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Rituximab (Rituxan)

 

Rituximab (Rituxan, Mabthera)

Rituximab was the first monoclonal antibody on the market. It goes by the brand name of Rituxan in the United States and Canada. In most of Europe it is known by the name Rituximab, and in Australia Mabthera.

Since its' debut in the USA in 1997 it has been the first new treatment to make a dramatic improvement in response rates, and survival rates for many forms of B-cell lymphomas. It is now approved in most countries around the world. Rituxan targets the CD20 antigen found on most B lymphocytes, both healthy and cancerous ones.

Rituxan was originally approved as a single agent treatment for relapsed indolent lymphoma. Response rates were modest. There was a 6% complete remission rate and a 42% partial remission rate for an overall response rate of 48%. (1)

Further studies consistently showed that it had a synergistic effect when combined with most chemotherapy regimens. The first groundbreaking study by Bertrand Coiffier et al (2) proved a significant improvement in response rates for elderly patients with Diffuse Large B-cell Lymphoma when treated with CHOP+Rituxan versus CHOP alone.

It is now standard practice to combine Rituxan with most chemotherapy regimens when treating B-cell lymphoma. Study after study has shown it dramatically improves the results.

Maintenance Rituxan

Maintenance Rituxan has become standard practice by many physicians for patients with indolent lymphoma. Maintenance simply means that the patient receives doses of Rituxan on an ongoing basis while in remission. There are several different schedules for maintenance Rituxan but the two most common are to have one dose every 2 or 3 months, or to have an infusion every week for four weeks, repeated every six months. Maintenance continues for 2 years, though some studies have investigated using it for longer than 2 years. The primary reason it only continues for 2 years is that Rituxan suppresses the immune system by depleting the lymphocytes. There is concern that extended immune suppression can lead to complication such as opportunistic infections. In fact there is evidence to suggest that the maintenance schedule of one infusion every 2 months is more toxic than one infusion every 3 months, and no more effective. (3) Therefore it is possible once every 3 months may soon be the new standard.

Over the years there has been a great deal of controversy about whether or not it was beneficial.  What is generally accepted now is that maintenance Rituxan will increase the length of the progression free survival, but not the overall survival. In other words a patient will stay in remission longer, but their survival is not improved. (4) The time until stronger chemotherapy is required is also not improved. Therefore the use of maintenance Rituxan becomes a personal choice between the doctor and the patient. Remember that people on maintenance still have to go to the hospital on a regular basis to receive their treatment, and the treatment is expensive. This must be weighed against the benefit of remaining in remission longer, and delaying the time until you need stronger chemotherapy. There is no right or wrong choice.  Below are a variety of studies on the topic. They are grouped into studies that generally favour maintenance Rituxan, and those that have a neutral or negative view. However the first link is the National Lymphocare study, which was the largest study ever undertaken to examine Maintenance Rituxan. It is quite a comprehensive review of the current knowledge on the topic.

The use and effectiveness of rituximab maintenance in patients with follicular lymphoma diagnosed between 2004 and 2007 in the United States

Next is an explanation of the results of that study from HemOnc today

Maintenance rituximab extended PFS, not OS in follicular lymphoma

Generally in favour of maintenance Rituxan

  1. What is the role of maintenance Rituxan in follicular lymphoma?

  2. Should maintenance Rituximab for follicular NHL be routine?

  3. Updated 6 Year Follow-Up Of The PRIMA Study Confirms The Benefit Of 2-Year Rituximab Maintenance In Follicular Lymphoma Patients Responding To Frontline Immunochemotherapy

  4. Rituximab Maintenance Treatment of Relapsed/Resistant Follicular Non-Hodgkin's Lymphoma: Long-Term Outcome of the EORTC 20981 Phase III Randomized Intergroup Study

  5. Maintenance Rituximab After Cyclophosphamide, Vincristine, and Prednisone Prolongs Progression-Free Survival in Advanced Indolent Lymphoma: Results of the Randomized Phase III ECOG1496 Study

  6. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide and mitoxantrone (R-FCM) 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 (GLSG)

  7. Individualized Rituximab Dosing for Patients With CD20-Positive Lymphoproliferative Disorders

Generally neutral or negative perspective

  1. 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

  2. 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

  3. Maintenance or Eradication of Residual Disease in Indolent Lymphoma: Where Do We Stand

  4. Rituximab Extended Schedule or Re-Treatment Trial for Low–Tumor Burden Follicular Lymphoma: Eastern Cooperative Oncology Group Protocol E4402

    1. A peer review of the above study

  5. Rituximab-CHOP Versus CHOP Alone or With Maintenance Rituximab in Older Patients With Diffuse Large B-Cell Lymphoma

  6. Rituximab maintenance for patients with aggressive B-cell lymphoma in first remission: results of the randomized NHL13 trial.

