Novel Three-Drug Combination of Ibrutinib plus Lenalidomide and Rituximab Shows Promising Anti-Lymphoma Activity in Relapsed/Refractory DLBCL

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma, rising in incidence among older populations. The standard of care for the approximate one-third of DLBCL patients who do not achieve remission with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone) is salvage high-dose chemotherapy followed by consolidative autologous stem cell transplant, which leads to long-term disease-free survival for only 10-20 percent of relapsed/refractory patients. Patients who relapse within a year of initial therapy, those who relapse after transplant, and those who are ineligible for transplant due to age or comorbidities face the most significant unmet treatment need.

With an eye toward improving therapeutic options and outcomes for this patient population, the Lymphoma Program team, led by Dr. Jia Ruan, collaborated with colleagues nationwide and contributed significantly to a study examining the maximum tolerated dose and preliminary safety and activity of a novel three-drug combination – ibrutinib plus lenalidomide and rituximab – in treatment of relapsed/refractory DLBCL. The team’s encouraging findings were published in the American Society of Hematology’s Blood journal.

The study population consisted of 45 transplant-ineligible DLBCL patients whose disease returned after at least one prior therapy. Patients received oral ibrutinib daily, intravenous rituximab on every first day of six 28-day cycles, and oral lenalidomide on the first 21 days of each cycle. The treatment was provided as continuous chronic therapy in an outpatient clinic setting for as long as patients could derive benefit.

Forty-four percent of patients responded to the triplet, and 28 percent achieved a complete response. The combination performed particularly well (ORR: 65%, CR: 41%) in patients with non-germinal center b cell (non-GCB) DLBCL, a molecular subtype based on disease cell of origin that is not typically associated with favorable prognosis. Common treatment side effects included gastrointestinal complications, fatigue, myelosuppression (reduced blood cell production), hypokalemia (low blood potassium), peripheral edema and skin rash. Side effects could be monitored and mitigated by dose adjustment in the outpatient setting.

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Dr. Jia Ruan

“This novel treatment consists of two oral agents typically used to treat B-cell lymphoma, plus the anti-CD20 antibody rituximab, and can be easily administered in the clinic or patient’s home,” said Dr. Jia Ruan. “This effective low-intensity approach makes it very appealing to a broad range of R/R DLBCL patients in need of treatment.”

 

Promising Long-Term Outcome of Chemo-Free Mantle Cell Lymphoma Treatment Published in Blood Journal

The long-term outcome of the first-ever study of a non-chemotherapy frontline treatment approach to mantle cell lymphoma (MCL) was recently published in the American Society of Hematology’s prestigious Blood Journal.

Led by Dr. Jia Ruan, clinical investigators at four medical centers across the United States launched a phase two clinical trial in 2011 to evaluate the novel biological pairing of lenalidomide plus rituximab as induction (initial) and maintenance (relapse prevention) therapy. The team’s treatment goals were to provide disease control and extend survival, while maintaining quality of life.

Read more about the study here.

Of 36 evaluable patients, about 92 percent responded to treatment, with 64 percent achieving complete remission. At five-year follow-up, 77 percent of participants were alive and well, and 64 percent remained free of disease progression.

To determine how well the lenalidomide plus rituximab combination works, the team also measured the status of minimal residual disease (MRD) – the small amount of cancer cells that may be left after treatment that have the potential to lead to relapse. Eight out of a subset of ten evaluable patients tested MRD-negative.

Overall, the chemotherapy-free drug combination has produced durable remission rates with potential to achieve MRD-negative remissions. Chronic maintenance therapy with lenalidomide and rituximab has manageable side effects, including infections, cytopenias (low blood count), and some expected secondary primary malignancies.

This outcome represents a major stride in treatment and care of the MCL patient population, who harbor a rare and generally incurable disease where intensive chemotherapy regimens do not necessarily translate to cure and may not be tolerated by all patients.

Ruan Face“The introduction of novel agents – including the immunomodulatory agent lenalidomide and Bruton’s tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib, which are FDA-approved for MCL – is poised to transform MCL management by making effective ‘chemo-free’ treatment accessible to all patients in both relapsed/refractory and frontline settings,” says Jia Ruan, MD, PhD.

 

2018 American Society of Clinical Oncology (ASCO) Annual Meeting

The American Society of Clinical Oncology (ASCO) is the world’s leading organization for physicians and oncology professionals who care for people with cancer. Each year, ASCO’s Annual Meeting brings together over 30,000 oncology professionals from around the world to discuss state-of-the-art treatment modalities, new therapies and ongoing controversies in the field.

Our Lymphoma Program is proud to have been part of several research studies presented at this year’s meeting, contributing to new discoveries across a range of lymphoma subtypes. Here are the latest updates from our team:


T-Cell Lymphoma

An unmet treatment need exists for peripheral T-cell lymphoma patients, especially those with relapsed/refractory disease. Dr. Jia Ruan was part of a research team testing immunotherapy agent pembrolizumab within this patient population.

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Follicular Lymphoma

Dr. Peter Martin was involved in a clinical trial investigation of acalabrutinib in treatment of follicular lymphoma, which yielded promising response rates.

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Data supporting vitamin D supplementation in indolent lymphoma patients treated with rituximab were presented at this year’s meeting. Dr. John Leonard is Weill Cornell Medicine and NewYork-Presbyterian’s principal investigator evaluating the vitamin’s effects in an ongoing phase III trial. Trial information here.

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Diffuse Large B-Cell Lymphoma (DLBCL) 

Dr. Jia Ruan was involved in the clinical trial assessment of single-agent acalabrutinib in relapsed/refractory DLBCL patients.

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Waldenstrom’s Macroglobulinemia

Dr. Richard Furman was senior author on a study demonstrating acalabrutinib as an effective and well-tolerated therapy for people with Waldenstrom’s macroglobulinemia.

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Chronic Lymphocytic Leukemia (CLL)  

Dr. John Allan, along with Dr. Richard Furman, collaborated with research colleagues to investigate the demographic impact on incidence and treatment outcomes in people with chronic lymphocytic leukemia (CLL).

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Dr. John Allan is Weill Cornell Medicine and NewYork-Presbyterian’s principal investigator for a phase II clinical trial of ibrutinib and venetoclax – two non-chemotherapeutic agents – in people with previously untreated chronic lymphocytic leukemia (CLL). Trial information here.

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Non-Hodgkin Lymphoma

People with human immunodeficiency virus (HIV) are at increased risk for developing aggressive non-Hodgkin lymphomas frequently associated with two herpes viruses: Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpes virus (KSHV). Weill Cornell Medicine pathologist Ethel Cesarman, MD, PhD, contributed to a phase II trial conducted through the AIDS Malignancy Consortium (AMC) to test HDAC inhibitor vorinostat’s effects on HIV-related non-Hodgkin lymphoma.

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Dr. Peter Martin, the Principal Investigator for the Lymphoma Epidemiology of Outcomes (LEO) consortium at Weill Cornell Medicine and NewYork-Presbyterian Hospital, aided in a study of vulnerability to undesirable outcomes in people with newly diagnosed non-Hodgkin lymphoma. Vulnerable status was measured overall, and by age, gender and clinical features.

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As always, we are proud of our team’s active commitment to advancing the overall understanding of lymphoma and improving clinical outcomes and quality of life for all those affected by the disease.