by Drs. C.D. Buckner M.D. and C.H. Weaver M.D. updated 7/2021

Rituxan is a targeted therapy that binds to a marker known as CD20 on the surface of B-cells. This binding prompts the immune system to destroy the cell, and also has direct anticancer effects on the cell. Rituxan is commonly used for the initial treatment and as maintenance therapy fo B-cell non-Hodgkin’s lymphomas (NHL) and chronic lymphocytic leukemia (CLL).1,2

Maintenance therapy refers to longer-term treatment that is given after a patient achieves a remission. The goal of maintenance therapy is to prolong the remission and increase survival duration.

Maintenance Therapy in the COVID-19 Era

Individuals impacted by a cancer diagnosis should consider two different strategies to reduce their risk during the pandemic. The first is to ensure they take appropriate precautions to avoid unnecessary exposure to the virus. The second is to carefully consider the risks and potential benefits of treatment and whether changes to their treatment strategy could be implemented to reduce their risk of corona virus infection. 

Maintenance therapy is immunosuppressive which means it can increase an individuals risk of developing an infection and cancer patients diagnosed with COVID-19 have a higher mortality than non-cancer patients. Maintenance is used because it delays the time to cancer recurrence, but only prolongs survival in certain types of lymphoma. In the COVID-19 era does it make sense to stay on prolonged therapy that suppresses the immune system if there is no or little survival benefit? There are many kinds of B-Cell lymphomas and not all of them benefit the same from maintenance therapy-patients should discuss the potential benefits and risk of maintenance therapy for "their" lymphoma with their physician.

Maintenance Therapy for DLBCL?

Rituxan maintenance therapy is not recommended in the National Comprehensive Cancer Network clinical guidelines for the management of Diffuse Large B Cell Lymphoma (DLBCL). Meta-analyses of several trials however shows that Rituxan does improve survival and there is increasing evidence that men are relatively under-dosed with the “standard” dose of Rituxan compared to women. Men might benefit from a higher Rituxan dose or longer duration of treatment with Rituxan.11,12

The German High Grade non-Hodgkin Lymphoma Study Group (GHLSG) reported that men >60 years old had more rapid Rituxan clearance than women and the resultant higher plasma Rituxan levels in women might be the explanation for the observed superior treatment outcome with R-CHOP in women than in men.13,14

To evaluate this the GHLSG tested a higher dose of Rituxan in men in the SEXIE-R-CHOP-14 study.5 This study investigated six cycles of R-CHOP-14 dosed at 500 mg/m2 in men, but the dose of Rituxan in women was the standard 375 mg/m2. Pharmacokinetic assays were included within the study and showed that men achieved higher peak levels of Rituxan, but their total exposure to the drug was approximately the same as that of women because of more rapid drug clearance. The 3-year progression-free survival in men was 74% versus 68% in women, the overall survival was also not significantly different.15

What the authors did discover in a prospective fashion is that maintenance Rituxan appeared to improve the outcome in men but not women, with no obvious impact of age on the outcome. The authors concluded that maintenance Rituxan eliminated the previously found poorer outcome in men with DLBCL.  Men should be made aware of the data and older men should be offered a higher dose of Rituxan or maintenance.

Rituxan Maintenance Therapy for Follicular Lymphoma

Rituxan maintenance therapy was evaluated in a phase III clinical trial known as PRIMA in patients with stage III or IV follicular lymphoma whose disease had been reduced or eliminated by initial treatment with a combination of chemotherapy and Rituxan. Half the study participants were assigned to receive an additional two years of Rituxan as maintenance therapy and half received no maintenance therapy.2,3

The study results initially published in the The Lancet demonstrated that three-year progression-free survival was 75% among patients given Rituxan maintenance therapy compared with 57% of patients given no maintenance therapy suggesting that maintenance therapy with Rituxan prolonged remission among patients in a remission with follicular lymphoma.

Additional long-term follow-up results published in The July 2019 J Clin Oncology confirm the initially reported benefit. The average duration of survival without lymphoma recurrence increased to 10.5 years compared to only 4.1 years if no maintenance therapy was administered. Overall survival was similar however; ~ 80% for those receiving and not receiving Rituxan maintenance therapy.3

The study authors observed that “Despite the lack of a survival advantage, it is noteworthy that more than half of the patients receiving Rituxan maintenance remain free of disease progression and have not required new anti-lymphoma treatment beyond 10 years.” Moreover research suggests that Rituxan maintenance is cost effective.9

Maintenance Rituxan for Relapsed/Refractory Follicular and Mantle Cell NHL

According to results presented at the 42nd annual meeting of the American Society of Clinical Oncology (ASCO), additional therapy with Rituxan® following initial therapy with fludarabine/cyclophosphamide/mitoxantrone/Rituxan (R-FCM) lengthens anticancer responses in patients with relapsed or refractory follicular or mantle cell lymphoma. There is also a trend toward improved overall survival with R-FCM in these patients.

