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Current Treatment Strategies in MCL

Published Online: Mar 14,2018
BTK INHIBITORS

A pair of agents, speci cally BTK inhibitors, are available in the treatment landscape of MCL. First, ibrutinib, a BTK inhibitor, was granted accelerated approval by the FDA in November 2013 for patients with MCL who have received at least 1 prior therapy.10 Ibrutinib is considered standard of care in the second-line setting. The approval was based on data from the open-label phase II PCYC-1104 trial in which ibrutinib was studied in 111 previously treated patients with a median age of 68 years (Table 3).11 Most patients were heavily pretreated (≥3 prior treatments) and had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.

 

The registration trial for ibrutinib in MCL used the revised International Working Group response evaluation criteria for non-Hodgkin lymphoma (NHL) to assess response rates.11 Results from the registrational trial showed durable responses with ibrutinib in the R/R MCL population. Ibrutinib demonstrated an overall response rate (ORR) of 68%, complete remission (CR) rate of 21%, median progression-free survival (PFS) of 13.9 months, and duration of response (DOR) of 17.5 months (Table 4).11 Median overall survival (OS) was not reached; at 18 months, the estimated OS rate was 58%. In 2015, updated results were reported from the PCYC-1104 trial.12 After a median follow-up of 26.7 months, the ORR was 67% (23% CR rate), median PFS was 13 months, median DOR was 17.5 months, and median OS was 22.5 months.

Ibrutinib has demonstrated safety in patients with R/R high risk MCL.13 The most common adverse events (AEs) reported were fatigue (any grade, 43.3%; grade 3/4, 3.3%) and diarrhea (any grade, 42.5%; grade 3/4, 2.5%). The most common AEs of grade ≥3 were neutropenia (20.8%), thrombocytopenia (13.3%), and pneumonia (12.5%). Any-grade hemorrhagic AEs were reported in 45 patients (37.5%); major hemorrhagic AEs were uncommon (3; 2.5%). The median time to initial hemorrhagic AE was 84 days (range, 1-515), with a median duration of 22 days (95% CI, 8-31). Notably, atrial brillation (AF) was reported in 6% to 9% of patients and was grade 3/4 in 6 patients (5%). AEs led to dose reductions in 8 patients (6.7%).

 

However, Alaina Vrontikis, MD, and colleagues14 have developed a proposed algorithm for the management of ibrutinib-related AF (IRAF). Their algorithm allows for the individualization of decisions in the management of IRAF based on patient preferences, disease, availability of other antineoplastic agents, and patient comorbidities. Branches of the algorithm involve the establishment of rate/rhythm control and the assessment of bleeding and stroke risk using the CHA2DS2-VASc score and HAS-BLED scoring.

In addition, acalabrutinib, a newer BTK inhibitor, was granted accelerated approval by the FDA in October 2017 for the treatment of patients with MCL who have received at least 1 prior therapy.15 This agent also does not inhibit off-target kinases, such as epidermal growth factor receptor (EGFR) and interleukin 2-inducible T cell kinase (ITK).16 Its approval was based on data from the open-label phase II ACE-LY-004 trial. Acalabrutinib was studied in 124 previously treated patients with a median age of 68 years (Table 5).17 The median number of prior therapies was 2, and 24% were refractory to their most recent prior treatment. Most patients also had an ECOG PS 0 or 1. No patients with cardiovascular disease were included.

 

The registrational trial for acalabrutinib in MCL used the 2014 Lugano classification response criteria for NHL to assess response rates.17 After a median follow-up of 15.2 months, acalabrutinib demonstrated efficacy with an ORR of 81% and CR rate of 40% (Table 6)17; medians for DOR, PFS, and OS were not reached. At 12 months, acalabrutinib achieved rates of 67% for PFS, 72% for DOR, and 87% for OS. An independent review committee also assessed response using the 2007 International Working Group criteria and noted an ORR of 75% and CRs in 30% of patients.

Regarding safety, acalabrutinib has demonstrated an acceptable toxicity profile in patients with R/R high-risk MCL.17 The most common AEs of any grade reported in the acalabrutinib study were headache (38%), diarrhea (31%), fatigue (27%), myalgia (21%), cough (19%), nausea (18%), and pyrexia (15%). The most common grade ≥3 AEs were neutropenia (11%), anemia (9%), and pneumonia (5%). AEs led to treatment discontinuations in 6% of patients.

 

Serious AEs reported in the acalabrutinib prescribing information include hemorrhage, infections, and AF.18 In a database of 612 patients treated with acalabrutinib monotherapy across clinical trials, 18% of patients experienced grade ≥3 infections, most frequently pneumonia (4%). In this safety group, AF and atrial utter of any grade occurred in 3% of patients, with 1% having a grade 3 AE. Overall, bleeding, bruising, or petechiae AEs of any grade occurred in approximately 50% of patients, with AEs of grade ≥3 seen in 2%. 

No head-to-head studies between acalabrutinib and ibrutinib have yet been performed in MCL, which researchers say would be needed to compare the safety pro les and clinical activity between the 2 BTK inhibitors.5 If a head-to-head study was to be performed, use of the same response criteria and patient characteristics, which differed in the studies that led to each agent's approval, would allow for the data to be comparable. According to Michael Wang, MD, the principal investigator of the acalabrutinib trial, “[Acalabrutinib] is another potent [BTK] inhibitor that...seems to have a different side effect pro le compared with ibrutinib, so those who are intolerant of one inhibitor may be able to try the other.”5



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