Second-generation Bruton's Tyrosine Kinase Inhibitor Research Articles

MAHOGANY: A phase 3 trial of zanubrutinib plus anti-CD20 antibodies vs lenalidomide plus rituximab in patients with relapsed or refractory follicular or marginal zone lymphoma.

TPS7590 Background: Inhibition of Bruton tyrosine kinase (BTK) has emerged as a strategy for treatment of patients (pts) with B-cell malignancies including indolent non-Hodgkin lymphomas. Zanubrutinib is a second-generation, potent, and specific BTK inhibitor and has shown to be more effective and better tolerated than first-generation BTK inhibitors in several diseases including chronic lymphocytic leukemia/small lymphocytic lymphoma and Waldenström macroglobulinemia. Zanubrutinib is approved in >15 countries, including the United States and European Union, for pts with relapsed or refractory (R/R) marginal zone lymphoma (MZL) who received ≥1 anti-CD20–based regimen, based on the single-arm MAGNOLIA trial (Opat et al. Clin Cancer Res 2021). In R/R follicular lymphoma (FL), ROSEWOOD, a phase 2 randomized study of zanubrutinib plus obinutuzumab (ZO) vs obinutuzumab, met its primary endpoint of increased overall response rate (ORR) at primary analysis (Zinzani et al. J Clin Oncol 2022). In this trial, ZO in pts with R/R FL demonstrated deep and durable responses with a favorable safety profile. Methods: MAHOGANY (BGB-3111-308, NCT05100862) is a phase 3 randomized, open-label trial that compares efficacy and safety of a combination of zanubrutinib plus anti-CD20 monoclonal antibody vs lenalidomide plus rituximab in 2 independent cohorts, for pts with either R/R FL or MZL. Key eligibility criteria include histologically confirmed FL (grades 1-3A) or MZL, previously treated with ≥1 anti-CD20–based regimen, relapsed after or refractory to the most recent systemic therapy, in need of treatment, no prior BTK inhibitor exposure, and no prior resistance to a lenalidomide-based regimen. In the FL cohort, pts will be randomized 1:1 to ZO (N = 300) and lenalidomide plus rituximab (N = 300). Randomization is stratified by age (≥60 years vs < 60 years), number of prior lines of therapy (1-2 vs > 2) and rituximab-refractory status (yes vs no). The primary endpoint is progression-free survival (PFS) assessed by an independent review committee (IRC), according to Lugano 2014 criteria. Key secondary endpoints are ORR by IRC assessment and overall survival. In the MZL cohort, pts will be randomized 1:1 to zanubrutinib plus rituximab (N = 75) and lenalidomide plus rituximab (N = 75). Randomization is stratified by age (≥60 years vs < 60 years) and number of prior lines of therapy (1-2 vs > 2). The primary endpoint is PFS assessed by IRC according to Lugano 2014 criteria. The key secondary endpoint is ORR by IRC assessment. Zanubrutinib is given at 160 mg twice daily or 320 mg once daily according to investigator, until progression or unacceptable toxicity. Obinutuzumab or rituximab are given for up to 8 infusions. Lenalidomide is given according to approved label for up to 12 cycles. Recruitment is ongoing. Clinical trial information: NCT05100862 .

