Durable response with single-agent acalabrutinib in patients with relapsed or refractory mantle cell lymphoma

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; Jain, Preetesh; Frigault, Melanie M.; Izumi, Raquel; Nguyen, Dorothy D.; Patel, Priti; Yin, Ming; Długosz-Danecka, Monika

doi:10.1038/s41375-019-0575-9

Cited by 86 publications

(72 citation statements)

References 6 publications

(20 reference statements)

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“…Unfortunately, second-generation BTK inhibitors such as acalabrutinib, zanubrutinib, or tirabrutinib are not able to overcome the resistance caused by BTK C481S since they bind to the same protein region as ibrutinib. Their advantage is their higher selectivity with less off-targets ( Supplementary Table 1 ) and lesser toxicities than ibrutinib, making them more feasible for patients intolerant to ibrutinib ( 168 – 172 ). Acalabrutinib has recently been approved for CLL and MCL and zanubrutinib for MCL ( 171 , 173 ).…”

Section: Targeting Ibrutinib Resistancementioning

confidence: 99%

Genetic and Non-Genetic Mechanisms of Resistance to BCR Signaling Inhibitors in B Cell Malignancies

Ondrisova

Mráz

2020

Front. Oncol.

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The approval of BTK and PI3K inhibitors (ibrutinib, idelalisib) represents a revolution in the therapy of B cell malignancies such as chronic lymphocytic leukemia (CLL), mantle-cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), or Waldenström’s macroglobulinemia (WM). However, these “BCR inhibitors” function by interfering with B cell pathophysiology in a more complex way than anticipated, and resistance develops through multiple mechanisms. In ibrutinib treated patients, the most commonly described resistance-mechanism is a mutation in BTK itself, which prevents the covalent binding of ibrutinib, or a mutation in PLCG2, which acts to bypass the dependency on BTK at the BCR signalosome. However, additional genetic aberrations leading to resistance are being described (such as mutations in the CARD11 , CCND1 , BIRC3, TRAF2, TRAF3, TNFAIP3, loss of chromosomal region 6q or 8p, a gain of Toll-like receptor (TLR)/MYD88 signaling or gain of 2p chromosomal region). Furthermore, relative resistance to BTK inhibitors can be caused by non-genetic adaptive mechanisms leading to compensatory pro-survival pathway activation. For instance, PI3K/mTOR/Akt, NFkB and MAPK activation, BCL2, MYC, and XPO1 upregulation or PTEN downregulation lead to B cell survival despite BTK inhibition. Resistance could also arise from activating microenvironmental pathways such as chemokine or integrin signaling via CXCR4 or VLA4 upregulation, respectively. Defining these compensatory pro-survival mechanisms can help to develop novel therapeutic combinations of BTK inhibitors with other inhibitors (such as BH3-mimetic venetoclax, XPO1 inhibitor selinexor, mTOR, or MEK inhibitors). The mechanisms of resistance to PI3K inhibitors remain relatively unclear, but some studies point to MAPK signaling upregulation via both genetic and non-genetic changes, which could be co-targeted therapeutically. Alternatively, drugs mimicking the BTK/PI3K inhibition effect can be used to prevent adhesion and/or malignant B cell migration (chemokine and integrin inhibitors) or to block the pro-proliferative T cell signals in the microenvironment (such as IL4/STAT signaling inhibitors). Here we review the genetic and non-genetic mechanisms of resistance and adaptation to the first generation of BTK and PI3K inhibitors (ibrutinib and idelalisib, respectively), and discuss possible combinatorial therapeutic strategies to overcome resistance or to increase clinical efficacy.

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Section: Targeting Ibrutinib Resistancementioning

confidence: 99%

Genetic and Non-Genetic Mechanisms of Resistance to BCR Signaling Inhibitors in B Cell Malignancies

Ondrisova

Mráz

2020

Front. Oncol.

