Adult Non-Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version
Treatment for Indolent Stage I and Indolent, Contiguous Stage II Adult NHL
Although localized presentations are uncommon in non-Hodgkin lymphoma (NHL), the goal of treatment is to cure the disease in patients who are shown to have truly localized occurrence after undergoing appropriate staging procedures.
Standard Treatment Options for Indolent Stage I and Indolent, Contiguous Stage II Adult NHL
Standard treatment options for indolent stage I and indolent, contiguous stage II adult NHL include the following:
In a prospective randomized trial, 150 patients with stage I or stage II follicular lymphoma were randomly assigned to 30 Gy of involved-field radiation therapy alone or radiation therapy plus six cycles of R-CVP (rituximab, cyclophosphamide, vincristine, prednisolone). With a median follow-up of 9.6 years, the 10-year progression-free survival favored combined modality therapy 59% (95% confidence interval (CI), 46%–74%) versus 41% (95% CI, 30%–57%) (P = .033), but with no difference in overall survival (OS) (87% and 95%, P = .40).[Level of evidence: 1iiDiii]
The National Lymphocare Study identified 471 patients with stage I follicular lymphoma. Of those patients, 206 were rigorously staged with a bone marrow aspirate and biopsy, and computed tomography (CT) scans or positron emission tomography (PET)-CT scans. Nonrandomized treatments included radiation therapy (27%), rituximab-chemotherapy (R-chemotherapy) (28%), watchful waiting (17%), R-chemotherapy plus radiation therapy (13%), and rituximab alone (12%), although more than one-third of the patients started with expectant therapy. With a median follow-up of 57 months, PFS favored R-chemotherapy or R-chemotherapy plus radiation therapy, but OS was nearly identical, all over 90%.[Level of evidence: 3iiiD] Clinical trials are required to answer questions such as:
If the PET-CT scan is clear after excisional biopsy, is watchful waiting or radiation therapy preferred?
Should rituximab be added to radiation therapy for stage I follicular lymphoma?
Is there any role for R-chemotherapy plus radiation therapy?
Long-term disease control within radiation fields can be achieved in a significant number of patients with indolent stage I or stage II NHL by using dosages of radiation that usually range from 25 Gy to 40 Gy to involved sites or to extended fields that cover adjacent nodal sites.[1,4-6] Almost half of all patients treated with radiation therapy alone will relapse out-of-field within 10 years.[1,6,7] Very low-dose radiation therapy with 4 Gy (2 Gy × 2 fractions) can result in 50% remission rates for patients who cannot tolerate higher doses. In situations in which mediastinal radiation would encompass the left side of the heart or would increase breast cancer risk in young female patients, proton therapy may be considered to reduce the radiation dose to organs at risk.
Rituximab with or without chemotherapy
For symptomatic patients who require therapy, when radiation therapy is contraindicated or when an alternative treatment is preferred, rituximab with or without chemotherapy can be employed (as outlined below for more advanced-stage patients). The value of adjuvant treatment with radiation to decrease relapse, plus rituximab (an anti–CD20 monoclonal antibody) either alone or in combination with chemotherapy, has been extrapolated from trials of patients with advanced-stage disease and has not been confirmed.[10,11]
Watchful waiting can be considered for asymptomatic patients. Watchful waiting has never been compared with upfront radiation therapy in a prospective randomized trial; a retrospective analysis of the Surveillance, Epidemiology and End Results Program (SEER) database over 30 years showed improved outcomes for upfront radiation therapy.