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Inhibition of Bruton tyrosine kinase (BTK) has emerged as a strategy for treatment of patients (pts) with B-cell malignancies including indolent non-Hodgkin lymphomas. Zanubrutinib is a second-generation, potent, and specific BTK inhibitor and has shown to be more effective and better tolerated than first-generation BTK inhibitors in several diseases including chronic lymphocytic leukemia/small lymphocytic lymphoma and Waldenström macroglobulinemia. Zanubrutinib is approved in >15 countries, including the United States and European Union, for pts with relapsed/refractory (R/R) marginal zone lymphoma (MZL) who received ≥1 anti-CD20–based regimen, based on the single-arm MAGNOLIA trial (Opat et al. Clin Cancer Res 2021). In R/R follicular lymphoma (FL), ROSEWOOD, a phase 2 randomized study of zanubrutinib plus obinutuzumab versus obinutuzumab, met its primary endpoint of increased overall response rate (ORR) at primary analysis (Zinzani et al. J Clin Oncol 2022). In this trial, zanubrutinib plus obinutuzumab in pts with R/R FL demonstrated deep and durable responses with a favorable safety profile. Methods: MAHOGANY (BGB-3111-308, NCT05100862) is a phase 3 randomized, open-label trial that compares efficacy and safety of a combination of zanubrutinib plus anti-CD20 monoclonal antibody versus lenalidomide plus rituximab in 2 independent cohorts, for pts with either R/R FL or MZL. Key eligibility criteria include histologically confirmed FL (grades 1–3A) or MZL, previously treated with ≥1 anti-CD20-based regimen, relapsed after or refractory to the most recent systemic therapy, in need of treatment, no prior BTK inhibitor exposure, and no prior resistance to a lenalidomide-based regimen. In the FL cohort, pts will be randomized 1:1 to zanubrutinib plus obinutuzumab (N = 300) and lenalidomide plus rituximab (N = 300). Randomization is stratified by age (≥60 vs. <60 years), number of prior lines of therapy (1–2 vs. >2), and rituximab-refractory status (yes vs. no). The primary endpoint is progression-free survival (PFS) assessed by an independent review committee (IRC) according to Lugano 2014 criteria. Key secondary endpoints are ORR by IRC assessment and overall survival. In the MZL cohort, pts will be randomized 1:1 to zanubrutinib plus rituximab (N = 75) and lenalidomide plus rituximab (N = 75). Randomization is stratified by age (≥60 vs. <60 years) and number of prior lines of therapy (1–2 vs. >2). The primary endpoint is PFS assessed by IRC according to Lugano 2014 criteria. The key secondary endpoint is ORR by IRC assessment. Zanubrutinib is given at 160 mg twice daily or 320 mg once daily according to investigator, until progression or unacceptable toxicity. Obinutuzumab or rituximab are given for up to 8 infusions. Lenalidomide is given according to approved label for up to 12 cycles. Recruitment is ongoing. Encore Abstract—previously submitted to ASCO 2023 and EHA 2023 The research was funded by: BeiGene Keywords: aggressive B-cell non-Hodgkin lymphoma, combination therapies Conflicts of interests pertinent to the abstract L. Sehn Consultant or advisory role AbbVie, Seattle Genetics, Janssen, Amgen, Roche/Genentech, Gilead Sciences, Kite, a Gilead Company, Merck, Teva, TG Therapeutics, AstraZeneca, Incyte, Sandoz-Novartis, Genmab, Celgene/BMS, BeiGene Honoraria: Amgen, AbbVie, Gilead Sciences, Janssen-ORtho, Kite, a Gilead Company, Merck, Roche/Genentech, Seattle Genetics, Teva, AstraZeneca, Incyte, Sandoz-Novartis, Genmab, Celgene/BMS, BeiGene Research funding: Roche/Genentech, Teva C. Sarkozy Consultant or advisory role Janssen, GSK, Incyte, BMS Honoraria: AbbVie Research funding: Roche Educational grants: Roche, Incyte Other remuneration: Incyte A. Salar Consultant or advisory role BeiGene, Roche Research funding: Roche, AbbVie Other remuneration: Kite, a Gilead Company, Janssen J. Trotman Consultant or advisory role BeiGene WM Advisory Board 2022 (uncompensated) Research funding: BeiGene, Janssen, Pharmacyclics, Roche, Celgene/BMS, Selectar P. L. Zinzani Consultant or advisory role Celltrion, Gilead Sciences, Janssen-Cilag, BMS, Servier, Sandoz, MSD, Roche, EUSA Pharma, Kyowa Kirin, Takeda, Secura Bio, TG Therapeutics, Novartis, ADC Therapeutics, Incyte, BeiGene, Novartis J. Zhang Employment or leadership position: BeiGene Stock ownership: BeiGene P. Fustier Employment or leadership position: BeiGene Stock ownership: BeiGene R. Delarue Employment or leadership position: Celgene/BMS, BeiGene Stock ownership: Celgene/BMS, BeiGene L. Nastoupil Consultant or advisory role Sirpant, Iterus Bios Honoraria: Gilead Sciences, Novartis, Janssen Oncology, TG Therapeutics, BMS, ADC Therapeutics, Morphosys, Epizyme, Genmab, Takeda, Genentech/Roche, Caribou Biosciences Research funding: Janssen Biotech, Genentech/Roche, Epizyme, Novartis, IgM Biosciences, Gilead Sciences, Allogene Therapeutics, Takeda, BMS/Celgene Educational grants: Genentech/Roche

Determination of Orelabrutinib in Human Plasma Using LC-MS/MS.

Orelabrutinib is a second-generation Bruton tyrosine kinase inhibitor that improves the management of B-cell malignancies. The objective of this study was to develop and validate an LC-MS/MS method for quantifying orelabrutinib in human plasma. Plasma samples were processed using acetonitrile to precipitate proteins. Ibrutinib-d5 was used as the internal standard. The mobile phase comprised 10 mM ammonium formate containing 0.1% formic acid and acetonitrile (62:38, vol/vol). The multiple reaction monitoring transitions at m / z = 428.1 → 411.2 and 446.2 → 309.2 were selected for orelabrutinib and ibrutinib-d5, respectively, after ionization in the positive mode. Total runtime was 4.5 minutes. The validated curve ranges were 1.00-500 ng/mL. This method exhibited acceptable selectivity, dilution integrity, matrix effects, and recovery. Interrun and intrarun accuracy ranged from -3.4% to 6.5%, and interrun and intrarun precision was between 2.8% and 12.8%. Stability was studied under different conditions. The incurred sample reanalysis demonstrated good reproducibility. The LC-MS/MS method provided a simple, specific, and rapid quantification of orelabrutinib in the plasma of patients with mantle cell lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma. The results indicated that orelabrutinib exhibits large variability between individuals and should be prudently used in combination with CYP3A4 inhibitors.

"Real-Life" Data of Zanubrutinib in Patients with Waldenström Macroglobulinemia - a Multi-Center Retrospective Study

