Our Team’s Take on the Most Influential ASH 2018 Lymphoma Research

At the end of each year, the American Society of Hematology (ASH) Annual Meeting & Exposition brings together over 25,000 hematology professionals from around the world to discuss the latest research into the treatment of blood diseases. Highlights of ASH is a two-day program designed to update clinicians and researchers unable to attend the Annual Meeting with the findings most likely to impact daily clinical practice.

Our Lymphoma Program Chief, Dr. Peter Martin was selected to represent the Highlights of ASH Lymphoma Committee for a post-meeting update in January 2019. Here’s his take on the latest lymphoma research.

Diffuse Large B-Cell Lymphoma (DLBCL)

According to the FLYER study, patients younger than 60 with low-risk diffuse large B-cell lymphoma (DLBCL) had excellent outcomes with a shortened regimen of four cycles of R-CHOP chemotherapy versus the standard six cycles. The reduction in chemotherapy may allow for minimizing potential toxic side effects for this patient population.

Our Team’s Take
It is now clear that most young people with stage 1, low-risk DLBCL can be effectively treated with just four cycles of R-CHOP, but providers should use caution in extrapolating these results to rarer subtypes of DLBCL (e.g., primary mediastinal B-cell lymphoma, transformed lymphomas, etc.) that may not have been included in large numbers in the FLYER trial.

SOURCE 781- Excellent Outcome of Young Patients (18-60 years) with Favourable-Prognosis Diffuse Large B-Cell Lymphoma (DLBCL) Treated with 4 Cycles CHOP Plus 6 Applications of Rituximab: Results of the 592 Patients of the Flyer Trial of the Dshnhl/GLA

R-CHOP chemotherapy is the standard treatment for people with previously untreated DLBCL. The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has shown activity in people with a subtype of DLBCL known as non-germinal center B cell DLBCL (non-GCB DLBCL) whose disease has relapsed following treatment. The phase III PHOENIX trial examined whether adding ibrutinib to R-CHOP would improve treatment efficacy in previously untreated non-GCB DLBCL patients. Results demonstrated that R-CHOP plus ibrutinib was equivalent to R-CHOP alone. The study did note, however, that ibrutinib may provide some benefit in patients older than 60.

Our Team’s Take
For now, R-CHOP remains the gold-standard for most people with DLBCL, including non-GCB DLBCL. That said, it appears that BTK inhibitors have the potential to improve outcomes if the optimal patient population can be identified.

SOURCE 784 – A Global, Randomized, Placebo-Controlled, Phase 3 Study of Ibrutinib Plus Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (RCHOP) in Patients with Previously Untreated Non-Germinal Center B-Cell-like (GCB) Diffuse Large B-Cell Lymphoma (DLBCL)

Follicular Lymphoma

Our own Dr. John Leonard led the global phase III AUGMENT clinical trial comparing the efficacy and safety of combined lenalidomide plus rituximab versus rituximab alone in people with previously treated indolent lymphoma, including follicular and marginal zone lymphoma. Lenalidomide-rituximab treatment resulted in superior progression-free survival (PFS) and overall survival (OS) outcomes when compared to rituximab treatment alone, representing an important new treatment option for this patient population.

Our Team’s Take
The impressive overall survival benefit seen in the AUGMENT trial implies that single-agent rituximab may no longer be appropriate for some people with previously treated follicular lymphoma.

SOURCE 445 – AUGMENT: A Phase III Randomized Study of Lenalidomide Plus Rituximab (R2) Vs Rituximab/Placebo in Patients with Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

Hodgkin Lymphoma

A currently accepted standard of care treatment for early-stage low-risk Hodgkin lymphoma is two cycles of ABVD chemotherapy followed by radiotherapy. In the HD16 trial examining the possibility of omitting radiotherapy from the treatment regimen, investigators found that two cycles of ABVD alone does not provide adequate disease control.

Our Team’s Take
A primary goal of cancer care is to deliver a maximally effective treatment regimen while sparing patients from excessive treatment-related side effects. Yet, this research demonstrates that two cycles of ABVD alone does not provide sufficient control of early-stage, favorable risk classical Hodgkin lymphoma. Outside of clinical trials, providers should consider either the addition of radiation or additional chemotherapy.

SOURCE 925 – PET-Guided Treatment of Early-Stage Favorable Hodgkin Lymphoma: Final Results of the International, Randomized Phase 3 Trial HD16 By the German Hodgkin Study Group)

T-Cell Lymphoma

Following the positive results of a phase I trial combining brentuximab vedotin (BV) with CHP (CHOP chemotherapy minus vincristine) in frontline treatment of T-cell lymphoma, researchers tested the combination in patients with newly diagnosed CD30+ anaplastic large cell lymphoma (ALCL), a type of T-cell lymphoma, in the ECHELON-2 trial. Brentuximab vedotin plus CHP was shown to produce better outcomes than standard CHOP for these patients.

Our Team’s Take
BV-CHP represents a new standard of care for anaplastic large cell lymphoma (ALK-positive and ALK-negative). It is less clear that BV adds significantly to CHOP in non-ALCL T-cell lymphomas regardless of CD30 status.

SOURCE 997 – The ECHELON-2 Trial: Results of a Randomized, Double-Blind, Active-Controlled Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Versus CHOP in the Frontline Treatment of Patients with CD30+ Peripheral T-Cell Lymphomas

BONUS: Chimeric Antigen Receptor (CAR) T Cell Update

Multiple observational studies suggested that commercial, FDA-approved CAR T cell products used as part of standard practice resulted in outcomes that were comparable to outcomes seen in clinical trials prior to the approval of CAR T cells. Even patients with characteristics that might have resulted in exclusion from clinical trials (e.g., low blood counts) appeared to have comparable outcomes.

Our Team’s Take
CAR T cells clearly have a role in people with treatment-refractory DLBCL. Nonetheless, more research will be required to further improve the efficacy and safety of CAR T cells so that patients outside of academic medical centers might have access to this new treatment approach.

SOURCE 91 – Axicabtagene Ciloleucel (Axi-cel) CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma: Real World Experience; 92 – Axicabtagene Ciloleucel in the Real World: Outcomes and Predictors of Response, Resistance and Toxicity

 

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.

 

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.”