Other therapies as designated for patients with advanced-stage disease
Patients with involvement that is not able to be encompassed by radiation therapy are treated as outlined for patients with stage III or stage IV low-grade lymphoma.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
MacManus M, Fisher R, Roos D, et al.: Randomized Trial of Systemic Therapy After Involved-Field Radiotherapy in Patients With Early-Stage Follicular Lymphoma: TROG 99.03. J Clin Oncol 36 (29): 2918-2925, 2018. [PUBMED Abstract]
Friedberg JW, Byrtek M, Link BK, et al.: Effectiveness of first-line management strategies for stage I follicular lymphoma: analysis of the National LymphoCare Study. J Clin Oncol 30 (27): 3368-75, 2012. [PUBMED Abstract]
Montoto S: Management of localized-stage follicular lymphoma: changing the paradigm? J Clin Oncol 30 (27): 3328-9, 2012. [PUBMED Abstract]
Haas RL, Poortmans P, de Jong D, et al.: High response rates and lasting remissions after low-dose involved field radiotherapy in indolent lymphomas. J Clin Oncol 21 (13): 2474-80, 2003. [PUBMED Abstract]
Guckenberger M, Alexandrow N, Flentje M: Radiotherapy alone for stage I-III low grade follicular lymphoma: long-term outcome and comparison of extended field and total nodal irradiation. Radiat Oncol 7: 103, 2012. [PUBMED Abstract]
Brady JL, Binkley MS, Hajj C, et al.: Definitive radiotherapy for localized follicular lymphoma staged by 18F-FDG PET-CT: a collaborative study by ILROG. Blood 133 (3): 237-245, 2019. [PUBMED Abstract]
Guadagnolo BA, Li S, Neuberg D, et al.: Long-term outcome and mortality trends in early-stage, Grade 1-2 follicular lymphoma treated with radiation therapy. Int J Radiat Oncol Biol Phys 64 (3): 928-34, 2006. [PUBMED Abstract]
Hoskin PJ, Kirkwood AA, Popova B, et al.: 4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial. Lancet Oncol 15 (4): 457-63, 2014. [PUBMED Abstract]
Dabaja BS, Hoppe BS, Plastaras JP, et al.: Proton therapy for adults with mediastinal lymphomas: the International Lymphoma Radiation Oncology Group guidelines. Blood 132 (16): 1635-1646, 2018. [PUBMED Abstract]
Kelsey SM, Newland AC, Hudson GV, et al.: A British National Lymphoma Investigation randomised trial of single agent chlorambucil plus radiotherapy versus radiotherapy alone in low grade, localised non-Hodgkins lymphoma. Med Oncol 11 (1): 19-25, 1994. [PUBMED Abstract]
Seymour JF, Pro B, Fuller LM, et al.: Long-term follow-up of a prospective study of combined modality therapy for stage I-II indolent non-Hodgkin's lymphoma. J Clin Oncol 21 (11): 2115-22, 2003. [PUBMED Abstract]
Advani R, Rosenberg SA, Horning SJ: Stage I and II follicular non-Hodgkin's lymphoma: long-term follow-up of no initial therapy. J Clin Oncol 22 (8): 1454-9, 2004. [PUBMED Abstract]
Pugh TJ, Ballonoff A, Newman F, et al.: Improved survival in patients with early stage low-grade follicular lymphoma treated with radiation: a Surveillance, Epidemiology, and End Results database analysis. Cancer 116 (16): 3843-51, 2010. [PUBMED Abstract]
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 are 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 provide guidance to 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 NHL, 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:
The rate of relapse is fairly constant over time, even in patients who have achieved complete responses (CR) 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) can be considered.[2,5-7] The Follicular Lymphoma International Prognostic Index (FLIPI) and the revised FLIPI-2 can predict progression-free survival (PFS) and overall survival (OS), but the scores cannot be used to establish the need for therapy in asymptomatic patients.[8,9]
All three trials showed no difference in cause-specific or OS.