Background: Waldenström macroglobulinemia (WM) is a rare indolent lymphoma accompanied by the secretion of clonal IgM. While chemo-immunotherapy (CIT) is still a widely adopted approach in treatment-naïve (TN) patients (pts), Bruton's tyrosine kinase (BTK) inhibition has become the new standard of care, especially in pts with relapsed/refractory (RR) disease. Zanubrutinib (ZAN, BGB-3111) is a second-generation BTK inhibitor with high specificity for BTK and reduced off-target inhibition of structurally related kinases. ZAN has recently been approved by the FDA and EMA for the treatment of WM in any line of therapy. This was based on a phase 2 study (Trotman et al, Blood 2020) and a randomized phase 3 study demonstrating non-inferiority to ibrutinib and an improved safety profile (Tam et al, Blood 2020). Between November 2020 and January 2022, an expanded access program of ZAN opened in Israel for the treatment of patients with RR-WM or those ineligible for CIT or ibrutinib in first line. We herein aim to provide real-world data on ZAN in pts with WM in Israel. Methods: This is a multi-center retrospective study of patients with WM who were treated with ZAN within an expanded access program in Israel. Demographic and clinical data were collected from electronic files and coded according to center. ZAN dose, safety, and efficacy measures were recorded. Adverse events (AEs) of interest were specifically investigated. The response was evaluated by investigator-assessment according to the 6th International Workshop on WM (Br J Haematol. 2013). The program was closed by the sponsor for new accrual in January 2022. Active patients gradually transitioned to commercial ZAN once it was reimbursed by the Israeli Health Ministry. The study was approved by local IRB of each participating center. Results: Thirteen pts (12 RR; 1 TN) were enrolled from December 2020 to January 2022 across 8 medical centers in Israel. The median age at ZAN initiation was 71 years (range, 50-85); 6 were males; 12 were Jewish with a representative Ashkenazi-Sepharadi ratio and 1 Arab pt. RR pts had a median of 1 (range, 1-4) prior lines of therapy: mostly with rituximab-cyclophosphamide-dexamethasone (RCd)-like regimens (n=8), bendamustine-rituximab (n=7), and ibrutinib (n=4). One pt underwent an autologous stem cell transplantation. Other than progressive disease after CIT, the most common consideration for choosing ZAN were pts' age and/or comorbidities (n=5), as well as ibrutinib toxicity. In one representative case ibrutinib was associated with complete atrioventricular block; the patient was started on ZAN after AICD implantation. ZAN dose was 160 mg bid (n=8) or 320 mg once daily (n=1), yet 4 pts were given a reduced dose (160 mg per day) due to frailty. The median time on ZAN was 6.4 months (range 2-19.2). Of 12 evaluable pts, the overall response rate (ORR) was 83% with 3 (25%) minor responses, 6 (50%) partial responses, and 1 case of very good partial response (VGPR). Two pts had stable disease (SD). The median time to best response was 120 days. With a median follow up of 196 days (range, 61-585), 9 patients are still on therapy, 2 pts eventually progressed, 1 while on ZAN and 1 after ZAN was stopped due to an AE. The median PFS and OS were not reached (Figure 1). Eight (61%) pts had AEs of any grade, and 3 (23%) had grade 3-4 AEs. One patient died from GI bleeding 2 months after ZAN initiation. AEs of interest are depicted in Table 1. Three pts stopped ZAN due to the following AEs: GI bleeding, congestive heart failure, and extreme fatigue (one each). Conclusion: The results of this real-world expanded access program are consistent with previously published data from trials with ZAN in WM. There were no new safety signals in this elderly frail cohort. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study Evaluating the Efficacy and Safety of Orelabrutinib Plus R-CHOP Versus Placebo Plus R-CHOP in Treatment-Naïve Patients with Mcd Subtype Diffuse Large B-Cell Lymphoma

Background: Diffuse large B-cell lymphomas (DLBCLs) are heterogeneous diseases including genetic subtypes that have distinct gene expression profiles, immune microenvironments, and outcomes following immunochemotherapy. LymphGen algorithm classified DLBCL into 7 genetic subtypes: MCD, N1, BN2, ST2, A53, EZB (MYC+) and EZB (MYC-). Newly diagnosed DLBCL patients with different subtypes had distinct responses to the standard immunochemotherapy. Among those subgroups, patients with the MCD subtype reported the poorest prognosis with a 5-year overall survival (OS) rate of 40%. MCD subtype acquires mutations that promote chronic active BCR signaling, which can be targeted by Bruton tyrosine kinase inhibitors (BTKi). Orelabrutinib, a second-generation BTKi, was designed to have fewer off-target activities and improved efficacy and safety. Orelabrutinib is a potent (IC50 1.6 nM), irreversible BTK inhibitor with high selectivity for BTK and a sustained BTK occupancy for 24h post dose. In December 2020, orelabrutinib monotherapy received its first approval in China for the superior clinical activity in Chinese patients with relapse/refractory mantle cell lymphoma (NCT03494179) and chronic lymphocytic leukemia (NCT03493217). Orelabrutinib was generally well tolerated in clinical trials of B-cell lymphoma. With the superior safety and efficacy profiles, orelabrutinib is potential to fulfill the unmet medical need of patients with MCD subtype. The study described herein is designed to evaluate the safety and efficacy of orelabrutinib combined with R-CHOP regimen versus placebo with R-CHOP in the treatment of treatment-naïve patients with MCD subtype DLBCL. Methods: This ongoing phase 3, randomized, double-blind, placebo-controlled study will enroll approximately 150 patients to be randomized 1:1, stratified by IPI score (2 vs 3-5). Patients will be treated for 6-8 cycles with 21 days per cycle. In the experimental arm, patients will receive 150 mg of oral orelabrutinib once daily with R-CHOP (rituximab 375 mg/m2 intravenously [IV], cyclophosphamide 750 mg/m2 IV, doxorubicin 50 mg/m2 IV, vincristine 1.4 mg/m2 [max 2mg] IV, and prednisone orally on day 1 of each cycle) every 3 weeks for 6-8 cycles or until disease progression, unacceptable toxicity, or withdrawal of consent. In the control arm, patients will receive placebo with R-CHOP at the same schedule. Eligible patients must have histopathologically confirmed CD20 positive DLBCL with MCD genetic subtype and be aged 18-80 years with defined medical conditions (IPI≥2; Ann Arbor stage II-IV or stage I with bulky lesion ⌀ >7.5cm; Eastern Cooperative Oncology Group [ECOG] score of 0-2). Disease response will be assessed per the 2014 Lugano Classification for non-Hodgkin lymphoma. The co-primary endpoints are progression-free survival (PFS) and the complete response rate (CRR) at the completion of combination therapy both determined by IRC. Key secondary end points include CRR and PFS by investigator assessment, ORR, ORR at the completion of combination therapy, duration of response (DOR), OS, and safety. Recruitment is ongoing.

