpoints in cancer clinical trials. In 1981, the WHO first published tumor response criteria, mainly for use in clinical trials, where tumor response was the primary endpoint. These criteria presented a concept of overall assessment of tumor burden by summing the products of bidimensional lesion measurements and determined response to therapy by evaluation of change from baseline while on treatment.159

Confusion in interpretation of trial results led to a need for standardization and simplifying the response criteria. International Working Party that was formed in mid-1990s created a new criterion, a Response Evaluation Criteria in Solid Tumors (RECIST) criterion. It was published in 2000. The new response criteria introduced definitions of minimum size of measurable lesions, instructions on how many lesions to follow (maximum of 10 total, maximum 5 per organ site), and unidimensional measures for overall evaluation of tumor burden. RECIST criteria have been accepted as an appropriate guideline for treatment response by regulatory agencies and were widely adopted for trials where the primary endpoints are objective response or progression.160 A decade later, new revised criteria, RECIST guideline (version 1.1) was established. This revision defined the following:

• The number of lesions required to assess the tumor burden has been reduced from a maximum of 10 to a maximum of 5 in total (and from maximum 5 to 2 per organ); lymph nodes with a short axis of ≥15 mm are considered measurable and assessable as target lesions. The measurement of short axis is included in the sum of lesions in calculations of tumor response.

• Nodes which decreased in size to less than 10 mm in short axis are considered normal.

• Confirmation of response is no more required for randomized studies but only for trials with response primary endpoint.

• In addition to the previous definition of disease, progression in target disease of 20% increase in sum, a 5 mm absolute increase is now required.

• Section of new lesions and interpretation of 18F-FDG PET scan assessment is included, as well as new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions.161

RECIST committee recommended standard criteria for lymph node measurements to be more accurate by adopting the short axis measurement thus allowing their use in response assessment better aligned with clinical radiology practice.162

Since some limitations exist in anatomic imaging alone using standard WHO, RECIST, and RECIST 1.1, Wahl et al. proposed including functional metabolic criteria to include 18F-FDG SUV response in a new guideline, PERCIST 1, for use in clinical trials and in quantitative clinical reporting.163

There are several different response criteria created by different cancer treatment groups who performed clinical investigations in NHLs. Those guidelines were based on solid tumor criteria but were quite different from each other, and subsequently resulted in confusion (Table 21.8). NHL requires separate response criteria from solid tumors since lymphomas differ from other malignant tumors. Standardized response criteria are important for NHLs, to conduct clinical research as well as individual patient management. The guidelines should facilitate interpretation, comparisons between clinical trials, and evaluation of new therapeutic agents. The uniform guidelines ensure a reliable analysis and comparison of patient groups among studies and data reproducibility. Therefore, The International Working Group (IWG) criteria for response assessment were established in 1999 to enable comparison between clinical trials; they were based mostly on computed tomography, without contribution of PET imaging (Table 21.9).164

TABLE 21.8

INTERIM FDG PET IN CHEMOTHERAPY RESPONSE ASSESSMENT

TABLE 21.9

RESPONSE CRITERIA FOR NHL

Since 18F-FDG PET was performed routinely in the evaluation of the treatment response in lymphoma, it has become clear that these criteria needed to be updated. Because of the high degree of accuracy of 18F-FDG PET in evaluating treatment response in patients with DLBCL NHLs and HD, it has been incorporated into the International Workshop Criteria to provide more accurate response evaluation. The International Harmonization Project Imaging Committee created the guidelines to interpret 18F-FDG PET in treatment assessment in lymphoma. It was aimed to ensure reliability of PET interpretation for both clinical trials as well as in routine clinical practice. The technique to perform and interpret 18F-FDG PET in lymphoma has been standardized into a consensus document. The new guidelines incorporated 18F-FDG PET, immunohistochemistry, and flow cytometry to define response assessment in HD and NHL in 2007.165

The standardized response criteria are necessary to interpret and compare clinical trials and provide data for approval of new therapeutic agents for regulatory agencies. According to the revised PET guidelines, the recommendations to use PET scans include the following:

• Timing of PET scans after treatment with standardized definitions of endpoints of clinical trials.

