- TABLE OF CONTENTS
- Etiology and risk factors
- Signs and symptoms
- Screening and diagnosis
- Staging and prognosis
- Follicular lymphoma
- Chronic lymphocytic leukemia/small lymphocytic lymphoma
- Splenic marginal zone lymphoma
- Nodal marginal zone lymphoma
- Extranodal marginal zone B-cell lymphoma of MALT type
- Lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia
- Diffuse large B-cell lymphoma
- Mantle cell lymphoma
- Burkitt and Burkitt-like lymphoma
- Primary mediastinal large B-Cell lymphoma
- Peripheral T-cell lymphoma, unspecified
- Angioimmunoblastic T-cell lymphoma
- Anaplastic large-cell lymphoma, T-/null-cell, primary systemic type
- Hepatosplenic T-cell lymphoma
- Extranodal NK/T-cell lymphoma, nasal-type
- Enteropathy-associated T-cell lymphoma
- Adult T-cell leukemia/lymphoma
- Cutaneous T-cell lymphomas
- Cutaneous B-cell lymphomas
- CD4+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma)
- HIV-related lymphomas
- Posttransplantation NHL
- Primary CNS lymphoma
- Tumor lysis syndrome
- Suggested reading
The therapeutic approach for NHL differs for each subtype. Chemotherapy remains the most important modality (Tables 9 and 10). However, in select instances, radiation therapy or, rarely, surgical resection plays a critical role. Biologic approaches, including monoclonal antibodies (Table 11) and recombinant conjugates, have shown significant clinical activity and are now incorporated into treatment paradigms. Autologous and allogeneic stem cell transplantations (SCTs), traditionally reserved for recurrent or refractory disease, are being evaluated as part of initial therapy in high-risk settings. This section will be organized by NHL subtype to best illustrate the biologic characteristics and therapeutic considerations that determine the management strategy for individual patients. Common NHLs will be covered in depth, whereas less frequent entities will be described in limited detail.
Follicular lymphoma comprises 22% of all NHLs; only DLBCL is more common. The clinical presentation may be nodal or extranodal, and bone marrow involvement occurs in the majority of cases. Extensive intra-abdominal adenopathy without peripheral node enlargement is not uncommon. Clinical behavior is variable, reflecting the heterogeneity of the underlying biology; some patients survive decades, whereas others progress rapidly to resistant disease or transform to a more aggressive histology. There are rare spontaneous remissions. Transformation is common, occurring in 3% to 6% of patients each year and ultimately 30% to 50% of all patients. Although generally responsive to treatment, the clinical course of follicular lymphoma is characterized by repeated relapses. Although there was no improvement in survival for patients with follicular lymphoma for many years, there is now evidence that outcomes are improving. Median survival has reached 10 or more years. It is likely that this is, in part, attributable to use of rituximab(Drug information on rituximab) in combination with chemotherapy, but survival was already improving before the approval of rituximab.
It is crucial to distinguish between reactive follicular hyperplasia and follicular lymphoma, as the former is a benign condition. Morphologic features as well as the absence of Bcl-2 staining within the follicle and the absence of CD10 and/or Bcl-6 protein expression in the interfollicular areas help to distinguish reactive follicular hyperplasia from follicular lymphoma. Follicular lymphoma is graded according to the number of admixed centroblasts within the neoplastic follicles. Grade 3 follicular lymphoma, previously known as follicular large cell lymphoma, is now subdivided into two subtypes: Grade 3a is characterized by a mixture of centrocytes and centroblasts within the follicle, whereas grade 3b has only sheets of centroblasts with no residual centrocytes. The neoplastic lymphocytes in follicular lymphoma express the pan-B markers CD19, CD20, CD22, and CD79a and antigens of the germinal center (including CD10 and Bcl-6). Most follicular lymphomas express Bcl-2 protein, which is highly correlated with the t(14;18)(q32;q21). This translocation results in the juxtaposition of the bcl-2 oncogene into the immunoglobulin H heavy-chain locus on chromosome 14, resulting in its constitutive expression. Follicular lymphoma grade 3b with bcl-6 rearrangement but no t(14;18)(q32;21) may be more closely related to DLBCL than to other follicular lymphomas.