First- versus second-generation Bruton tyrosine kinase inhibitors in Waldenström's Macroglobulinemia: A systematic review and meta-analysis.

Bruton tyrosine kinase inhibitors (BTKi) are important treatment options in Waldenström's macroglobulinemia (WM). Whether second-generation BTKi are associated with improved outcomes and/or better safety profile remains unclear. We did a systematic review and meta-analysis of clinical trials that reported data on the outcomes of patients with WM who received either first- or second-generation BTKi in the period between January 2010 and August 2021. Studies with twenty or fewer patients were excluded. The primary outcomes were efficacy measured by response and survival data. Eleven studies met the eligibility criteria and were included in the final analysis (n= 730 patients). A total of 298 patients received 1st-generation BTKi and 432 received a 2nd-generation BTKi. Pooled overall response rate (ORR) and major response rate (MRR) for both generations were similar (94.2% and 78.5% in 1st vs. 88.9% and 75.1% in 2nd, respectively). MRR for both generations was higher in MYD88 Mut/CXCR4 WT patients compared to MYD88 Mut/CXCR4 Mut patients (odds ratio [OR]: 3.9, 95% CI: 2.2 to 5.5). Pooled 18-mo progression-free survival (PFS) was similar for both generations (88.5% vs. 87.3%). Grade 3/4 atrial fibrillation was higher in 1st-generation BTKi (3.1% vs. 0.4%); however, grade-3/-4 infections and neutropenia were more frequent in 2nd-generarion BTKi (20.9% vs. 13.2%, 17.7% vs. 12%, respectively). The efficacy of 1st- and 2nd-generation BTKis is comparable. The 1st-generation BTKi were associated with a higher risk of atrial fibrillation, whereas infections and neutropenia occurred more frequently in 2nd-generation BTKi.

Guideline for the treatment of chronic lymphocytic leukaemia

Guideline for the treatment of chronic lymphocytic leukaemia

Molecular pathogenesis and therapeutic development of primary central nervous system lymphoma: update and future perspectives

Primary central nervous system lymphoma (PCNSL) is a rare extra-nodal non-Hodgkin's lymphoma confined to the central nervous system with a diffuse large B-cell lymphoma (DLBCL) histology and is highly prevelant in elderly patients. Whole brain radiotherapy (WBRT) does not provide considerable remission; rather it is highly involved in the development of leukoencephalopathy with delayed neurotoxicity, notably in elderly patients. Standard care for newly diagnosed patients with PCNSL comprised induction with high-dose methotrexate (HD-MTX)-based multi-agent immunochemotherapy, such as R-MPV (rituximab, MTX, procarbazine, vincristine) yielding 70-75% complete response rate, followed by HD-cytarabine consolidation. Consolidation high-dose chemotherapy with the key drug thiotepa supported by autologous stem cell transplant has recently been investigated to replace WBRT in multiple randomized trials, demonstrating non-inferiority to WBRT with less neurotoxicity. Comprehensive genetic analyses have revealed high rates of oncogenic mutations in CD79B and MYD88 genes, the hallmarks for MCD/C5 subtype of DLBCL, leading to constitutive activation of NF-κB signaling pathways in PCNSL. Bruton's tyrosine kinase (BTK), an intermediate kinase downstream to CD79B/MYD88, has emerged as a promising therapeutic target. Furthermore, tirabrutinib, a second-generation BTK inhibitor, has shown substantial activity against relapsed/refractory PCNSL, resulting in its approval in 2020 in Japan. Additionally, other new agents against PI3-kinase and immunotherapies including immunomodulatory agents, immune checkpoint blockade, and CAR-T have been actively tested in clinical trials.

Perspectives on Precision Medicine in Primary Central Nervous System Lymphoma

Primary central nervous system lymphoma(PCNSL)is an aggressive, extranodal non-Hodgkin lymphoma that arises from the central nervous system, eyes, leptomeninges, and the spinal cord. Most PCNSLs are a type of diffuse large B-cell lymphoma(DLBCL), and the majority are categorized as a non-germinal center B-cell(GCB)subtype. Recent genetic studies have revealed several common genetic abnormalities in PCNSL, such as MYD88 and CD79B mutations, suggesting dependence on the B-cell receptor/Toll-like receptor signaling pathway. These genetic findings have rationalized targeted therapy targeting Bruton's tyrosine kinase(BTK), a key molecule of the B-cell receptor pathway in PCNSL and systemic non-GCB DLBCL. The first-generation BTK inhibitor ibrutinib has been widely studied in clinical trials for PCNSL and systemic non-GCB DLBCL. In Japan, a second-generation BTK inhibitor tirabrutinib was studied in a phase I/II trial and approved by the Japanese Ministry of Health and Welfare in March 2020 for relapsed and refractory PCNSL. While the current standard-of-care therapy for PCNSL is methotrexate(MTX)-based multi-agent induction immunochemotherapy like R-MPV(rituximab, MTX, procarbazine, and vincristine)followed by consolidation chemotherapy and/or radiation therapy, further investigation into the optimal use of BTK inhibitors in the standard-of-care therapy of PCNSL is warranted.

Bruton Tyrosine Kinase Inhibitors in B-Cell Malignancies: Their Use and Differential Features.

