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The U.S. Food and Drug Administration (FDA) expanded the approval of Rituxan® (rituximab) to include the treatment of certain patients with chronic lymphocytic leukemia (CLL).

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 may also have direct anticancer effects on the cell. Rituxan is commonly used in the treatment of non-Hodgkin’s lymphoma, and studies have shown that it’s also active against CLL.

For patients with CD20-positive CLL, Rituxan may be used for previously treated or previously untreated patients. Rituxan is administered with two other chemotherapy drugs, fludarabine and cyclophosphamide.

The approval of Rituxan for CLL was based on studies that showed that the combination of Rituxan and chemotherapy delayed cancer progression to a greater extent than chemotherapy alone.1

The effect of Rituxan in combination with chemotherapy for the treatment of CLL was evaluated in two Phase III clinical trials. Both studies compared chemotherapy alone (with fludarabine and cyclophosphamide) to chemotherapy plus Rituxan.

The first study, known as the CLL8 study, assessed 817 previously untreated patients with advanced, CD20-positive CLL. Patients treated with chemotherapy plus Rituxan remained free of cancer progression for a median of 42.8 months, compared with 32.3 months among patients treated with chemotherapy alone. Severe side effects that were more common in the Rituxan group included low white blood cell counts (neutropenia and leukocytopenia).2

The second study, known as the REACH study, assessed 552 previously treated patients with relapsed or refractory, CD20-positive CLL.3 Patients treated with chemotherapy plus Rituxan remained free of cancer progression for a median of 30.6 months, compared with 20.6 months among patients treated with chemotherapy alone.

Possible side effects of Rituxan include infusion reactions (which may result in hives, low blood pressure, chills, fever, and nausea), low white blood cell counts, rashes, and skin and mouth sores.

FCR - Lite

Patients with chronic lymphocytic leukemia (CLL) treated with Fludara® (fludarabine), followed by consolidation with Cytoxan® (cyclophosphamide), and finally consolidation with Rituxan® (rituximab) (F→C→R) achieved high-quality responses that improved with each phase of therapy, according to the results of a study published in the Journal of Clinical Oncology.4,5

Leukemia CancerConnect 490
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Researchers have been evaluating several different drug combinations and doses for the treatment of CLL. Concomitant (used in combination) Fludara/Cytoxan/Rituxan (FCR) has been shown to produce responses yet is also associated with high toxicity. FCR-Lite is a lower dose version of the same combination that has also been shown to produce responses. In this study researchers evaluated the efficacy of sequential (rather than concomitant) delivery of the same drugs, F→C→R. The researchers speculated that sequential delivery would allow them “to take advantage of the activity of these agents without sacrificing dose-intensity with the goal of inducing high-quality sustained responses.”

The study involved 36 previously untreated patients with CLL. Patients received Fludara on days one through five every four weeks for six cycles. This was followed by consolidation with Cytoxan administered every three weeks for three cycles. Finally, patients received consolidation with weekly Rituxan for four cycles.

Thirty-two patients (89%) achieved a response, 22 of which (61%) were complete responses. Consolidation therapy with Cytoxan improved responses in 13 patients (36%), and nine of these patients (25%) then experienced further improvement in response with consolidation therapy with Rituxan. The five-year survival rate for the entire group was 71%.

The researchers concluded that sequential therapy with F→C→R results in high-quality responses in patients with CLL. Thus far, there have been no studies to directly compare this regimen with concomitant FCR.

FCR is a common treatment regimen for CLL, however, it is associated with high levels of the side effect neutropenia. Neutropenia is an abnormally low level of specific immune cells that makes patients susceptible to life-threatening infections.

Researchers from the University of Pittsburgh Cancer Centers recently conducted a study to determine whether lower doses of Fludara and cyclophosphamide combined with higher doses of Rituxan (the mFCR regimen) are as effective as FCR with less incidence of severe neutropenia. The mFCR regimen was used as initial treatment of 20 patients with CLL.

  • 100% of patients achieved an anticancer response.
  • Complete responses (CR-complete disappearances of detectable cancer) were achieved in 68% of patients.
  • Partial responses (partial disappearances of detectable cancer) were achieved in 32% of patients.
  • Severe neutropenia occurred in only 10.5% of treatment courses.
  • There were no episodes of neutropenia accompanied by a fever.

The researchers concluded that mFCR provides high activity in previously untreated CLL, with 100% of patients responding. Furthermore, severe neutropenia was significantly reduced compared to FCR and treatment was well tolerated. Longer follow-up will provide additional long-term data.

CML Newsletter 490


  1. FDA approves Rituxan to treat chronic lymphocytic leukemia. Available at: Accessed February 19, 2010.
  2. Hallek M, Fingerle-Rowson G, Fink A-M et al. Immunochemotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) versus fludarabine and cyclophosphamide (FC) improves response rates and progression-free survival (PFS) of previously untreated patients (pts) with advanced chronic lymphocytic leukemia (CLL). Presented at the 50th Annual Meeting of the American Society of Hematology. San Francisco, CA, December 6-9, 2008. Abstract 325.
  3. Robak T, Moiseev SI, Dmoszynska A et al. Rituximab, fludarabine, and cyclophosphamide (R-FC) prolongs progression free survival in relapsed or refractory chronic lymphocytic leukemia (CLL) compared with FC alone: final results from the international randomized Phase III REACH trial. Presented at the 50th Annual Meeting of the American Society of Hematology. San Francisco, CA, December 6-9, 2008. Abstract LBA-1.
  4. Tarhini A, Land S, Lim F, et al. Early Results of Modified Fludrabine, Cyclophosphamide, and Rituximab (mFCR) for Patients with Previously Untreated Advanced Chronic Lymphocytic Leukemia (CLL). Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Ga. June 2006. Abstract # 6599.
  5. Lamanna N, Jurcic JG, Noy A, et al. Sequential therapy with fludarabine, high-dose cyclophosphamide, and rituximab in previously untreated patients with chronic lymphocytic leukemia produces high-quality responses: Molecular remissions predict for durable complete responses. Journal of Clinical Oncology. 2009; 27: 491-497.