• Visual assessment is considered as adequate to determine if an 18F-FDG PET scan is positive; SUV is not considered to be necessary. A positive scan was defined as focal or diffuse 18F-FDG uptake above background in a location incompatible with normal anatomy or physiology, without a specific SUV cutoff.

• PET is recommended in several histologic types of lymphoma, HD, and NHL with specified timing of performance.166

Currently, the use of 18F-FDG PET is reserved primarily for patients with HL and DLBCL before treatment and after therapy since the degree of 18F-FDG uptake in low-grade NHL is generally low although 18F-FDG will identify more sites of disease than 67Ga and will also detect transformation of a low-grade lymphoma to a higher grade (Table 21.10).

The criteria suggested by the International Harmonization Project are valid only for the end-treatment response evaluation by PET. On the other hand, during the past several years, interim PET has a significant role in predicting the treatment outcome in Hodgkin lymphoma and diffuse large B-cell non-Hodgkin lymphoma (DLBCL NHL). A systematic review of interim PET studies by Terasawa et al.167 reported a sensitivity of 65% to 100% and specificity of 94% to 100% for HD; whereas 50% to 100% and 73% to 100% for DLBCL NHL, respectively. Some authors state that PET is better than IPI or IPS in HD and DLBCL NHL.156,168

TABLE 21.10

TIMING OF PET (PET/CT) SCANS IN LYMPHOMA TRIALS

Several meetings of International Workshop on Interim-PET-Scan under the auspices of Groupe d’Etude des Lymphomes de l’Adulte (GELA) was held with the aim of reaching a consensus on simple and reproducible criteria for interpretation of HD and DLBCL NHL. A five-point visual assessment as the initial evaluation with the additional value of SUV analysis was proposed in evaluation for both HD and DLBCL NHLs. The five-point scale assessment includes (1) no uptake; (2) uptake ≤mediastinum; (3) uptake >mediastinum but ≤liver; (4) uptake moderately more than liver uptake, at any site; and (5) markedly increased uptake at any site and new sites of disease.169

CONCLUSIONS AND FUTURE CONSIDERATIONS

For the past decade, 18F-FDG PET/CT has served as the biomarker of choice for the initial assessment (staging) of patients with Hodgkin lymphoma and NHL, both high-grade aggressive lymphomas as well as low-grade lymphomas despite the relatively low SUVs observed in patients with low-grade lymphoma. In the symptomatic patient with the diagnosis of low-grade lymphoma, 18F-FDG PET/CT serves to identify the extent of the lymphadenopathy and to exclude transformation to a higher grade. 18F-FDG PET/CT also serves to identify a response to therapy and is useful in surveillance of patients who have responded to therapy. Further studies are necessary to determine if imaging early in the course of therapy is a useful biomarker to shorten the current duration of chemotherapy protocols in responsive patients as well as to provide a basis to discontinue a therapeutic course and replace it with a more aggressive alternate therapy if the 18F-FDG PET/CT biomarker indicates that the duration of response will be brief. The principal short-coming of 18F-FDG PET/CT is the occasional nonspecific finding of foci with increased SUVs secondary to inflammation. Hence, an imaging biomarker that identifies proliferative activity rather than just increased metabolism would be more specific for the demonstration of tumor activity. 18F-fluorothymidine (18F-FLT) is fluorinated analog of thymidine that is phosphorylated by thymidine kinase during the S-phase of the cell cycle but not incorporated into DNA. Nevertheless, it can serve as an imaging marker of cell proliferation. In most cases, the findings correlate with 18F-FDG PET imaging as well as Ki-67 evidence of proliferative activity (Fig. 21.6).170172 In an exhaustive review of the literature, Bertagna et al. identified nine publications that dealt with the value of 18F-FLT PET in the hematologic malignancies. In general, the results correlated with 18F-FDG PET in terms of identifying disease activity and the response to therapy. Bertagna et al.173 concludes that there was no advantage compared to 18F-FDG PET except in the central nervous system where there is no 18F-FLT uptake in the normal grey matter thus providing a better lesion to background contrast.

