Mantle Cell Lymphoma PALIBR Outcomes Published Online in Blood Journal

The oral Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has become a mainstay in the treatment of mantle cell lymphoma (MCL), producing a response in nearly 70 percent of all patients. Yet, the majority of MCL patients treated with ibrutinib develop resistance to the drug within about a year.

Preclinical research conducted at Weill Cornell Medicine demonstrated that sustained inhibition of CDK4 (a protein that promotes growth of MCL cells) by the oral drug palbociclib can not only prevent proliferation of MCL cells, but also make them more sensitive to attack by ibrutinib.

Based on these findings, Weill Cornell Medicine and NewYork-Presbyterian Lymphoma Program Chief Dr. Peter Martin and colleagues initiated a phase I study of palbociclib plus ibrutinib (PALIBR) in patients with previously treated MCL. Results from the all-oral regimen were recently published online in the American Society of Hematology (ASH) Blood Journal.

The addition of palbociclib to ibrutinib appeared to produce deeper, more durable responses compared to what is traditionally produced by ibrutinib alone, with over half of all patients remaining free of disease progression at the two-year post-treatment mark. The most prevalent side effect was low blood counts.

Weill Cornell Medicine“The first person to be treated on the study in August of 2014 achieved a complete response within three months and remains in a complete response today,” said Dr. Martin. “We were all excited by the results.”

Physicians and researchers at the Lymphoma Program look forward to learning more about the efficacy of PALIBR in the ongoing AFT-32 phase II trial, which incorporates genetic profiling that may help to identify the features associated with drug resistance.

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

 

The Body’s Military Defense

Lymphoma is a collective term representing over 100 different types of the disease. Disease subtyping allows clinicians to determine a more precise diagnosis for each individual patient and plan optimal treatment accordingly.

A small percentage of lymphomas in the United States are classified as Hodgkin lymphomas, with the remaining majority falling under the non-Hodgkin category. Further, approximately 90 percent of non-Hodgkin lymphomas are B-cell malignancies, versus 10 percent T-cell.

Here’s how B and T cells act like branches of the military to protect the body from disease – and what happens when these immune cells are unable to perform their jobs adequately.

The Body's Military Defense

For the origin of this analogy, check out this episode of the Leukemia and Lymphoma Society’s Bloodline podcast, featuring our own Dr. John Leonard.