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Study Favors As-Needed Treatment Over Maintenance Therapy For Patients With Follicular Lymphoma

December 12, 2011

Asymptomatic patients diagnosed with nonbulky follicular lymphoma, a slow-growing type of non-Hodgkin lymphoma, have traditionally been watched for signs or symptoms of disease progression and then treated with a combination of rituximab and chemotherapy or rituximab alone for select cases. Recent trials have suggested a role for treatment of asymptomatic patients with single-agent rituximab followed by additional periodic dosing, called “maintenance therapy.” However, new research suggests that these patients may have similar success rates simply with as-needed treatment. Results from the study will be presented today at the 53rd Annual Meeting of the American Society of Hematology.

“Current research aims to ensure that we are not only giving our patients the best possible chance to live long, healthy lives after their cancer diagnoses, but also improving their quality of life while reducing their health-care costs,” said Jane N. Winter, MD, moderator of the press conference and Professor of Medicine in the Division of Hematology-Oncology at Northwestern University Feinberg School of Medicine in Chicago. “If we can limit the frequency of treatment or reduce the need for chemotherapy and still maintain good outcomes, we can reduce some of the burdens on both the patients and the health care community.”

This press conference will take place on Sunday, December 11, at 8:00 a.m. PST.

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 [LBA-6]

Results from a study evaluating two different strategies for management of asymptomatic low-tumor-burden (LTB) follicular lymphoma (FL) patients found that, following an induction course of rituximab, repeated treatment with the therapy at time of progression is just as effective in managing the disease as ongoing maintenance therapy.

Historically, patients with LTB (defined as small tumor size, limited lymph node involvement, limited or no symptoms, and other factors) disease have been observed rather than treated, with treatment deferred until the patient was symptomatic or the disease progressed, risking the individual´s well-being. This has been called the “watch and wait” strategy, which allows physicians to delay chemotherapy treatment for their patients for three years or more. Researchers have hypothesized that rituximab could delay the need for chemotherapy and that maintenance rituximab (MR) would provide disease control superior to rituximab retreatment (RR) when the disease progressed. In order to evaluate the two different rituximab dosing strategies for LTB follicular lymphoma, researchers embarked on the Eastern Cooperative Oncology Group Protocol E4402 (RESORT), a randomized, Phase III clinical trial.

The primary endpoint was time to treatment failure (TTTF), defined as disease that progresses within six months of the last rituximab treatment, disease that doesn´t respond to therapy, need for alternative therapy, or inability to complete the treatment protocol. Secondary endpoints included time to first chemotherapy, quality of life (QOL), and safety.

The RESORT trial compared the treatment strategies for 384 patients with previously untreated LTB FL. All patients received rituximab for four weeks, and the 274 patients who achieved a complete or partial response were then randomized to MR (single dose of rituximab every three months, n=140) or RR (four weekly doses of rituximab at disease progression, n=134). Patients were evaluated every three months and were followed until treatment failure. The average number of total doses in the MR arm was 15.8 per patient versus 4.5 doses per patient in the RR arm.

The analysis showed that TTTF was 3.9 years for MR-treated FL patients versus 3.6 years for RR-treated patients, rates longer than historical “watch and wait” strategies in this population. At three years of follow-up, 95 percent of MR patients had avoided cytotoxic therapy, as compared with 86 percent of RR patients. Less than 5 percent of patients in the trial experienced any severe hematologic or non-hematologic toxicities. At 12 months after randomization, there was no discernible difference in health-related quality of life or burden of stress between the two study arms.

“In summary, our study found no significant difference between administering maintenance therapy and re-treating with rituximab as needed for this patient population. In addition, given the significant difference in total doses administered, re-treatment with rituximab is less costly than rituximab maintenance therapy,” said lead author Brad S. Kahl, MD, Assistant Professor of Medicine at the University of Wisconsin in Madison, Wis. “We believe the re-treatment strategy is the preferred option to help patients with low-tumor-burden FL manage their disease.”

Dr. Kahl will present this study in the Late-Breaking Abstracts Session on Tuesday, December 13, at 7:30 a.m. PST at the San Diego Convention Center in Hall AB.

