Initial Treatment with Lenalidomide Plus Rituximab for Mantle Cell Lymphoma (MCL): 7-Year Analysis from a Multi-Center Phase II Study

At the 2020 Annual Meeting of the American Hematology Society (ASH), the Weill Cornell Medicine mantle cell lymphoma research team presented the 7-year long-term outcome analysis of the first study of a non-chemotherapy frontline treatment regimen with lenalidomide plus rituximab as induction and maintenance therapy for mantle cell lymphoma (MCL).  

The multi-center phase 2 study, led by study chair Dr. Jia Ruan, was initiated in 2011 and previously reported early efficacy in the New England Journal of Medicine (NEJM) and 5-year follow-up results in Blood, which was highly effective with an overall response rate (ORR) of 92%, and complete response (CR) of 64%. It was also well tolerated, with durable responses, including the 5-year progression free survival (PFS) and overall survival (OS) of 64% and 77% respectively. Dr. Samuel Yamshon, a second-year hematology and medical oncology fellow at Weill Cornell Medicine and NewYork-Presbyterian Hospital led the oral presentation of the 7-year follow up analysis at this year’s ASH meeting.

The study treatment is conveniently administered in the outpatient setting, with the oral agent lenalidomide given on days 1-21 of a 28-day cycle and rituximab provided once very other cycle during maintenance. The treatment continues until progression of disease, with an option to stop therapy after 3 years of remission.

A total of 38 clinical trial participants were enrolled at four participating centers across the United States. Of the 36 evaluable patients, 19 (53%) of the patients remain in remission, including 12 (33%) beyond 7 years. Of the patients in remission, 10 remain on treatment, while 9 patients in remission opted to stop therapy after at least 3 years of study treatment due to side effects or patient preference. The median progression free survival (PFS) and duration of response have not been reached. The 7-year PFS rate was estimated at 60%, and 7-year OS rates at 73%. With long-term maintenance treatment, there were no new safety concerns, and close follow up limited toxicity for those who wished to remain on therapy.

The long-term outcome of the lenalidomide plus rituximab regimen represents a major stride in the treatment and care of MCL patients – a population of patients who harbor a rare and generally incurable disease where intensive chemotherapy regimens do not necessarily translate into cure and may not be tolerated by all. It is notable that this combination therapy offers a chemotherapy-free initial treatment approach that compares favorably in outcome to conventional chemotherapy-based regimens such as bendamustine-rituximab, VR-CAP, and R-CHOP with rituximab maintenance. The National Comprehensive Cancer Network (NCCN) has incorporated this evidence into their treatment guidelines for MCL patients. The Weill Cornell Lymphoma Program researchers concluded that the evaluation of this active regimen in larger, randomized frontline trials comparing novel agents with chemoimmunotherapy is warranted. 

704 Initial Treatment with Lenalidomide Plus Rituximab for Mantle Cell Lymphoma (MCL): 7-Year Analysis from a Multi-Center Phase II Study
Type: Oral presentation
Session: 623. Mantle Cell and Indolent B-Cell Lymphoma – CAR-T and immunotherapy clinical studies

Monday, December 7, 2020: 2:30 PM 

ASH 2020 Weill Cornell Medicine Lymphoma Program Conference Coverage

Multi-Center Phase II Study of Oral Azacitidine (CC-486) Plus CHOP As Initial Treatment for Peripheral T-Cell Lymphoma (PTCL)

Today, at the 2020 Annual Meeting of the American Hematology Society (ASH), the Weill Cornell Medicine T-cell lymphoma research team reported the outcome of the first phase 2 study evaluating the novel combination of oral azacitidine plus CHOP as initial treatment for patients with peripheral T-cell lymphoma (PTCL).

This multi-center phase 2 study, led by Dr. Jia Ruan, is the first of its kind to incorporate epigenetic priming with a hypomethylating agent in the frontline setting as a chemo-sensitizing strategy for PTCL. 

The study enrolled 21 PTCL patients, with the majority of them (17 patients) having the diagnosis of angioimmunoblastic T-cell lymphoma, also known as PTCL with T-follicular helper phenotype (PTCL-TFH). This phenotype is known to have recurrent genetic mutations in epigenetic regulation, providing therapeutic targets for hypomethylating agents such as azacitidine. During study treatment, the patients received CHOP on day 1 of each cycle for 6 cycles, while oral azacitidine was given for 7 days prior to CHOP cycle 1, and for 14 days before CHOP cycles 2-6.  The primary study objective was to see if the novel combination would improve complete response rates following 6 cycles of treatment.  

The study treatment was well tolerated with expected side effects associated with CHOP chemotherapy. Eighteen patients were able to complete all 6 cycles of treatment without the need for chemotherapy dose reduction. Ten patients underwent successful stem cell transplant while in remission. Complete remission (CR) was achieved in 75% of clinical trial participants at the end of 6 cycles of treatment, exceeding the pre-determined efficacy threshold (60%) to declare the treatment as effective. Notably, within the subgroup of patients with the PTCL-TFH subtype, the treatment appears to work even better with a CR rate of 88%. The one-year progression-free survival (PFS) for all patients was 66%, and for the PTCL-TFH subgroup was 70%. The one-year overall survival (OS) for all patients was 81% and PTCL-TFH patients 94%. The research team is further analyzing sequencing biomarkers to correlate with response and survival. 

This study provides the first demonstration that the addition of epigenetic hypomethylating agent oral azacitidine (CC486) to CHOP as initial therapy is safe, and highly effective to induce complete remission in PTCL. This combination will be further evaluated in the upcoming ALLIANCE/Intergroup randomized study A051902, comparing oral azacitidine-CHO(E)P with duvelisib-CHO(E)P against CHO(E)P in CD30 negative PTCL.

Abstract 40: Multi-Center Phase II Study of Oral Azacitidine (CC-486) Plus CHOP As Initial Treatment for Peripheral T-Cell Lymphoma (PTCL)

Type: Oral presentation
Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma—Clinical Studies: Clinical Studies in T/NK Cell Lymphoma
Saturday, December 5, 2020: 7:45 AM PST

ASH 2020 Weill Cornell Medicine Lymphoma Program research coverages continues throughout the conference.

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