As previously mentioned, the FLIPI is a prognostic index designed specifically for follicular lymphomas based on five adverse prognostic factors (Table 7). Age is the most important factor. Three risk categories have been defined, each consisting of approximately one-third of patients. More than two-thirds of low-risk patients but only one-third of high-risk patients survive 10 years. A new prognostic scoring system, the FLIPI2, is based on prospectively collected data from the rituximab-era (Table 7), and has progression-free survival rather than overall survival as its principal endpoint. Among patients receiving rituximab-containing therapy, it is a robust predictor of clinical outcome. Whereas clinical parameters are surrogates for biologic characteristics, biologic correlates such as gene expression signatures may soon supersede clinical prognostic indicators.
As noted before, investigators from the NCI have described two gene-expression signatures associated with vastly different clinical outcomes in follicular lymphoma. These two signatures represent the expression of immunoregulatory genes in the nonmalignant cells infiltrating the malignant lymphoma at the time of diagnosis. Others have reported that the number of tumor-associated macrophages, or specific T-cell subsets was an independent predictor of overall survival in follicular lymphoma, also underscoring the importance of host response in follicular lymphoma.
Treatment of early-stage disease
For the relatively small number of patients with stage I or II follicular lymphoma, radiotherapy continues to be the recommended approach because of the potential for long-term disease-free survival and possible cure. Results from the Princess Margaret Hospital's series of involved-field radiotherapy (IFRT) for early-stage disease show cumulative relapse rates of 54% and 56% at 15 and 25 years, with only a 2% risk of relapse beyond 15 years. A recently published analysis of the SEER database for adults with stage I or II follicular lymphoma diagnosed between 1973 and 2004 showed improved disease-specific survival and overall survival with upfront IFRT, compared with all other approaches. Combined-modality therapy has also resulted in excellent disease control, and a randomized trial comparing IFRT with combined-modality therapy is ongoing.
Despite the excellent outcomes associated with radiotherapy, the National Lymphocare Study revealed that the majority of patients in the United States are either observed or treated with rituximab alone or in combination with chemotherapy, foregoing the potential for cure, even in young patients. Use of functional imaging with PET may improve the results of IFRT by more accurately identifying patients with truly localized disease.
For clinical stages I and IIA low-grade follicular lymphoma, irradiation alone is directed to the entire involved lymphoid region, as defined by Kaplan and coworkers, or the involved region plus one additional uninvolved region on each side of the involved nodes. Targeting just the involved lymph nodes with a margin up to 5 cm, compared with routinely covering the entire lymph node region has been shown by a Canadian study to give equally good results. Radiation to large intra-abdominal or pelvic area maybe associated with increased morbidity and thus must be judiciously considered. Conformal or intensity-modulated radiation therapy (IMRT) may be required to spare sensitive organs such as the kidneys and liver. The recommended dose is approximately 30 Gy for nonbulky disease showing prompt regression and 36 Gy for bulky or slowly regressive disease, in 1.75 to 2.0 Gy daily fractions. A trial from the United Kingdom showed equivalent results comparing 24 Gy with 40 Gy (published in abstract format). As the majority of subsequent relapses occur outside previous radiation fields, often in adjacent or distal lymph nodes, extended-field or total lymphoid irradiation has been used to try to improve cure rates. Clinical series have shown improvement in freedom from relapse only, with no significant difference in long-term survival.
Treatment of advanced-stage disease
The asymptomatic patient The standard management of asymptomatic patients with follicular lymphoma has been a "watch-and-wait" approach. Treatment is delayed until symptoms or cytopenias intervene or there is impending compromise of vital organs. In the pre-rituximab era, multiple phase III randomized trials comparing immediate chemotherapy with observation for asymptomatic patients with advanced-stage follicular lymphoma have shown no difference in outcome. A phase III trial comparing the watch-and-wait approach with rituximab therapy for asymptomatic advanced-stage disease has been completed in Europe and a preliminary analysis presented recently. Although the median time to new therapy had not been reached at 4 years, there was no survival benefit to initiating therapy with rituximab in asymptomatic patients compared with the watch-and-wait strategy (see sidebar). Although an increasing number of asymptomatic patients with low-burden disease and their physicians are opting to start treatment with rituximab before they are symptomatic or meet standard criteria for therapy, the watch-and-wait strategy continues to be the recommended approach.
At the same time, an American intergroup trial comparing two different rituximab dosing regimens in patients with low tumor burden indolent lymphoma who are asymptomatic has met accrual, but the results are not yet available.