American Society of Hematology 53rd Annual Meeting

The study authors and press program moderator will be available for interviews after the press conference or by telephone. Additional press briefings will take place throughout the meeting on new treatment techniques for patients with bleeding and clotting disorders, targeted therapies for acute and chronic leukemia, improving recovery and outcomes in transplantation, and assessing therapeutic strategies for sickle cell disease. For the complete annual meeting program and abstracts, visit www.hematology.org/2011abstracts. Get up-to-date information about the annual meeting by following ASH on Twitter @ASH_hematology.

The American Society of Hematology is the world´s largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems by promoting research, clinical care, education, training, and advocacy in hematology. The official journal of ASH is Blood, the most cited peer-reviewed publication in the field, which is available weekly in print and online.

[LBA-6] 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

Brad S. Kahl, MD1, Fangxin Hong, PhD2*, Michael E Williams, M.D.3, Randy D. Gascoyne, MD4, Lynne I Wagner, PhD5*, John C. Krauss, MD6* and Sandra J. Horning, MD7

1Department of Medicine-Hematology/Oncology, University of Wisconsin, Madison, WI
2Biostatisics, Dana Farber Cancer Institute, Boston, MA
3Dept. of Medicine, University of Virginia School of Medicine, Charlottesville, VA
4Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada
5northwestern university, Chicago, IL
6University of Michigan, Ann Arbor, MI
7Senior VP Global Head, Clinical Dev. (Hem./Onc.), Genentech, Inc., South San Francisco, CA

Background: Optimal management for low tumor burden (LTB) follicular lymphoma (FL) in the rituximab (R) era is uncertain. Historical data with watch and wait (W & W) approaches are associated with an average of 3 years to initiation of chemotherapy. We hypothesized that rituximab could delay the need for chemotherapy and that maintenance rituximab (MR) would provide disease control superior to rituximab retreatment (RR) at progression. E4402 is a randomized phase III study comparing MR and RR for patients (pt) with previously untreated, LTB (by GELF criteria) FL.

Methods: Pt received R 375 mg/m2 weekly x 4 and responders were randomized to MR (single dose R q 3 mo) or RR (R weekly x 4 at disease progression). Each strategy was continued until treatment failure. The primary endpoint, time to treatment failure (TTTF), was defined as progression within 6 mo of last R, no response to R retreatment, initiation of alternative therapy, or inability to complete protocol therapy. Pt were evaluated every 3 mo, with restaging CT scans every 6 mo. The study had 81% power to detect a TTTF hazard ratio of 0.64 favoring MR. Secondary endpoints included time to first cytotoxic therapy (TTCT), quality of life (QOL) and safety. The ECOG Data Monitoring Committee recommended release of study results at a planned interim analysis in September 2011.

Results: From 11/03 to 9/08, 384 with FL were enrolled. Complete or partial response was achieved in 274 pt (71%), who were then randomized to MR (n=140) or RR (n=134). Demographic features were similar in the two arms: median age 59 yr; PS 0-1 in all pt; and FLIPI low-risk (14.9 vs. 16.4%), intermediate-risk (46.3 vs. 42.9%) and high-risk (38.8 vs. 40.7%) for MR vs. RR, respectively. The mean number of R doses/pt (including the 4 induction doses) was 15.8 (range 5- 31) for MR and 4.5 (range 4-16) for RR. With a median follow-up of 3.8 yrs, TTTF was and 3.9 yr for MR vs. 3.6 yr for RR (p=NS, Fig 1). A detailed analysis of treatment failure, by type, will be presented. At 3 yrs, 95% of MR vs. 86% of RR pt (p=.027, Fig 2) remained free of cytotoxic therapy. Grade 3-4 hematologic and non-hematologic toxicities occurred in < 5% of pt; 1 death on study occurred in each Arm. At 12 months post randomization, there was no discernible difference in health related QOL and anxiety between the two arms.

Conclusions: In previously untreated, low tumor burden, follicular lymphoma, no difference in TTTF for MR vs. RR was observed. Notably, the time to initiation of cytotoxic therapy was delayed in both arms compared to historical W & W strategies with similarly defined LTB FL populations. MR was slightly superior to RR for TTCT but at a cost of 3x more R. MR did not improve QOL or anxiety. In summary, RR produces outcomes comparable to MR in this patient population.

Disclosures: Kahl:Genentech: Consultancy Roche: Consultancy. Williams:Genentech: Consultancy. Gascoyne: Roche: Consultancy Genentech: Consultancy. Horning:Genentech: Employment, Equity Ownership.

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