acp-196 and Lymphoma--Mantle-Cell

Greater understanding of the mechanisms involved in the disease progression of haematological malignancies has led to the introduction of novel targeted therapies with reduced toxicity compared with chemotherapy-based regimens, which has expanded the treatment options for patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). Ibrutinib is a first-in-class Bruton tyrosine kinase (BTK) inhibitor indicated for the treatment of patients with CLL/SLL or relapsed/refractory MCL. However, next-generation BTK inhibitors have been developed with improved specificity and the potential to reduce the off-target toxicity observed with ibrutinib. Acalabrutinib is a highly selective, next-generation BTK inhibitor, which was granted accelerated approval by the US Food and Drug Administration in 2017 for the treatment of adult patients with MCL who have received at least one prior therapy. In November 2019, it was also granted approval for the treatment of adult patients with CLL/SLL on the basis of two phase 3 clinical trials. This review describes the current understanding of acalabrutinib according to clinical study data for the treatment of MCL and CLL/SLL and shares recommendations from our practice on how it should be used when treating patients in the clinic, including dosing, administration and management of adverse events.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Benzamides; Clinical Trials as Topic; Disease Progression; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Middle Aged; Piperidines; Practice Patterns, Physicians'; Pyrazines; Safety; Treatment Outcome; United States; United States Food and Drug Administration

Topics: Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Humans; Lymphoma, Mantle-Cell; Protein Kinase Inhibitors; Pyrazines

Mantle cell lymphoma is a rare subtype of B-cell non-Hodgkin's lymphomas that is generally classified as an aggressive lymphoma requiring front-line chemo-immunotherapy with stem cell rescue. Despite effective treatment, many patients relapse or are refractory to front-line therapy. In addition, these patients may also develop drug resistance requiring novel modalities for subsequent lines. Bruton's tyrosine kinase inhibitors have demonstrated a well-tolerated safety and efficacy profile across several B-cell malignancies. Ibrutinib, acalabrutinib, and zanubrutinib are FDA-approved as treatment options for patients with Mantle cell lymphoma following one prior line of therapy. Various factors should be considered which include the adverse event profile of these agents and ability to adhere to therapy. In this article, we review the role of Bruton's tyrosine kinase inhibitors for the management of Mantle cell lymphoma and review the clinical pharmacology, pharmacokinetics, safety and efficacy, and future directions.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Benzamides; Humans; Immunotherapy; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines

The Bruton tyrosine kinase inhibitors (BTKi), acalabrutinib, ibrutinib, and zanubrutinib, are all approved in the United States for the treatment of relapsed mantle cell lymphoma (MCL). BTKi as a class have become the preferred therapy for most of the patients with relapsed MCL, and ongoing clinical trials are evaluating whether combining BTKi with other targeted agents may deepen response and further improve outcomes. Emerging evidence supports the efficacy of BTKi-containing combinations as frontline treatment, and clinical studies to define the role of this class of drugs for newly diagnosed patients with MCL are in progress.

Topics: Agammaglobulinaemia Tyrosine Kinase; Benzamides; Humans; Lymphoma, Mantle-Cell; Neoplasm Proteins; Piperidines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines

Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphoma that can be either aggressive or indolent. Although MCL usually responds well to initial treatment with chemotherapy-based regimens, the disease often relapses or becomes refractory within a few years. Acalabrutinib is a highly selective, potent, covalent Bruton tyrosine kinase inhibitor with minimal off-target activity. WIthout head-to-head clinical trial data, estimation of the comparative efficacy and safety of new therapeutic entities provides valuable information for patients, clinicians, and health care payers. The objective of this analysis was to compare the efficacy and safety of acalabrutinib versus other targeted therapies employed for the treatment of relapsed/refractory MCL by using matching-adjusted indirect comparisons.. Individual data from 124 patients treated with acalabrutinib in the Phase II ACE-LY-004 trial were adjusted to match average baseline characteristics of populations from studies using alternative targeted treatment regimens for relapsed/refractory MCL (for monotherapy: ibrutinib, bortezomib, lenalidomide, and temsirolimus; for combination therapies: ibrutinib + rituximab, bendamustine + rituximab, and lenalidomide + rituximab). Patient populations were matched on age, sex, race, Eastern Cooperative Oncology Group performance status, Simplified MCL International Prognostic Index score, tumor bulk, lactate dehydrogenase concentration, extranodal disease, bone marrow involvement, and number of previous treatment regimens. Outcomes assessed included overall response rate (ORR), complete response (CR) rate, overall survival (OS), progression-free survival (PFS), and adverse events.. After matching, acalabrutinib was associated with significant increases in ORR and CR rate (estimated treatment difference [95% CI]) versus ibrutinib (ORR, 9.3% [0.3-18.3]; CR, 14.9% [5.4-24.3]), bortezomib (ORR, 50.6% [40.2-61.0]; CR, 18.8% [9.1-28.5]), lenalidomide (ORR, 38.1% [27.1-49.1]; CR, 43.5% [34.8-52.3]), and temsirolimus (ORR, 40.7% [31.0-50.4]; CR, 27.1% [19.2-35.0]). PFS (hazard ratio [95% CI]) with acalabrutinib was significantly increased versus bortezomib (0.36 [0.26-0.51]), lenalidomide (0.65 [0.48-0.89]), lenalidomide + rituximab (0.57 [0.35-0.93]), and temsirolimus (0.33 [0.24-0.45]). Acalabrutinib was associated with significantly increased OS (hazard ratio) versus bortezomib (0.36 [0.22-0.61]) and temsirolimus (0.32 [0.23-0.44]). The overall safety profile of acalabrutinib was similar or better compared with the monotherapies; however, infection risk increased versus bendamustine + rituximab, and anemia increased risk versus lenalidomide + rituximab and ibrutinib + rituximab.. This comparison of targeted therapies used in the treatment of relapsed/refractory MCL showed that acalabrutinib has the potential to provide increased response rates, with trends for increased PFS and OS, and an improved safety profile.

Topics: Adenine; Antineoplastic Agents; Benzamides; Bortezomib; Humans; Lenalidomide; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Piperidines; Pyrazines; Pyrazoles; Pyrimidines; Rituximab; Sirolimus; Treatment Outcome

Although advances in mantle cell lymphoma (MCL) therapy have improved overall survival (OS), managing relapsed/refractory (R/R) cases remains a great challenge. Bruton tyrosine kinase (BTK) inhibitors have broadened therapeutic options in MCL and became the backbone of second-line strategies. Areas covered: Ibrutinib, the first-in-class BTK inhibitor registered for MCL therapy, is efficient, with clear benefits of its use. However, ibrutinib-related adverse events due to off-target inhibition of other kinases led to the development of more selective molecules with comparable efficacy and better safety profiles. Expert commentary: Acalabrutinib, a new BTK inhibitor, currently being evaluated in numerous clinical studies is approved by FDA in relapsing/refractory MCL. Its role will evolve over the next few years. Efficacy and good tolerability of acalabrutinib gives even greater opportunity for potential upfront use and new therapeutic combinations, including monoclonal antibodies, antibody-drug conjugates, immune checkpoint inhibitors, bcl-2 (B-cell lymphoma-2) or IP3K (phosphoinositide 3-kinase) inhibitors.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Benzamides; Humans; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Survival Rate

Mantle cell lymphoma (MCL) is a unique type of non-Hodgkin lymphoma characterized by the overexpression of cyclin D1. MCL patients typically live for years but experience multiple relapses. Acalabrutinib is a novel second-generation oral Bruton tyrosine kinase inhibitor approved by the US Food and Drug Administration for relapsed MCL based on a clinical trial demonstrating an overall response rate of 81%. It provides a valuable new treatment option for MCL patients and is now being tested upfront.

