Dr. Jia Ruan and Colleagues Encouraged by Long-Term Results of Chemo-Free MCL Treatment Regimen

Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin lymphoma that occurs primarily in older adults. The disease is typically managed in the initial treatment setting with a combination of chemotherapy and immunotherapy, which tends not to be curative and may impart toxic side effects in some patients.

In search of an effective, less toxic treatment option for those afflicted by MCL, Dr. Jia Ruan and colleagues explored an alternative regimen free of conventional chemotherapy – lenalidomide plus rituximab – to be used in the initial treatment setting. Their multi-center phase II clinical trial of the novel biological pairing was the first-ever study of a non-chemotherapy first-line MCL treatment approach.

Thirty-eight MCL patients enrolled in the trial from July 2011 to April 2014. They received lenalidomide on days 1-21 of a 28-day cycle, and rituximab was administered four times per week during the first cycle, then once every other cycle. The first 12-cycle treatment was considered induction, or initial therapy, and was followed by a maintenance phase, in which therapy is provided to prevent relapse. Treatment was continuous until disease progression, and patients had the option to cease therapy after three years if in remission.

At the 2017 American Society of Hematology Annual Meeting, the researchers examined the long-term outcomes of the trial in a 5-year follow-up analysis to reveal that the drug combination shows promise for effective management of MCL, with the majority of trial participants doing well and maintaining good quality of life. About 90 percent of patients responded to the therapy, and over 60 percent remain in remission.

The research team also measured minimal residual disease (MRD) in patients’ blood, the small number of cancer cells that may be left after treatment that have the potential to grow and cause the patient to relapse. In the small subset of patients with available tumor tissues for MRD analysis, about 80 percent of patients were found to be MRD negative, further demonstrating the novel treatment regimen’s activity and feasibility as an additional therapeutic option for people with MCL.

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Dr. Jia Ruan

“We are encouraged by the quality and durability of the responses with the biologic doublet of lenalidomide plus rituximab as initial therapy for mantle cell lymphoma,” said Dr. Ruan. “We hope to bring this active combination to larger studies where it can be combined with other agents and compared to conventional chemotherapy.”

New Treatment Combination Poses Potential Way to Combat Chemo-Resistant DLBCL

Each year, roughly 20,000 Americans are diagnosed with diffuse large B-cell lymphoma (DLBCL), an aggressive cancer of abnormal B-cells. Most people with DLBCL are cured with the standard chemotherapy regimen rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), but 30-40 percent of cases are resistant to chemotherapy for reasons that may be related to the way that genes are regulated within the cancer cells.

Prior WCM laboratory research demonstrated that certain genes within chemotherapy-resistant DLBCL cells are often inappropriately turned off and that long-term exposure to low doses of oral hypomethylating agent azacitidine (also known as CC-486) can turn those genes back on, thereby re-sensitizing the cells to chemotherapy.

Lymphoma Program chief Dr. Peter Martin, Dr. Leandro Cerchietti, Dr. John P. Leonard, Dr. Maria Revuelta and Dr. ldefonso Ismael Rodriguez-Rivera, and colleagues from around the country, set out to test a novel therapeutic alternative for these chemo-resistant cases with a phase I, open-label, multicenter trial of oral azacitidine plus R-CHOP in people with high-risk, previously untreated DLBCL, grade 3B follicular lymphoma (FL), or transformed lymphoma. The trial was conducted in collaboration with Alliance Foundation Trials (AFT), a research organization that develops cancer clinical trials with pharmaceutical companies, scientific investigators and the Alliance for Clinical Trials in Oncology (ACTO) institutional member network.

Patients in the trial received CC-486 for seven days prior to R-CHOP initiation, then for 14 days prior to each of five following R-CHOP cycles. The research team found that the combination of CC-486 plus R-CHOP was safe and well tolerated, and that it produced a higher-than-anticipated complete response (CR) rate, or disappearance of signs of cancer, exceeding 85 percent. Dr. Cerchietti’s lab also identified key changes in genes and gene expression consistent with the anticipated CC-486 effect. Dr. Martin presented the team’s findings at the American Society of Hematology Annual Meeting and Exposition on December 9, 2017, in Atlanta, GA.

Weill Cornell Medicine

“We are at an exciting moment in time: CC-486 is emerging simultaneously with a peak in collaborative efforts between scientists, physicians and patients,” said Dr. Martin. “We are working day and night to move this concept forward, including the possible opening of randomized trials.”