Starting with the first-in-class agent ibrutinib, the development of Bruton tyrosine kinase (BTK) inhibitors has led to dramatic improvements in the management of B-cell malignancies. Subsequently, more-highly selective second-generation BTK inhibitors (including acalabrutinib, zanubrutinib, tirabrutinib and orelabrutinib) have been developed, primarily with an aim to reduce off-target toxicities. More recently, third-generation agents including the non-covalent BTK inhibitors pirtobrutinib and nemtabrutinib have entered later-stage clinical development. BTK inhibitors have shown strong activity in a range of B-cell malignancies, including chronic lymphocytic leukaemia/small lymphocytic lymphoma, mantle cell lymphoma, Waldenström’s macroglobulinaemia and marginal zone lymphoma. The agents have acceptable tolerability, with adverse events generally being manageable with dosage modification. This review article summarises the evidence supporting the role of BTK inhibitors in the management of B-cell malignancies, including highlighting some differential features between agents.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11523-021-00857-8.

Monitoring and Managing BTK Inhibitor Treatment-Related Adverse Events in Clinical Practice.

Bruton tyrosine kinase (BTK) inhibitors represent an important therapeutic advancement for B cell malignancies. Ibrutinib, the first-in-class BTK inhibitor, is approved by the US FDA to treat patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL; after ≥1 prior therapy); and by the European Medicines Agency (EMA) for adult patients with relapsed/refractory (R/R) MCL and patients with CLL. Ibrutinib treatment can be limited by adverse events (AEs) including atrial fibrillation, arthralgias, rash, diarrhea, and bleeding events, leading to drug discontinuation in 4%–26% of patients. Acalabrutinib, a second-generation BTK inhibitor, is approved by the FDA to treat adult patients with CLL/SLL or MCL (relapsed after 1 prior therapy); and by the EMA to treat adult patients with CLL or R/R MCL. The most common AE associated with acalabrutinib is headache of limited duration, which occurs in 22%–51% of patients, and is mainly grade 1–2 in severity, with only 1% of patients experiencing grade ≥3 headache. Furthermore, acalabrutinib is associated with a low incidence of atrial fibrillation. Zanubrutinib, a selective next-generation covalent BTK inhibitor, is approved by the FDA to treat adult patients with MCL who have received ≥1 prior therapy, and is under investigation for the treatment of patients with CLL. In the phase 3 SEQUOIA trial in patients with CLL, the most common grade ≥3 AEs were neutropenia/neutrophil count decreased and infections. This review provides an overview of BTK inhibitor-related AEs in patients with CLL, and strategies for their management.

Cardiovascular adverse events in patients with chronic lymphocytic leukemia receiving acalabrutinib monotherapy: pooled analysis of 762 patients.

Cardiovascular (CV) toxicities of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib may limit use of this effective therapy in patients with chronic lymphocytic leukemia (CLL). Acalabrutinib is a second-generation BTK inhibitor with greater BTK selectivity. This analysis characterizes pooled CV adverse events (AE) data in patients with CLL who received acalabrutinib monotherapy in clinical trials (clinicaltrials gov. Identifier: NCT02029443, NCT02475681, NCT02970318 and NCT02337829). Acalabrutinib was given orally at total daily doses of 100–400 mg, later switched to 100 mg twice daily, and continued until disease progression or toxicity. Data from 762 patients (median age: 67 years [range, 32–89]; median follow-up: 25.9 months [range, 0–58.5]) were analyzed. Cardiac AE of any grade were reported in 129 patients (17%; grade ≥3, n=37 [5%]) and led to treatment discontinuation in seven patients (1%). The most common any-grade cardiac AE were atrial fibrillation/flutter (5%), palpitations (3%), and tachycardia (2%). Overall, 91% of patients with cardiac AE had CV risk factors before acalabrutinib treatment. Among 38 patients with atrial fibrillation/flutter events, seven (18%) had prior history of arrhythmia or atrial fibrillation/flutter. Hypertension AE were reported in 67 patients (9%), 43 (64%) of whom had a preexisting history of hypertension; no patients discontinued treatment due to hypertension. No sudden cardiac deaths were reported. Overall, these data demonstrate a low incidence of new-onset cardiac AE with acalabrutinib in patients with CLL. Findings from the head-to-head, randomized trial of ibrutinib and acalabrutinib in patients with high-risk CLL (clinicaltrials gov. Identifier: NCT02477696) prospectively assess differences in CV toxicity between the two agents.

Bruton tyrosine kinase inhibitors for Waldenström macroglobulinemia: A review.

The objective of this review is to evaluate the available evidence for the Bruton tyrosine kinase inhibitors in the treatment of Waldenström macroglobulinemia. A search of the PubMed database was conducted using the following search terms: ibrutinib, PCI-32765, acalabrutinib, ACP-196, zanubrutinib, BGB-3111, and Waldenström macroglobulinemia. Prospective clinical trials evaluating the efficacy and safety of ibrutinib, acalabrutinib, and zanubrutinib in patients with Waldenström macroglobulinemia were evaluated. Abstracts from the American Society of Hematology and American Society of Clinical Oncology annual meetings were reviewed as well as the prescribing information for each drug. The first-generation Bruton tyrosine kinase inhibitor ibrutinib received Food and Drug Administration approval for Waldenström macroglobulinemia in 2015; this was the first drug approved for this rare condition. Ibrutinib has been evaluated as monotherapy and in combination with rituximab for the treatment of Waldenström macroglobulinemia. Since then, second-generation Bruton tyrosine kinase inhibitors, acalabrutinib and zanubrutinib, have been evaluated in prospective clinical trials for the treatment of Waldenström macroglobulinemia. All three agents have demonstrated high overall response rates and durable responses. Bruton tyrosine kinase inhibitors have demonstrated significant clinical activity in the treatment of Waldenström macroglobulinemia, both in treatment naïve as well as the relapsed/refractory patient populations.