Rituximab For patients with symptoms or other reasons for treatment, there are many treatment options, including single or multiagent chemotherapy, monoclonal antibodies or radioimmunoconjugates, combinations of chemotherapy and immunotherapy with anti-idiotype vaccines, and new agents such as bortezomib(Drug information on bortezomib) (Velcade) or bendamustine (Treanda). There is little data on the treatment of high tumor burden disease with single agent rituximab. Among patients with low burden disease, overall response rates have ranged from 47 % to 74%.
In relapsed or refractory indolent lymphomas, treatment with rituximab results in overall response rates of nearly 50%, with a median response duration of approximately 1 year.
To improve on response rates and duration of response, additional doses of rituximab have been administered as "maintenance therapy." The median event-free survival is prolonged with this approach, especially for previously untreated patients. With a median follow-up of over 9 years, an early trial of single-agent rituximab has shown that among untreated patients who responded to rituximab, 45% of those who received an additional four doses of rituximab were without progression or other events at 8 years. In previously treated patients, the total duration of benefit from rituximab appears to be the same whether patients receive maintenance rituximab on a scheduled basis or reinduction with rituximab only at the time of disease progression. A confirmatory trial (ECOG 4402) in asymptomatic untreated patients with a low tumor burden has met accrual, and the results are eagerly awaited. Maintenance regimens have varied, and the impact of the frequency of administration on the duration of response is unknown.
Rituximab maintenance also impacts progression-free survival among patients treated with chemotherapy alone and those receiving rituximab plus chemotherapy. Among previously untreated patients with folllicular lymphoma who responded to immunochemotherapy (R-CVP, R-CHOP, or R-FCM), rituximab maintenance resulted in a significant improvement in progression-free survival over observation in the PRIMA phase III trial (3-year, 79% vs 60%, P < .0001), according to Salles and colleagues. The most common grade 3/4 adverse events were infection (39% for rituximab maintenance vs 24% for observation). Among relapsed/refractory patients treated with CHOP or rituximab-CHOP (R-CHOP) maintenance, rituximab also improved progression-free survival. Whether these results will translate into an overall survival benefit remains to be seen. Questions also remain regarding the impact of maintenance rituximab on the quality of life and the cost of care. Compared with observation, maintenance rituximab has been associated with an increased risk of infectious complications.
Chemotherapy with and without rituximab For patients with high-tumor burden disease and/or symptoms, the addition of rituximab to chemotherapy has resulted in major improvements in clinical outcome including overall survival. Four phase III trials comparing combinations of chemotherapy and rituximab with chemotherapy alone in previously untreated patients have all shown benefit for the combination establishing chemoimmunotherapy as the standard of care for symptomatic patients or high-tumor burden disease. Overall response rates and either median time to treatment failure or event-free survival were superior in the chemoimmunotherapy arm in every series. An overall survival benefit has been demonstrated in three of the four trials and in the high-risk subset of the fourth study. The combination of the new agent bendamustine (Treanda) and rituximab was compared to R-CHOP as first-line therapy in previously untreated patients with follicular, indolent, and mantle cell lymphomas, resulting in significantly longer median progression-free survival (54.8 months vs 34.8 months, P = .0002). In a multicenter, randomized phase III trial that enrolled 549 patients, bendamustine plus rituximab was less myelosuppressive than R-CHOP and resulted in fewer infections, less peripheral neuropathy, and fewer episodes of stomatitis. This combination has become the backbone for the new US Intergroup trial in which rituximab-bortexomib-bendamustine is compared to rituximab-bendamustine.
Radioimmunotherapy The anti-CD20 radioimmunoconjugates Y-90 ibritumomab (Zevalin) and I-131 tositumomab (Bexxar) both deliver ionizing radiation to target cells and their neighbors and have proven to be relatively easy to administer, safe, and effective. Response rates are higher and remissions more durable when radioimmunoconjugates are used early in the clinical course. Both agents are likely to have their greatest impact when used in previously untreated patients.
