Adult Non-Hodgkin Lymphoma Treatment (PDQ®) 3/3 —Health Professional Version - National Cancer Institute

Adult Non-Hodgkin Lymphoma Treatment (PDQ®)—Health Professional Version - National Cancer Institute

Treatment for Indolent Stage I and Indolent, Contiguous Stage II Adult NHL

In This Section

• Standard Treatment Options for Indolent Stage I and Indolent, Contiguous Stage II Adult NHL
  • Radiation therapy
  • Rituximab with or without chemotherapy
  • Watchful waiting
  • Other therapies as designated for patients with advanced-stage disease
• Current Clinical Trials

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:

1. Radiation therapy.
2. Rituximab with or without chemotherapy.
3. Watchful waiting.
4. Other therapies as designated for patients with advanced-stage disease.

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).[1][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.[2] 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%.[2][Level of evidence: 3iiiD] Clinical trials are required to answer questions such as:[3]

• 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?

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.[1,4-8] Almost half of all patients treated with radiation therapy alone will relapse out-of-field within 10 years.[1,9] 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.[10] 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.[11]

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.[12,13]

Watchful waiting

Watchful waiting can be considered for asymptomatic patients.[14] 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.[15]

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.

References

1. 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]
2. 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]
3. Montoto S: Management of localized-stage follicular lymphoma: changing the paradigm? J Clin Oncol 30 (27): 3328-9, 2012. [PUBMED Abstract]
4. Mac Manus MP, Hoppe RT: Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University. J Clin Oncol 14 (4): 1282-90, 1996. [PUBMED Abstract]
5. Vaughan Hudson B, Vaughan Hudson G, MacLennan KA, et al.: Clinical stage 1 non-Hodgkin's lymphoma: long-term follow-up of patients treated by the British National Lymphoma Investigation with radiotherapy alone as initial therapy. Br J Cancer 69 (6): 1088-93, 1994. [PUBMED Abstract]
6. Denham JW, Denham E, Dear KB, et al.: The follicular non-Hodgkin's lymphomas--I. The possibility of cure. Eur J Cancer 32A (3): 470-9, 1996. [PUBMED Abstract]
7. 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]
8. 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]
9. 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]
10. 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]
11. 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]
12. 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]
13. 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]
14. 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]
15. 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

In This Section

• Standard Treatment Options for Indolent, Noncontiguous Stage II/III/IV Adult NHL
  • Watchful waiting for asymptomatic patients
  • Rituximab with or without chemotherapy
  • Maintenance rituximab
  • Obinutuzumab
  • P13K inhibitors
  • Lenalidomide and rituximab
  • Radiolabeled anti-CD20 monoclonal antibodies
• Treatment Options Under Clinical Evaluation for Indolent, Noncontiguous Stage II/III/IV Adult NHL
• Current Clinical Trials

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.[1]; [2][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:

1. Watchful waiting for asymptomatic patients.
2. Rituximab with or without chemotherapy.
3. Maintenance rituximab.
4. Obinutuzumab.
5. Phosphatidylinositol 3-kinase (P13K) inhibitors.
6. Lenalidomide and rituximab.
7. Radiolabeled anti-CD20 monoclonal antibodies.

Watchful waiting for asymptomatic patients

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]

Evidence (watchful waiting):

1. Three randomized trials compared watchful waiting with immediate chemotherapy.[6,10]; [11][Level of evidence: 1iiA]
   • 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).
2. 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.[12][Level of evidence: 3iiiDiii] This implies that watchful waiting remains a relevant approach even in the rituximab era.

Rituximab with or without 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.[13-15]

• Rituximab alone, as was shown in the ECOG-E4402 (NCT00075946) trial, for example.[16-20]
• R-bendamustine: rituximab + bendamustine.[21-23]
• R-F: rituximab + fludarabine.[24]
• R-CVP: rituximab + cyclophosphamide + vincristine + prednisone.[25-28]
• 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.[32][Level of evidence: 1iiA]
• R-FM: rituximab + fludarabine + mitoxantrone.[27,28,33]
• R-FCM: rituximab + fludarabine + cyclophosphamide + mitoxantrone.[34]

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 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).[27][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.[22][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.

Maintenance rituximab

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):

1. 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.[40][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.
2. 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.[41][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]).[41][Level of evidence: 1iiC]
   • This study suggested that for some patients, watch and wait resulted in watch and worry.[42] However, from the perspective of OS and histologic transformation rates, no benefit could be seen with rituximab maintenance.
3. 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.[19][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.[43][Level of evidence: 1iiA]
4. 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.[44][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):

1. 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.[45][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.
2. 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.[46][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.
3. 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).[47][Level of evidence: 1iiA]

For previously treated patients, there is more evidence to suggest an OS advantage with the use of rituximab maintenance.

Obinutuzumab

Obinutuzumab is a glycoengineered type II anti–CD20 monoclonal antibody with greater antibody-dependent cellular cytotoxicity than rituximab.

1. 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).[48] 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).[48][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.

P13K inhibitors

Copanlisib

In a phase II study of 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.[49][Level of evidence: 3iiiDiv]

Idelalisib

In a phase II study of 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.[50][Level of evidence: 3iiiDiv] In a follow-up analysis of only follicular lymphoma histology with early relapse within 1 year of chemoimmunotherapy, the response rates were equivalent.[51][Level of evidence: 3iiiDiv]

Duvelisib

In a phase II study, published in abstract form, of 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.[52][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.

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).[53] 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).[53][Level of evidence: 1iiA]

This trial establishes 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, published in abstract form, of 358 patients with resistant/refractory indolent lymphoma (usually follicular lymphoma), rituximab plus lenalidomide (R2 regimen) was compared with rituximab alone.[54] With a median follow-up of 28 months, the median PFS was 39.4 months for R2 and 14.1 months for rituximab alone (P < .0001), with no difference in OS.[54][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).[57][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).[57] 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.[58][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.[57]

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.

1. 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]
2. Phase III trials comparing chemotherapy alone versus chemotherapy followed by anti-idiotype vaccine.[71-73]
3. Extended-field radiation therapy (stage III patients only).[74]
4. Ofatumumab—human anti–CD20 monoclonal antibody.[75]
5. Short-course low-dose, palliative radiation therapy (2 × 2 Gy).[76,77]

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.