Researchers affiliated with the German Low Grade Lymphoma Study Group (GLSG) presented final analysis of a trial that evaluated the use of maintenance Rituxan following induction with R-FCM in relapsed or refractory follicular or mantle cell lymphoma. Patients either received initial therapy with R-FCM with no follow-up treatment (observation group) or were treated with R-FCM followed by maintenance Rituxan.

  • Three year survival rates were 82% for those treated with maintenance Rituxan and 55% for those in the observation group.

The researchers concluded that maintenance Rituxan for the treatment of relapsed/refractory follicular lymphoma or mantle cell lymphoma following induction R-FCM significantly improves progression-free survival with trend toward improved overall survival compared to observation

Results from another phase III clinical trial indicate that maintenance therapy with Rituxan® improves progression-free survival in patients with follicular NHL. The results of this trial were so promising that the trial was stopped early.

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Researchers associated with the EORTC conducted a phase III clinical trial in 18 countries to evaluate maintenance therapy in 465 patients with recurrent indolent (follicular) NHL. Patients were initially treated with Rituxan plus CHOP or with CHOP chemotherapy alone. The next part of the trial involved evaluating the effectiveness of two years of Rituxan as maintenance therapy compared to placebo (inactive substitute) in these patients. 

At approximately 18 months follow-up, both groups of patients (those treated initially with Rituxan/CHOP and those treated only with CHOP) experienced an improvement in progression-free survival when treated with maintenance Rituxan compared to placebo.

Maintenance Rituxan 2 vs 3 Months?

Maintenance therapy with Rituxan administered every 2 months is considered standard for individuals with indolent or follicular non-Hodgkin lymphomas and mantle cell lymphoma following completion of CHOP, CVP and BR chemotherapy.

Doctors published a study calling into question whether Rituxan is better administered every 3 months. They reviewed the medical records of patients with B-cell indolent non-Hodgkin lymphoma or mantle cell lymphoma treated at their cancer center with R-CHOP/R-CVP or BR as first-line induction followed by maintenance (375 mg/m2) every 2 months or every 3 months.

  • Of the patients treated with BR, 31% experienced side effects during MR compared with 16% of those who received R-CHOP/R-CVP.
  • Side effects were observed in 41% of patients in the every-2-months compared to 15% in the every-3-month group.
  • There was a trend toward higher 3-year survival without cancer progression for 3-month RM therapy compared with every 2 months.

Patients receiving Rituxan maintenance every 2 months were 3.4 times more likely to experience side effects and showed a trend toward shorter survival without cancer progression which may be the result of more dose delays/omissions and, ultimately, early treatment discontinuation. It's unclear from the study that 3 month RM is superior to 2 month but patients experiencing dose delays and side effects should probably not be overly concerned that these delays are compromising their treatment.

Immediate vs Delayed Maintenance?

Among patients with low-tumor-burden follicular lymphoma who have received initial treatment with Rituxan® waiting until the lymphoma progresses to start Rituxan appears as effective as immediate ongoing, maintenance Rituxan.10

To compare these two different approaches to Rituxan treatment, researchers conducted a Phase III clinical trial known as RESORT. The study enrolled 384 people with previously untreated, low-tumor-burden follicular lymphoma. All of the study participants initially received Rituxan for four weeks and then were assigned to ongoing maintenance therapy with Rituxan every three months or treatment as needed with four weekly doses of Rituxan when their lymphoma showed signs of worsening.

  • Patients in the as-needed group received many fewer doses of Rituxan than patients in the maintenance therapy group (4.5 doses on average, versus 15.8 doses).
  • Time to treatment failure was 3.6 years in the as-needed group and 3.9 years in the maintenance therapy group. The difference between the two study groups was not statistically significant, suggesting that it could have occurred by chance alone.
  • A secondary outcome of interest was time to chemotherapy. After three years of follow-up, 86 percent of patients in the as-needed group had avoided the need for chemotherapy, compared with 95 percent of patients in the maintenance therapy group. This difference favored the maintenance therapy group and was statistically significant (unlikely to be due to chance), but also required many additional Rituxan doses.

These results suggest both approaches to Rituxan are effective for low-tumor-burden follicular lymphoma. The as-needed approach, however, has the advantage of requiring many fewer doses of Rituxan.

