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Bruton Tyrosine Kinase Inhibitors for the Treatment of Mantle Cell Lymphoma: Review of Current Evidence and Future Directions

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Bruton Tyrosine Kinase Inhibitors for the Treatment of Mantle Cell Lymphoma: Review of Current Evidence and Future Directions Bruton Tyrosine Kinase Inhibitors for the Treatment of Mantle Cell Lymphoma: Review of Current Evidence and Future Directions David A. Bond, MD, Lapo Alinari, MD, and Kami Maddocks, MD Dr Bond is a clinical fellow, Dr Alinari Abstract: Mantle cell lymphoma (MCL) is a heterogeneous and is an assistant professor, and Dr uncommon non-Hodgkin lymphoma that affects predominantly Maddocks is an associate professor in older patients and often is associated with an aggressive clinical the Department of Internal Medicine, course. MCL relies upon B-cell receptor signaling through Bruton Division of Hematology, at the Arthur G. James Comprehensive Cancer tyrosine kinase (BTK); therefore, the development of the BTK Center of The Ohio State University inhibitors ibrutinib and acalabrutinib represents a therapeutic Wexner Medical Center in Columbus, breakthrough. In this review, we provide a summary of the efficacy Ohio. and safety data from the landmark trials of single-agent ibrutinib and acalabrutinib that led to US Food and Drug Administration approval of these agents for patients with relapsed or refrac- Corresponding author: Kami Maddocks, MD tory MCL. Toxicities of interest observed with ibrutinib include Division of Hematology bleeding, atrial fibrillation, and increased risk for infection. The Department of Internal Medicine selectivity of acalabrutinib for BTK is greater than that of ibrutinib, The Ohio State University Wexner which mitigates the risk for certain off-target toxicities, including Medical Center atrial fibrillation; however, these toxicities, along with frequent 320 W 10th Street headaches, still occur. Ongoing clinical trials are investigating both A350C Starling Loving Hall Columbus, OH 43210 alternate BTK inhibitors and BTK inhibitors in combination with E-mail: [email protected] chemo-immunotherapy or other targeted agents in an effort to enhance the depth and duration of response. Trials to evaluate the use of these agents in the frontline setting are emerging and are likely to build upon the success of BTK inhibitors in patients with MCL. Introduction Mantle cell lymphoma (MCL) is a rare non-Hodgkin lymphoma (NHL) characterized by a translocation of CCND1 on chromosome 11q13 with the IGH promoter on chromosome 14q32. This results in the upregulation of cyclin D1, which in complex with CDK4 and CDK6 leads to proliferation via the dysregulation of G1 to S cell cycle arrest. Although MCL accounts for fewer than 10% of all cases of NHL, the incidence appears to have increased in recent decades.1,2 Keywords Challenges that arise in the treatment of MCL include an often Acalabrutinib, B-cell receptor, ibrutinib, aggressive clinical course, with options for intensive therapies limited tirabrutinib, zanubrutinib by patient age and comorbidities; the median age at diagnosis is 68 Clinical Advances in Hematology & Oncology Volume 17, Issue 4 April 2019 223 BOND ET AL IgH IgL P Cytoplasmic membrane PIP3 PIP2 CD19 CD79A/B P P P P LYN LYN SYK P P P13K-d FYN BTK PLCγ2 P GRB2 VAV AKT P BLNK DAG IP3 ERK NF-κB Survival and proliferation PKC-b Nuclear translocation Figure. In the B-cell antigen receptor signaling pathway, stimulation of the immunoglobulin M B-cell receptor results in phosphorylation of the intracellular domain of CD79A and CD79B. This results in the recruitment and phosphorylation of SYK and LYN, which in turn lead to the recruitment and phosphorylation of BTK. BTK is bound to scaffolding protein, including BLNK. PI3K phosphorylates PIP2 to PIP3, thereby activating the AKT signaling pathway and promoting BTK signaling. Phosphorylated BTK phosphorylates PLCγ2, which in turn activates PKC-b. This then leads to downstream activation of ERK/ MAPK and degradation of IκB-α, followed by the release of NF-κB. Together, these processes result in survival and proliferation of the malignant B cell. BLNK, B-cell linker protein; BTK, Bruton tyrosine kinase; DAG, diacyl-glycerol; ERK, extracellular signal-regulated kinase, also known as mitogen-activated protein kinase (MAPK); GRB2, growth factor receptor-bound protein 2; IgH, immunoglobulin heavy; IgL, immunoglobulin light; IκB-α, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; IP3, inositol triphosphate; NF-κB, nuclear factor– κB; PI3Kd, phosphoinositide 3-kinase delta; PIP2, phosphatidylinositol bisphosphate; PIP3, phosphatidylinositol triphosphate; PKC-b, protein kinase C beta; PLCγ2, phospholipase C gamma 2; SYK, spleen tyrosine kinase. years.1 Although intensive frontline treatment strategies multiple B-cell malignancies, including MCL.5-9 The BTK result in a median event-free