Michael Wang, MD from MD Anderson discusses a paper from Nature entitled Durable response with single-agent acalabrutinib in patients with relapsed or refractory mantle cell lymphoma.
Bruton tyrosine kinase (BTK) inhibitors have substantially expanded the range of treatment choices for mantle cell lymphoma (MCL) [1,2,3,4]. Acalabrutinib is a highly selective, orally administered, and active, off-target BTK inhibitor[5]. Acalabrutinib was approved for treatment of relapsed / refractory MCL by the US Food and Drug Administration in 2017 on the basis of clinical evidence from the open-label, multicenter, phase 2 ACE-LY-004 acalabrutinib 100 mg twice daily[1]. Here, after a 26 month median follow-up, we present updated findings from the ACE-LY-004 analysis.
Previously published eligibility requirements and research design (Supplementary methods) [1]. Minimal residual disease (MRD) analysis was performed using the quantitative ClonoSEQ next-generation sequencing (5 ⇠10-6) assay (Adpative Biotechnologies, Seattle, WA , USA) after complete response ( CR) or partial response (PR) was obtained in consenting patients with available paired archival tumor and whole blood samples. The data will be revised with effect from 12 February 2018.
A total of 124 patients were registered and cared across 40 centres; demographic statistics were previously published (Supplementary Table 1) [1]. Classical (n = 89[72 percent]), blastoid / pleomorphic (n = 26 [21 percent]) or other (n = 9 [7 percent]) cytomorphological variants were included. 96 patients (77 percent) had Ki-67 data available; 32/96 patients (33 percent) had a Ki-67 proliferation index of about 50 percent. The mean Ki-67 proliferation index for blastoid / pleomorphic patients ( n = 21) was 55.8 per cent (SD: 22.3) versus 34.5 per cent (SD: 22.6) in classical MCL patients ( n = 68); seven Ki-67 patients were in the other variant group.
The median follow-up time (range, 0.3-35.1) was 26 months. Forty per cent of patients stay on medication, while 61 per cent stay on survival follow-up (Supplementary Table 2). Six patients received allogeneic stem-cell transplants after discontinuation of acalabrutinib, at a median of 19 days after discontinuation (range, 1-95).
Acalabrutinib response was identical to the original report[1], with an overall response rate (ORR) of 81 per cent and a CR rate of 43 per cent (Supplementary Table 3). The median response period (DOR) was 26 months, with an approximate 24-month DOR of 52.4 per cent (95 per cent CI, 41.5, 62.2; Fig . 1a). The median progression-free survival (PFS) was 20 months (95 % CI, 16.5, 27.7), with an approximate 24-month PFS rate of 49.0% (95 % CI, 39.6, 57.8; Fig . 1b). The overall median survival (OS) was not achieved, with an average 24-month OS rate of 72.4 percent (95 percent CI, 63.5, 79.5; Fig. 1c). Despite patients with a higher mean Ki-67 index of about 50 percent, ORR was consistent in patients with refractory disease and patients with blastoid / pleomorphic MCL, indicating that certain patients with worse prognosis might also benefit from acalabrutinib (Supplementary Table 4). In patients with low / intermediate Mantle Cell Lymphoma International Prognostic Index ratings, classical MCL, and Ki-67 index < 50 percent (Supplementary Figs. 1"“4), however, prolonged median DOR, median PFS, and 24-month OS rates were observed.
For time-to – event endpoints, Kaplan-Meier curves. The curves shown are response period (a), progression-free survival (b), and overall survival (c) in responding patients. DOR response time, NR not achieved, overall survival of the operating system, progression-free survival of the PFS
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For MRD study, twenty-nine patients (23 percent) had evaluable samples available (Supplementary Fig. 5). Seven out of 29 patients (24%) had MRD-negative disease (5 or 10−6) in the peripheral blood after a response (CR or PR) was achieved. Both seven MRD-negative-disease patients were in CR. Approximately 6 months after the first, seventeen of the 29 patients had a second blood sample, including five of the seven MRD-negative patients. Sustained negativity to MRD in four of the five patients was observed. In the second study, an additional patient with CR who was MRD positive in the first study became MRD negative. Therefore, for acalabrutinib monotherapy, a total of 8/29 patients (28 percent) achieved MRD negativity at any time. These findings, despite small samples, indicate that continued use of acalabrutinib can lead to undetectable MRD in CR patients. As most patients with MRD data are still on medication (27/29), at this time relationships can not be made between MRD negativity and durability of reply.