References

1. Hagenbeek A, Eghbali H, Monfardini S, et al.: Phase III intergroup study of fludarabine phosphate compared with cyclophosphamide, vincristine, and prednisone chemotherapy in newly diagnosed patients with stage III and IV low-grade malignant Non-Hodgkin's lymphoma. J Clin Oncol 24 (10): 1590-6, 2006. [PUBMED Abstract]
2. Gribben JG: How I treat indolent lymphoma. Blood 109 (11): 4617-26, 2007. [PUBMED Abstract]
3. Jacobs JP, Murray KJ, Schultz CJ, et al.: Central lymphatic irradiation for stage III nodular malignant lymphoma: long-term results. J Clin Oncol 11 (2): 233-8, 1993. [PUBMED Abstract]
4. Mendenhall NP, Million RR: Comprehensive lymphatic irradiation for stage II-III non-Hodgkin's lymphoma. Am J Clin Oncol 12 (3): 190-4, 1989. [PUBMED Abstract]
5. Eek R, Falkson G: The low-grade lymphoproliferative disorders. Oncology 54 (6): 441-58, 1997 Nov-Dec. [PUBMED Abstract]
6. Ardeshna KM, Smith P, Norton A, et al.: Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet 362 (9383): 516-22, 2003. [PUBMED Abstract]
7. Portlock CS, Rosenberg SA: No initial therapy for stage III and IV non-Hodgkin's lymphomas of favorable histologic types. Ann Intern Med 90 (1): 10-13, 1979.
8. Solal-Céligny P, Roy P, Colombat P, et al.: Follicular lymphoma international prognostic index. Blood 104 (5): 1258-65, 2004. [PUBMED Abstract]
9. Federico M, Bellei M, Marcheselli L, et al.: Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol 27 (27): 4555-62, 2009. [PUBMED Abstract]
10. Brice P, Bastion Y, Lepage E, et al.: Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d'Etude des Lymphomes Folliculaires. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 15 (3): 1110-7, 1997. [PUBMED Abstract]
11. Young RC, Longo DL, Glatstein E, et al.: The treatment of indolent lymphomas: watchful waiting v aggressive combined modality treatment. Semin Hematol 25 (2 Suppl 2): 11-6, 1988. [PUBMED Abstract]
12. Solal-Céligny P, Bellei M, Marcheselli L, et al.: Watchful waiting in low-tumor burden follicular lymphoma in the rituximab era: results of an F2-study database. J Clin Oncol 30 (31): 3848-53, 2012. [PUBMED Abstract]
13. Kim WS, Buske C, Ogura M, et al.: Efficacy, pharmacokinetics, and safety of the biosimilar CT-P10 compared with rituximab in patients with previously untreated advanced-stage follicular lymphoma: a randomised, double-blind, parallel-group, non-inferiority phase 3 trial. Lancet Haematol 4 (8): e362-e373, 2017. [PUBMED Abstract]
14. Davies A, Merli F, Mihaljević B, et al.: Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial. Lancet Haematol 4 (6): e272-e282, 2017. [PUBMED Abstract]
15. Jurczak W, Moreira I, Kanakasetty GB, et al.: Rituximab biosimilar and reference rituximab in patients with previously untreated advanced follicular lymphoma (ASSIST-FL): primary results from a confirmatory phase 3, double-blind, randomised, controlled study. Lancet Haematol 4 (8): e350-e361, 2017. [PUBMED Abstract]
16. Ghielmini M, Schmitz SF, Cogliatti SB, et al.: Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood 103 (12): 4416-23, 2004. [PUBMED Abstract]
17. Witzig TE, Vukov AM, Habermann TM, et al.: Rituximab therapy for patients with newly diagnosed, advanced-stage, follicular grade I non-Hodgkin's lymphoma: a phase II trial in the North Central Cancer Treatment Group. J Clin Oncol 23 (6): 1103-8, 2005. [PUBMED Abstract]
18. Hainsworth JD, Litchy S, Shaffer DW, et al.: Maximizing therapeutic benefit of rituximab: maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin's lymphoma--a randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 23 (6): 1088-95, 2005. [PUBMED Abstract]
19. Kahl BS, Hong F, Williams ME, et al.: Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: eastern cooperative oncology group protocol e4402. J Clin Oncol 32 (28): 3096-102, 2014. [PUBMED Abstract]
20. Buske C, Hiddemann W: Rituximab maintenance therapy in indolent NHL: a clinical review. Leuk Res 30 (Suppl 1): S11-5, 2006. [PUBMED Abstract]
21. Robinson KS, Williams ME, van der Jagt RH, et al.: Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin's lymphoma. J Clin Oncol 26 (27): 4473-9, 2008. [PUBMED Abstract]
22. Rummel MJ, Niederle N, Maschmeyer G, et al.: Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 381 (9873): 1203-10, 2013. [PUBMED Abstract]
23. Flinn IW, van der Jagt R, Kahl BS, et al.: Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood 123 (19): 2944-52, 2014. [PUBMED Abstract]
24. Czuczman MS, Koryzna A, Mohr A, et al.: Rituximab in combination with fludarabine chemotherapy in low-grade or follicular lymphoma. J Clin Oncol 23 (4): 694-704, 2005. [PUBMED Abstract]
25. Marcus R, Imrie K, Belch A, et al.: CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 105 (4): 1417-23, 2005. [PUBMED Abstract]
26. Marcus R, Imrie K, Solal-Celigny P, et al.: Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol 26 (28): 4579-86, 2008. [PUBMED Abstract]
27. Federico M, Luminari S, Dondi A, et al.: R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol 31 (12): 1506-13, 2013. [PUBMED Abstract]
28. Luminari S, Ferrari A, Manni M, et al.: Long-Term Results of the FOLL05 Trial Comparing R-CVP Versus R-CHOP Versus R-FM for the Initial Treatment of Patients With Advanced-Stage Symptomatic Follicular Lymphoma. J Clin Oncol 36 (7): 689-696, 2018. [PUBMED Abstract]
29. Czuczman MS, Weaver R, Alkuzweny B, et al.: Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol 22 (23): 4711-6, 2004. [PUBMED Abstract]
30. Hainsworth JD, Litchy S, Morrissey LH, et al.: Rituximab plus short-duration chemotherapy as first-line treatment for follicular non-Hodgkin's lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 23 (7): 1500-6, 2005. [PUBMED Abstract]
31. Hiddemann W, Kneba M, Dreyling M, et al.: Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 106 (12): 3725-32, 2005. [PUBMED Abstract]
32. Itchaki G, Gafter-Gvili A, Lahav M, et al.: Anthracycline-containing regimens for treatment of follicular lymphoma in adults. Cochrane Database Syst Rev 7: CD008909, 2013. [PUBMED Abstract]
33. Zinzani PL, Pulsoni A, Perrotti A, et al.: Fludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with follicular lymphoma. J Clin Oncol 22 (13): 2654-61, 2004. [PUBMED Abstract]
34. Forstpointner R, Dreyling M, Repp R, et al.: The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 104 (10): 3064-71, 2004. [PUBMED Abstract]
35. Herold M, Haas A, Srock S, et al.: Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. J Clin Oncol 25 (15): 1986-92, 2007. [PUBMED Abstract]
36. Salles GA, Mounier N, de Guibert S, et al.: Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: final analysis of the GELA-GOELAMS FL2000 study with a 5-year follow-up. [Abstract] Blood 110 (11): A-792, 2007.
37. Schulz H, Bohlius J, Skoetz N, et al.: Combined immunochemotherapy with rituximab improves overall survival in patients with follicular and mantle cell lymphoma: updated meta-analysis results. [Abstract] Blood 108 (11): A-2760, 2006.
38. Dupuis J, Berriolo-Riedinger A, Julian A, et al.: Impact of [(18)F]fluorodeoxyglucose positron emission tomography response evaluation in patients with high-tumor burden follicular lymphoma treated with immunochemotherapy: a prospective study from the Groupe d'Etudes des Lymphomes de l'Adulte and GOELAMS. J Clin Oncol 30 (35): 4317-22, 2012. [PUBMED Abstract]
39. Trotman J, Fournier M, Lamy T, et al.: Positron emission tomography-computed tomography (PET-CT) after induction therapy is highly predictive of patient outcome in follicular lymphoma: analysis of PET-CT in a subset of PRIMA trial participants. J Clin Oncol 29 (23): 3194-200, 2011. [PUBMED Abstract]
40. Salles G, Seymour JF, Offner F, et al.: Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 377 (9759): 42-51, 2011. [PUBMED Abstract]
41. Ardeshna KM, Qian W, Smith P, et al.: Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial. Lancet Oncol 15 (4): 424-35, 2014. [PUBMED Abstract]
42. Ansell SM: Follicular lymphoma: watch and wait is watch and worry. Lancet Oncol 15 (4): 368-9, 2014. [PUBMED Abstract]
43. Taverna C, Martinelli G, Hitz F, et al.: Rituximab Maintenance for a Maximum of 5 Years After Single-Agent Rituximab Induction in Follicular Lymphoma: Results of the Randomized Controlled Phase III Trial SAKK 35/03. J Clin Oncol 34 (5): 495-500, 2016. [PUBMED Abstract]
44. Barta SK, Li H, Hochster HS, et al.: Randomized phase 3 study in low-grade lymphoma comparing maintenance anti-CD20 antibody with observation after induction therapy: A trial of the ECOG-ACRIN Cancer Research Group (E1496). Cancer 122 (19): 2996-3004, 2016. [PUBMED Abstract]
45. van Oers MH, Tönnissen E, Van Glabbeke M, et al.: BCL-2/IgH polymerase chain reaction status at the end of induction treatment is not predictive for progression-free survival in relapsed/resistant follicular lymphoma: results of a prospective randomized EORTC 20981 phase III intergroup study. J Clin Oncol 28 (13): 2246-52, 2010. [PUBMED Abstract]
46. Pettengell R, Schmitz N, Gisselbrecht C, et al.: Rituximab purging and/or maintenance in patients undergoing autologous transplantation for relapsed follicular lymphoma: a prospective randomized trial from the lymphoma working party of the European group for blood and marrow transplantation. J Clin Oncol 31 (13): 1624-30, 2013. [PUBMED Abstract]
47. Vidal L, Gafter-Gvili A, Salles G, et al.: Rituximab maintenance for the treatment of patients with follicular lymphoma: an updated systematic review and meta-analysis of randomized trials. J Natl Cancer Inst 103 (23): 1799-806, 2011. [PUBMED Abstract]
48. Marcus R, Davies A, Ando K, et al.: Obinutuzumab for the First-Line Treatment of Follicular Lymphoma. N Engl J Med 377 (14): 1331-1344, 2017. [PUBMED Abstract]
49. Dreyling M, Santoro A, Mollica L, et al.: Phosphatidylinositol 3-Kinase Inhibition by Copanlisib in Relapsed or Refractory Indolent Lymphoma. J Clin Oncol 35 (35): 3898-3905, 2017. [PUBMED Abstract]
50. Gopal AK, Kahl BS, de Vos S, et al.: PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 370 (11): 1008-18, 2014. [PUBMED Abstract]
51. Gopal AK, Kahl BS, Flowers CR, et al.: Idelalisib is effective in patients with high-risk follicular lymphoma and early relapse after initial chemoimmunotherapy. Blood 129 (22): 3037-3039, 2017. [PUBMED Abstract]
52. Flinn IW, Miller CB, Ardeshna KM, et al.: Dynamo: a phase 2 study demonstrating the clinical activity of duvelisib in patients with relapsed refractory indolent non-Hodgkin lymphoma. [Abstract] Blood 128 (22): A-1218, 2016.
53. Morschhauser F, Fowler NH, Feugier P, et al.: Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma. N Engl J Med 379 (10): 934-947, 2018. [PUBMED Abstract]
54. Leonard JP, Trnený M, Izutsu K, et al.: Augment: a phase III randomized study of lenalidomide Plus rituximab (R2) vs rituximab/placebo in patients with relapsed/refractory indolent non-Hodgkin lymphoma. [Abstract] Blood 132 (Suppl 1): A-445, 2018.
55. Press OW, Unger JM, Braziel RM, et al.: Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non-Hodgkin's lymphoma: five-year follow-up of Southwest Oncology Group Protocol S9911. J Clin Oncol 24 (25): 4143-9, 2006. [PUBMED Abstract]
56. Scholz CW, Pinto A, Linkesch W, et al.: (90)Yttrium-ibritumomab-tiuxetan as first-line treatment for follicular lymphoma: 30 months of follow-up data from an international multicenter phase II clinical trial. J Clin Oncol 31 (3): 308-13, 2013. [PUBMED Abstract]
57. Shadman M, Li H, Rimsza L, et al.: Continued Excellent Outcomes in Previously Untreated Patients With Follicular Lymphoma After Treatment With CHOP Plus Rituximab or CHOP Plus 131I-Tositumomab: Long-Term Follow-Up of Phase III Randomized Study SWOG-S0016. J Clin Oncol 36 (7): 697-703, 2018. [PUBMED Abstract]
58. Morschhauser F, Radford J, Van Hoof A, et al.: 90Yttrium-ibritumomab tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin lymphoma: updated results after a median follow-up of 7.3 years from the International, Randomized, Phase III First-LineIndolent trial. J Clin Oncol 31 (16): 1977-83, 2013. [PUBMED Abstract]
59. Fisher RI, Kaminski MS, Wahl RL, et al.: Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin's lymphomas. J Clin Oncol 23 (30): 7565-73, 2005. [PUBMED Abstract]
60. Leahy MF, Seymour JF, Hicks RJ, et al.: Multicenter phase II clinical study of iodine-131-rituximab radioimmunotherapy in relapsed or refractory indolent non-Hodgkin's lymphoma. J Clin Oncol 24 (27): 4418-25, 2006. [PUBMED Abstract]
61. van Besien K, Sobocinski KA, Rowlings PA, et al.: Allogeneic bone marrow transplantation for low-grade lymphoma. Blood 92 (5): 1832-6, 1998. [PUBMED Abstract]
62. van Besien K, Loberiza FR Jr, Bajorunaite R, et al.: Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma. Blood 102 (10): 3521-9, 2003. [PUBMED Abstract]
63. Deconinck E, Foussard C, Milpied N, et al.: High-dose therapy followed by autologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by GOELAMS. Blood 105 (10): 3817-23, 2005. [PUBMED Abstract]
64. Sebban C, Mounier N, Brousse N, et al.: Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Blood 108 (8): 2540-4, 2006. [PUBMED Abstract]
65. Lenz G, Dreyling M, Schiegnitz E, et al.: Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group. Blood 104 (9): 2667-74, 2004. [PUBMED Abstract]
66. Rohatiner AZ, Nadler L, Davies AJ, et al.: Myeloablative therapy with autologous bone marrow transplantation for follicular lymphoma at the time of second or subsequent remission: long-term follow-up. J Clin Oncol 25 (18): 2554-9, 2007. [PUBMED Abstract]
67. Gopal AK, Rajendran JG, Gooley TA, et al.: High-dose [131I]tositumomab (anti-CD20) radioimmunotherapy and autologous hematopoietic stem-cell transplantation for adults > or = 60 years old with relapsed or refractory B-cell lymphoma. J Clin Oncol 25 (11): 1396-402, 2007. [PUBMED Abstract]
68. Gyan E, Foussard C, Bertrand P, et al.: High-dose therapy followed by autologous purged stem cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by the GOELAMS with final results after a median follow-up of 9 years. Blood 113 (5): 995-1001, 2009. [PUBMED Abstract]
69. Al Khabori M, de Almeida JR, Guyatt GH, et al.: Autologous stem cell transplantation in follicular lymphoma: a systematic review and meta-analysis. J Natl Cancer Inst 104 (1): 18-28, 2012. [PUBMED Abstract]
70. Schaaf M, Reiser M, Borchmann P, et al.: High-dose therapy with autologous stem cell transplantation versus chemotherapy or immuno-chemotherapy for follicular lymphoma in adults. Cochrane Database Syst Rev 1: CD007678, 2012. [PUBMED Abstract]
71. Bendandi M, Gocke CD, Kobrin CB, et al.: Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma. Nat Med 5 (10): 1171-7, 1999. [PUBMED Abstract]
72. Neelapu SS, Gause BL, Nikcevich DA, et al.: Phase III randomized trial of patient-specific vaccination for previously untreated patients with follicular lymphoma in first complete remission: protocol summary and interim report. Clin Lymphoma 6 (1): 61-4, 2005. [PUBMED Abstract]
73. Inogès S, Rodrìguez-Calvillo M, Zabalegui N, et al.: Clinical benefit associated with idiotypic vaccination in patients with follicular lymphoma. J Natl Cancer Inst 98 (18): 1292-301, 2006. [PUBMED Abstract]
74. Ha CS, Kong JS, Tucker SL, et al.: Central lymphatic irradiation for stage I-III follicular lymphoma: report from a single-institutional prospective study. Int J Radiat Oncol Biol Phys 57 (2): 316-20, 2003. [PUBMED Abstract]
75. Czuczman MS, Fayad L, Delwail V, et al.: Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study. Blood 119 (16): 3698-704, 2012. [PUBMED Abstract]
76. Chan EK, Fung S, Gospodarowicz M, et al.: Palliation by low-dose local radiation therapy for indolent non-Hodgkin lymphoma. Int J Radiat Oncol Biol Phys 81 (5): e781-6, 2011. [PUBMED Abstract]
77. Rossier C, Schick U, Miralbell R, et al.: Low-dose radiotherapy in indolent lymphoma. Int J Radiat Oncol Biol Phys 81 (3): e1-6, 2011. [PUBMED Abstract]

