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. For patients randomized 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 years).[2,4,5][Level of evidence: 1iiA] An ongoing international study, known as the PRIMA trial, is comparing watchful waiting to immediate rituximab, the anti-CD20 monoclonal antibody, with or without maintenance doses. Numerous prospective clinical trials, including SWOG-8809, of interferon-alpha 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. Since none of these therapies are curative for advanced-stage disease, 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.[3,18] [Level of evidence: 1iiDiii]

However, 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 to 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 = 0.63 [0.51–0.79] for the meta-analysis).[19-23][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 a prospective randomized trial of 465 patients with relapsed follicular lymphoma, responders to R-CHOP or CHOP were further randomly assigned to rituximab maintenance (one dose every 3 months for 2 years) or no maintenance. With 39 months' median follow-up, rituximab maintenance was better by median progression-free survival (52 months vs. 15 months, P < .0001) and by 3-year OS (85% vs. 77%, P = .011).[24] This benefit for maintenance was evident even for patients who received rituximab during induction therapy.

For patients with indolent, noncontiguous stage II and stage III lymphoma, central lymphatic radiation therapy has been proposed but is not usually recommended as a form of treatment.[25,26]

Standard treatment options:

1. For asymptomatic patients, deferred therapy with careful observation.[2,27]



2. Rituximab may be considered as first-line therapy.
   • Rituximab alone.[28-32]
   • R-F: rituximab plus fludarabine.[33]
   • R-CVP: rituximab plus cyclophosphamide plus vincristine plus prednisone.[21,34]
   • R-CHOP: rituximab plus cyclophosphamide plus doxorubicin plus vincristine plus prednisone.[20,35,36]
   • R-FM: rituximab plus fludarabine plus mitoxantrone.[37]
   • R-FCM: rituximab plus fludarabine plus cyclophosphamide plus mitoxantrone.[38]



3. Purine nucleoside analog:
   • Fludarabine.[18,39,40]
   • 2-chlorodeoxyadenosine.[41,42]



4. Oral alkylating agents (with or without steroids):
   • Cyclophosphamide.[43]
   • Chlorambucil.



5. Combination chemotherapy alone:
   • CVP: cyclophosphamide plus vincristine plus prednisone.[18,44]
   • C-MOPP: cyclophosphamide plus vincristine plus procarbazine plus prednisone.[45,46]
   • CHOP: cyclophosphamide plus doxorubicin plus vincristine plus prednisone.[43,47]
   • FND: fludarabine plus mitoxantrone plus or minus dexamethasone, as evidenced in the SWOG-9501 trial, for example.[48,49]



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 evidenced in the SWOG S-9911 trial, for example.[50,51] Randomized prospective studies are required to determine the optimal utilization of this modality.



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.[52-61]



8. Phase III trials comparing chemotherapy alone versus chemotherapy followed by anti-idiotype vaccine.[62-64]



9. Extended-field radiation therapy (stage III patients only).[65]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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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