Treatment for Indolent, Noncontiguous Stage II/III/IV Adult NHL
Optimal treatment of advanced stages of low-grade non-Hodgkin lymphoma (NHL) 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 response to treatment. Indeed, relapse may occur many years after treatment. 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.; [Level of evidence: 1iiDiii]
For patients with indolent, noncontiguous stage II and stage III non-Hodgkin lymphoma, central lymphatic radiation therapy has been proposed but is not usually recommended as a form of treatment.[3,4]
Standard Treatment Options for Indolent, Noncontiguous Stage II/III/IV Adult NHL
Standard treatment options for indolent, noncontiguous stage II/III/IV adult NHL include the following:
Watchful waiting for asymptomatic patients
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 considered.[2,17-19]
Evidence (watchful waiting):
- Three randomized trials compared watchful waiting with immediate chemotherapy.[18,20]; [Level of evidence: 1iiA]
- 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 years).
- A selected group of 107 patients with advanced stage follicular lymphoma were managed with initial watchful waiting; with a median delay of 55 months, subsequent therapy resulted in equivalent freedom from treatment failure and OS compared with a similar cohort treated immediately with rituximab.[Level of evidence: 3iiiDiii] This implies that watchful waiting remains a relevant approach even in the rituximab era.
Rituximab may be considered as first-line therapy, either alone or in combination with other agents.
- Rituximab alone, as was shown in the ECOG-E4402 (NCT00075946) trial, for example.[23-27]
- R-Bendamustine: rituximab + bendamustine.[28,29]
- R-F: rituximab + fludarabine.
- R-CVP: rituximab + cyclophosphamide + vincristine + prednisone.[31,32]
- R-CHOP: rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone.[33-35] A Cochrane meta-analysis could not identify any OS benefit to adding doxorubicin to chemotherapy regimens with rituximab or to chemotherapy regimens without rituximab.[Level of evidence: 1iiA]
- R-FM: rituximab + fludarabine + mitoxantrone.
- R-FCM: rituximab + fludarabine + cyclophosphamide + mitoxantrone.
Standard therapy includes rituximab, an anti-CD20 monoclonal antibody, either alone or in combination with purine nucleoside analogs such as fludarabine or 2-chlorodeoxyadenosine, alkylating agents (with or without steroids), or combination chemotherapy.
A prospective, randomized trial of 534 patients with previously untreated, advanced-stage follicular lymphoma compared R-CHOP, R-FM, and R-CVP. With a median follow-up of 34 months, there was no difference in OS, but the 3-year PFS favored R-CHOP (68%) and R-FM (63%) over R-CVP (52%) (P for the three regimens = .011).[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.[32,35,40]; [41,42][Level of evidence: 1iiA]
- Rituximab plus chemotherapy was superior in terms of event-free survival or progression-free survival (PFS) (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).
- All of these trials were performed in symptomatic patients who required therapy. These results do not negate watchful waiting when appropriate.
- FDG-PET-CT (fluorine-18-fluorodeoxyglucose–positron-emission tomography–computed tomography) scan status at the completion of rituximab plus chemotherapy induction therapy is strongly predictive of outcome. It is not yet known if acting on the results of the scans translates into better outcomes.[43,44]
Obinutuzumab is an alternative CD20-binding monoclonal antibody with alternative epitope binding and is being studied in patients with recurrent follicular lymphoma. This agent has shown responses in 20% to 30% of patients when used alone and in 80% of patients when combined with CHOP or FC (fludarabine and cyclophosphamide) in relapsed follicular lymphoma patients.[45,46][Level of evidence: 3iiiDiv]
Purine nucleoside analogs
Alkylating agents (with or without steroids)
- Cyclophosphamide (oral or intravenous).
- Chlorambucil (oral).
- In a prospective randomized trial NCT00991211, 527 patients with indolent and mantle cell lymphoma were randomly assigned to a bendamustine-plus-rituximab arm versus an R-CHOP arm.[Level of evidence: 1iiDiii]
- With a median follow-up of 45 months, the median PFS favored the bendamustine arm (69 months vs. 31 months [HR, 0.58; 95 % confidence intervaI (CI), 0.44–0.74; P < .0001]) but with no difference in OS.
- The bendamustine arm was associated with significantly lower rates of alopecia, hematologic toxicity, stomatitis, peripheral neuropathy, and infections than was the R-CHOP arm.
