Elsevier

The Lancet Haematology

Volume 7, Issue 2, February 2020, Pages e112-e121
The Lancet Haematology

Articles
Acalabrutinib monotherapy in patients with Waldenström macroglobulinemia: a single-arm, multicentre, phase 2 study

https://doi.org/10.1016/S2352-3026(19)30210-8Get rights and content

Summary

Background

Chemoimmunotherapy is typically the standard of care for patients with Waldenström macroglobulinemia; however, infectious and hematologic toxic effects are problematic. Acalabrutinib is a selective, potent Bruton tyrosine-kinase inhibitor. The aim of this trial was to evaluate the activity and safety of acalabrutinib in patients with Waldenström macroglobulinemia.

Methods

This single-arm, multicentre, phase 2 trial was done in 19 European academic centres in France, Italy, Greece, the Netherlands, and the UK, and eight academic centres in the USA. Eligible patients were 18 years or older and had treatment naive (declined or not eligible for chemoimmunotherapy) or relapsed or refractory (at least one previous therapy) Waldenström macroglobulinemia that required treatment, an Eastern Cooperative Oncology Group performance status of 2 or less, and received no previous Bruton tyrosine-kinase inhibitor therapy. Patients received 100 mg oral acalabrutinib twice per day in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response (at least a minor response) according to the 6th International Workshop for Waldenström Macroglobulinemia (IWWM) and the modified 3rd IWWM workshop criteria. The primary outcome and safety were assessed in all patients who received at least one dose of treatment. This study is registered with ClinicalTrials.gov, number NCT02180724, and is ongoing, but no longer enrolling.

Findings

Between Sept 8, 2014, and Dec 24, 2015, 122 patients were assessed for eligibility, of which 106 (87%) patients were given acalabrutinib (14 were treatment naive and 92 had relapsed or refractory disease). With a median follow-up of 27·4 months (IQR 26·0–29·7), 13 (93% [95% CI 66–100]) of 14 treatment naive patients achieved an overall response and 86 (93% [86–98]) of 92 relapsed or refractory patients per both the modified 3rd and 6th IWWM criteria. Seven (50%) of 14 treatment naive patients and 23 (25%) of 92 relapsed or refractory patients discontinued treatment on study. Grade 3–4 adverse events occurring in more than 5% of patients were neutropenia (17 [16%] of 106 patients) and pneumonia (7 [7%]). Grade 3–4 atrial fibrillation occurred in one (1%) patient and grade 3–4 bleeding occurred in three (3%) patients. The most common serious adverse events were lower respiratory tract infection (n=7 [7%]), pneumonia (n=7 [7%]), pyrexia (n=4 [4%]), cellulitis (n=3 [3%]), fall (n=3 [3%]), and sepsis (n=3 [3%]). Pneumonia (n=5 [5%]) and lower respiratory tract infection (n=4 [4%]) were considered treatment related. One treatment-related death was reported (intracranial hematoma).

Interpretation

This study provides evidence that acalabrutinib is active as single-agent therapy with a manageable safety profile in patients with treatment-naive, or relapse or refractory Waldenström macroglobulinemia. Further studies are needed to establish its efficacy against current standard treatments and to investigate whether outcomes can be improved with combination therapies.

Funding

Acerta Pharma.

Introduction

Waldenström macroglobulinemia is a rare, lymphoproliferative disorder characterised by lymphoplasmacytic bone marrow infiltration and immunoglobulin M (IgM) paraproteinemia; clinical features include anaemia, constitutional symptoms, hyperviscosity syndrome, and peripheral neuropathy.1 Chemoimmunotherapy with rituximab in combinations with alkylators (bendamustine and bortezomib) is the typical standard of care of these patients; however, infectious and hematologic toxic effects are concerning.2

Bruton tyrosine-kinase is a crucial component of B-cell signalling and is constitutively activated in Waldenström macroglobulinemia.3, 4, 5 Bruton tyrosine-kinase activation might occur because of an activating somatic mutation of myeloid differentiation factor 88 (MYD88),5 an adaptor protein that mediates Toll-like receptor and interleukin 1 receptor signalling to regulate diverse immune responses.6 The MYD88L265P (Leu265Pro) mutation has been reported in up to 90% of patients with Waldenström macroglobulinemia and results in downstream NFκB activation.6 Bruton tyrosine-kinase was validated as a target in Waldenström macroglobulinemia based on activity of the Bruton tyrosine-kinase inhibitor ibrutinib. Ibrutinib is effective in patients with relapsed or refractory Waldenström macroglobulinemia, but is associated with toxic effects such as bleeding, diarrhoea, skin rash, and atrial fibrillation (grade ≥2, 5–10%).7, 8 Combining rituximab with ibrutinib might improve activity over rituximab monotherapy (overall response of 92% after a median follow-up of 26·5 months) but is also associated with toxic effects (eg, grade 3–4 atrial fibrillation in 12% of patients).9