FIGURE 21.6. 18F-fluorothymidine (18F-FLT) and 18F-fluorodeoxyglucose (18F-FDG) in a patient with mantle cell lymphoma (MCL). Multiple tumor sites are 18F-FDG positive and 18F-FLT negative. Other sites are both 18F-FDG positive and 18F-FLT positive. The 18F-FDG-positive, 18F-FLT-negative sites did not respond as well to chemotherapy whereas the 18F-FDG-positive, 18F-FLT-negative sites are smaller and have a decrease in SUV.

LEUKEMIA

INTRODUCTION

Leukemia is a malignancy characterized by excess, uncontrolled production of white blood cells which overload the BM and spill out into the circulation. The patient may be profoundly ill with fever and weakness or relatively asymptomatic (at least initially) with the disease first identified on routine blood count examination. There are many variants of the disease as any of the components of the white blood cell lineage may give rise to a malignant clone. The various types cannot be identified based on clinical symptoms but precise diagnosis is important as it determines the choice of therapy and the potential course of the disease. As stated, diagnosis is based on examining the peripheral blood as well as the BM. There are four principal groups of leukemia: Acute and chronic myelogenous leukemia and acute and chronic lymphatic leukemia. The acute designation is characterized by a predominance of immature blast cells in the BM and the peripheral circulation whereas the chronic forms have more mature but excessive numbers of the cell type. As might be expected, acute leukemia follows a more aggressive course leading to death unless remission is achieved by initial therapeutic efforts. Even when a clinical and laboratory response is achieved, most patients will relapse. Hence, the so-called consolidation therapy is usually employed; that is, additional therapeutic intervention despite normalization of the differential blood count and BM.

DIAGNOSTIC IMAGING

Other than demonstrating splenomegaly and expanded BM cavity activity, diagnostic imaging including nuclear scintigraphy and PET or PET/CT has little to offer in terms of management of the patient with leukemia. Nevertheless, the nuclear medicine physician should recognize the findings when present although they are usually nonspecific.

Bone Scintigraphy

On skeletal imaging, there is usually diffuse increase in the radiotracer throughout the skeleton consistent with increased bone mineral turnover secondary to the stress on the skeleton from the expanded and hypermetabolic BM. The bone scintigraphy findings, however, are nonspecific and similar to the pattern seen in myeloid metaplasia, other causes of BM expansion such as Gaucher disease, and even the superscan seen secondary to diffuse BM infiltration by metastatic soft tissue tumor.

Liver–Spleen Colloid Scintigraphy

Splenomegaly is identified on any radiocolloid scan but the findings has no significance on management decisions nor is it likely informative beyond the clinical assessment of the patient’s abdomen.

18F-FDG PET and PET/CT

18F-FDG PET and PET/CT are likely to demonstrate diffuse marrow activity as well as solid organ foci if infiltrated by leukemic cells. The SUV is expected to be elevated but this finding has no impact on management. 18F-FDG PET has demonstrated extramedullary involvement that was subsequently confirmed on biopsy. In addition, 18F-FDG PET has potential to identify complications such as Richter conversion to DLBCL as well as to identify coexisting neoplasms or infection complicating the clinical course and management.174

18F-FLT PET/CT

Buck et al. evaluated the merit of 18F-FLT in ten patients with acute myeloid leukemia (AML) prior to and following initial therapy. Utilizing 18F-FLT in doses similar to those used with 18F-FDG PET imaging, they recorded dynamic images for the initial 60 minutes. BM and spleen had the most activity with BM mean SUV of 11.5 versus 6.6 in control subjects. Spleen SUV was 6.1 versus 1.1 in controls. Activity in other organs such as the brain or testes was confirmed on biopsy to represent leukemic infiltrates. Although there was no demonstrable relationship between marrow SUV and BM blast cell count, absent activity was demonstrated in a patient who received myeloablative therapy.175 Using a similar 18F-FLT PET imaging protocol, Eary et al. demonstrated a 50% and 35% decrease in BM SUV in two patients following therapy. In a third patient the SUV increased but no correlation with the subsequent clinical course was reported.176 Vanderhoek et al.177 similarly concluded that 18F-FLT PET might be useful to confirm disease control during induction chemotherapy.