Treatment for Indolent, Recurrent Adult NHL

In This Section

• Standard Treatment Options for Indolent, Recurrent Adult NHL
  • Chemotherapy (single agent or combination)
  • Rituximab
  • Obinutuzumab
  • Lenalidomide
  • Radiolabeled anti-CD20 monoclonal antibodies
  • Palliative radiation therapy
• Treatment Options Under Clinical Evaluation for Indolent, Recurrent Adult NHL
• Current Clinical Trials

In general, treatment with standard agents rarely produces a cure in patients whose disease has relapsed. Sustained remissions after relapse can often be obtained in patients with indolent lymphomas, but relapse will usually ensue. Favorable survival after relapse has been associated with an age younger than 60 years, complete remission rather than partial remission, and duration of response longer than 2 years.[1] Even the most favorable subset, however, has a tenfold greater mortality compared with age-adjusted U.S. population rates.[2]

Patients who experience a relapse with indolent lymphoma can often have their disease controlled with single agent or combination chemotherapy, rituximab (an anti–CD20 monoclonal antibody), lenalidomide, radiolabeled anti–CD20 monoclonal antibodies, or palliative radiation therapy.[3,4] Long-term freedom from second relapse, however, is uncommon and multiple relapses will usually occur. Patients with indolent lymphoma may experience a relapse with a more aggressive histology. If the clinical pattern of relapse suggests that the disease is behaving in a more aggressive manner, a biopsy can be performed. Documentation of conversion to a more aggressive histology requires an appropriate change to therapy applicable to that histologic type.[5] Rapid growth or discordant growth between various disease sites may indicate a histologic conversion.

In a retrospective review of 325 patients between 1972 and 1999, the risk of histologic transformation was 30% by 10 years from diagnosis.[6] In this series, high-risk factors for subsequent histologic transformation were advanced stage, high-risk Follicular Lymphoma International Prognostic Index, and expectant management. The median survival after transformation was 1 to 2 years, with 25% of patients alive at 5 years and with approximately 10% to 20% of patients alive 10 years after re-treatment.[7]

A prospective trial of 631 patients with follicular lymphoma and with a median follow-up of 60 months in the rituximab era (2002–2009) found a 5-year transformation rate (11%) to a higher-grade histology.[8] The median overall survival (OS) after transformation was 50 months, and the 5-year OS rate was 66%, if the transformation occurred more than 18 months after a diagnosis of follicular lymphoma. This series describes a better prognosis for patients with transformation than was experienced by patients in the prerituximab era.

(Refer to the Treatment for Aggressive, Recurrent Adult NHL section of this summary for descriptions of the regimens used to treat histologic conversions.) The durability of the second remission may be short, and clinical trials canbe considered.

Standard Treatment Options for Indolent, Recurrent Adult NHL

Standard treatment options for indolent, recurrent adult non-Hodgkin lymphoma (NHL) include the following:

1. Chemotherapy (single agent or combination).
2. Rituximab.
3. Obinutuzumab.
4. Lenalidomide.
5. Radiolabeled anti-CD20 monoclonal antibodies.
6. Palliative radiation therapy.

Chemotherapy (single agent or combination)

Significant activity for fludarabine and 2-chlorodeoxyadenosine has been demonstrated in relapsed low-grade lymphomas, both as single agents and in combination with other drugs.[9-14] Patients may respond to the original induction regimen again, especially if the duration of remission exceeds 1 year. For relapsing patients, rituximab alone or in combination with agents not previously used may induce remissions.

Rituximab

Rituximab results in a 40% to 50% response rate in patients who relapse with indolent B-cell lymphomas.[15-18] Rituximab can also be combined with combination chemotherapy.[19]

Evidence (rituximab):

• In three randomized, prospective studies involving previously treated patients with relapsed indolent lymphoma, patients were randomly assigned to rituximab maintenance after re-treatment with combination chemotherapy (with or without rituximab during induction) or rituximab alone; all trials showed prolongation of response duration,[20-22] and one trial demonstrated improvement in median progression-free survival (PFS) (3.7 years vs. 1.3 years, P < .001) and OS (74% vs. 64%, P= .07) at 5 years with a median follow-up of 39 months favoring maintenance rituximab.[21]

Obinutuzumab

Obinutuzumab is a CD20-binding monoclonal antibody with alternative epitope binding.

Evidence (obinutuzumab):

1. In a randomized prospective trial (NCT01059630) involving 396 patients with rituximab-refractory indolent lymphoma (mostly follicular lymphoma), patients received obinutuzumab plus bendamustine followed by obinutuzumab maintenance therapy versus bendamustine alone with no maintenance therapy.[23][Level of evidence: 1iiDiii]
   • With a median follow-up of 21.9 months, the PFS was significantly longer in the obinutuzumab group, demonstrating a median PFS not reached (95% confidence interval [CI], 22.5 months to not reached) versus 14.9 months for the control arm of bendamustine (95% CI, 12.8‒16.6 months).
   • There was no difference noted in OS.

Lenalidomide

Responses of 20% to 56% have been reported for lenalidomide, especially in patients with follicular lymphoma and small lymphocytic lymphoma, with even higher responses noted for the combination of lenalidomide and rituximab.[24,25][Level of evidence: 3iiiDiv]

Radiolabeled anti-CD20 monoclonal antibodies

Durable responses to radiolabeled monoclonal antibodies, such as yttrium Y 90 (90Y)-ibritumomab tiuxetan (commercially available) and iodine I 131-tositumomab (commercially unavailable), have also been reported before and after cytotoxic chemotherapy.[26-28][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.[28]

A prospective trial of 409 patients with follicular lymphoma who responded to induction chemotherapy were randomly assigned to 90Y-ibritumomab tiuxetan or no further consolidation; with a median follow-up of 7.3 years, the 8-year PFS favored 90Y-ibritumomab tiuxetan (41% vs. 22% [hazard ratio, 0.47; P < .001]), but there was no difference in OS.[29][Level of evidence: 1iiDiii]

Palliative radiation therapy

Palliation may be achieved with very low-dose (4 Gy) involved-field radiation therapy in two fractions for patients with indolent and aggressive relapsed disease.[30] In a prospective randomized trial, treatment with 4 Gy was inferior to treatment with 24 Gy in 12 fractions in PFS (77% vs. 92%, P < .0001).[31][Level of evidence: 1iiDiii]

Treatment Options Under Clinical Evaluation for Indolent, Recurrent Adult NHL

Treatment options under clinical evaluation include the following:

• Stem cell transplant. In many institutions, autologous or allogeneic stem cell transplantations (SCT) are being used for patients whose disease has relapsed. Such an approach is still under evaluation but can be considered in the context of a clinical trial.[32-36]

Evidence (stem cell transplant):

• The German Low-Grade Lymphoma Study Group treated 307 patients with follicular lymphoma with two cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like induction chemotherapy and then randomly assigned them to autologous SCT versus interferon maintenance.[37] With a median follow-up of 4.2 years, the 5-year PFS was 65% for transplantation versus 33% for interferon (P < .001), but with no difference in OS.[37][Level of evidence: 1iiDiii]

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.