The adverse event AE profile was largely consistent with earlier reporting[1] after an additional year of follow-up, with no new safety signals. The most popular AEs (almost 20%) were grade 1/2 and included headache (38%), diarrhea (36%), exhaustion (28%), cough (22%), and myalgia (21%; supplementary Table 5). The most common cases, headache and diarrhea, were mainly 1/2 category, occurred early in care and were treating. Headache events occurred mostly during the first month of treatment, and the bulk of diarrhea events occurred during the first six months of treatment (Table 1 and Table 6). The percentage of patients with grade 3 AEs or extreme AEs was close to that recorded earlier (Supplementary Table 7), implying that continued use of acalabrutinib does not lead to cumulative toxicity[1].
Table 1 Occurrence by 6-month periods of selected adverse events
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Thirteen patients (10 percent) had heart attacks, including 3/4 cases in four classes (3 percent). As previously mentioned, one patient each had acute coronary syndrome (considered treatment related by investigator), acute myocardial infarction (not treatment related), and cardiorespiratory arrest (not treatment related) [1]; one grade 3 incident (coronary artery disease [not treatment related]) occurred during this long-term follow-up. There have been no new atrial fibrillation incidents (Table 1), in line with the previous report[1]. Initially, one patient with a history of paroxysmal atrial fibrillation was evaluated as having an AE of atrial fibrillation, but the investigator reconsidered the AE as the condition was preexisting and the study drug did not worsen. There were no new cases of hypertension with long-term follow-up. As previously recorded, there were hypertension events in four patients (3 per cent) with one grade 3 event[1]. Bleeding incidents of any grade occurred in 33% of patients, most often contusion (13%) and petechiae (9%), and decreased markedly over time (Table 1). All bleeding events (gastrointestinal hemorrhage, hematuria, hematoma) were grade 1/2 except for three grade 3 events. Two of the three major hemorrhage events occurred after the previous study, while the rate of major hemorrhage events (2%) remains the lowest recorded for a 2-year follow-up BTK inhibitor[1, 6]. Anticoagulant use was reported in 57 patients (46%) during the study period, but no simultaneous anticoagulant use was reported in patients with three Grade 3 bleeding events during the case. According to previous studies, most infections were degree 1/2 and were considered unrelated to treatment research, and were not severe. We also show here that levels of any grade, grade 3, and extreme infections have decreased over time (Table 1). In 15 percent of patients, Grade 3/4 infections occurred, most usually pneumonia (n = 7 [6 percent]); no Grade 5 infections took place. As reported earlier, one case of cytomegalovirus viremia and one case of pneumocystis jiroveci pneumonia (both grade 2) with no Aspergillus infections were reported[1]. Over time, the mean immunoglobulin levels did not improve much (Supplementary Fig . 6). Rashes were uncommon, and mostly one-half grade. Second primary cancers occurred in 10 patients (8 per cent; Table 8 supplement).
The key reasons for discontinuation of treatment were progressive illness (n = 54 [44 percent]) and AEs (n = 10 [8 percent]). Ten patients stopped care due to AEs; each AE occurred in one patient. AEs that resulted in discontinuation were aortic stenosis, large diffuse B-cell lymphoma, blood blister and petechiae (both in one patient with grade 3 acute coronary syndrome treated with clopidogrel), dyspnea and leukostasis syndrome (both in one patient), non-cardiac chest pain, pulmonary fibrosis, rash, thrombocytopenia, non-small cell lung cancer, and pulmonary embolism. AEs in 39 patients (31 percent) resulted in dose delays (missed ⇠1 dose) and dose changes (⇠1 dose at 100 mg once daily) in two patients (2 percent; supplementary table 9).
43 deaths (35%), most notably from progressive disease (n = 29 [23%]), occurred. Six patients (5 percent) died from AEs, including bilateral pulmonary embolism, aortic stenosis (a history of aortic stenosis), myelodysplastic syndrome, pneumonia, suicide, and lung cancer of non-small cells. Two patients (2%) died from unexplained causes 198 days after the last dose, and one patient (1%) died 176 days after the last dose due to multi-organ failure. Five patients (4%) died from “other” causes (secondary acute myeloid leukemia 2277 days after last dose [n=2]; intestinal obstruction 63 days after last dose [n=1]; lung cancer 728 days after last dose [n=1]; and graft-vs-host disease 275 days after last dose [n=1; patient received stem-cell allogeneic transplantation 95 days after last dose]).
In relapsed / refractory MCL, prolonged follow-up of a median of 26 months showed continued efficacy and favorable protection with single-agent acalabrutinib. Differences between patient populations and staging requirements in the current study and the one-arm study of the other approved BTK inhibitor ibrutinib preclude comparison between the trials, regardless of comparable follow-up period (27 months in the ibrutinib trial)[6]. Nevertheless, of all approved single-agent therapies for the treatment of relapsed / refractory MCL, the response rates and median DOR based on the Lugano classification in this study are the highest recorded. In addition, four PR patients converted to CR with extended follow-up suggesting change in response (similar to ibrutinib[2, 6]) and most respondents retained a more than 2-year response.