Research in context

Evidence before this study

Despite progress in understanding the pathophysiology of Waldenström macroglobulinemia and improved treatment options, Waldenström macroglobulinemia remains an incurable disease with substantial mortality. Bruton tyrosine-kinase is a validated target based on clinical activity of ibrutinib, an inhibitor of bruton tyrosine-kinase, in Waldenström macroglobulinemia. Bruton tyrosine-kinase could be of increased importance in Waldenström macroglobulinemia because of the high prevalence of the MYD88L265P (Leu265Pro) mutation, which activates NFκB through bruton tyrosine-kinase. Before the start of the enrolment of this study in September 2014, bruton tyrosine-kinase inhibition with ibrutinib was reported to trigger cell death of Waldenström macroglobulinemia cells with MYD88L265P in vitro and showed clinical activity in patients with Waldenström macroglobulinemia in a phase 1 study. This activity was validated in later phase clinical trials. Ibrutinib, however, has additional kinase targets beyond bruton tyrosine-kinase, including EGFR, ErbB2, Src, and interleukin 2–inducible T-cell kinase, which could contribute to adverse events, such as diarrhoea, rash, bleeding, and atrial fibrillation. These adverse events could lead to discontinuation of an effective treatment and support the development of alternative bruton tyrosine-kinase inhibitors for the treatment of Waldenström macroglobulinemia to overcome these issues. Acalabrutinib is a bruton tyrosine-kinase inhibitor that is more potent and selective than ibrutinib, as indicated by kinase selectivity profiling against 395 human kinases. In patients with treatment naive and relapsed or refractory chronic lymphocytic leukaemia, acalabrutinib has shown efficacy and acceptable safety. Here we report the activity and safety results of acalabrutinib treatment in patients with Waldenström macroglobulinemia.

Added value of this study

To our knowledge, this is the first clinical analysis of acalabrutinib in patients with Waldenström macroglobulinemia, expanding existing literature of clinical activity and safety with bruton tyrosine-kinase inhibition in Waldenström macroglobulinemia by using a highly selective bruton tyrosine-kinase inhibitor.

Implications of all the available evidence

An effective bruton tyrosine-kinase inhibitor monotherapy with a differentiate safety profile would offer another viable therapeutic option for patients with Waldenström macroglobulinemia.

Acalabrutinib is a highly selective, covalent Bruton tyrosine-kinase inhibitor that received accelerated approval by the US Food and Drug Administration for the treatment of adult patients with relapsed or refractory mantle cell lymphoma,10, 11 and is also in clinical development for chronic lymphocytic leukaemia and diffuse large B-cell lymphoma. Acalabrutinib shows little effect on EGFR, Tec, Src family kinases, or interleukin 2–inducible T-cell kinase signalling,12 which could contribute to a differentiated profile.

We present results from a single-arm, multicentre, international, phase 2 study evaluating acalabrutinib monotherapy in patients with treatment naive or relapsed or refractory Waldenström macroglobulinemia.

Section snippets

Study design and participants

In this single-arm, multicentre, phase 2 study, we enrolled patients aged 18 years or older with a diagnosis of Waldenström macroglobulinemia requiring treatment, based on the investigator's assessment at eight US centres and 19 European centres in France, Italy, Greece, the Netherlands, and the UK (appendix p 2). Eligible patients had relapsed or refractory disease (received at least one previous therapy) or were treatment naive who declined or had comorbidities that would preclude treatment

Results

Between Sept 8, 2014 and Dec 24, 2015, 122 patients with Waldenström macroglobulinemia were assessed for eligibility. 16 patients were excluded (12 did not meet inclusion criteria or met exclusion criteria, and four withdrew consent). 106 patients (14 treatment naive, 92 relapsed or refractory) were enrolled (figure 1; appendix p 2). Baseline characteristics are shown in table 1. Median number of previous therapies for relapsed or refractory patients was two (range 1–7), with 41 (45%) of 92

Discussion

This phase 2, single-arm, multicentre study is, to our knowledge, the first prospective study of acalabrutinib in patients with Waldenström macroglobulinemia, and the largest prospective study in these patients to date. As understanding of the aberrant signalling in Waldenström macroglobulinemia has improved, Bruton tyrosine kinase inhibitors have shown an increasingly important role in Waldenström macroglobulinemia treatment. With a median follow-up of over 2 years, acalabrutinib was

Data sharing

Acerta Pharma is committed to data transparency and will consider data sharing requests on a case-by-case basis. Any requests for de-identified patient data can be submitted to Acerta Pharma 3 months post-publication and ending 5 years after publication of the article describing the aims of the original proposal. In addition, Acerta Pharma will provide the study protocol, statistical analysis plan, and informed consent form, and post results on clinicaltrials.gov as required.

References (21)

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