For patients randomly assigned to watchful waiting, the median time to require therapy was 2 to 3 years and one-third of patients receiving watchful waiting 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 with or without chemotherapy
Standard therapy includes rituximab, an anti–CD20 monoclonal antibody, either alone, as was shown in the ECOG-E4402 (NCT00075946) trial,[13-17] or in combination with purine nucleoside analogs, such as fludarabine or 2-chlorodeoxyadenosine, alkylating agents (with or without steroids), or combination chemotherapy. Rituximab may be considered as first-line therapy, either alone or in combination with other agents. Rituximab may be given intravenously or subcutaneously, and biosimilar versions, such as CT-P10 and GP2013, have shown equivalent efficacy and safety.[18-20] Combinations include the following:
R-CHOP: rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone.[27-31] A Cochrane meta-analysis could not identify any OS benefit of adding doxorubicin to chemotherapy regimens with rituximab or to chemotherapy regimens without rituximab.[Level of evidence: 1iiA]
Evidence (rituximab with or without 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 84 months, there was no difference in OS (8-year OS, 83%; 95% confidence interval (CI), 79%–87%), but the 8-year PFS favored R-CHOP (52%) and R-FM (49%) over R-CVP (42%) (P for the three regimens = .037).[Level of evidence: 1iiDiii]
Four randomized prospective studies of previously untreated patients (involving more than 1,300 patients) and one Cochrane meta-analysis that included both untreated and previously treated patients (involving almost 1,000 patients) have compared rituximab plus combination chemotherapy with chemotherapy alone.[26,31,35]; [36,37][Level of evidence: 1iiA]
Rituximab plus chemotherapy was superior in terms of event-free survival (EFS) or 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.
Fluorine F 18-fludeoxyglucose positron emission tomography–computed tomography (18F-FDG PET-CT) scan status at the completion of rituximab plus chemotherapy induction therapy is strongly predictive of outcome. It is not yet known whether acting on the results of the scans translates into better outcomes.[38,39]
In a prospective randomized trial, NCT00991211, 527 patients with indolent and mantle cell lymphoma were randomly assigned to a bendamustine-and-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% 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.
In a similar prospective randomized trial, 447 patients with indolent and mantle cell lymphoma were assigned to bendamustine and rituximab versus R-CHOP or R-CVP.[Level of evidence: 1iiDiii]
With a median follow-up of 65 months, the 5-year PFS favored bendamustine and rituximab, 65.5% versus 55.8% (HR, 0.61; 95% CI, 0.45–0.85; P = .0025), but with no difference in OS.
Increased deaths in the bendamustine-and-rituximab arm from cardiovascular causes (seven versus one) and from secondary malignancies other than lymphoma (five versus three) may have contributed to the lack of OS advantage.
After induction therapy with rituximab only or with rituximab plus chemotherapy, rituximab can be used once every 2 to 3 months. Several studies have evaluated this approach.
Evidence (maintenance rituximab for previously untreated patients):
In the PRIMA (NCT00140582) study, 1,019 high-risk, previously untreated, symptomatic patients achieved CR or partial response (PR) 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% CI, 0.44–0.68; P < .0001) but with no difference in OS.
In the United Kingdom/International Study (NCT00112931), 379 previously untreated patients with asymptomatic, low-burden disease were randomly assigned to watchful waiting versus rituximab induction only versus rituximab induction followed by 2 years of rituximab maintenance.[Level of evidence: 1iiC]
Although OS and histologic transformation rates were no different at 3 years, maintenance rituximab was favored based on quality-of-life (QOL) studies (Mental Adjustment to Cancer Scale P = .0004 at 7 months; Illness Coping Score P = .0012 at 7 months) and time-to-initiation of new treatment by 3 years (54% for watchful waiting vs. 12% for rituximab maintenance [HR, 0.21; 95% CI, 0.14–0.31; P < .0001]).[Level of evidence: 1iiC]
This study suggested that for some patients, watch and wait resulted in watch and worry. However, from the perspective of OS and histologic transformation rates, no benefit could be seen with rituximab maintenance.
In the RESORT (NCT00075946) study, 289 previously untreated patients with asymptomatic, low-burden disease were randomly assigned to rituximab induction alone, with a re-treatment strategy that used rituximab at relapse, or rituximab induction plus maintenance rituximab every 13 weeks until treatment failure.[Level of evidence: 1iiC]
With a median follow-up of 4.5 years, there was no difference in median time-to-treatment failure (defined as failing rituximab alone) or in health-related QOL. A re-treatment strategy achieved comparable disease control using significantly fewer doses of rituximab.
