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Emerging Treatment Strategies in MCL

Published Online: Mar 14,2018
Ibrutinib and the BCL-2 inhibitor venetoclax have demonstrated synergy in cell lines and primary cells, and study findings have indicated the potential for combining these agents in the treatment of MCL.13,14 The phase II open-label AIM study15 evaluated ibrutinib plus venetoclax in patients with R/R MCL. At 16 weeks, the ORR was 71% and the CR rate was 63%. After a median follow-up of 8.3 months, the PFS rate was 74% and the overall survival (OS) rate was 81%. The most common AEs were fatigue (71%), diarrhea (67%), nausea (50%), upper respiratory tract infection (38%), gastroesophageal re ux (33%), neutropenia (33%), cough (25%), and bruising (21%).

Acalabrutinib Combinations

Acalabrutinib is another oral BTK inhibitor, and it binds covalently to C481.4 In evaluating pharmacokinetic properties of acalabrutinib in healthy adult patients with B-cell malignancies, rapid absorption and fast elimination was observed.

The phase III ACE-LY-309 study16 of acalabrutinib in combination with rituximab versus ibrutinib versus acalabrutinib for the treatment of R/R MCL was halted prior to enrollment. The ongoing phase Ib ACE-LY-016 trial17 is investigating the combination of acalabrutinib plus bendamustine (Treanda) and rituximab in patients with treatment-naïve and R/R MCL. The primary outcome measure is safety as determined by the number of participants with treatment-emergent AEs.

 

CAR T-Cell Therapy

Ongoing studies are exploring anti-CD19 CAR T-cell therapy in patients with chemorefractory MCL.18 CAR T-cell therapy involves the modication of T cells via lentiviral transduction to express specific CARs; in B-cell lymphomas, CD19 is a common target for T cells.3 A phase I/II study is currently underway to investigate the safety and ef cacy of anti-CD19 CAR T-cell therapy in older patients with R/R MCL.19 The phase II ZUMA-2 study is evaluating axicabtagene ciloleucel (KTE-C19; Yescarta) in patients with ibrutinib refractory MCL (Figure).20 The estimated study completion date is July 2018.

According to Raphael Steiner, MD, and colleagues, “In order for CAR T-cell therapies to be more widely adopted in chemorefractory relapsed or refractory MCL, they will have to demonstrate an ability to safely induce responses in patients who would not be eligible for allogeneic stem cell transplant. The toxicities associated with CAR T cells at present may limit applicability to patients [with MCL] who are commonly older and have comorbid conditions.”1

Immune Checkpoint Inhibitors

Antibodies targeting programmed cell death-1 protein (PD-1) have been investigated in lymphoid malignancies with varying levels of activity and a favorable toxicity profile.21 The first checkpoint inhibitor approved for lymphomas was nivolumab, a PD-1 inhibitor, which was approved in May 2016 for patients with R/R Hodgkin lymphoma. Currently, data on response to immune checkpoint inhibition and combinations with checkpoint blockade in MCL are limited. However, an ongoing phase I/ Ib trial is investigating the safety and maximum-tolerated dose (MTD) of the PD-1 inhibitor pembrolizumab (Keytruda) combined with ibrutinib in patients with non-Hodgkin lymphoma (NHL), including those with MCL.22

Venetoclax

Venetoclax (Venclexta) is an oral small molecule BCL-2 inhibitor that has been investigated for the treatment of NHL. BCL-2 is an antiapoptotic factor involved in the regulation of cyclin D1; targeting BCL-2 may also induce apoptosis.2

A phase I study investigated the safety, pharmacokinetics, and ef cacy of venetoclax in patients with NHL.23 A total of 106 patients with R/R NHL, including 26 with diagnosed MCL, were enrolled in the study, which consisted of a dose-escalation stage and a safety expansion stage. Preliminary results show impressive single-agent activity in R/R MCL, with negligible toxicity, apart from risk of tumor lysis syndrome (TLS). An ORR of 75% (21/28) was observed among the patients with a diagnosis of MCL. The median DOR was 5.3 months (range, 0.2-46.0) for the total study population but was not reported speci cally for patients with MCL. The most common any-grade AEs were nausea (48%), diarrhea (45%), and fatigue (42%). The most common grade ≥3 AEs were anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Laboratory TLS was reported in 3 patients, with no cases of clinical TLS observed.




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