Overall, nuclear imaging, including PET and PET/CT, currently has no role in the management of the leukemic patient. Nevertheless, there are findings on 99mTc-MDP imaging, 67Ga scintigraphy, and 18F-FDG PET and PET/CT that are seen in patients with leukemia. There is a potential future role for 18F-FDG and possibly other imaging biomarkers such as 18F-FLT to serve as biomarkers of responsiveness to chemo- or other therapy.

TARGETED RADIONUCLIDE THERAPY

Radioimmunotherapy of Lymphoma

Over the past quarter century, the classification of both Hodgkin lymphoma and NHL has grown increasingly complex. This insight into the diverse features of this group of tumors arising from lymphoid tissue has provided many benefits as recognition of specific markers has enabled more appropriate and patient-specific treatment. In particular, the identification of specific cell surface markers has led to the development of antibodies which have altered the management of many patients with NHL. An antibody to the lymphocyte cell marker, CD20, is now commonly used as a component of the initial chemotherapy protocol for patients with lymphomas expressing CD20. This antibody, rituximab, is a chimeric immunoglobulin derived from the murine immunoglobulin ibritumomab and is marketed in the United States as Rituxan. It is used as a maintenance form of therapy in many patients. Both rituximab and another anti-CD20 immunoglobulin known as tositumomab are components of two different FDA approved radioimmunotherapy regimens (Zevalin and Bexxar) for the treatment of patients with lymphoma.

Zevalin and Bexxar

Both Zevalin and Bexxar involve infusion of an unlabeled (cold) antibody followed by the radiolabeled antibody. Zevalin consists of rituximab and Yttrium-90 (90Y)-ibritumomab tiuxetan and involves infusion of the unlabeled at the initiation of the regimen, followed a week late by a second rituximab infusion at the same dose level after which the 90Y-ibritumomab tiuxetan is infused.

The Bexxar regimen consists of infusing the unlabeled tositumomab followed by a 185 to 222 MBq (5 to 6 mCi) dose of 131I-labeled tositumomab to perform whole-body dosimetry by obtaining whole-body counts, usually at three time points over the following 7 days. From this data, the whole-body radiation absorbed dose per unit of radioactivity is calculated. From this data, one determines the amount of radioactivity that would deliver 65 or 75 cGy to the whole body. Subsequently, this dose is infused after an infusion of unlabeled tositumomab. Both rituximab and tositumomab are anti-CD20 immunoglobulins. The labeled anti-CD20 antibody delivers a β-Emitting radionuclide to B-cells, combining the direct cytotoxic effect of immunoglobulin fixation with a delivery of a local radiation flux, thus altering the life cycle of cells even if they have not been directly bound with antibody. The unlabeled antibody infusion prior to administration of the labeled immunoglobulin occupies a good portion of the circulating B lymphocyte CD20 epitope, resulting in prolongation of plasma half-life and a greater fraction of the administered dose accumulated in tumor sites.178

As expected, radioimmunotherapy has resulted in further improvement in clinical responses compared to immunotherapy alone. This is because of the added cytotoxicity of radiation in addition to the direct cytotoxic effect of the antibody augmented by the crossfire effect so that cells are irradiated even if they have not been directly targeted by the radiolabeled antibody.

Both Bexxar and Zevalin were initially approved by the FDA for use in patients with refractory or relapsed low-grade FL. Other requirements included confirmation on biopsy material that the tumors were CD20+, had less than 25% BM involvement, and a platelet count ≥150 K/μL. Allowance was made for patients with platelets below 150 K but >100 K/μL. The principal toxicity of both Zevalin and Bexxar is hematologic with reduction of platelet count being the greatest concern. Patients should be monitored with complete blood and platelet counts weekly after infusion. In general, the platelets nadir from 4 to 7 weeks and generally return to about 80% of the pretherapy level. Many patients can be managed with observation alone but platelet infusions may become necessary. The absolute neutrophil count also may decline to 1,000 cells/mm2.

