Toward New Treatments for Mantle-Cell Lymphoma?
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Mantle-cell lymphoma is a lymphoma subtype characterized by the overexpression of cyclin D1 and the dysregulation of the cell cycle. Many secondary genetic events contribute to growth in mantle-cell lymphoma, including the loss of DNA damage-response capacity, the activation of cell-survival pathways, and the inhibition of apoptosis.1,2 The prognosis in mantle-cell lymphoma is the worst among B-cell lymphomas. Remissions achieved with conventional chemotherapy are often short-lived, and very intensive regimens, including stem-cell transplantation, seem necessary to improve the outcome, but they are feasible in only a limited number of patients.3 Ibrutinib (PCI-32765) is an orally active irreversible inhibitor of . . .Cite
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Mantle cell lymphoma (MCL) comprises about 3% of all newly diagnosed non-Hodgkin’s lymphoma cases and is thought to be incurable with conventional chemotherapy [1]. Ibrutinib, approved in Japan in ...
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Mantle cell lymphoma (MCL) accounts for about 5% of all lymphomas. Its clinical and histological features are heterogeneous. After a frequently good initial response, the disease generally and repeatedly relapses and finally the outcome is poor. Particularly severe is the prognosis of the rare occurrence of CNSi (Central Nervous System involvement). Ibrutinib, an oral inhibitor of Bruton tyrosine kinase (BTK), has shown strong activity in relapsing patients with Chronic Lymphocytic Leukemia (CLL) and MCL. Few reports are available about treatment with ibrutinib of patients presenting CNSi by lymphoproliferative diseases (LPD). In all of them, ibrutinib, at the dosage between 420 and 560 mg/day, showed an impressive effectiveness. Here we describe a case of MCL with CNS relapse showing an excellent response to ibrutinib administered at the unusual dose of 280 mg/day because of concomitant treatment of cardiological disease.
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Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin lymphoma. Ibrutinib is a first-in-class, oral inhibitor of Bruton's tyrosine kinase which acts by downstream inhibition of the B-cell receptor. Early clinical trials have demonstrated excellent tolerability and a modest side-effect profile in relapsed/refractory MCL. Although the majority of disease responses are partial, efficacy data are impressive with more than two-thirds of patients demonstrating a durable response. This article focuses on all aspects of ibrutinib in the context of MCL, including a summary of the basic pharmacology and pharmacokinetics; a review of the safety and efficacy data published to date and a discussion of the future implications in MCL.
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Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of mantle-cell lymphoma. Complete response rates of 21% have been observed for each agent when administered as long-term continuous therapy. Preclinical models predict synergy in combination.We conducted a single-group, phase 2 study of daily oral ibrutinib and venetoclax in patients, as compared with historical controls. Patients commenced ibrutinib monotherapy at a dose of 560 mg per day. After 4 weeks, venetoclax was added in stepwise, weekly increasing doses to 400 mg per day. Both drugs were continued until progression or an unacceptable level of adverse events. The primary end point was the rate of complete response at week 16. Minimal residual disease (MRD) was assessed by flow cytometry in bone marrow and by allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in blood.The study included 24 patients with relapsed or refractory mantle-cell lymphoma (23 patients) or previously untreated mantle-cell lymphoma (1 patient). Patients were 47 to 81 years of age, and the number of previous treatments ranged from none to six. Half the patients had aberrations of TP53, and 75% had a high-risk prognostic score. The complete response rate according to computed tomography at week 16 was 42%, which was higher than the historical result of 9% at this time point with ibrutinib monotherapy (P<0.001). The rate of complete response as assessed by positron-emission tomography was 62% at week 16 and 71% overall. MRD clearance was confirmed by flow cytometry in 67% of the patients and by ASO-PCR in 38%. In a time-to-event analysis, 78% of the patients with a response were estimated to have an ongoing response at 15 months. The tumor lysis syndrome occurred in 2 patients. Common side effects were generally low grade and included diarrhea (in 83% of the patients), fatigue (in 75%), and nausea or vomiting (in 71%).In this study involving historical controls, dual targeting of BTK and BCL2 with ibrutinib and venetoclax was consistent with improved outcomes in patients with mantle-cell lymphoma who had been predicted to have poor outcomes with current therapy. (Funded by Janssen and others; AIM ClinicalTrials.gov number, NCT02471391 .).
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Abstract The U.S. Food and Drug Administration (FDA) approved the targeted therapy ibrutinib for treating patients with mantle cell lymphoma who have received at least one prior therapy. The drug is the second designated by the FDA as a “breakthrough therapy” to be granted approval by the agency.
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For treating relapsed mantle-cell lymphoma (MCL), the Bruton tyrosine kinase inhibitor ibrutinib has been approved in the U.S. and Europe, and the mTOR (mammalian target of rapamycin) inhibitor temsirolimus is approved in Europe. Investigators compared the two drugs in a multinational, open-label trial funded by ibrutinib's manufacturer.
The researchers randomized 280 patients (median age, 68) with relapsed or refractory MCL to …
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