These three randomized trials in previously untreated patients show no advantage for the use of rituximab maintenance versus observation and reinduction of therapy at the time of relapse. The trials suggest a benefit for maintenance rituximab after reinduction for relapsed disease. Many questions remain about rituximab maintenance, particularly about truncating therapy at 2 years and long-term safety and efficacy. A trial extending rituximab maintenance to 5 years showed similar EFS or OS versus 1 year of maintenance after induction therapy with rituximab in previously untreated patients.[Level of evidence: 1iiA]
In a trial that studied the use of induction without rituximab (cyclophosphamide, vincristine, prednisone), 387 patients were randomly assigned to receive 2 years of rituximab maintenance.[Level of evidence: 1iiDiii]
With a median follow-up of 11.5 years, there was improved PFS with maintenance (4.8 years vs. 1.3 years; HR, 0.49; P < .0001) but no difference in OS (10-year OS, 59%–67%).
For previously untreated patients, all of the studies showed improvement of PFS, with no change in OS.
Evidence (maintenance rituximab for previously treated patients):
In a prospective randomized trial of 465 patients with relapsed follicular lymphoma, responders to R-CHOP or CHOP were further randomly assigned to receive rituximab maintenance (1 dose every 3 months for 2 years) or no maintenance.[Level of evidence: 1iiDiii]
At a median follow-up of 6 years, 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 postprotocol salvage treatment.
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 receive 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 nine randomized clinical trials with a total of 2,586 patients with follicular lymphoma, most of whom had relapsed disease, compared rituximab maintenance with no maintenance and showed improved OS for rituximab maintenance in previously treated patients (HRdeath, 0.72; 95% CI, 0.57–0.91).[Level of evidence: 1iiA]
For previously treated patients, there is more evidence to suggest an OS advantage with the use of rituximab maintenance.
Obinutuzumab is a glycoengineered type II anti–CD20 monoclonal antibody with greater antibody-dependent cellular cytotoxicity than rituximab.
A prospective randomized trial (NCT01332968) of 1,202 patients with previously untreated follicular lymphoma compared obinutuzumab combined with bendamustine (50%), cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (33%), or cyclophosphamide, vincristine, and prednisone (CVP) (10%) with rituximab combined with the same chemotherapy regimens (based on investigator choice). After six cycles of combination therapy, patients had 2 years of maintenance therapy, receiving the same antibody every 2 months.
With a median follow-up of 34.5 months, the PFS rate (80%) at 3 years favored the obinutuzumab group versus the PFS rate (73.3%) at 3 years for the rituximab group (HR, 0.66; 95% CI, 0.51–0.85, P = .001).[Level of evidence: 1iiDiii]
There was no difference in OS.
There was a high rate of toxic deaths among patients using bendamustine in the obinutuzumab arm (5.6%) and in the rituximab arm (4.4%) compared with what has been seen historically. For patients with indolent low-grade lymphoma, with median survivals exceeding 15 years, the number of toxic deaths during first-line therapy seems excessive. By comparison, the toxic death rate was 1% to 2% when either antibody was combined with CHOP or CVP.
Several issues have been raised about this study:
The side effects were significantly higher with obinutuzumab in terms of infusion reactions and subsequent adverse events.
Obinutuzumab costs significantly more than rituximab.
In summary, in the absence of any change in OS, switching from rituximab to obinutuzumab in combination with chemotherapy for previously untreated follicular lymphoma is a difficult choice. The PFS differences may be attributable to the imbalance in monoclonal antibody dosing, and the increased side effects and costs are mitigating factors. In this trial, bendamustine combined with either antibody led to unacceptable rates of toxic death.
A phase II study included 142 patients with relapsed and refractory indolent lymphoma.
Treatment with copanlisib resulted in a 59% objective response rate (12% CR), with a median duration of response of 22.6 months.[Level of evidence: 3iiiDiv]
A phase II study included 125 patients with relapsed and refractory indolent lymphoma.