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“…Acalabrutinib demonstrated an ORR of 81% (CR rate of 43%) in a phase II study (ACE-LY-2004, n = 124) of relapsed/refractory MCL leading to its FDA approval [11]. At a median follow-up time of 26 months, the median PFS and OS were 20 months and not reached, respectively [11,12]. The most common side effects included headache (34%), infection (41%), diarrhea (25%), and bleeding (25%).…”

Section: Small Molecule Targeted Therapies Btk Inhibitorsmentioning

confidence: 99%

Emerging therapies in mantle cell lymphoma

Hanel

Epperla

2020

J Hematol Oncol

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Mantle cell lymphoma (MCL) is a rare, B cell non-Hodgkin's lymphoma with highly heterogeneous clinical presentation and aggressiveness. First-line treatment consists of intensive chemotherapy with autologous stem cell transplant for the fit, transplant eligible patients, or less intensive chemotherapy for the less fit (and transplantineligible) patients. Patients eventually relapse with a progressive clinical course. Numerous therapeutic approaches have emerged over the last few years which have significantly changed the treatment landscape of MCL. These therapies consist of targeted approaches such as BTK and BCL2 inhibitors that provide durable therapeutic responses. However, the optimum combination and sequencing of these therapies is unclear and is currently investigated in several ongoing studies. Furthermore, cellular therapies such as chimeric antigen receptor (CAR) T cells and bispecific T cell engager (BiTe) antibodies have shown impressive results and will likely shape treatment approaches in relapsed MCL, especially after failure with BTK inhibitors. Herein, we provide a comprehensive review of past and ongoing studies that will likely significantly impact our approach to MCL treatment in both the frontline (for transplant eligible and ineligible patients) as well as in the relapsed setting. We present the most up to date results from these studies as well as perspectives on future studies in MCL.

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“…Nonetheless, almost one-third of MCL patients are resistant to ibrutinib therapy, and sensitive patients eventually acquire resistance, experiencing a more aggressive disease [26,83,84]. The second FDA-approved BTK inhibitor, acalabrutinib, potentially more "kinase-selective", showed durable response in patients with R/R MCL as single agent [85,86]. However, a longer follow-up is needed to conclude on acalabrutinib efficacy.…”

Section: Resistance To Btk and Pi3k Inhibitorsmentioning

confidence: 99%

Management of Drug Resistance in Mantle Cell Lymphoma

Roué

Sola

2020

Cancers

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Mantle cell lymphoma (MCL) is a rare but aggressive B-cell hemopathy characterized by the translocation t(11;14)(q13;q32) that leads to the overexpression of the cell cycle regulatory protein cyclin D1. This translocation is the initial event of the lymphomagenesis, but tumor cells can acquire additional alterations allowing the progression of the disease with a more aggressive phenotype and a tight dependency on microenvironment signaling. To date, the chemotherapeutic-based standard care is largely inefficient and despite the recent advent of different targeted therapies including proteasome inhibitors, immunomodulatory drugs, tyrosine kinase inhibitors, relapses are frequent and are generally related to a dismal prognosis. As a result, MCL remains an incurable disease. In this review, we will present the molecular mechanisms of drug resistance learned from both preclinical and clinical experiences in MCL, detailing the main tumor intrinsic processes and signaling pathways associated to therapeutic drug escape. We will also discuss the possibility to counteract the acquisition of drug refractoriness through the design of more efficient strategies, with an emphasis on the most recent combination approaches.

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Durable response with single-agent acalabrutinib in patients with relapsed or refractory mantle cell lymphoma

Abstract: et al. Mutations in SETBP1 are recurrent in myelodysplastic syndromes and often coexist with cytogenetic markers associated with disease progression. Br J Haematol. 2013;163:235-9.

Cited by 86 publications

References 6 publications

Genetic and Non-Genetic Mechanisms of Resistance to BCR Signaling Inhibitors in B Cell Malignancies

Genetic and Non-Genetic Mechanisms of Resistance to BCR Signaling Inhibitors in B Cell Malignancies

Emerging therapies in mantle cell lymphoma

Management of Drug Resistance in Mantle Cell Lymphoma

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