The initial clinical trials and postapproval experience have been excellent but total sales of both products have suffered for a variety of reasons that proponents of radioimmunotherapy consider nonsubstantive. Nevertheless, the failure of the oncology community to embrace radioimmunotherapy despite the impressive clinical results has had a negative effect on sales of the products.179,180 In fact, in late 2013, the distributors of Bexxar announced that distribution of the product would be discontinued in February 2014. Accordingly, the remainder of this section on radioimmunotherapy will be devoted primarily to Zevalin. Additional clinical details about both Bexxar and Zevalin are described in several recent reviews.178,181

Zevalin

Zevalin is the only commercial product currently available in Europe and the United States. Zevalin is actually a regimen: A combination of the unlabeled anti-CD20 antibody, rituximab, followed by an infusion of a 90Y-labeled antibody, ibritumomab. Ibritumomab is a murine antibody from which rituximab, a chimeric antibody, is derived. The anti-CD20 portion is similar in both the rituximab and ibritumomab molecules. Rituximab infusion precedes administration of the radiolabeled immunoglobulin to occupy the abundant CD20 binding sites on circulating B and splenic B-lymphocytes. Although somewhat counterintuitive, tumor uptake of the radiolabeled form of the antibody is actually greater when nonradiolabeled immunoglobulin is infused prior to the infusion of the radiolabeled immunoglobulin. Initially, clinical studies involved the infusion of an 111In-labeled ibritumomab preceded by a Rituxan infusion to obtain dosimetry data and confirm biodistribution of the radiolabeled immunoglobulin. Currently, within both the European and United States communities, use of the In-labeled form of the immunoglobulin followed by imaging is no longer required. Nevertheless, since the initial clinical trials involved the infusion of a potentially therapeutic amount of Rituxan (450 mg/m2), the entire regimen still consists of the initial infusion of the nonlabeled rituximab followed 1 week later by a repeat infusion of rituximab followed by 90Y-ibritumomab.

The dose of 90Y-ibritumomab employed is based upon the patient’s weight and platelet count. 15 MBq/kg if platelets are ≥150 K/μL; 11 MBq/kg if platelets are <150 K/μL but >100 K/μL; maximum dose 4.44 GBq. The dose of 90Y-ibritumomab employed is based upon the patient’s weight and platelet count. BM involvement in the nonmyeloablative setting should be <25%.182,183

In the initial efficacy trials comparing rituximab to Zevalin in patients with indolent low-grade lymphoma who had relapsed after chemotherapy, the Zevalin regimen had an overall response rate (ORR) of 82% compared to rituximab alone which had an ORR of 33% with no complete responses (CRs). By contrast, the Zevalin-treated group had 26% CR (Table 21.11).184

In a subsequent randomized trial comparing Zevalin to rituximab alone in patients who had relapsed or been refractory to chemotherapy but were rituximab naïve, Zevalin had an 89% ORR compared to a 56% ORR in patients receiving only rituximab. Zevalin had a 30% CR compared to 16% for rituximab.185 In general, patients with a CR have a longer PFS than patients only achieving a PR.

A subsequent clinical trial has demonstrated the beneficial effect of Zevalin as consolidation therapy in patients who achieved a CR or PR following initial chemotherapy such as CHOP, CHOP-R, CVP, CVP-R, or fludarabine. Compared to the randomized control group who did not receive consolidation therapy, there was an increase in the median PFS threefold (36 months versus 13 months). In patients achieving a CR, the median PFS in the group who received Zevalin was 54 months.186

TABLE 21.11

ZEVALIN THERAPY (90Y-IBRITUMOMAB TIUXETAN + RITUXIMAB)

FIGURE 21.7. A 49-year-old man with a history of diffuse large-cell lymphoma, diagnosed 11 years earlier. At that time, patient had undergone classical chemotherapy (CHOP). Relapsed after 5 years with pleural involvement; responded after pleural resection, rituximab infusions, and two cycles of DICE. Second relapse, 6 years later; referred for radioimmunotherapy. Left, preradioimmunotherapy 18F-FDG MIP demonstrating large abdominal mass; right, repeat 18F-FDG MIP 5.5 months later demonstrates resolution of abdominal mass. 18F-FDG + foci in left thorax are granulation tissue which persist following pleurectomy.