Treating CLL with Bruton Tyrosine Kinase Inhibitors: The Role of the Outpatient Oncology Nurse.

To summarize the role of Bruton tyrosine kinase (BTK) inhibitors in the management of chronic lymphocytic leukemia with a focus on the nursing role in relation to patients with chronic lymphocytic leukemia being treated with BTK inhibitors. These include published articles (PubMed) and national and international guideline documents. BTK inhibitors have revolutionized the therapy of chronic lymphocytic leukemia and have become the most frequently used therapy today. Despite the many advantages of BTK inhibitors, adverse events remain a leading cause of treatment discontinuation, particularly for the first-in-class BTK inhibitor. Second-generation BTK inhibitors appear to have a better tolerability profile but still require adverse event management given their prolonged duration of therapy. Awareness and management of side effects by the oncology care team is essential for ensuring both compliance and safety with ongoing treatment. Chronic lymphocytic leukemia is a chronic illness with a long-life expectancy. For the patients who require therapy, BTK inhibitor therapy is a frequently applied treatment with impressive efficacy. BTK inhibitors are continued indefinitely until disease progression or significant toxicity; therefore, the overall principles of careful assessment for side effects, diligent management for these, and individualized patient support provided by oncology nurses is vital in this patient population.

BCL-2 Inhibition as Treatment for Chronic Lymphocytic Leukemia.

At the end of the 1990s, with the advent of imatinib for chronic myeloid leukemia and rituximab for B cell lymphoproliferative diseases with CD20 expression, there was a great conceptual evolution in the treatment of onco-hematological diseases. Researchers from around the world and the pharmaceutical industry began to focus their efforts on the so-called target therapy used alone or associated with classic chemotherapeutic drugs. In chronic lymphocytic leukemia, the development of second-generation anti-CD20 antibodies, biosimilars, PI3K (phosphatidylinositol 3-kinases) inhibitors, BTK (Bruton's tyrosine kinase) inhibitors, and anti-bcl 2 drugs represented mainly by venetoclax brought new, broader, and more effective opportunities in the treatment of this disease. This breakthrough occurred mainly regarding patients with alteration in 17p or mutation of the p53 gene for whom selecting the new drugs that act on B cell signaling (BTK and PI3K inhibitors) in the first line is mandatory. In fit patients with immunoglobulin heavy chain mutation, it is still acceptable to use the chemotherapy regimen with fludarabine, cyclophosphamide, and rituximab (FCR) and, in those who do not fit or are not IgVH-mutated, bendamustine-rituximab regimen. However, the first-line use of ibrutinib or venetoclax associated with immunotherapy within the concepts of infinite (ibrutinib) or finite (venetoclax) treatment has been increasingly used. In the second line, venetoclax, ibrutinib, and idelalisib have become the preferred treatments. I believe that a process of instruction and decision shared with patients considering the risks-benefits-cost and access to treatments should guide the choices within these concepts. Another fundamental aspect to discuss is the objective of the treatment for chronic lymphocytic leukemia (CLL) for a specific patient: the increase progression-free survival and overall survival and/or the achievement of minimal residual disease. CLL is the most common leukemia in adults with a median age at diagnosis of 72 years. The clinical course is heterogeneous, and outcomes are influenced by individual clinical presentation and disease biology. Molecular and genomic factors, including fluorescence in situ hybridization (FISH) testing, karyotype, and immunoglobulin heavy chain variable region gene (IGHV) mutational status, are important to treatment decisions and to predict the clinical course. However, despite disease biology, the presence of active disease is the most important criteria to initiate treatment. In the past decade, target therapies that inhibit B cell receptor signaling pathways and, more recently, BCL2 antagonists have emerged as a new treatment paradigm: chemo-free with fixed duration therapy. Bruton's tyrosine kinase inhibitors (BTK) are a class of oral medications approved for frontline and relapsed disease, effective for achieving lasting response and disease control with a good safety profile. BTK inhibitors are an attractive option for high-risk patients who are not candidates for an intensive regimen. However, it is a continuous therapy, and drug resistance or severe adverse events could lead to treatment suspension. BCL2 antagonists are an attractive alternative to BTK inhibitors. Anti-apoptotic BCL2 is associated with tumor genesis and chemotherapy resistance. The BCl2, an anti-apoptotic protein located in the mitochondrial membrane, is a major contributor to the pathogenesis of lymphoid malignancies and is overexpressed in CLL cells promoting clonal cell survival. Venetoclax is a potent and selective member of the BH3 mimetic drugs and a physiologic antagonist of BCL2. Venetoclax has demonstrated quick and durable responses in naïve and relapsed or refractory CLL (r/r CLL) patients, including high-risk patients. Furthermore, it has shown deeper responses, achieving a higher incidence of negative minimal residual disease (MRD) with a fixed duration therapy. In the past decade, there was a remarkable progress in CLL treatment. However, neither of the new target therapies is considered curative or free of toxicity. This article will focus on the treatment approach of CLL patients with BCl2 antagonists. Treatment strategy (combined versus monotherapy; continuous versus limited duration therapy), toxicity profile, and future directions will be exposed in this review.

ESCALADE: A phase 3 study of acalabrutinib in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for patients ≤65y with untreated non-germinal center B-cell–like (non-GCB) diffuse large B-cell lymphoma (DLBCL).