survival of more than 7 years inhibitor ibrutinib has been shown in preclinical models of in younger patients, these therapies typically are not cura- B-cell malignancies, including MCL, to have therapeutic tive, with late relapses occurring at extended follow-up.3 activity via inhibition of downstream BCR signaling, leading to cell death and inhibition of cell migration and Bruton Tyrosine Kinase proliferation.10-13 A phase 1 trial of ibrutinib in patients with relapsed or refractory (R/R) B-cell malignancies Bruton tyrosine kinase (BTK) is a Tec family tyrosine demonstrated objective responses across multiple B-cell kinase that is integral to proximal B-cell receptor (BCR) malignancies, including MCL, supporting further clinical signaling via the phosphorylation of phospholipase C development and providing proof of principle for the gamma 2 (PLCγ2), which leads to the activation of therapeutic potential of small-molecule BTK inhibitors.14 multiple downstream pathways that include nuclear factor–κB (NF-κB) and mitogen-activated protein kinase Approved BTK Inhibitors in Mantle Cell (MAPK; Figure). Germline mutations in BTK cause Lymphoma the arrest of B-cell maturation, leading to low serum immunoglobulin levels (defined as the immunodeficiency Ibrutinib syndrome X-linked agammaglobulinemia).4 Dependence The US Food and Drug Administration (FDA) on constitutive BCR signaling is a common feature of granted accelerated approval to ibrutinib (Imbruvica, 224 Clinical Advances in Hematology & Oncology Volume 17, Issue 4 April 2019 BRUTON TYROSINE KINASE INHIBITORS FOR THE TREATMENT OF MCL Pharmacyclics/Janssen) as a single agent, dosed orally at Toxicities of interest that were more common in the 560 mg daily, for patients with previously treated MCL. patients treated with ibrutinib included bleeding, cardiac Approval was based on results of the phase 2 open-label arrhythmia, arthralgia, hypertension, and opportunistic PCYC-1104-CA trial (Safety and Efficacy of PCI-32765 infection. An increased incidence of atrial fibrillation has in Participants With Relapsed/Refractory Mantle Cell been observed in prospective trials of ibrutinib in multiple Lymphoma).15 A total of 115 patients with previously disease types, with an incidence of 6.5% reported in a treated MCL were enrolled, with 111 patients receiv- pooled analysis of 1505 patients treated with ibrutinib ing at least 1 dose of therapy. The median age of the at a median follow-up of 16.6 months.21 Although the patients was 68 years, the median number of prior thera- incidence of atrial fibrillation appears to be highest within pies was 3, and the disease of nearly half of the patients the first 6 months after the start of therapy, an increas- had been refractory to their last prior therapy. A total ing incidence has been reported with extended exposure of 86% of cases were considered intermediate- or high- (estimated incidence of >10% with extended follow- risk according to the simplified Mantle Cell Lymphoma up).21,22 In addition to atrial arrhythmia, recent reports International Prognostic Index (MIPI) score.16 The over- suggest an association between ibrutinib and ventricular all response rate (ORR) was 68% and included a 21% arrhythmia.23,24 Increased susceptibility to infection, rate of complete response (CR). Common toxicities including fungal and other opportunistic infection, has of any grade included diarrhea (50%), fatigue (40%), been observed in patients treated with ibrutinib, with the nausea (30%), and decreased appetite (20%). Grade 3 risk highest in the first 6 months of therapy.25-30 Although or 4 hematologic events included neutropenia (11%), B-cell inhibition contributes in part to the infectious risk, anemia (10%), and thrombocytopenia (11%). Bleeding the mechanism of increased susceptibility to Aspergillus events included subdural hematoma in 4 patients, and fumigatus infection appears to be due primarily to inhi- 5 patients had grade 3 bleeding events. With extended bition of the macrophage response as a BTK-dependent follow-up, median progression-free survival (PFS) was effect.31 Serious bleeding events have been seen in patients 13 months, median duration of response (DOR) was on ibrutinib monotherapy, and early reports of major 17.5 months, and median overall survival (OS) was 22.5 bleeding in patients receiving concomitant warfarin anti- months.17 A subsequent phase 3 international trial called coagulation led to the exclusion of patients on warfarin MCL3001 (Study of Ibrutinib [a Bruton’s Tyrosine from subsequent ibrutinib trials.18,32 A recent meta-analysis Kinase Inhibitor], Versus Temsirolimus in Patients With found a higher overall incidence of bleeding but not major Relapsed or Refractory Mantle Cell Lymphoma Who bleeding events with ibrutinib monotherapy than with Have Received at Least One Prior Therapy) included alternate treatments.33 280 patients randomly assigned to
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