In previously treated patients, Y-90 ibritumomab, a high-energy beta-emitter, yielded an overall response rate of 80% for relapsed or refractory follicular or transformed CD20+ B-cell NHL, with a median duration of response of 14 months. For patients whose disease is refractory to rituximab, response rates with Y-90 ibritumomab are high (74% overall response rate), but the median duration of response is relatively short (6.4 months; range, 0.5–25+ months). The dose-limiting feature of this approach is hematologic toxicity. Short-lived myelosuppression occurs 7 to 9 weeks posttreatment. Dosing is based on weight (0.4 mCi/kg), with a reduction (0.3 mCi/kg) for those with mild thrombocytopenia (< 100,000/µL). When used to consolidate first partial or complete remission, Y-90 ibritumomab prolonged progression-free survival from 13.5 to 37 months. However, only 14% of the 414 patients enrolled on this randomized phase III trial received a rituximab-containing regimen for induction. Now that the addition of rituximab to chemotherapy has become standard of care based on demonstrated improvement in progression-free and overall survival rates, the benefit of consolidation with radioimmunotherapy will need to be evaluated in large numbers of patients treated first with chemoimmunotherapy.
I-131 tositumomab is both a gamma- and beta-emitter and is individually dosed on the basis of dosimetry to deliver 75 cGy of total-body irradiation. Similar to Y-90 ibritumomab, it is effective in both heavily pretreated relapsed and refractory patients. Heavily pretreated patients with refractory low-grade or transformed NHL had an overall response rate of 65% (20% complete response rate), with a median duration of response of 6.5 months. These rates were notable in view of a response rate of only 28% in the preceding chemotherapy regimen. Like Y-90 ibritumomab, I-131 tositumomab is associated with predictable myelosuppression. Secondary myelodysplasia and leukemia have occurred in patients treated with radioimmunotherapy, but only in patients previously treated with chemotherapy and thereby already at risk. In previously untreated patients, the complete response rate was 75%, with a 5-year progression-free survival of 59%. These data must be interpreted carefully, as this study enrolled a relatively young patient population (median age, 49 years), with low-bulk disease, a group that some physicians would choose to observe rather than treat.
I-131 tositumomab has been used to consolidate responders following induction with CHOP chemotherapy. In a phase II trial of previously untreated patients with follicular lymphoma, the percentage of complete response/unconfirmed complete response increased from 39% following CHOP chemotherapy to 69% following consolidation with I-131 tositumomab. With a median follow-up of 5.1 years, 66% of patients are alive and disease-free. Based on these phase II results and the encouraging outcome of patients treated with R-CHOP, the American intergroup has completed a phase III trial comparing CHOP followed by I-131 tositumomab with R-CHOP in treatment-naive patients. The results of this study will be forthcoming in the near future. New strategies to enhance tumoricidal effects and reduce toxicity of radioimmunoconjugates are under study including the use of radiosensitizers, fractionation, pretargeting, and production of humanized antibodies.
Interferon-α The use of interferon (IFN)-α in follicular lymphoma has been extensively investigated both in combination with chemotherapy and as maintenance therapy, with varying results. In most studies, IFN-α was associated with a prolongation of remission but not overall survival. A notable exception was the GELF86 trial, in which overall survival was prolonged. The SWOG reported the results of a large phase III trial in which patients with indolent lymphomas were randomized to receive IFN-α or observation following induction with an intensive anthracycline-containing regimen and in some cases radiotherapy. Postremission therapy did not prolong progression-free or overall survival. Although these results, along with the toxicities associated with IFN-α, have led many physicians to abandon its use altogether, a large phase III study is currently ongoing in Germany comparing standard vs intensive dose maintenance.
Irradiation Radiation is not typically used in conjunction with systemic therapy. However, radiation may be effective when used locally for palliation of symptomatic sites of disease. Abbreviated fractionated schedules (25 to 30 Gy in 2.5 to 3 Gy daily fractions, respectively) are often used. A low-dose regimen of 4 Gy in 2 fractions has been shown to be effective, with an overall response rate of approximately 80% in the palliation of symptoms, and is well tolerated. Total-body irradiation, usually consisting of 12 Gy in 2 Gy fractions twice a day, is used as part of preparative regimens for bone marrow transplantation.
Anti-idiotype vaccines Lymphoma-specific idiotypes serve as tumor-specific antigens in follicular lymphoma and constitute the basis for vaccine therapy. In early vaccine trials, immunized patients who generated an anti-idiotype response experienced longer remissions than those who failed to mount a response. In phase I trials, vaccination resulted in tumor shrinkage in some patients, and in a phase II trial, anti-idiotype vaccine eliminated minimal residual disease detectable only by PCR after intensive chemotherapy.