Topics: Antineoplastic Agents; Benzamides; Humans; Lymphoma, Mantle-Cell; Protein Kinase Inhibitors; Pyrazines

Mantle cell lymphoma (MCL) is a heterogeneous and uncommon non-Hodgkin lymphoma that affects predominantly older patients and often is associated with an aggressive clinical course. MCL relies upon B-cell receptor signaling through Bruton tyrosine kinase (BTK); therefore, the development of the BTK inhibitors ibrutinib and acalabrutinib represents a therapeutic breakthrough. In this review, we provide a summary of the efficacy 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 refractory MCL. Toxicities of interest observed with ibrutinib include bleeding, atrial fibrillation, and increased risk for infection. The selectivity of acalabrutinib for BTK is greater than that of ibrutinib, which mitigates the risk for certain off-target toxicities, including atrial fibrillation; however, these toxicities, along with frequent headaches, still occur. Ongoing clinical trials are investigating both alternate BTK inhibitors and BTK inhibitors in combination with 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.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antigens, CD20; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cardiovascular Diseases; Clinical Trials as Topic; Forecasting; Gastrointestinal Neoplasms; Hemorrhage; Humans; Immunologic Factors; Lymphocytosis; Lymphoma, Mantle-Cell; Molecular Targeted Therapy; Neoplasm Proteins; Opportunistic Infections; Piperidines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Salvage Therapy

Acerta Pharma is developing the Bruton's tyrosine kinase inhibitor acalabrutinib (Calquence

Topics: Adult; Agammaglobulinaemia Tyrosine Kinase; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Dose-Response Relationship, Drug; Drug Approval; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazines; Treatment Outcome; United States; United States Food and Drug Administration

Acalabrutinib, a selective Bruton tyrosine kinase (BTK) inhibitor, was granted accelerated approval by the FDA on 31 October 2017 for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Areas covered: This narrative review provides an overview of acalabrutinib, its use in clinical practice and potential future developments. Expert commentary: BTK inhibitors have demonstrated efficacy in patients with relapsed or refractory MCL. To prepare patients for therapy, all preexisting infections should be diagnosed and treated, and infection prophylaxis undertaken. Serious adverse reactions are rare with acalabrutinib; however, patients should be made aware of common adverse events such as headaches, which usually resolve within one month without medical treatment. Interaction with other drugs appears to be less of an issue with acalabrutinib than with ibrutinib; however, patients receiving acalabrutinib therapy must be advised not to take any additional medications without first consulting with their treating physician. A key unmet medical need is treatment options for patients in whom BTK inhibitors are discontinued, because of either intolerance or refractory disease. Patients not tolerating ibrutinib could be switched to acalabrutinib, which has improved selectivity and increased tolerability. First-line treatment with acalabrutinib is being investigated.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Benzamides; Humans; Infection Control; Infections; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines

Bruton's tyrosine kinase (BTK) is crucial in B-cell development and survival. The role of BTK as a downstream kinase in the B-cell receptor (BCR) signaling pathway is well described. As a key player in the pathogenesis of B-cell malignancies, targeting of dysregulated BCR signaling has been explored by development of inhibitors of downstream mediators. Discovery of the biological function of BTK and the development of covalent inhibitors for clinical use, ibrutinib as the lead agent and acalabrutinib as the second clinically approved BTK inhibitor, have revolutionized the treatment options for B-cell malignancies. Currently, ibrutinib is approved for mantle cell lymphoma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, small lymphocytic lymphoma, marginal zone lymphoma and chronic graft versus host disease, while acalabrutinib is approved for mantle cell lymphoma. Potential expansion of indications in other diseases is under investigation in several clinical trials, while combination of BTK inhibitors with either chemoimmunotherapy or other targeted agents is being systematically explored in B-cell malignancies.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; B-Lymphocytes; Benzamides; Drug Therapy, Combination; Humans; Lymphoma, B-Cell; Lymphoma, Mantle-Cell; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines

This multicenter, open-label, phase I study assessed the safety and antitumor activity of acalabrutinib in Japanese patients with relapsed/refractory (r/r) B-cell malignancies. Parts 1 (dose confirmation) and 2 (dose expansion) of this three-part study are reported. Treatment was a single dose of 100 mg acalabrutinib (day 1), followed by a washout period and then twice daily 100 mg acalabrutinib in part 1, or twice daily 100 mg acalabrutinib in part 2. Patients from parts 1 and 2 with r/r chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), and r/r mantle cell lymphoma (MCL) were assessed as r/r CLL/SLL and r/r MCL cohorts, respectively. Twenty-five patients received treatment (part 1, n = 6). Median age was 71.0 years. Nine (one patient from part 1) and 13 (two patients from part 1) patients were included in the r/r CLL/SLL and r/r MCL cohorts, respectively. Treatment-related adverse events (AEs) occurred in 88% of patients (grade ≥3, 36%); the most common were headache (28%) and purpura (24%), both grade 1/2. No AEs resulted in treatment discontinuation or death. Median duration of treatment was 31, 20, and 7 months for part 1, r/r CLL/SLL cohort, and r/r MCL cohort, respectively. Overall response rate (ORR) was 89% and 62% for the r/r CLL/SLL and r/r MCL cohorts, respectively. The median progression-free survival (PFS) was not reached for the r/r CLL/SLL cohort and was 7 months for the r/r MCL cohort. Acalabrutinib (100 mg twice daily) was generally safe and well-tolerated in adult Japanese patients with B-cell malignancies.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Benzamides; Drug Administration Schedule; Female; Headache; Humans; Japan; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Purpura; Pyrazines; Survival Analysis; Treatment Outcome

Topics: Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antineoplastic Agents; Benzamides; Cell Proliferation; Disease Progression; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Ki-67 Antigen; Lymphoma, Mantle-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm, Residual; Pyrazines; Time Factors; Treatment Outcome

Bruton tyrosine kinase is a clinically validated target in mantle cell lymphoma. Acalabrutinib (ACP-196) is a highly selective, potent Bruton tyrosine kinase inhibitor developed to minimise off-target activity.. In this open-label, phase 2 study, oral acalabrutinib (100 mg twice per day) was given to patients with relapsed or refractory mantle cell lymphoma, until disease progression or unacceptable toxicity. The primary endpoint was overall response assessed according to the Lugano classification, and safety analyses were done in all participants. This trial is registered with ClinicalTrials.gov, number NCT02213926.. From March 12, 2015, to Jan 5, 2016, 124 patients with relapsed or refractory mantle cell lymphoma were enrolled and all patients received treatment; median age 68 years. Patients received a median of two (IQR 1-2) previous therapies. At a median follow-up of 15·2 months, 100 (81%) patients achieved an overall response and 49 (40%) patients achieved a complete response. The Kaplan-Meier estimated medians for duration of response, progression-free survival, and overall survival were not reached; the 12-month rates were 72% (95% CI 62-80), 67% (58-75), and 87% (79-92%), respectively. The most common adverse events were primarily grade 1 or 2 and were headache (47 [38%]), diarrhoea (38 [31%]), fatigue (34 [27%]), and myalgia (26 [21%]). The most common grade 3 or worse adverse events were neutropenia (13 [10%]), anaemia (11 [9%]), and pneumonia (six [5%]). There were no cases of atrial fibrillation and one case of grade 3 or worse haemorrhage. The median duration of treatment was 13·8 months. Treatment was discontinued in 54 (44%) patients, primarily due to progressive disease (39 [31%]) and adverse events (seven [6%]).. Acalabrutinib treatment provided a high rate of durable responses and a favourable safety profile in patients with relapsed or refractory mantle cell lymphoma. These findings suggest an important role for acalabrutinib in the treatment of this disease population.. Acerta Pharma, a member of the AstraZeneca Group.

Topics: Aged; Benzamides; Dose-Response Relationship, Drug; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Protein Kinase Inhibitors; Pyrazines; Recurrence; Survival Analysis; Treatment Outcome