References

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18. Hainsworth JD, Litchy S, Shaffer DW, et al.: Maximizing therapeutic benefit of rituximab: maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin's lymphoma--a randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 23 (6): 1088-95, 2005. [PUBMED Abstract]
19. Forstpointner R, Dreyling M, Repp R, et al.: The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 104 (10): 3064-71, 2004. [PUBMED Abstract]
20. van Oers MH, Van Glabbeke M, Giurgea L, et al.: Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol 28 (17): 2853-8, 2010. [PUBMED Abstract]
21. van Oers MH, Klasa R, Marcus RE, et al.: Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood 108 (10): 3295-301, 2006. [PUBMED Abstract]
22. Martinelli G, Schmitz SF, Utiger U, et al.: Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol 28 (29): 4480-4, 2010. [PUBMED Abstract]
23. Sehn LH, Chua N, Mayer J, et al.: Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol 17 (8): 1081-93, 2016. [PUBMED Abstract]
24. Witzig TE, Wiernik PH, Moore T, et al.: Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin's Lymphoma. J Clin Oncol 27 (32): 5404-9, 2009. [PUBMED Abstract]
25. Leonard JP, Jung SH, Johnson J, et al.: Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance). J Clin Oncol 33 (31): 3635-40, 2015. [PUBMED Abstract]
26. Fisher RI, Kaminski MS, Wahl RL, et al.: Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin's lymphomas. J Clin Oncol 23 (30): 7565-73, 2005. [PUBMED Abstract]
27. Leahy MF, Seymour JF, Hicks RJ, et al.: Multicenter phase II clinical study of iodine-131-rituximab radioimmunotherapy in relapsed or refractory indolent non-Hodgkin's lymphoma. J Clin Oncol 24 (27): 4418-25, 2006. [PUBMED Abstract]
28. Shadman M, Li H, Rimsza L, et al.: Continued Excellent Outcomes in Previously Untreated Patients With Follicular Lymphoma After Treatment With CHOP Plus Rituximab or CHOP Plus 131I-Tositumomab: Long-Term Follow-Up of Phase III Randomized Study SWOG-S0016. J Clin Oncol 36 (7): 697-703, 2018. [PUBMED Abstract]
29. Morschhauser F, Radford J, Van Hoof A, et al.: 90Yttrium-ibritumomab tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin lymphoma: updated results after a median follow-up of 7.3 years from the International, Randomized, Phase III First-LineIndolent trial. J Clin Oncol 31 (16): 1977-83, 2013. [PUBMED Abstract]
30. Haas RL, Poortmans P, de Jong D, et al.: Effective palliation by low dose local radiotherapy for recurrent and/or chemotherapy refractory non-follicular lymphoma patients. Eur J Cancer 41 (12): 1724-30, 2005. [PUBMED Abstract]
31. 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]
32. Freedman A, Friedberg JW, Gribben J: High-dose therapy for follicular lymphoma. Oncology (Huntingt) 14 (3): 321-6, 329; discussion 330-2, 338, 2000. [PUBMED Abstract]
33. Brice P, Simon D, Bouabdallah R, et al.: High-dose therapy with autologous stem-cell transplantation (ASCT) after first progression prolonged survival of follicular lymphoma patients included in the prospective GELF 86 protocol. Ann Oncol 11 (12): 1585-90, 2000. [PUBMED Abstract]
34. Khouri IF, McLaughlin P, Saliba RM, et al.: Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood 111 (12): 5530-6, 2008. [PUBMED Abstract]
35. Sebban C, Brice P, Delarue R, et al.: Impact of rituximab and/or high-dose therapy with autotransplant at time of relapse in patients with follicular lymphoma: a GELA study. J Clin Oncol 26 (21): 3614-20, 2008. [PUBMED Abstract]
36. Thomson KJ, Morris EC, Milligan D, et al.: T-cell-depleted reduced-intensity transplantation followed by donor leukocyte infusions to promote graft-versus-lymphoma activity results in excellent long-term survival in patients with multiply relapsed follicular lymphoma. J Clin Oncol 28 (23): 3695-700, 2010. [PUBMED Abstract]
37. Lenz G, Dreyling M, Schiegnitz E, et al.: Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group. Blood 104 (9): 2667-74, 2004. [PUBMED Abstract]

Treatment for Aggressive Stage I and Aggressive, Contiguous Stage II Adult NHL

In This Section

• Standard Treatment Options for Aggressive Stage I and Aggressive, Contiguous Stage II Adult NHL
  • R-CHOP with or without IF-XRT
• Treatment Options Under Clinical Evaluation for Aggressive Stage I and Aggressive, Contiguous Stage II Adult NHL
• Current Clinical Trials

Patients with aggressive stage I or aggressive, contiguous stage II diffuse large B-cell lymphoma are candidates for combination chemotherapy with or without involved-field radiation therapy (IF-XRT).

Standard Treatment Options for Aggressive Stage I and Aggressive, Contiguous Stage II Adult NHL

Standard treatment options for aggressive stage I and aggressive, contiguous stage II adult non-Hodgkin lymphoma (NHL) include the following:

1. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without IF-XRT.

R-CHOP with or without IF-XRT

The confirmation of efficacy for rituximab in advanced-stage disease has suggested the use of R-CHOP with or without radiation therapy but its use is only supported by retrospective comparisons.[1][Level of evidence: 3iiiDiii]

• R-CHOP (four to six cycles).
• R-CHOP (three to six cycles) + IF-XRT.

In a randomized prospective trial of 334 patients with nonbulky (≤7 cm) stage I or stage II diffuse large B-cell lymphoma (DLBCL), after receiving four to six cycles of R-CHOP-14 (R-CHOP delivered every 2 weeks), patients were randomly assigned to receive or not receive 40 Gy of radiation therapy.[2] After a median follow-up of 64 months, the 5-year event-free survival (EFS) (89%–92%, P = .18) and 5-year overall survival (OS) (92%–96%, P = .32) were the same.[2][Level of evidence: 1iiA] Similar to the results of randomized studies of radiation therapy in the prerituximab era, radiation therapy can be deferred in nonbulky early-stage patients. For patients unable to tolerate prolonged-course chemotherapy, three cycles of R-CHOP plus radiation therapy has produced equivalent results based on single-arm retrospective trials.[1]

In a randomized prospective trial, published only in abstract form, of 592 patients younger than 60 years with nonbulky (<7.5 cm) stage I or stage II DLBCL, patients were randomly assigned to four versus six cycles of R-CHOP.[3] With a 66-month median follow-up, the 3-year EFS was 89% in both arms (P = NS) and the 3-year OS was 98% in both arms (P = NS).[3][Level of evidence: 1iiA] For patients with favorable early-stage DLBCL, four cycles of R-CHOP is sufficient.

Conclusion: For patients with favorable prognosis nonbulky (<7 cm) stage I or stage II DLBCL, four cycles of R-CHOP is sufficient. For patients with unfavorable prognosis, six cycles of R-CHOP or three cycles of R-CHOP and 40 Gy of radiation therapy can be utilized. Early-stage patients with bulky disease (>7.5 cm) have not been studied in randomized trials; combined modality therapy with R-CHOP for four to six cycles plus radiation therapy is usually chosen.

Treatment Options Under Clinical Evaluation for Aggressive Stage I and Aggressive, Contiguous Stage II Adult NHL

Treatment options under clinical evaluation include the following:

• R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone).[4,5]

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.

References

1. Persky DO, Unger JM, Spier CM, et al.: Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group study 0014. J Clin Oncol 26 (14): 2258-63, 2008. [PUBMED Abstract]
2. Lamy T, Damaj G, Soubeyran P, et al.: R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma. Blood 131 (2): 174-181, 2018. [PUBMED Abstract]
3. Poeschel V, Held G, Ziepert M, et al.: Excellent outcome of young patients (18–60 years) with favourable-prognosis diffuse large B-cell lymphoma (DLBCL) treated with 4 cycles CHOP plus 6 applications of rituximab: results of the 592 patients of the flyer trial of the Dshnhl/GLA. [Abstract] Blood 132 (Suppl 1): A-781, 2018. Also available online. Exit Disclaimer Last accessed January 14, 2019.
4. Reyes F, Lepage E, Ganem G, et al.: ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med 352 (12): 1197-205, 2005. [PUBMED Abstract]
5. Ketterer N, Coiffier B, Thieblemont C, et al.: Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B). Ann Oncol 24 (4): 1032-7, 2013. [PUBMED Abstract]

Treatment for Aggressive, Noncontiguous Stage II/III/IV Adult NHL

In This Section

• Standard Treatment Options for Aggressive, Noncontiguous Stage II/III/IV Adult NHL
  • R-CHOP
  • Additive radiation therapy
  • Other combination chemotherapy
  • Stage IE or IIE gastric DLBCL
  • Prognostic factors
  • Treatment of tumor lysis syndrome
  • CNS prophylaxis
• Treatment Options Under Clinical Evaluation for Aggressive, Noncontiguous Stage II/III/IV Adult NHL
• Current Clinical Trials

The treatment of choice for patients with advanced stages of aggressive non-Hodgkin lymphoma (NHL) is combination chemotherapy, either alone or supplemented by local-field radiation therapy.[1]

The following drug combinations are referred to in this section:

• ACVBP: doxorubicin + cyclophosphamide + vindesine + bleomycin + prednisone.
• CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone.
• m-BACOD: methotrexate + bleomycin + doxorubicin + cyclophosphamide + vincristine + dexamethasone + leucovorin.
• MACOP-B: methotrexate + doxorubicin + cyclophosphamide + vincristine + prednisone fixed dose + bleomycin + leucovorin.
• ProMACE CytaBOM: prednisone + doxorubicin + cyclophosphamide + etoposide + cytarabine + bleomycin + vincristine + methotrexate + leucovorin.
• R-ACVBP: rituximab, an anti-CD20 monoclonal antibody, + doxorubicin + cyclophosphamide + vindesine + bleomycin + prednisone.
• R-CHOP: rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone.

Standard Treatment Options for Aggressive, Noncontiguous Stage II/III/IV Adult NHL

Standard treatment options for aggressive, noncontiguous stage II/III/IV adult NHL include the following:

1. R-CHOP.
2. Other combination chemotherapy.

R-CHOP

The following studies established R-CHOP as the standard regimen for newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL).[2] Dose intensification of R-CHOP by a 14-day versus a 21-day cycle did not result in improved outcomes.[3]

Evidence (R-CHOP):

1. R-CHOP showed improvement in event-free survival (EFS) and overall survival (OS) compared with CHOP alone in 399 advanced-stage patients with DLBCL older than 60 years (EFS, 57% vs. 38%; P = .002, and OS, 70% vs. 57%; P = .007 at 2 years).[4][Level of evidence: 1iiA] At 10-years' median follow-up, the OS of patients who received R-CHOP compared with patients who received CHOP was 44% versus 28%, P < .0001.[5]
2. Similarly, for 326 evaluable patients younger than 61 years, R-CHOP showed improvement in EFS and OS compared with CHOP alone (EFS, 79% vs. 59%, P = .001, and OS, 93% vs. 84%, P = .001 at 3 years).[6][Level of evidence: 1iiA]
3. A randomized study (DSHNHL-1999-1A [NCT00052936]) of 1,222 patients older than 60 years compared R-CHOP given every 2 weeks for six or eight cycles with CHOP given every 2 weeks for six or eight cycles.[7] With a median follow-up of 72 months, the EFS favored R-CHOP given every 2 weeks for six or eight cycles (EFS at 6 years, 74% vs. 56%; P < .0001). The OS favored R-CHOP for only six cycles because of increased toxicity in the eight-cycle arm (OS at 6 years, 90% vs. 80%; P = .0004).[7][Level of evidence: 1iiA] There was no comparison with standard R-CHOP or CHOP given every 3 weeks.
4. A trial (NCT00140595) of 380 patients younger than 60 years with DLBCL and an age-adjusted International Prognostic Index (IPI) rating of 1 randomly assigned treatment of patients to ACVBP and R-ACVBP plus consolidation with methotrexate, ifosfamide, etoposide, and cytarabine versus CHOP and rituximab.[8] With a median follow-up of 44 months, 3-year OS favored R-ACVBP (92% vs. 84%; hazard ratio, 0.44; 95% confidence interval (CI), 0.28–0.81, P = .007).[8][Level of evidence: 1iiA] The significantly worse toxicities with R-ACVBP, the narrow target population (<60 years with either elevated lactate dehydrogenase (LDH) or stage III-stage IV disease, but not both), and the lack of a confirmatory trial may inhibit adoption of R-ACVBP as a new standard of care.