  7. Two years rituximab maintenance vs. observation after first-line treatment with bendamustine plus rituximab (B-R) in patients with mantle cell lymphoma: First results of a prospective, randomized, multicenter phase II study (a subgroup study of the StiL NHL7-2008 MAINTAIN trial)

What follows is a discussion by 2 experts about how they feel about maintenance Rituxan taking into consideration all the studies above. Arguing in favour is Dr. Richard Fisher, MD and CEO for Fox Chasse Cancer Center in  Philadelphia, Pennsylvania USA. Arguing against in Dr. Andrew Zelenetz, MD Vice Chair for Medical Informatics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Yes or No for Maintenance Rituximab in Follicular Lymphoma?

Rituxan Risks

While Rituxan is arguably the safest treatment used for NHL it is not entirely risk free. Perhaps the best source of risk information is Rituxan's own boxed warnings.

Here are some articles about the possible risks of Rituxan treatment. Hypogammaglobulinemia is the most frequent. This big word just means low levels of the gamma globulin (antibodies) in the immune system. The other common risk is late onset neutropenia. This is where your neutrophils take a dive, long after Rituxan treatment is over. It is usually mild and reversible. See the first link below for information about LON.

  1. Late-onset Neutropenia Following Rituximab Therapy
  2. High incidence of non-neutropenic infections induced by Rituximab plus Fludarabine and associated with hypogammaglobulinemia: a frequently unrecognized and easily treatable complication

  3. Infectious complications of rituximab in patients with lymphoma during maintenance therapy: a systematic review and meta-analysis

  4. B-cell recovery following Rituximab-based therapy is associated with perturbations in stromal derived factor-1 and granulocyte homeostasis

  5. Progressive multifocal leukoencephalopathy: a focused Google search

  6. Adjuvant Rituximab causes prolonged hypogammaglobulinaemia following autologous stem cell transplant for non-Hodgkin's lymphoma.

  7. Delayed redistribution of CD27, CD40 and CD80 positive B cells and the impaired in vitro immunoglobulin production in patients with non-Hodgkin lymphoma after Rituximab treatment as an adjuvant to autologous stem cell transplantation.

  8. Hypogammaglobulinemia with a selective delayed recovery in memory B cells and an impaired isotype expression after rituximab administration as an adjuvant to autologous stem cell transplantation for non-Hodgkin lymphoma

  9. Hepatitis B Virus Reactivation in Lymphoma Patients With Prior Resolved Hepatitis B Undergoing Anticancer Therapy With or Without Rituximab

  10. Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome

  11. Acute Pulmonary Fibrosis

Infectious events due to low lymphocyte counts are also quite common. These can occur months after treatment with Rituximab. One of the more commonly documented is Pneumonitis. There are many studies that document this as a rare complication, but no single study that summarizes them all. For more information go to our search page and type in "pneumonitis Rituximab" without the quotes, then choose either Blood Journal or the NLM as your site to search, and you will find much more information.

Additional reading

  1. How Rituxan works. A detailed, but very technical look at its mechanism of action and causes of resistance
  2. Rituximab maintenance therapy: a step forward in follicular lymphoma

  3. Rituximab immunotherapy results in the induction of a lymphoma idiotype-specific T-cell response in patients with follicular lymphoma: support for a "vaccinal effect" of rituximab

  4. Click here for a focused search about Maintenance Rituxan from PubMed

  5. Click here for a focused search about Maintenance Rituxan from Blood

How it all started

Development of monoclonal antibodies began decades ago. But it was 1997 when Rituxan was first approved. It was at this point that some serious studies began, trying to figure out all the ways it could be used, and the best ways to use it. Below are some of those early studies, which some countries used as the basis for their own health agency approval process.

  1. Effect of the addition of rituximab to front line therapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) on the remission rate and time to treatment failure (TTF) compared to CHOP alone in mantle cell lymphoma (MCL): Results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG).  
  2.  Randomized intergroup trial of first line treatment for patients <=60 years with diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) with a CHOP-like regimen with or without the anti-CD20 antibody rituximab - early stopping after the first interim analysis.  

  3. Randomized phase II study of concurrent and sequential combinations of rituximab (R) plus CHOP (R-CHOP) in untreated indolent B-cell non-Hodgkin's lymphoma (B-NHL).

  4. Maintenance Rituximab After Cyclophosphamide, Vincristine, and Prednisone Prolongs Progression-Free Survival in Advanced Indolent Lymphoma: Results of the Randomized Phase III ECOG1496 Study

References

  1. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program

  2. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma

  3. Maintenance rituximab every 2 months is more toxic than every 3 months in patients with non-Hodgkin lymphoma

  4. 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)

 


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