Indolent, Noncontiguous Stage II/III/IV Adult Non-Hodgkin Lymphoma

Maintenance Rituximab
Current Clinical Trials

Optimal treatment of advanced stages of low-grade lymphoma is controversial because of low cure rates with the current therapeutic options. Numerous clinical trials are in progress to settle treatment issues, and patients should be urged to participate. The rate of relapse is fairly constant over time, even in patients who have achieved complete responses to treatment. Indeed, relapse may occur many years after treatment. In this category, deferred treatment (i.e., watchful waiting until the patient becomes symptomatic before initiating treatment) should be given consideration.[1-3] Three randomized trials compared watchful waiting to immediate chemotherapy. All three trials showed no difference in cause-specific or overall survival (OS). For patients randomly assigned to watchful waiting, the median time to require therapy was 2 to 3 years and one-third of patients never required treatment with watchful waiting (half died of other causes and half remained progression-free after 10 y).[2,4];[5][Level of evidence: 1iiA] The PRIMA trial compared watchful waiting to immediate rituximab, the anti-CD20 monoclonal antibody, with or without maintenance doses. Numerous prospective clinical trials of interferon-alpha, including SWOG-8809, have shown no consistent benefit; the role of interferon in patients with indolent lymphoma remains controversial.[6-17]

Standard therapy includes rituximab, an anti-CD20 monoclonal antibody, either alone or in combination with purine nucleoside analogs such as fludarabine or 2-chlorodeoxyadenosine, oral alkylating agents (with or without steroids), or combination chemotherapy. However, none of these therapies are curative for advanced-stage disease, but innovative approaches are under clinical evaluation. The approaches include intensive therapy with chemotherapy and total-body irradiation (TBI) followed by autologous or allogeneic bone marrow transplantation (BMT) or peripheral stem cell transplantation, and the use of idiotype vaccines and radiolabeled monoclonal antibodies. Currently, no randomized trials guide clinicians about the initial choice of watchful waiting, rituximab, nucleoside analogs, alkylating agents, combination chemotherapy, radiolabeled monoclonal antibodies, or combinations of these options.[18];[3] [Level of evidence: 1iiDiii]

Four randomized, prospective studies of previously untreated patients (involving more than 1,300 patients) and one Cochrane meta-analysis including both untreated and previously treated patients (involving almost 1,000 patients) have compared rituximab plus combination chemotherapy with chemotherapy alone. Rituximab plus chemotherapy was superior in terms of event-free or progression-free survival (ranging from 2–3 years) in all of the studies and in terms of OS in all but one study (absolute benefit ranging from 6%–13% at 4 years, P < .04 and hazard ratio [HR], 0.63 [0.51–0.79] for the meta-analysis).[19-22];[23][Level of evidence: 1iiA] All of these trials were performed in symptomatic patients who required therapy. These results do not negate watchful waiting when appropriate.

In three randomized, prospective studies involving previously treated patients with relapsed indolent lymphoma, patients were randomly assigned to rituximab maintenance after retreatment with combination chemotherapy (with or without rituximab during induction) or observation alone; all trials showed prolongation of response duration,[24-26] and one trial demonstrated improvement in median progression-free survival (3.7 years vs. 1.3 years, P < .001) and overall survival (OS) (74% vs. 64%, P = .07) at 5 years with a median follow-up of 39 months favoring maintenance rituximab.[25][Level of evidence: 1iiDiii]

In the PRIMA study, 1,019 previously untreated high-risk patients who required treatment achieved complete or partial response after induction therapy with immunochemotherapy (usually R-CHOP) and were then randomly assigned to 2 years of maintenance rituximab versus no maintenance.[27] With a median follow-up of 36 months, progression-free survival favored rituximab maintenance 74.9% to 57.6% (HR, 0.56; 95% confidence interval, 0.44–0.68, P< .0001), but with no difference in overall survival.[27][Level of evidence: 1iiDiii]

Many questions remain about rituximab maintenance, particularly about truncating therapy at 2 years and long-term safety and efficacy. The most salient question is whether a strategy of observation after induction with rituximab therapy at time of symptomatic progression is equivalent or superior to mandated rituximab maintenance.[28]

Standard treatment options:

1. For asymptomatic patients, deferred therapy with careful observation.[2,29]

2. Rituximab may be considered as first-line therapy.
   • Rituximab alone, as shown in the ECOG-E4402 (NCT00075946) trial, for example.[30-34]
   • R-F: rituximab plus fludarabine.[35]
   • R-CVP: rituximab plus cyclophosphamide plus vincristine plus prednisone.[21,36]
   • R-CHOP: rituximab plus cyclophosphamide plus doxorubicin plus vincristine plus prednisone.[20,37,38]
   • R-FM: rituximab plus fludarabine plus mitoxantrone.[39]
   • R-FCM: rituximab plus fludarabine plus cyclophosphamide plus mitoxantrone.[40]

3. Purine nucleoside analog:
   • Fludarabine.[18,41,42]
   • 2-chlorodeoxyadenosine.[43,44]

4. Oral alkylating agents (with or without steroids):
   • Cyclophosphamide.[45]
   • Chlorambucil.
   • Bendamustine.[46]

5. Combination chemotherapy alone:
   • CVP: cyclophosphamide plus vincristine plus prednisone.[18,47]
   • CVP followed by rituximab maintenance.[48]
   • C-MOPP: cyclophosphamide plus vincristine plus procarbazine plus prednisone.[49,50]
   • CHOP: cyclophosphamide plus doxorubicin plus vincristine plus prednisone.[45,51]
   • FND: fludarabine plus mitoxantrone plus or minus dexamethasone, as evidenced in the SWOG-9501 trial, for example.[52,53]

6. Yttrium-90-labeled ibritumomab tiuxetan and iodine-131-labeled tositumomab are available for previously untreated and relapsing patients with minimal (<25%) or no marrow involvement with lymphoma, as was shown in the SWOG-9911 trial, for example.[54,55] Randomized prospective studies are required to determine the optimal utilization of this modality.[56]

7. Intensive therapy with chemotherapy with or without TBI or high-dose radioimmunotherapy followed by autologous or allogeneic BMT or peripheral stem cell transplantation is under clinical evaluation.[57-67]

8. Phase III trials comparing chemotherapy alone versus chemotherapy followed by anti-idiotype vaccine.[68-70]

9. Extended-field radiation therapy (noncontiguous stage II and stage III patients).[71-73]

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with indolent, noncontiguous stage II adult non-Hodgkin lymphoma, indolent, stage III adult non-Hodgkin lymphoma and indolent, stage IV adult non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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