Clinical trials continue to explore modifications of CHOP and rituximab with CHOP by increasing doses, reducing intervals between cycles, combining new drugs with new mechanisms of action, or applying extra doses of rituximab at the start and after completion of chemotherapy.[3,9-15] None of these trials establishes a survival advantage for reduced intervals between cycles or for increasing doses of the chemotherapy.

Additive radiation therapy

After R-CHOP chemotherapy, involved-field radiation therapy (IF-XRT) has been proposed for initial bulky sites of disease (≥7.5 cm) or to extralymphatic sites; a nonrandomized cohort study (RICOVER-noRTH) suggested improved EFS, but not PFS or OS.[16][Level of evidence: 3iiiDi] Future trials will focus on whether mid-treatment or end-of-treatment positron emission tomography–computed tomography can define whether radiation therapy can be used after systemic therapy.

Other combination chemotherapy

Doxorubicin-based combination chemotherapy produces long-term disease-free survival in 35% to 45% of patients.[2,4,5] Higher cure rates have been reported in single-institution studies than in cooperative group trials.

Evidence (other combination chemotherapy):

1. A prospective, randomized trial of four regimens (CHOP, ProMACE CytaBOM, m-BACOD, and MACOP-B) for patients with DLBCL showed no difference in OS or time-to-treatment failure at 3 years.[17][Level of evidence: 1iiA]
2. Other randomized trials have confirmed no advantage among the standard doxorubicin-based combinations versus CHOP.[18]; [19]Level of evidence: 1iiA]

A randomized clinical trial failed to demonstrate a beneficial effect of adjuvant radiation therapy in advanced-stage aggressive NHL.[20]

Stage IE or IIE gastric DLBCL

Four case series involving more than 100 patients with stage IE or IIE disease (with or without associated mucosa-associated lymphatic tissue) and with positive Helicobacter pylori infection reported that more than 50% of patients attained a durable complete remission after appropriate antibiotic therapy to eradicate H. pylori.[21-24][Level of evidence: 3iiiDiv]

Prognostic factors

The National Comprehensive Cancer Network (NCCN) IPI for aggressive NHL (diffuse large cell lymphoma) identifies five significant risk factors prognostic of OS:[25]

• Age <40 years: 0; 41–60 years: 1; 61–75 years: 2; >75 years: 3.
• Stage III/IV: 1.
• Performance status 2/3/4: 1.
• Serum LDH normalized: 0; >1x to 3x: 1; >3x: 2.
• Number of extranodal sites ≥2: 1.

Risk scores:

• Low (0 or 1): 5-year OS, 96%; PFS, 91%.
• Low intermediate (2 or 3): 5-year OS, 82%; PFS, 74%.
• High intermediate (4 or 5): 5-year OS, 64%; PFS, 51%.
• High (>6): 5-year OS, 33%; PFS, 30%.

Age-adjusted and stage-adjusted modifications of this IPI are used for younger patients with localized disease.[26] Shorter intervals of time between diagnosis and treatment appear to be a surrogate for poor prognostic biologic factors.[27]

The BCL2 gene and rearrangement of the MYC gene or dual overexpression of the MYCgene, or both, confer a particularly poor prognosis.[28-31] Patients at high risk of relapse may be considered for clinical trials.[32] Molecular profiles of gene expression using DNA microarrays may help to stratify patients in the future for therapies directed at specific targets and to better predict survival after standard chemotherapy.[33,34]

Treatment of tumor lysis syndrome

Patients with bulky and extensive lymphadenopathy and elevations of serum uric acid and LDH are at increased risk of tumor lysis syndrome resulting in metabolic derangements such as hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and subsequent acute renal failure.[35] Treatment options include: alkaline hydration, allopurinol, and rasburicase, a recombinant urate oxidase.[36]

CNS prophylaxis

Central nervous system (CNS) prophylaxis (usually with four to six injections of methotrexate intrathecally) is recommended for patients with paranasal sinus or testicular involvement. Some clinicians are employing high-dose intravenous methotrexate (usually four doses) as an alternative to intrathecal therapy because drug delivery is improved and patient morbidity is decreased.[37] CNS prophylaxis for bone marrow involvement is controversial; some investigators recommend it, and others do not.[17,38]

• A retrospective analysis of 605 patients with diffuse large cell lymphoma who did not receive prophylactic intrathecal therapy identified an elevated serum LDH and more than one extranodal site as independent risk factors for CNS recurrence. Patients with both risk factors have a 17% probability of CNS recurrence at 1 year after diagnosis (95% CI, 7%–28%) versus 2.8% (95% CI, 2.7%–2.9%) for the remaining patients.[39][Level of evidence: 3iiiDiii]

Patients with diffuse, small, noncleaved-cell/Burkitt's lymphoma or lymphoblastic lymphoma have a 20% to 30% lifetime risk of CNS involvement. CNS prophylaxis is recommended for these histologies.

Treatment Options Under Clinical Evaluation for Aggressive, Noncontiguous Stage II/III/IV Adult NHL

Treatment options under clinical evaluation include the following:

• Bone marrow transplant (BMT) or stem cell transplantation (SCT).
  Several randomized, prospective trials evaluated the role of autologous BMT or SCT consolidation versus chemotherapy alone in patients in first remission with diffuse large cell lymphoma.[40-47]; [48-50][Level of evidence: 1iiA] Although some of these trials demonstrated significant increases in EFS (by 10% to 20%) among patients who received high-dose therapy, significant differences in OS could not be demonstrated prospectively in any of the series.
  Retrospective analyses of high-intermediate (two risk factors) or high-risk (more than three risk factors) patients as defined by IPI suggest improved survival with BMT in two of the trials.[41,47] These studies do not establish that high-dose consolidation is of value to patients with aggressive lymphoma who are truly at high risk of relapse, and they also demonstrate that EFS may be a poor surrogate for OS for these patients.[51]
• Radiation therapy consolidation to sites of bulky disease.
  After R-CHOP induction chemotherapy (or similar regimens), the addition of IF-XRT to sites of initial bulky disease (≥5–10 cm) or to extralymphatic sites remains controversial.[16,52,53] Increased risks, such as long-term toxicities (e.g., second malignancies), must be considered.

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.