TPS7572 Background: R-CHOP remains the standard of care for DLBCL. Although most patients (pts) can be cured, 35–40% will experience relapsed/refractory disease, leading to poor outcomes in the majority of pts. Covalent irreversible Bruton tyrosine kinase inhibitors (BTKi) have shown higher responses in pts with non-GCB DLBCL than with GCB DLBCL. In untreated non-GCB DLBCL pts, the phase 3 PHOENIX study (Younes et al. J Clin Oncol. 2019;37:1285-95) showed that addition of the BTKi ibrutinib to R-CHOP (R-CHOP-I) did not improve outcomes in the intent-to-treat population. However, pts age &lt; 60y treated with R-CHOP-I had significantly improved progression-free survival (PFS) and overall survival (OS) compared with those receiving R-CHOP alone. Acalabrutinib (A) is a second-generation BTKi with enhanced kinase selectivity and potential for better efficacy and tolerability than first-generation BTKis. There is a strong rationale for combining A with R-CHOP in pts with untreated DLBCL, and safety of A + R-CHOP has been shown in a phase 1b/2 study (Davies et al. ASH 2020). The aim of this study is to determine if the addition of A to R-CHOP leads to improved PFS in pts age ≤65y with untreated non-GCB DLBCL. Methods: ESCALADE (ACE-LY-312; NCT04529772) is a phase 3, randomized, global, double-blind study of A vs placebo in combination with R-CHOP for treatment of newly diagnosed non-GCB DLBCL. The study is recruiting adults ≥18y and ≤65y with previously untreated DLBCL stage II–IV disease with a Revised International Prognostic Index (R-IPI) score of 2–5. Prior to randomization, all pts will receive an initial R-CHOP cycle (cycle 1) as standard-of-care treatment to prevent delays in therapy initiation. Based on central Gene Expression Profile (GEP) testing performed after enrollment, pts with non-GCB DLBCL (activated B-cell like or unclassified) will be randomized into 2 arms to receive A 100 mg twice daily plus R-CHOP or placebo plus R-CHOP from cycle 2 to cycle 6 followed by 2 additional cycles of rituximab + A or placebo (cycles 7 and 8). All pts will receive primary prophylaxis with granulocyte colony-stimulating factors accompanying all R-CHOP cycles. The study aims to randomize 600 pts (̃300 per arm). The primary objective is to evaluate whether the addition of A to R-CHOP will prolong PFS. Secondary endpoints include event-free survival, complete response rate, OS, pharmacokinetics, and safety. Key exclusion criteria are central nervous system involvement, primary mediastinal lymphoma, high-grade B-cell lymphoma, diagnosis or treatment of malignancy other than DLBCL, and history of indolent lymphoma. Approximately 250 sites globally will enroll pts. Enrollment began in Q3 of 2020. Clinical trial information: NCT04529772.

Zanubrutinib (BGB-3111), a Second-Generation Selective Covalent Inhibitor of Bruton's Tyrosine Kinase and Its Utility in Treating Chronic Lymphocytic Leukemia.

The understanding of the B cell receptor (BCR) pathway and its contribution to chronic lymphocytic leukemia (CLL) pathogenesis have led to the development of targeted BCR inhibitors which have transformed the treatment paradigm of CLL. Ibrutinib is a first-in-class oral Bruton’s tyrosine kinase (BTK) inhibitor which has demonstrated improvements in both progression free (PFS) and overall survival (OS) in both the treatment naïve and relapsed/refractory setting as compared to traditional chemoimmunotherapy. Despite its clinical efficacy, many patients discontinue treatment due to adverse events, which are thought to be mediated through off-target kinase inhibition. Zanubrutinib is a second-generation non-covalent BTK inhibitor with higher potency, allowing for inhibition of BTK with fewer off target effects. Early phase clinical trials have demonstrated excellent efficacy and a well-tolerated safety profile. Long-term follow-up is needed, but zanubrutinib holds promise to be an effective therapy for CLL with a manageable side effect profile and will be an exciting addition to our treatment paradigm.

An update on acalabrutinib to treat chronic lymphocytic leukemia.

Acalabrutinib was approved by the U.S. Food and Drug Administration (FDA) for treatment-naive (TN) and relapsed/refractory (R/R) use for patients with chronic lymphocytic leukemia (CLL) in November 2019 following the phase III ASCEND and ELEVATE-TN registration trials. Acalabrutinib is a second-generation Bruton tyrosine kinase inhibitor (BTKi) that was developed after ibrutinib, the first-in-class BTKi. Ibrutinib is usually well tolerated and provides durable remissions; however, some patients experience toxicities from the off-target effects that lead to treatment discontinuation. A recent press release of the phase III ELEVATE-RR trial comparing acalabrutinib to ibrutinib in relapsed high-risk CLL reported noninferior progression-free survival and statistically significantly lower rates of atrial fibrillation; however, publication of this data is pending. There is currently 53 months of follow-up for patients receiving acalabrutinib compared with 8 years for those on ibrutinib. Acalabrutinib is approved as monotherapy in the R/R or TN setting, and in the TN setting can be combined with the anti-CD20 monoclonal antibody obinutuzumab. The data for acalabrutinib development and clinical use are discussed in this review.