In general, the clinical response (ORR, CR, PR) with the radioimmunotherapy agent Zevalin used for the treatment of patients with CD20+ NHL who have relapsed after initial therapy are greater, and of greater duration, than repeat chemotherapies. In fact, radioimmunotherapy is safe and effective even in patients who fail to respond or relapse after response following immunotherapy. The CR and ORR are even better when used as first-line treatment in conjunction with chemotherapy or as “consolidation” therapy. The principle toxicity of Zevalin as a radioimmunotherapeutic is hematologic; secondary to BM irradiation from labeled antibody in blood and specific deposition on tumor cells in the BM. Patients should be followed with weekly CBC and platelet count: Supportive measures such as growth factors and/or transfusions may be required but serious consequences are rare. In the event of relapse (disease recurrence) after radioimmunotherapy, patients tolerate subsequent therapy as well or better than equivalent patients who have not received radioimmunotherapy (Fig. 21.7). Radiation exposure of family members and health care personnel is low.187

Radiolabeled Peptide Therapy of Lymphoma

Since lymphocytes express somatostatin receptors and aggressive lymphomas (high-grade large B-cell lymphoma and HD) have been imaged with 111In-Octreoscan, clinical trials have been performed to evaluate the therapeutic potential of 90Y and 177Lu octapeptides for the treatment of lymphoma. A thoughtful and analytic review from Rotterdam concludes that because of the low number of high affinity somatostatin receptors on lymphomas including HD, despite occasional reports of a transient response, there is little likelihood of this class of radiolabeled compounds becoming effective therapeutics. However, they conclude by stating that a high degree of expression of somatostatin receptors may not be necessary because of the radiosensitivity of Hodgkin lymphoma and NHLs.188

Radioimmunotherapy of Leukemia

Although there are no radiolabeled antibodies, antibody fragments or small molecules available clinically for the treatment of leukemias, leukemic cells represent an attractive target for this therapeutic approach as access to the tumor cells is readily achieved. Indeed, there is a substantial and ongoing investigational effort to treat various leukemias with specific immunoglobulins, both unlabeled and labeled.189191 At the present time, none of these are approved for clinical use in the United States, Europe, Asia, or elsewhere. An interesting aspect of these investigations has been the development and evaluation of specific immunoglobulins labeled with α-emitters. Since, in the case of leukemia, the tumor cell is circulating in the blood pool and residing in the BM where there is ample perfusion, the characteristic very short range of α particles (50 to 80 μm) compared to β particles (0.8 to 5 mm) is satisfactory to severely damage the tumor cells and limit radiobiologic damage to other tissues and marrow precursors that do not express the specific epitope. Furthermore, Scheinberg et al. at Memorial Sloan Kettering have developed a nanogenerator in which the immunoglobulin is labeled with a precursor α-emitter that subsequently decays into a second α-emitter.189 Trials in animal models have been encouraging.

CONCLUSIONS AND FUTURE CONSIDERATIONS

Radiolabeled molecules, principally immunoglobulins have been used in preclinical trials to treat lymphoma and leukemia. In the case of lymphoma, following extensive clinical trials, two products have been approved by the FDA in the United States. The results in terms of clinical response, both complete and partial, and the therapeutic–toxic ratio have been very favorable. Moreover, these two products (Bexxar and Zevalin) have demonstrated efficacy in a variety of clinical applications beyond the original approval. Patients have tolerated the BM exposure well and fair, no worse upon relapse, and retreatment than patients who have not received targeted radionuclide therapy. Nevertheless, acceptance by clinicians who see the patients initially and upon whom referral is dependant has been disappointing. It is likely that there will be additional advances in identifying cell targets for the delivery of radiation. Significant impact on the management of these diseases, lymphoma and leukemia, depends upon recognition and utilization by the larger clinical community.

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