- CVP: cyclophosphamide + vincristine + prednisone.[1,52]
- CVP followed by rituximab maintenance.
- C-MOPP: cyclophosphamide + vincristine + procarbazine + prednisone.[54,55]
- CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone.[51,56] A Cochrane meta-analysis could not identify any OS benefit to adding doxorubicin to chemotherapy regimens with rituximab or to chemotherapy regimens without rituximab.[Level of evidence: 1iiA]
- FND: fludarabine + mitoxantrone +/- dexamethasone, as evidenced in the SWOG-9501 trial, for example.[57,58]
Yttrium-90–labeled ibritumomab tiuxetan
Yttrium-90–labeled ibritumomab tiuxetan is available for previously untreated and relapsing patients with minimal (<25%) or no marrow involvement with lymphoma (iodine-131–labeled tositumomab is no longer available because of commercial disengagement).[59-61] In a randomized, prospective trial, 554 patients with previously untreated advanced-stage follicular lymphoma received either R-CHOP times six cycles or CHOP times six cycles followed by I-131 tositumomab radioimmunotherapy (RIT); with a median follow-up of 4.9 years, there was no significant difference between the PFS and OS (2-year OS, R-CHOP, 97%; CHOP-RIT, 93%; P = .08).[Level of evidence: 1iiD] Because a significant prolongation of PFS was seen for R-CHOP followed by rituximab maintenance compared with R-CHOP alone, this lack of benefit for CHOP-RIT was particularly disappointing. Iodine-131–labeled tositumomab became commercially unavailable in 2013.
In a randomized trial of 409 patients with stage III or IV follicular lymphoma who achieved a complete or partial response, yttrium-90 ibritumomab tiuxetan consolidation versus no consolidation was evaluated. The radiolabelled antibody consolidation improved median PFS by 3 years (P < .001), and median time to next treatment was improved by 5.1 years (P < .001); however, there was no change in OS.[Level of evidence: 1iiDiii]
Evidence (maintenance rituximab):
- 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.[Level of evidence: 1iiDiii]
- At 6 years' median follow-up, rituximab maintenance was better for median PFS (44 months vs. 16 months, P < .001) and borderline for 5-year OS (74% vs. 64%, P = .07).
- This benefit for maintenance was evident even for patients who received rituximab during induction therapy. Most patients in both arms received extensive rituximab during post-protocol salvage treatment.
- In the PRIMA (NCT00140582) study, 1,019 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.[Level of evidence: 1iiDiii]
- With a median follow-up of 36 months, PFS favored rituximab maintenance 74.9% to 57.6% (HR, 0.56; 95% confidence interval [CI], 0.44–0.68; P <.0001) but with no difference in OS.
- In a prospective, randomized trial of 280 patients with relapsed follicular lymphoma, responders to chemotherapy and autologous stem cell transplantation consolidation were randomly assigned to four doses of rituximab maintenance or no maintenance.[Level of evidence: 1iiDiii]
- With an 8.3 year median follow-up, the 10-year PFS favored maintenance (54% vs. 37% [HR, 0.66; 95%CI, 0.47–0.91, P = .012]), but there was no difference in OS.
- A meta-analysis of 2,586 patients with follicular lymphoma in nine randomized clinical trials that compared rituximab maintenance with no maintenance showed improved OS for rituximab maintenance in previously treated patients (HRdeath, 0.72; 95% CI, 0.57–0.91).[Level of evidence: 1iiA]
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.
Treatment Options Under Clinical Evaluation for Indolent, Noncontiguous Stage II/III/IV Adult NHL
Since none of the standard therapies listed above 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 (PSCT), and the use of idiotype vaccines and radiolabeled monoclonal antibodies.
- Intensive therapy with chemotherapy with or without TBI or high-dose radioimmunotherapy followed by autologous or allogeneic BMT or PSCT is under clinical evaluation.[69-78]
- Phase III trials comparing chemotherapy alone versus chemotherapy followed by anti-idiotype vaccine.[79-81]
- Extended-field radiation therapy (stage III patients only).
- Ofatumumab—human anti-CD20 monoclonal antibody.
- Short-course low-dose, palliative radiation therapy (2 × 2 Gy).[84,85]
Current Clinical Trials
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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