Mantle cell lymphoma (MCL) is a moderately aggressive lymphoma subtype, generally viewed as incurable. For younger, fit patients, the standard of care remains various high-dose cytarabine-based induction regimens followed by autologous hematopoietic cell transplant and 3 years of rituximab maintenance. Despite reasonably good outcomes, with median progression-free survival in the range of 7 to 9 years, most patients eventually relapse, indicating a need to improve the safety and tolerability of remission induction strategies.. Given the impressive activity of bendamustine/rituximab (BR) in older patients with MCL, we developed an induction regimen modeled after the Nordic Regimen but substituted BR in place of R-CHOP. In a second pilot study, we incorporated the second-generation Bruton tyrosine kinase inhibitor (BTKi), acalabrutinib, into the regimen. The primary endpoint of both studies was stem cell mobilization success rate.. All patients successfully underwent stem cell harvest in both studies.. The experience from our single institution pilot study suggested that sequential rather than alternating BR and cytarabine/rituximab (CR) was easier to administer from the standpoint of toxicities and subsequent dose modifications. Safety and efficacy data from the 2 pilot studies, FitMCL 1.0 and 2.0, were similar. The pilot studies provided preliminary safety data supporting the development of the NCTN trial EA4181, assessing three different induction regimens with or without acalabrutinib.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Cytarabine; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Pilot Projects; Rituximab

Topics: Antineoplastic Agents; Benzamides; Combined Modality Therapy; Disease Progression; Drug Substitution; Exome Sequencing; Follow-Up Studies; Humans; Immunotherapy, Adoptive; Kaplan-Meier Estimate; Lymphoma, Mantle-Cell; Mutation; Protein Kinase Inhibitors; Pyrazines; Recurrence; Salvage Therapy; Sample Size; Treatment Outcome; Withholding Treatment

Acalabrutinib is a selective Bruton tyrosine kinase inhibitor approved for patients with relapsed or refractory mantle cell lymphoma, an aggressive B-cell malignancy. Treatment-related adverse events (AEs) can have a negative effect on treatment adherence.. This article aims to provide nurses with firsthand guidance so that they can better support patients with mantle cell lymphoma initiating acalabrutinib.. Safety data from the acalabrutinib ACE-LY-004 phase 2 trial in 124 patients with relapsed or refractory mantle cell lymphoma were reviewed, and strategies implemented at the University of Texas MD Anderson Cancer Center to manage trial AEs are described.. The most common AEs of any grade were headache and diarrhea, but no patients discontinued treatment because of them. When doses were missed or modified, patients were reeducated about the importance of adherence and how to manage AEs. Grade 1-2 AEs were managed with over-the-counter medication, if needed. These strategies allowed for the tracking of occurrences of nonadherence, providing the opportunity to advise and educate patients and to manage AEs more effectively.

Topics: Adult; Antineoplastic Agents; Benzamides; Clinical Trials, Phase II as Topic; Humans; Lymphoma, Mantle-Cell; Protein Kinase Inhibitors; Pyrazines

The B-cell receptor and the phosphatidylinositol 3-kinase (PI3K) signalling pathways, together with their downstream partners, represent important therapeutic targets for B-cell lymphomas. Here, we evaluated the activity of acalabrutinib (ACP-196) and ACP-319 (AMG-319), second generation inhibitors of Bruton tyrosine kinase (BTK) and PI3Kδ inhibitor, respectively, in lymphoma pre-clinical models. The two compounds showed activity in activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL), mantle cell lymphoma and marginal zone lymphoma. Two in vivo experiments with ABC DLBCL and MCL xenografts confirmed the effect of the single agents. Benefit was achieved by exposing the lymphoma cell lines to both acalabrutinib and ACP-319. Two cell lines presented a discordant response to first and second generation BTK inhibitors, probably due to the inhibition by ibrutinib of kinases other than BTK. In conclusion, our data sustain the on-going current trials with acalabrutinib and ACP-319 as single agents and provide the basis for the investigation of their combination as well.

Topics: Adenosine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cell Proliferation; Class I Phosphatidylinositol 3-Kinases; Drug Synergism; Humans; Lymphoma, B-Cell; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Mice, SCID; Protein Kinase Inhibitors; Pyrazines; Quinolines; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Topics: Benzamides; Humans; Lymphoma, Mantle-Cell; Pyrazines

Topics: Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents, Immunological; Benzamides; Drug Costs; Humans; Lymphoma, Mantle-Cell; Protein Kinase Inhibitors; Pyrazines; Signal Transduction; Treatment Outcome