Based on these encouraging results, a phase III randomized trial comparing vaccination plus KLH (keyhole limpet hemocyanin, a nonspecific immunostimulant) to KLH alone in previously untreated patients who achieved a complete remission with intensive anthracycline-containing combination chemotherapy was conducted. Patients receiving the vaccine who were in complete remission for six months after intensive chemotherapy experienced a marginally significant prolongation of cancer-free survival. However, disease-free survival was prolonged significantly for those patients who received an IgM-Id but NOT for those receiving an IgG-Id vaccine, compared with isotype controls. In contrast, two other placebo-controlled trials of anti-idiotype vaccination have shown no benefit. Compared with placebo, vaccination following induction chemotherapy with cyclophosphamide(Drug information on cyclophosphamide), vincristine, prednisone(Drug information on prednisone), or induction immunotherapy with rituximab did not impact progression-free or overall survival. Differences in study design are likely responsible for the differences in outcomes among the trials. New directions in vaccination include idiotype-pulsed dendritic cell and membrane proteoliposomal vaccines.
Novel agents New agents targeting specific molecular targets such as the ubiquitin-proteasome pathway, histone deacetylase, the mammalian target of rapamycin (mTOR), the microenvironment, and Bcl-2 have shown promise in the treatment of follicular lymphoma. New combinations such as bortezomib, bendamustine, and rituximab have shown promising activity in phase II trials. Novel antibody approaches to follicular lymphoma include new and improved anti-CD20s, antibodies that bind to alternative targets, and chemoimmunoconjugates and radioimmunoconjugates.
SCT The natural history of follicular lymphoma is characterized by response to therapy but repeated relapses and progressively shorter and shorter remissions, ultimately resulting in death from progressive disease. Autologous and allogeneic SCTs are alternative strategies often associated with durable remissions that may impact overall survival. Unfortunately, immediate and long-term toxicities are significant and must be considered when assessing the appropriate role of transplantation in the overall treatment plan for individual patients. Whether any of the new therapeutic strategies will prove to be as effective as autologous SCT in the relapsed setting remains to be seen.
Several groups have investigated the role of autologous SCT as consolidation therapy for patients in first complete or partial remission. Although progression-free survival may be prolonged, an impact on survival has not been demonstrated consistently. An increased incidence of secondary myelodysplasia following autologous SCT in first remission has reduced enthusiasm for this approach. Contemporary trials evaluating the role of autologous SCT for follicular lymphoma in first remission induced with rituximab-containing regimens are needed. The results of a GLSG trial comparing IFN maintenance with myeloablative chemotherapy with autologous SCT after induction with CHOP or R-CHOP are awaited.
An alternative approach to consolidating complete and partial remissions achieved with conventional induction therapy is the use of a sequential HDCT program, which culminates in an autologous SCT. The Italian cooperative groups have reported results of a phase III randomized trial comparing R-CHOP for 6 cycles with sequential HDCT with autologous SCT. Again, there was a significant difference in event-free survival but no difference in overall survival.
Single-institution studies as well as analysis of registry data suggest that a tumor-free graft is an important determinant of outcome in follicular lymphoma. Administration of rituximab during stem cell mobilization provides an "in vivo" purge, reducing contamination of the autograft with malignant lymphocytes. The long-term benefit of such an approach has not yet been demonstrated.
Allogeneic SCT has been investigated primarily in young patients with HLA-identical sibling donors and extensive disease and/or marrow involvement. Low relapse rates suggest that this approach is potentially curative but is associated with treatment-related morbidity and mortality. Reduced-intensity transplantation is based on the assumption that a graft-vs-lymphoma effect is operative and has the potential to cure follicular lymphoma. Whether this approach will reduce toxicity while maintaining the low relapse rates associated with standard myeloablative allotransplants remains to be established. A randomized trial comparing this strategy with autologous SCT in relapsed follicular lymphoma was initiated in the United States to answer this important question but closed early because of poor accrual.
Overall treatment strategy
Whereas treatment choices were once limited to single or combination alkylator-based treatment, we now are faced with choosing among a wide variety of strategies. There are many unanswered questions that can only be addressed through well-designed clinical trials. Hence, whenever possible, every patient with follicular lymphoma should be enrolled in prospective clinical studies. In the absence of symptoms or other indications for treatment, patients should be observed. A combination of rituximab and chemotherapy is recommended in the absence of a clinical trial for those who require treatment. Selected patients with comorbidities may be best served with rituximab alone. Radioimmunotherapy is a good option at the time of relapse, with transplantation reserved for selected patients in first or subsequent relapse.