References

1. Shankland KR, Armitage JO, Hancock BW: Non-Hodgkin lymphoma. Lancet 380 (9844): 848-57, 2012. [PUBMED Abstract]
2. Coiffier B: State-of-the-art therapeutics: diffuse large B-cell lymphoma. J Clin Oncol 23 (26): 6387-93, 2005. [PUBMED Abstract]
3. Cunningham D, Hawkes EA, Jack A, et al.: Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet 381 (9880): 1817-26, 2013. [PUBMED Abstract]
4. Coiffier B, Lepage E, Briere J, et al.: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346 (4): 235-42, 2002. [PUBMED Abstract]
5. Coiffier B, Thieblemont C, Van Den Neste E, et al.: Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood 116 (12): 2040-5, 2010. [PUBMED Abstract]
6. Pfreundschuh M, Trümper L, Osterborg A, et al.: CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7 (5): 379-91, 2006. [PUBMED Abstract]
7. Pfreundschuh M, Kuhnt E, Trümper L, et al.: CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol 12 (11): 1013-22, 2011. [PUBMED Abstract]
8. Récher C, Coiffier B, Haioun C, et al.: Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet 378 (9806): 1858-67, 2011. [PUBMED Abstract]
9. Blayney DW, LeBlanc ML, Grogan T, et al.: Dose-intense chemotherapy every 2 weeks with dose-intense cyclophosphamide, doxorubicin, vincristine, and prednisone may improve survival in intermediate- and high-grade lymphoma: a phase II study of the Southwest Oncology Group (SWOG 9349). J Clin Oncol 21 (13): 2466-73, 2003. [PUBMED Abstract]
10. Coiffier B: Increasing chemotherapy intensity in aggressive lymphomas: a renewal? J Clin Oncol 21 (13): 2457-9, 2003. [PUBMED Abstract]
11. Tilly H, Lepage E, Coiffier B, et al.: Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood 102 (13): 4284-9, 2003. [PUBMED Abstract]
12. Pfreundschuh M, Trümper L, Kloess M, et al.: Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood 104 (3): 626-33, 2004. [PUBMED Abstract]
13. Schmitz N, Nickelsen M, Ziepert M, et al.: Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1). Lancet Oncol 13 (12): 1250-9, 2012. [PUBMED Abstract]
14. Delarue R, Tilly H, Mounier N, et al.: Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial. Lancet Oncol 14 (6): 525-33, 2013. [PUBMED Abstract]
15. Pfreundschuh M, Poeschel V, Zeynalova S, et al.: Optimization of rituximab for the treatment of diffuse large B-cell lymphoma (II): extended rituximab exposure time in the SMARTE-R-CHOP-14 trial of the german high-grade non-Hodgkin lymphoma study group. J Clin Oncol 32 (36): 4127-33, 2014. [PUBMED Abstract]
16. Held G, Murawski N, Ziepert M, et al.: Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. J Clin Oncol 32 (11): 1112-8, 2014. [PUBMED Abstract]
17. Fisher RI, Gaynor ER, Dahlberg S, et al.: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med 328 (14): 1002-6, 1993. [PUBMED Abstract]
18. Gordon LI, Harrington D, Andersen J, et al.: Comparison of a second-generation combination chemotherapeutic regimen (m-BACOD) with a standard regimen (CHOP) for advanced diffuse non-Hodgkin's lymphoma. N Engl J Med 327 (19): 1342-9, 1992. [PUBMED Abstract]
19. Cooper IA, Wolf MM, Robertson TI, et al.: Randomized comparison of MACOP-B with CHOP in patients with intermediate-grade non-Hodgkin's lymphoma. The Australian and New Zealand Lymphoma Group. J Clin Oncol 12 (4): 769-78, 1994. [PUBMED Abstract]
20. O'Connell MJ, Harrington DP, Earle JD, et al.: Prospectively randomized clinical trial of three intensive chemotherapy regimens for the treatment of advanced unfavorable histology non-Hodgkin's lymphoma. J Clin Oncol 5 (9): 1329-39, 1987. [PUBMED Abstract]
21. Morgner A, Miehlke S, Fischbach W, et al.: Complete remission of primary high-grade B-cell gastric lymphoma after cure of Helicobacter pylori infection. J Clin Oncol 19 (7): 2041-8, 2001. [PUBMED Abstract]
22. Chen LT, Lin JT, Shyu RY, et al.: Prospective study of Helicobacter pylori eradication therapy in stage I(E) high-grade mucosa-associated lymphoid tissue lymphoma of the stomach. J Clin Oncol 19 (22): 4245-51, 2001. [PUBMED Abstract]
23. Chen LT, Lin JT, Tai JJ, et al.: Long-term results of anti-Helicobacter pylori therapy in early-stage gastric high-grade transformed MALT lymphoma. J Natl Cancer Inst 97 (18): 1345-53, 2005. [PUBMED Abstract]
24. Kuo SH, Yeh KH, Wu MS, et al.: Helicobacter pylori eradication therapy is effective in the treatment of early-stage H pylori-positive gastric diffuse large B-cell lymphomas. Blood 119 (21): 4838-44; quiz 5057, 2012. [PUBMED Abstract]
25. Zhou Z, Sehn LH, Rademaker AW, et al.: An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood 123 (6): 837-42, 2014. [PUBMED Abstract]
26. Møller MB, Christensen BE, Pedersen NT: Prognosis of localized diffuse large B-cell lymphoma in younger patients. Cancer 98 (3): 516-21, 2003. [PUBMED Abstract]
27. Maurer MJ, Ghesquières H, Link BK, et al.: Diagnosis-to-Treatment Interval Is an Important Clinical Factor in Newly Diagnosed Diffuse Large B-Cell Lymphoma and Has Implication for Bias in Clinical Trials. J Clin Oncol 36 (16): 1603-1610, 2018. [PUBMED Abstract]
28. Cuccuini W, Briere J, Mounier N, et al.: MYC+ diffuse large B-cell lymphoma is not salvaged by classical R-ICE or R-DHAP followed by BEAM plus autologous stem cell transplantation. Blood 119 (20): 4619-24, 2012. [PUBMED Abstract]
29. Johnson NA, Slack GW, Savage KJ, et al.: Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 30 (28): 3452-9, 2012. [PUBMED Abstract]
30. Green TM, Young KH, Visco C, et al.: Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 30 (28): 3460-7, 2012. [PUBMED Abstract]
31. Horn H, Ziepert M, Becher C, et al.: MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood 121 (12): 2253-63, 2013. [PUBMED Abstract]
32. Canellos GP: CHOP may have been part of the beginning but certainly not the end: issues in risk-related therapy of large-cell lymphoma. J Clin Oncol 15 (5): 1713-6, 1997. [PUBMED Abstract]
33. Rosenwald A, Wright G, Chan WC, et al.: The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346 (25): 1937-47, 2002. [PUBMED Abstract]
34. Lossos IS, Czerwinski DK, Alizadeh AA, et al.: Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med 350 (18): 1828-37, 2004. [PUBMED Abstract]
35. Coiffier B, Altman A, Pui CH, et al.: Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 26 (16): 2767-78, 2008. [PUBMED Abstract]
36. Cortes J, Moore JO, Maziarz RT, et al.: Control of plasma uric acid in adults at risk for tumor Lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone--results of a multicenter phase III study. J Clin Oncol 28 (27): 4207-13, 2010. [PUBMED Abstract]
37. Glantz MJ, Cole BF, Recht L, et al.: High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary? J Clin Oncol 16 (4): 1561-7, 1998. [PUBMED Abstract]
38. Bernstein SH, Unger JM, Leblanc M, et al.: Natural history of CNS relapse in patients with aggressive non-Hodgkin's lymphoma: a 20-year follow-up analysis of SWOG 8516 -- the Southwest Oncology Group. J Clin Oncol 27 (1): 114-9, 2009. [PUBMED Abstract]
39. van Besien K, Ha CS, Murphy S, et al.: Risk factors, treatment, and outcome of central nervous system recurrence in adults with intermediate-grade and immunoblastic lymphoma. Blood 91 (4): 1178-84, 1998. [PUBMED Abstract]
40. Haioun C, Lepage E, Gisselbrecht C, et al.: Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin's lymphoma: final analysis of the prospective LNH87-2 protocol--a groupe d'Etude des lymphomes de l'Adulte study. J Clin Oncol 18 (16): 3025-30, 2000. [PUBMED Abstract]
41. Haioun C, Lepage E, Gisselbrecht C, et al.: Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin's lymphoma: updated results of the prospective study LNH87-2. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 15 (3): 1131-7, 1997. [PUBMED Abstract]
42. Santini G, Salvagno L, Leoni P, et al.: VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group. J Clin Oncol 16 (8): 2796-802, 1998. [PUBMED Abstract]
43. Gianni AM, Bregni M, Siena S, et al.: High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 336 (18): 1290-7, 1997. [PUBMED Abstract]
44. Kluin-Nelemans HC, Zagonel V, Anastasopoulou A, et al.: Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin's lymphoma: randomized phase III EORTC study. J Natl Cancer Inst 93 (1): 22-30, 2001. [PUBMED Abstract]
45. Gisselbrecht C, Lepage E, Molina T, et al.: Shortened first-line high-dose chemotherapy for patients with poor-prognosis aggressive lymphoma. J Clin Oncol 20 (10): 2472-9, 2002. [PUBMED Abstract]
46. Martelli M, Gherlinzoni F, De Renzo A, et al.: Early autologous stem-cell transplantation versus conventional chemotherapy as front-line therapy in high-risk, aggressive non-Hodgkin's lymphoma: an Italian multicenter randomized trial. J Clin Oncol 21 (7): 1255-62, 2003. [PUBMED Abstract]
47. Milpied N, Deconinck E, Gaillard F, et al.: Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med 350 (13): 1287-95, 2004. [PUBMED Abstract]
48. Betticher DC, Martinelli G, Radford JA, et al.: Sequential high dose chemotherapy as initial treatment for aggressive sub-types of non-Hodgkin lymphoma: results of the international randomized phase III trial (MISTRAL). Ann Oncol 17 (10): 1546-52, 2006. [PUBMED Abstract]
49. Stiff PJ, Unger JM, Cook JR, et al.: Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma. N Engl J Med 369 (18): 1681-90, 2013. [PUBMED Abstract]
50. Chiappella A, Martelli M, Angelucci E, et al.: Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study. Lancet Oncol 18 (8): 1076-1088, 2017. [PUBMED Abstract]
51. Shipp MA, Abeloff MD, Antman KH, et al.: International Consensus Conference on high-dose therapy with hematopoietic stem-cell transplantation in aggressive non-Hodgkin's lymphomas: report of the jury. Ann Oncol 10 (1): 13-9, 1999. [PUBMED Abstract]
52. Kahl BS: Bulky aggressive B-cell lymphoma: to radiate or not to radiate--that is the question. J Clin Oncol 32 (11): 1097-8, 2014. [PUBMED Abstract]
53. Phan J, Mazloom A, Medeiros LJ, et al.: Benefit of consolidative radiation therapy in patients with diffuse large B-cell lymphoma treated with R-CHOP chemotherapy. J Clin Oncol 28 (27): 4170-6, 2010. [PUBMED Abstract]

Treatment for Lymphoblastic Lymphoma (LBL)/Acute Lymphocytic Leukemia (ALL)

In This Section

• Standard Treatment Options for LBL/ALL
  • Intensive therapy
  • Radiation therapy
• Treatment Options Under Clinical Evaluation for LBL/ALL
• Current Clinical Trials

LBL is a very aggressive form of non-Hodgkin lymphoma (NHL), which often occurs in young patients but not exclusively. LBL is the lymphomatous manifestation of ALL. The treatment paradigms are based on trials for ALL because LBL and ALL are considered different manifestations of the same biologic disease. LBL is commonly associated with large mediastinal masses and has a high predilection for disseminating to bone marrow and the central nervous system (CNS). (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.) Intensive combination chemotherapy with CNS prophylaxis is the standard treatment of this aggressive histologic type of NHL. Radiation therapy is sometimes given to areas of bulky tumor masses. Because these forms of NHL tend to progress quickly, combination chemotherapy is instituted rapidly once the diagnosis has been confirmed.

The most important aspects of the pretreatment staging workup include careful review of the following pathological specimens:

• Bone marrow aspirate.
• Biopsy specimen.
• Cerebrospinal fluid cytology.
• Lymphocyte marker.

Standard Treatment Options for LBL/ALL

Standard treatment options for LBL include the following:

1. Intensive therapy.
2. Radiation therapy.

(Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)

Intensive therapy

Standard treatment is intensive combination chemotherapy with CNS prophylaxis.

Radiation therapy

Radiation therapy is sometimes given to areas of bulky tumor masses.

Treatment Options Under Clinical Evaluation for LBL/ALL

New treatment approaches are being developed by the national cooperative groups. Other approaches include the use of bone marrow transplantation for consolidation. (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)

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.

Treatment for Diffuse, Small Noncleaved-Cell/Burkitt Lymphoma

In This Section

• Standard Treatment Options for Diffuse, Small Noncleaved-Cell/Burkitt Lymphoma
  • Aggressive multidrug regimens
  • CNS prophylaxis
• Current Clinical Trials

Diffuse, small, noncleaved-cell/Burkitt lymphoma typically involves younger patients and represents the most common type of pediatric NHL.[1]

Standard Treatment Options for Diffuse, Small Noncleaved-Cell/Burkitt Lymphoma

Standard treatment options for diffuse, small, noncleaved-cell/Burkitt lymphoma include the following:

1. Aggressive multidrug regimens.
2. CNS prophylaxis.

Aggressive multidrug regimens

Standard treatment for diffuse, small, noncleaved-cell/Burkitt lymphoma is usually with aggressive multidrug regimens similar to those used for the advanced-stage aggressive lymphomas (such as diffuse large cell).[2-4] Adverse prognostic factors include bulky abdominal disease and high serum lactate dehydrogenase.

Evidence (aggressive multidrug regimens):

• Aggressive combination chemotherapy patterned after that used in childhood Burkitt lymphoma has been very successful for adult patients. More than 60% of advanced-stage patients were free of disease at 5 years.[4-7]
• Rituximab has been incorporated into these aggressive combination chemotherapy regimens. A nonrandomized, single-arm, prospective, multicenter trial of 363 patients, aged 16 years to 85 years, showed a 5-year progression-free survival of 71% and a 5-year overall survival of 80%.[3][Level of evidence: 3iiiA]

CNS prophylaxis

Patients with diffuse, small, noncleaved-cell/Burkitt lymphoma have a 20% to 30% lifetime risk of CNS involvement. CNS prophylaxis with methotrexate is recommended for all patients, usually given as four to six intrathecal injections.[8] (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information).

Evidence (CNS prophylaxis):

• In a series of 41 patients treated with systemic and intrathecal chemotherapy, 44% of those who presented with CNS disease and 13% of those who relapsed with CNS involvement became long-term disease-free survivors.[9] CNS relapse patterns were similar whether or not patients received radiation therapy, but increased neurologic deficits were noted among those patients who received radiation therapy.

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.