Treatment with idelalisib resulted in a 57% objective response rate (6% CR), with a median duration of response of 12.5 months.[Level of evidence: 3iiiDiv]
In a follow-up analysis of only patients with follicular lymphoma histology with early relapse within 1 year of chemoimmunotherapy, the response rates were equivalent.[Level of evidence: 3iiiDiv]
A phase II study included 129 patients with relapsed and refractory indolent lymphoma.
Treatment with duvelisib resulted in a 46% objective response rate with a median duration of response of 9.9 months.[Level of evidence: 3iiiDiv]
The PI3K inhibitors have significant adverse effects including pneumonitis, colitis, transaminitis, hypertension, hyperglycemia, rash, and increased risk of infections. These adverse events have affected the use of these agents upfront until confirmatory trials can establish their added efficacy in combinations. They are currently approved for treatment of relapsed and refractory follicular lymphoma after two previously received lines of therapy.
Lenalidomide and rituximab
The combination of the immunomodulating agent lenalidomide with rituximab (the so-called R2 regimen) has been proposed as an alternative regimen to combinations involving cytotoxic agents and their subsequent short- and long-term toxicities.
Evidence (lenalidomide and rituximab):
In a randomized prospective trial of 1,030 patients with previously untreated follicular lymphoma, rituximab plus lenalidomide for 18 months was compared with rituximab plus chemotherapy (usually R-CHOP). All patients received rituximab maintenance for up to 2 years.
With a median follow-up of almost 3 years, the 3-year PFS (77%–78%) and 3-year OS (94%) were identical (HR, 0.94 [0.73–1.22]; P = .63 and HR, 1.16 [0.72–1.86], respectively).[Level of evidence: 1iiA]
This trial established that the R2 regimen is equally efficacious to rituximab plus cytotoxic chemotherapy options; analysis of long-term toxicities must await longer follow-up.
In a randomized prospective trial of 358 patients with resistant/refractory indolent lymphoma (usually follicular lymphoma), rituximab plus lenalidomide (R2 regimen) was compared with rituximab alone.
With a median follow-up of 28 months, the median PFS was 39.4 months for R2and 14.1 months for rituximab alone (P < .0001), with no difference in OS.[Level of evidence: 1iiDiii]
Radiolabeled anti-CD20 monoclonal antibodies
Yttrium Y 90 (90Y)-ibritumomab tiuxetan (Zevalin) is available for previously untreated and relapsing patients with minimal (<25%) or no marrow involvement with lymphoma (iodine I 131 [131I]-tositumomab (Bexxar) is no longer available because of commercial disengagement).[55,56]
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 131I-tositumomab radioimmunotherapy (RIT).
With a median follow-up of 10.3 years, there was improvement in PFS for RIT (56% vs. 42%, P = .01) but no significant difference in 10-year OS (OS R-CHOP, 81%; CHOP-RIT, 75%; P = 0.13).[Level of evidence: 1iiDiii]
In this trial, the cumulative incidence of death from myelodysplastic syndrome or acute myeloid leukemia is higher for the RIT arm (4% vs. 1%, P = .02).
131I-tositumomab became commercially unavailable in 2013.
In a randomized trial of 409 patients with stage III or IV follicular lymphoma who achieved a CR or PR, 90Y-ibritumomab tiuxetan consolidation versus no consolidation was evaluated.
The radiolabeled 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]
Durable responses to radiolabeled monoclonal antibodies, such as 90Y-ibritumomab tiuxetan (commercially available) and iodine I 131-tositumomab (commercially unavailable), have also been reported before and after cytotoxic chemotherapy.[57,59,60][Level of evidence: 1iiDiii] However, the cumulative incidence of death resulting from myelodysplastic syndrome or acute myeloid leukemia is higher (4% vs. 1%; P+/02) in one of the randomized trials versus nonradiolabeled antibody with chemotherapy.
Treatment Options Under Clinical Evaluation for Indolent, Noncontiguous Stage II/III/IV Adult NHL
Because 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 (SCT), 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 peripheral SCT is under clinical evaluation.[61-70]
Phase III trials comparing chemotherapy alone versus chemotherapy followed by anti-idiotype vaccine.[71-73]
Extended-field radiation therapy (stage III patients only).
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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