Treanda® and Rituxan® Effective for Relapsed CLL

In a Phase II clinical trial, the combination of Treanda® (bendamustine)®and Rituxan® produced promising results among patients with relapsed CLL.

CLL is the most common adult leukemia, with over 15,000 individuals diagnosed per year in the United States and more than 4,000 deaths. CLL is a disease characterized by high numbers of circulating abnormal lymphocytes (B-cells) in the peripheral blood. The disease often involves enlargement of lymph nodes in various parts of the body as well as enlargement of the spleen. It typically occurs in individuals between 65 and 70 years of age.

Treanda is a chemotherapy agent that has been approved for the treatment of CLL and certain types of non-Hodgkin®s lymphoma.

To evaluate the combination of Treanda and Rituxan in the treatment of CLL, researchers in Germany conducted a Phase II clinical trial among 81 patients with relapsed or refractory CLL (CLL that had returned after prior treatment, or that was resistant to prior treatment). All patients were treated with both drugs.

  • 77% of patients experienced a complete or partial disappearance of detectable cancer following treatment: 63% of patients had a partial response. 14% of patients had a complete response.
  • Severe side effects included low blood counts and infection.

These results suggest that the combination of Treanda and Rituxan is active against relapsed or refractory CLL. These results have led to a new trial comparing the efficacy of Treanda and Rituxan to Fludara® (fludarabine), Cytoxan® (cyclophosphamide) and Rituxan for treatment of newly diagnosed patients.

References:

  1. Friedberg JW. Rituximab maintenance in follicular lymphoma: PRIMA. The Lancet [early online publication]. December 21, 2010.
  2. Genentech news release. FDA approves Rituxan for first-line maintenance use in follicular lymphoma. January 28, 2011.
  3. J Clin Oncol. 2019 Jul 24. Epub ahead of print.
  4. Fischer K, Stilgenbauer S, Schweighofer CD et al. Bendamustine in combination with rituximab (BR) for patients with relapsed chronic lymphocytic leukemia (CLL): a multicentre phase II trial of the German CLL Study Group (GCLLSG). Presented at the 50th Annual Meeting of the American Society of Hematology, San Francisco, CA, December 6-9, 2008. Abstract 330.
  5. Roche. Phase III MabThera maintenance trial in lymphoma shows positive results earlier than expected. Available at: roche.com/med-cor-2005-10-26. Accessed October 2005
  6. Dreyling M, Forstpointer R, Gramatzki M, et al. Rituximab Maintenance Improves Progression-Free and Overall Survial Rates after Combined Immuno-Chemotherapy (R-FCM) I Patients with Relapsed Follicular and Mantle Cell Lymphoma: Final Results of a Prospective Randomized Trial of the German Low Grade Lymphoma Study Group (GLSG). Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, GA. June 2006. Abstract # 7502
  7. 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. The Lancet [early online publication]. December 21, 2010.
  8. Armin Rashidi, Eunhye Oak and Nancy L. Bartlett Blood 2015 125:3354-3355; doi: https://doi.org/10.1182/blood-2015-02-628362
  9. Hayslip JW, Simpson KN. Cost-effectiveness of extended adjuvant rituximab for US patients aged 65-70 years with follicular lymphoma in second remission. Clinical Lymphoma Myeloma. 2008;8:166-170.
  10. Kahl BS, Hong F, Williams ME et al. Results of Eastern Cooperative Oncology Group Protocol E4402 (RESORT): A randomized Phase III study comparing two different rituximab dosing strategies for low tumor burden follicular lymphoma. Presented at the 53rd Annual Meeting of the American Society of Hematology. December 10-13, 2011. Abstract LBA-6.
  11. Jaeger U, Trneny M, Melzer H, et al. Rituximab maintenance for patients with aggressive B-cell lymphoma in first remission: results of the randomized NHL13 trial. Haematologica. 2015;100(7):955–963.
  12. https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.15_suppl.7507

  13. Pfeundschuh M, Held G, Zeynalova S, et al. Increased rituximab (R) doses and effect on risk of elderly male patients with aggressive CD20+ B-cell lymphomas: results of the SEXIE-R-CHOP-14 trial of the DSHNHL. J Clin Oncol. 32:5s, 2014. (suppl; abstr 8501).

  14. 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. 2014;32(36):4127–4133

  15. Muller C, Murawski N, Wiesen MH, et al. The role of sex and weight on rituximab clearance and serum elimination half-life in elderly patients with DLBCL. Blood. 2012;119(14):3276–3284.