References

1. Blum KA, Lozanski G, Byrd JC: Adult Burkitt leukemia and lymphoma. Blood 104 (10): 3009-20, 2004. [PUBMED Abstract]
2. Thomas DA, Faderl S, O'Brien S, et al.: Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer 106 (7): 1569-80, 2006. [PUBMED Abstract]
3. Hoelzer D, Walewski J, Döhner H, et al.: Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial. Blood 124 (26): 3870-9, 2014. [PUBMED Abstract]
4. Dunleavy K, Pittaluga S, Shovlin M, et al.: Low-intensity therapy in adults with Burkitt's lymphoma. N Engl J Med 369 (20): 1915-25, 2013. [PUBMED Abstract]
5. Magrath I, Adde M, Shad A, et al.: Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol 14 (3): 925-34, 1996. [PUBMED Abstract]
6. Hoelzer D, Ludwig WD, Thiel E, et al.: Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood 87 (2): 495-508, 1996. [PUBMED Abstract]
7. Mead GM, Sydes MR, Walewski J, et al.: An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt's lymphoma: results of United Kingdom Lymphoma Group LY06 study. Ann Oncol 13 (8): 1264-74, 2002. [PUBMED Abstract]
8. Rizzieri DA, Johnson JL, Niedzwiecki D, et al.: Intensive chemotherapy with and without cranial radiation for Burkitt leukemia and lymphoma: final results of Cancer and Leukemia Group B Study 9251. Cancer 100 (7): 1438-48, 2004. [PUBMED Abstract]
9. Magrath IT, Haddy TB, Adde MA: Treatment of patients with high grade non-Hodgkin's lymphomas and central nervous system involvement: is radiation an essential component of therapy? Leuk Lymphoma 21 (1-2): 99-105, 1996. [PUBMED Abstract]

Treatment for Aggressive, Recurrent Adult NHL

In This Section

• Standard Treatment Options for Aggressive, Recurrent Adult NHL
  • Bone marrow or stem cell transplantation
  • Re-treatment with standard agents
  • Palliative radiation therapy
• Treatment Options Under Clinical Evaluation for Aggressive, Recurrent Adult NHL
• Current Clinical Trials

Standard Treatment Options for Aggressive, Recurrent Adult NHL

In a retrospective review of multiple international trials, 636 patients were identified as having refractory diffuse large B-cell lymphoma (DLBCL), which was defined as progression or stable disease during or just at completion of full-course chemotherapy or relapse within 1 year after autologous stem cell transplantation (SCT).[1] With subsequent therapy the objective response rate was 26%, complete response (CR) rate was 7%, median overall survival (OS) was 6.3 months, and only 20% of patients were alive at 2 years.

Standard treatment options for aggressive, recurrent adult non-Hodgkin lymphoma (NHL) include the following:

1. Bone marrow or stem cell transplantation.
2. Re-treatment with standard agents.
3. Palliative radiation therapy.

Bone marrow or stem cell transplantation

Bone marrow transplantation (BMT) is the treatment of choice for patients whose lymphoma has relapsed.[2] Preliminary studies indicate that approximately 20% to 40% of patients will have a long-term disease-free status, but the precise percentage depends on patient selection and the specific treatment used. Preparative drug regimens have varied; some investigators also use total-body irradiation. Similar success has been achieved using autologous marrow, with or without marrow purging, and allogeneic marrow.[3-7]

Evidence (BMT):

1. In a prospective, randomized study, (EORTC-PARMA), 215 patients in first or second relapse of aggressive lymphoma, younger than 60 years, and with no bone marrow or central nervous system involvement, were given two cycles of intensive combination chemotherapy. The 109 patients who responded were randomly assigned to receive four more cycles of chemotherapy and involved-field radiation therapy (IF-XRT) versus autologous BMT followed by IF-XRT. With a 5-year median follow-up, the event-free survival (EFS) was significantly improved with transplantation (46% vs. 12%). OS was also significantly better with transplantation (53% vs. 32%).[8][Level of evidence: 1iiA] Salvage BMT was unsuccessful for patients on the nontransplant arm whose disease relapsed.
   In general, patients who responded to initial therapy and who responded to conventional therapy for relapse before the BMT have had the best results.[9]
2. In a prospective trial, patients who relapsed late (>12 months after diagnosis) had better OS than patients who relapsed earlier (8-year survival was 29% vs. 13%, P = .001).[10][Level of evidence: 3iiiA]

Peripheral stem cell transplantation (SCT) has yielded results equivalent to standard autologous SCT.[11,12] Even patients who never experienced complete remission with conventional chemotherapy may have prolonged progression-free survival (31% at 5 years) after high-dose chemotherapy and hematopoietic SCT if they retain chemosensitivity to reinduction therapy.[13][Level of evidence: 3iiiDiii] Some patients who relapse after a previous autologous SCT can have durable remissions after myeloablative or nonmyeloablative allogeneic SCT.[14,15]; [16][Level of evidence: 3iiiDiv]

Evidence (peripheral SCT):

• In a randomized prospective trial, 396 patients with DLBCL in first relapse or who were refractory to first-line therapy received either R-ICE (rituximab, ifosfamide, etoposide, and carboplatin) or R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin) followed by autologous SCT; there was no difference in 3-year EFS or OS.[17][Level of evidence: 1iiA]
• In a randomized prospective trial, 619 patients with relapsed or refractory aggressive lymphoma received either R-DHAP or R-GDP (rituximab, gemcitabine, dexamethasone, and cisplatin) followed by autologous SCT; at a median follow-up of 53 months, there was no difference in EFS or OS, but patients who received R-GDP reported less toxicity.[18][Level of evidence: 1iiC]

Re-treatment with standard agents

In general, re-treatment with standard agents rarely produces a cure in patients whose lymphomas relapse.[19] Several salvage chemotherapy regimens are available.[20-22]

• Rituximab alone can induce responses in 33% of patients with relapsing aggressive lymphoma of appropriate phenotype (CD20-positive).[23]; [24][Level of evidence: 3iiiDiv]
• Radiolabeled anti-CD20 monoclonal antibodies, such as iodine I 131-tositumomab (no longer commercially available) and yttrium Y 90-ibritumomab tiuxetan, induce 60% to 80% response rates in patients with relapsed or refractory B-cell lymphoma.[25,26]; [27][Level of evidence: 3iiiDiv]
• In two phase II trials, 49 patients showed a 19% to 35% overall response rate to lenalidomide with or without rituximab.[28,29][Level of evidence: 3iiiDiv]

Relapse with indolent lymphoma

Durable responses to radiolabeled monoclonal antibodies have been reported for transformed low-grade B-cell lymphoma.[25,26] Not infrequently, an aggressive lymphoma may relapse as a small cell (indolent) lymphoma. Such a situation occurs with indolent lymphoma in the bone marrow and aggressive lymphoma in a nodal site. Patients may present in such a manner, and chemotherapy might successfully eradicate the peripheral disease while failing to eliminate the small cell component from the bone marrow. The clinical significance and natural history of this pattern of disease is not well defined.

CAR T-cell therapy

Two multicenter phase II studies reported on 138 patients with refractory large B-cell lymphoma who underwent an infusion of T cells that were engineered to express a chimeric antigen receptor (CAR) to target the CD19 antigen expressed on the malignant B cells.[30,31] Each study reported a 50% to 60% CR, but the durability of response is yet to be determined.[30,31][Level of evidence: 3iiiDiv] This represents a therapeutic option for patients with otherwise refractory or resistant disease. Patients who respond adequately may receive an autologous SCT or allogeneic SCT consolidation.

Palliative radiation therapy

In general, patients with aggressive lymphoma who relapse with indolent histology will benefit from palliative therapy.[32] Palliation may be achieved with very low-dose (4 Gy) IF-XRT for patients with indolent and aggressive relapsed disease.[33]

Treatment Options Under Clinical Evaluation for Aggressive, Recurrent Adult NHL

Treatment options under clinical evaluation include the following:

• SCT. The indolent lymphomas may relapse with an aggressive histology (i.e., histologic conversion). The durability of the second remission may be short, and clinical trials, such as autologous or allogeneic peripheral SCT, can be considered.[34-37]

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.

