Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial

Wang, Michael; Rule, Simon; Zinzani, Pier Luigi; Goy, André; Casasnovas, Olivier; Smith, Stephen D.; Damaj, Gandhi; Doorduijn, Jeanette K.; Lamy, Thierry; Morschhauser, Franck; Panizo, Carlos; Shah, Bijal; Davies, Andrew; Eek, Richard; Dupuis, Jehan; Jacobsen, Eric; Kater, Arnon P.; Gouill, Steven Le; Obéric, Lucie; Robak, Tadeusz; Covey, Todd; Dua, Richa; Hamdy, Ahmed; Huang, Xin; Izumi, Raquel; Patel, Priti; Rothbaum, Wayne; Slatter, J. Greg; Jurczak, Wojciech

doi:10.1016/s0140-6736(17)33108-2

Cited by 353 publications

(260 citation statements)

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“…B‐cell receptor (BCR) signalling pathway plays a major role in the growth and survival of mantle cell lymphoma (MCL) cells (Saba et al , ). Inhibition of Bruton tyrosine kinase (BTK) enzyme, a pivotal member of BCR signalling with ibrutinib (Wang et al , ) and acalabrutinib (Wang et al , ) is a major breakthrough in the treatment of patients with MCL. Ibrutinib is commonly used in the treatment of MCL as well as in small lymphocytic lymphoma/chronic lymphocytic leukaemia (SLL/CLL).…”

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confidence: 99%

Long‐term outcomes and mutation profiling of patients with mantle cell lymphoma (MCL) who discontinued ibrutinib

et al. 2018

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Long term outcomes and mutations in patients with mantle cell lymphoma (MCL) who discontinued ibrutinib have not been described. Using deep targeted next generation sequencing, we performed somatic mutation profiling from 15 MCL patients (including 5 patients with paired samples; before and after progression on ibrutinib). We identified 80 patients with MCL who discontinued ibrutinib therapy for various reasons. Median follow-up after ibrutinib discontinuation was 38 months. The median duration on ibrutinib was 7·6 months. Forty-one (51%) patients discontinued ibrutinib due to disease progression/transformation, 20 (25%) for intolerance, 7 (9%) due to patient choice, 5 (6%) for stem cell transplant, 4 (5%) due to second cancers and 3 (4%) other causes. The median survival after ibrutinib was 10 and 6 months for disease progression and transformation, respectively, and 25 months for patients with ibrutinib intolerance. Overall, BTK mutations were observed in 17% patients after progression on ibrutinib. Notably, TP53 alterations were observed after progression in 75% patients. Among the 4 patients with blastoid transformation, 3 (75%) had NSD2 mutations (co-existing with TP53). Ibrutinib-refractory MCL patients had a short survival. Demonstration of TP53 and NSD2 mutations in patients who developed blastoid transformation and ATM and TP53 mutations in patients who progressed, opens the door for future investigations in ibrutinib-refractory MCL.

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confidence: 99%

Long‐term outcomes and mutation profiling of patients with mantle cell lymphoma (MCL) who discontinued ibrutinib

et al. 2018

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“…However, it does sometimes happen that agents that are more selective might be less effective. Fortunately, a reduction in efficacy with the newer btk inhibitors is not evident, as shown in the acalabrutinib study by Wang et al 14 and the zanubrutinib study by Tam et al 17 , and a reduction in some bothersome aes is even suggested.…”

Section: Q How Do the Novel Btk Inhibitors Attempt To Improve On Ibrumentioning

confidence: 99%

“…To examine the efficacy and safety of acalabrutinib, a highly selective oral inhibitor of btk with minimal offtarget activity, in rr mcl 14,19 .…”

Section: Objectivementioning

confidence: 99%

“…With the success of ibrutinib in hematologic malignancies, novel btk inhibitors designed to improve on its safety and efficacy are being developed. Acalabrutinib (ACP-196) is a potent orally bioavailable novel btk inhibitor that also binds Cys481 in the btk active site, inactivating the enzyme and resulting in inhibition of proliferation and survival signals in malignant B-cells 14 . However, acalabrutinib is more highly selective than ibrutinib, resulting in less off-target activity; it is therefore predicted to have fewer adverse effects.…”

Section: Introductionmentioning

confidence: 99%

“…However, acalabrutinib is more highly selective than ibrutinib, resulting in less off-target activity; it is therefore predicted to have fewer adverse effects. During in vitro studies comparing acalabrutinib with ibrutinib, acalabrutinib showed more selective btk inhibition and higher in vivo potency 14 . Acalabrutinib was recently granted breakthrough designation for priority review by the U.S. Food and Drug Administration, and on 31 October 2017, it was granted accelerated approval by that agency for the treatment of patients with mcl who have received at least 1 prior therapy 15,16 .…”

Section: Introductionmentioning

confidence: 99%

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Updates from the 2017 American Society of Hematology Annual Meeting: Practice-Changing Studies in Relapsed and Refractory Mantle Cell Lymphoma

Kuruvilla

Christofides

2018

Current Oncology

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The 2017 annual meeting of the American Society of Hematology took place 9-12 December in Atlanta, Georgia. At the meeting, results from key studies in the treatment of relapsed and refractory mantle cell lymphoma were presented. Of those studies, oral presentations focused on the efficacy and safety of therapy with Bruton tyrosine kinase (btk) inhibitors. One study presented pooled data from three trials using ibrutinib, with a median follow-up of 3.5 years. A second phase ii study presented data on the efficacy and safety of acalabrutinib, a highly selective btk inhibitor with minimal off-target activity. The final study presented early phase ib data on the efficacy and safety of zanubrutinib, a novel, highly selective btk inhibitor, in patients with non-Hodgkin lymphoma. Our meeting report describes the foregoing studies and presents interviews with investigators and commentaries by Canadian hematologists about potential effects on Canadian practice.

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Clinical Experience with Drugs Targeting Bruton's Tyrosine Kinase (BTK)

Aronson

Mato

Coombs

et al. 2023

Precision Cancer Therapies, Volume 1 ‐ Targeting Oncogenic Drivers and Signaling Pathways in Lymphoid Malignancies

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Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial

Abstract: Acerta Pharma, a member of the AstraZeneca Group.

Cited by 353 publications

References 23 publications

Long‐term outcomes and mutation profiling of patients with mantle cell lymphoma (MCL) who discontinued ibrutinib

Long‐term outcomes and mutation profiling of patients with mantle cell lymphoma (MCL) who discontinued ibrutinib

Updates from the 2017 American Society of Hematology Annual Meeting: Practice-Changing Studies in Relapsed and Refractory Mantle Cell Lymphoma

Clinical Experience with Drugs Targeting Bruton's Tyrosine Kinase (BTK)

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