References

1. Crump M, Neelapu SS, Farooq U, et al.: Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood 130 (16): 1800-1808, 2017. [PUBMED Abstract]
2. Shipp MA, Abeloff MD, Antman KH, et al.: International Consensus Conference on high-dose therapy with hematopoietic stem-cell transplantation in aggressive non-Hodgkin's lymphomas: report of the jury. Ann Oncol 10 (1): 13-9, 1999. [PUBMED Abstract]
3. Freedman AS, Takvorian T, Anderson KC, et al.: Autologous bone marrow transplantation in B-cell non-Hodgkin's lymphoma: very low treatment-related mortality in 100 patients in sensitive relapse. J Clin Oncol 8 (5): 784-91, 1990. [PUBMED Abstract]
4. Phillips GL, Fay JW, Herzig RH, et al.: The treatment of progressive non-Hodgkin's lymphoma with intensive chemoradiotherapy and autologous marrow transplantation. Blood 75 (4): 831-8, 1990. [PUBMED Abstract]
5. Chopra R, Goldstone AH, Pearce R, et al.: Autologous versus allogeneic bone marrow transplantation for non-Hodgkin's lymphoma: a case-controlled analysis of the European Bone Marrow Transplant Group Registry data. J Clin Oncol 10 (11): 1690-5, 1992. [PUBMED Abstract]
6. Ratanatharathorn V, Uberti J, Karanes C, et al.: Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkin's lymphoma. Blood 84 (4): 1050-5, 1994. [PUBMED Abstract]
7. Mills W, Chopra R, McMillan A, et al.: BEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin's lymphoma. J Clin Oncol 13 (3): 588-95, 1995. [PUBMED Abstract]
8. Philip T, Guglielmi C, Hagenbeek A, et al.: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 333 (23): 1540-5, 1995. [PUBMED Abstract]
9. Vellenga E, van Putten WL, van 't Veer MB, et al.: Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20+ NHL: a prospective randomized HOVON trial. Blood 111 (2): 537-43, 2008. [PUBMED Abstract]
10. Guglielmi C, Gomez F, Philip T, et al.: Time to relapse has prognostic value in patients with aggressive lymphoma enrolled onto the Parma trial. J Clin Oncol 16 (10): 3264-9, 1998. [PUBMED Abstract]
11. Vose JM, Anderson JR, Kessinger A, et al.: High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-Hodgkin's lymphoma. J Clin Oncol 11 (10): 1846-51, 1993. [PUBMED Abstract]
12. Liberti G, Pearce R, Taghipour G, et al.: Comparison of peripheral blood stem-cell and autologous bone marrow transplantation for lymphoma patients: a case-controlled analysis of the EBMT Registry data. Lymphoma Working Party of the EBMT. Ann Oncol 5 (Suppl 2): 151-3, 1994. [PUBMED Abstract]
13. Vose JM, Zhang MJ, Rowlings PA, et al.: Autologous transplantation for diffuse aggressive non-Hodgkin's lymphoma in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol 19 (2): 406-13, 2001. [PUBMED Abstract]
14. van Kampen RJ, Canals C, Schouten HC, et al.: Allogeneic stem-cell transplantation as salvage therapy for patients with diffuse large B-cell non-Hodgkin's lymphoma relapsing after an autologous stem-cell transplantation: an analysis of the European Group for Blood and Marrow Transplantation Registry. J Clin Oncol 29 (10): 1342-8, 2011. [PUBMED Abstract]
15. Freytes CO, Loberiza FR, Rizzo JD, et al.: Myeloablative allogeneic hematopoietic stem cell transplantation in patients who experience relapse after autologous stem cell transplantation for lymphoma: a report of the International Bone Marrow Transplant Registry. Blood 104 (12): 3797-803, 2004. [PUBMED Abstract]
16. Rezvani AR, Norasetthada L, Gooley T, et al.: Non-myeloablative allogeneic haematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: a multicentre experience. Br J Haematol 143 (3): 395-403, 2008. [PUBMED Abstract]
17. Gisselbrecht C, Glass B, Mounier N, et al.: Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 28 (27): 4184-90, 2010. [PUBMED Abstract]
18. Crump M, Kuruvilla J, Couban S, et al.: Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol 32 (31): 3490-6, 2014. [PUBMED Abstract]
19. Larouche JF, Berger F, Chassagne-Clément C, et al.: Lymphoma recurrence 5 years or later following diffuse large B-cell lymphoma: clinical characteristics and outcome. J Clin Oncol 28 (12): 2094-100, 2010. [PUBMED Abstract]
20. Rodriguez MA, Cabanillas FC, Velasquez W, et al.: Results of a salvage treatment program for relapsing lymphoma: MINE consolidated with ESHAP. J Clin Oncol 13 (7): 1734-41, 1995. [PUBMED Abstract]
21. Rizzieri DA, Sand GJ, McGaughey D, et al.: Low-dose weekly paclitaxel for recurrent or refractory aggressive non-Hodgkin lymphoma. Cancer 100 (11): 2408-14, 2004. [PUBMED Abstract]
22. Kewalramani T, Zelenetz AD, Nimer SD, et al.: Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood 103 (10): 3684-8, 2004. [PUBMED Abstract]
23. Coiffier B, Haioun C, Ketterer N, et al.: Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood 92 (6): 1927-32, 1998. [PUBMED Abstract]
24. Tobinai K, Igarashi T, Itoh K, et al.: Japanese multicenter phase II and pharmacokinetic study of rituximab in relapsed or refractory patients with aggressive B-cell lymphoma. Ann Oncol 15 (5): 821-30, 2004. [PUBMED Abstract]
25. Fisher RI, Kaminski MS, Wahl RL, et al.: Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin's lymphomas. J Clin Oncol 23 (30): 7565-73, 2005. [PUBMED Abstract]
26. Witzig TE, Gordon LI, Cabanillas F, et al.: Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 20 (10): 2453-63, 2002. [PUBMED Abstract]
27. Wiseman GA, Gordon LI, Multani PS, et al.: Ibritumomab tiuxetan radioimmunotherapy for patients with relapsed or refractory non-Hodgkin lymphoma and mild thrombocytopenia: a phase II multicenter trial. Blood 99 (12): 4336-42, 2002. [PUBMED Abstract]
28. Zinzani PL, Pellegrini C, Gandolfi L, et al.: Combination of lenalidomide and rituximab in elderly patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 2 trial. Clin Lymphoma Myeloma Leuk 11 (6): 462-6, 2011. [PUBMED Abstract]
29. Wiernik PH, Lossos IS, Tuscano JM, et al.: Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin's lymphoma. J Clin Oncol 26 (30): 4952-7, 2008. [PUBMED Abstract]
30. Neelapu SS, Locke FL, Bartlett NL, et al.: Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med 377 (26): 2531-2544, 2017. [PUBMED Abstract]
31. Schuster SJ, Svoboda J, Chong EA, et al.: Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. N Engl J Med 377 (26): 2545-2554, 2017. [PUBMED Abstract]
32. Lee AY, Connors JM, Klimo P, et al.: Late relapse in patients with diffuse large-cell lymphoma treated with MACOP-B. J Clin Oncol 15 (5): 1745-53, 1997. [PUBMED Abstract]
33. Haas RL, Poortmans P, de Jong D, et al.: Effective palliation by low dose local radiotherapy for recurrent and/or chemotherapy refractory non-follicular lymphoma patients. Eur J Cancer 41 (12): 1724-30, 2005. [PUBMED Abstract]
34. Yuen AR, Kamel OW, Halpern J, et al.: Long-term survival after histologic transformation of low-grade follicular lymphoma. J Clin Oncol 13 (7): 1726-33, 1995. [PUBMED Abstract]
35. Bastion Y, Sebban C, Berger F, et al.: Incidence, predictive factors, and outcome of lymphoma transformation in follicular lymphoma patients. J Clin Oncol 15 (4): 1587-94, 1997. [PUBMED Abstract]
36. Williams CD, Harrison CN, Lister TA, et al.: High-dose therapy and autologous stem-cell support for chemosensitive transformed low-grade follicular non-Hodgkin's lymphoma: a case-matched study from the European Bone Marrow Transplant Registry. J Clin Oncol 19 (3): 727-35, 2001. [PUBMED Abstract]
37. Tsimberidou AM, O'Brien S, Khouri I, et al.: Clinical outcomes and prognostic factors in patients with Richter's syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. J Clin Oncol 24 (15): 2343-51, 2006. [PUBMED Abstract]

NHL During Pregnancy

In This Section

• General Information About NHL During Pregnancy
• Stage Information for NHL During Pregnancy
• Treatment Option Overview for NHL During Pregnancy
• Indolent NHL During Pregnancy
• Aggressive NHL During Pregnancy
  • Immediate therapy
  • Early delivery when feasible
  • Termination of pregnancy

General Information About NHL During Pregnancy

Non-Hodgkin lymphomas (NHL) occur more frequently than Hodgkin lymphoma in an older population. This age difference may account for fewer reports of NHL in pregnant patients.[1]

Stage Information for NHL During Pregnancy

To avoid exposure to ionizing radiation, magnetic resonance imaging is the preferred tool for staging evaluation.[2] (Refer to the Stage Information for Adult NHL section of this summary for more information.)

Treatment Option Overview for NHL During Pregnancy

Table 5. Treatment Options for Non-Hodgkin Lymphoma (NHL) During Pregnancy

Stage	Standard Treatment Options
Indolent NHL During Pregnancy	Delay treatment until after delivery
Aggressive NHL During Pregnancy	Immediate therapy
	Early delivery, when feasible
	Termination of pregnancy

Indolent NHL During Pregnancy

Treatment may be delayed for those women with an indolent NHL.

Aggressive NHL During Pregnancy

Immediate therapy

According to anecdotal case series, most NHL in pregnant patients are aggressive, and delay of therapy until after delivery appears to have poor outcomes.[1,3-5] Consequently, some investigators favor immediate therapy, even during pregnancy.[5] In a review of 121 patient case reports from 74 papers, one-half of the patients had very aggressive lymphomas, such as Burkitt lymphoma, and one-half of the patients had involvement of the breast, ovaries, uterus, or placenta.[6] One-half of the patients received therapy antepartum, and the 6-month survival was reported at 53%, with a live-birth rate of 83%.[6][Level of evidence: 3iiiDiv]

A multicenter retrospective analysis of 50 patients described pregnancy termination in 3 patients, deferral of therapy to postpartum in 15 patients (median 30 weeks gestation), and antenatal therapy applied to the remaining 32 patients (median 21 weeks gestation, all done after the first trimester).[7] With a median follow-up of 41 months, the 3-year progression-free survival was 53%, and overall survival was 82%, using R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) or modifications of this regimen.[7][Level of evidence: 3iiiDiv]

Early delivery when feasible

For some women, early delivery, when feasible, may minimize or avoid exposure to chemotherapy or radiation therapy.

Termination of pregnancy

Termination of pregnancy in the first trimester may be an option that allows immediate therapy for women with aggressive NHL.

Evidence (treatment effect on children exposed in utero):

• With follow-up ranging from several months to 11 years, children who were exposed to high-dose doxorubicin-containing combination chemotherapy in utero (especially during the second and third trimester) have been found to be normal.[5,8-10] For most of the chemotherapeutic agents used for the treatment of NHL, there are no data regarding long-term effects on children exposed in utero.
• In one anecdotal case, a newborn exposed to a rituximab-containing regimen in utero was born with no circulating B lymphocytes. The newborn was otherwise normal and recovered the circulating B lymphocytes by age 6 months with no unusual or persisting intercurrent infections.[11]

References

1. Ward FT, Weiss RB: Lymphoma and pregnancy. Semin Oncol 16 (5): 397-409, 1989. [PUBMED Abstract]
2. Nicklas AH, Baker ME: Imaging strategies in the pregnant cancer patient. Semin Oncol 27 (6): 623-32, 2000. [PUBMED Abstract]
3. Steiner-Salz D, Yahalom J, Samuelov A, et al.: Non-Hodgkin's lymphoma associated with pregnancy. A report of six cases, with a review of the literature. Cancer 56 (8): 2087-91, 1985. [PUBMED Abstract]
4. Spitzer M, Citron M, Ilardi CF, et al.: Non-Hodgkin's lymphoma during pregnancy. Gynecol Oncol 43 (3): 309-12, 1991. [PUBMED Abstract]
5. Gelb AB, van de Rijn M, Warnke RA, et al.: Pregnancy-associated lymphomas. A clinicopathologic study. Cancer 78 (2): 304-10, 1996. [PUBMED Abstract]
6. Horowitz NA, Benyamini N, Wohlfart K, et al.: Reproductive organ involvement in non-Hodgkin lymphoma during pregnancy: a systematic review. Lancet Oncol 14 (7): e275-82, 2013. [PUBMED Abstract]
7. Evens AM, Advani R, Press OW, et al.: Lymphoma occurring during pregnancy: antenatal therapy, complications, and maternal survival in a multicenter analysis. J Clin Oncol 31 (32): 4132-9, 2013. [PUBMED Abstract]
8. Avilés A, Díaz-Maqueo JC, Torras V, et al.: Non-Hodgkin's lymphomas and pregnancy: presentation of 16 cases. Gynecol Oncol 37 (3): 335-7, 1990. [PUBMED Abstract]
9. Moore DT, Taslimi MM: Multi-agent chemotherapy in a case of non-Hodgkin's lymphoma in second trimester of pregnancy. J Tenn Med Assoc 84 (9): 435-6, 1991. [PUBMED Abstract]
10. Nantel S, Parboosingh J, Poon MC: Treatment of an aggressive non-Hodgkin's lymphoma during pregnancy with MACOP-B chemotherapy. Med Pediatr Oncol 18 (2): 143-5, 1990. [PUBMED Abstract]
11. Mandal PK, Dolai TK, Bagchi B, et al.: B cell suppression in newborn following treatment of pregnant diffuse large B-cell lymphoma patient with rituximab containing regimen. Indian J Pediatr 81 (10): 1092-4, 2014. [PUBMED Abstract]

Changes to This Summary (02/22/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was comprehensively reviewed and extensively revised.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult non-Hodgkin lymphoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewer for Adult Non-Hodgkin Lymphoma Treatment is:

• Eric J. Seifter, MD (Johns Hopkins University)

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The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Adult Non-Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389492]

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• Updated: February 22, 2019