Adverse Events in Clinical Trials of Ibrutinib and Acalabrutinib for B-Cell Lymphoproliferative Disorders: A Systematic Review and Network Meta-Analysis

Introduction: Bruton tyrosine kinase (BTK) inhibitors are a class of drugs that inhibit B-cell receptor (BCR) and are increasingly used in B-cell lymphoproliferative neoplasms, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenstrom's macroglobulinemia. Ibrutinib, a first-generation BTK inhibitor has been associated with increased risk of cardiovascular adverse events (AEs), including atrial fibrillation (AF), hypertension (HTN) and bleeding. These unique AEs are thought to be due to off-target effects. Acalabrutinib, a second-generation BTK inhibitor is characterized by less off-target effects, and is thought to be associated with a decreased risk of cardiovascular and other AEs. However, a head to head comparison of ibrutinib and acalabrutinib has not been conducted. Herein, we conducted a systematic review and network meta-analysis of AEs from prospective clinical trials of ibrutinib and acalabrutinib in B-cell lymphoproliferative disorders to compare their safety profile. Methods: We searched PubMed, Embase, Scopus, and Web of Science from database inception through November 15th 2019. Only full-text articles were included. Other inclusion criteria included prospective trials (single arm or randomized) with ibrutinib, ibrutinib plus anti-CD20 antibody, or acalabrutinib as investigational agents. Trials investigating BTK inhibitor plus chemotherapy were excluded. When updated results of prospective trials were available, data were extracted from the most recent publication with the longest follow-up. Reports of 17 AEs of interest, including number of events (any grade and grade 3 or higher) were documented. Rate of discontinuation was investigated. Results: Twenty-seven prospective clinical trials, 12 multicenter single-arm, 9 multicenter randomized, 5 single center single-arm, and 1 single center randomized, were included. Data from 29 study arms including 3207 patients were analyzed in 3 groups - ibrutinib, ibrutinib plus anti-CD20 antibody, and acalabrutinib with augmented Bayesian network meta-analysis and meta-regression implemented in R including packages gemtc and rjags. The most common any grade AEs (&amp;gt;20%) with ibrutinib were diarrhea (46%, 95% CI 36-55%), myalgias/arthralgias (37%, 95%CI 28-46%), fatigue (33%, 95% CI 24-42%), cough (26%, 95% 17-36%), anemia (23%, 95% 15-30%), thrombocytopenia (22%, 95% 15-30%), and pyrexia (21%, 95% 13-30%). The most common any grade AEs with acalabrutinib were headache (37%, 95%CI 26-48%), diarrhea (30%, 95% 20-41%), peripheral edema (21%, 95% 15-28%), fatigue (20%, 95% 11-29%), and myalgias/arthralgias (16%, 95% 8-24%). The most common any grade cardiovascular AEs with ibrutinib were bleeding/bruising (32%, 95% 23-41%), HTN (23%, 95% 15-32%), AF (9%, 95% 3-15%). The most common any grade cardiovascular AEs with acalabrutinib were bleeding/bruising (41%, 95% CI 30-52%), and HTN (6%, 95% 1-11%). The rate of AEs with ibrutinib compared to ibrutinib plus anti-CD20 antibody were similar so the data was pooled. Of all AEs of interest, there was a significant difference in any grade AEs favoring ibrutinib for headache (12% vs. 37%), and infections (35% vs 57%). There was a significant difference in any grade AEs favoring acalabrutinib for myalgias/arthralgias (16% vs. 37%), anemia (6% vs. 23%), thrombocytopenia (5% vs. 22%), and HTN (6% vs. 23%). After adjusting for median follow-up and age, there was no significant difference in rates of bleeding/bruising and any grade infections between ibrutinib and acalabrutinib. However, there was a significant difference favoring acalabrutinib for any grade HTN (OR 0.26, 95% CI 0.17-0.40) p&amp;lt;0.0001, grade 3 HTN (OR 0.15, 95% 0.08-0.27) p&amp;lt;0.0001, any grade AF (OR 0.35, 95% 0.18-0.66), p=0.0012, grade 3 AF (OR 0.04, 95% 0.01-0.25) p=0.0009, and grade 3 infections (OR 0.62, 95% 0.46-0.85),p=0.003. Conclusions: Acalabrutinib appears to have an overall improved safety profile compared to ibrutinib. This is particularly true for anemia, thrombocytopenia, and cardiovascular AEs, including AF and HTN. Figure 1 Disclosures No relevant conflicts of interest to declare.

Dermatological Toxicities of Bruton's Tyrosine Kinase Inhibitors.

The development of Bruton's tyrosine kinase (BTK) inhibitors represents a major breakthrough in the treatment of chronic lymphocytic leukemia and other B cell malignancies. The first-generation inhibitor ibrutinib works by covalent irreversible binding to BTK, a non-receptor tyrosine kinase of the TEC (transient erythroblastopenia of childhood)family that plays a critical role in the B-cell receptor signaling pathway. It also induces an 'off-target' inhibition of a range of other kinases including (but not limited to) epidermal growth factor receptor (EGFR), SRC, and other kinases of the TEC family (interleukin-2-inducible T-cell kinase [ITK], Tec, BMX). Dermatological toxicities are among the most common toxicities of ibrutinib, but remain of mild to moderate intensity in most cases and are readily manageable. Their incidence is highest during the first year of treatment and declines over time. In addition, it has been postulated that ibrutinib-related dermatologic adverse events are mediated by the direct binding to both BTK and other 'off-target' kinases. Bruising, ecchymoses, and petechiae represent the most characteristic dermatologic adverse events. Nail and hair changes are also common, as skin infections (opportunistic infections including herpes simplex and herpes zoster virus reactivations, and Staphylococcus aureus superinfection), folliculitis, and other types of rashes. Panniculitis, aphthous-like ulcerations with stomatitis, neutrophilic dermatosis, peripheral edema, and skin cracking can also occur. Next-generation BTK inhibitors, acalabrutinib and zanubrutinib, have been designed to optimize BTK inhibition and minimize off-target inhibition of alternative kinases (Tec, ITK, EGFR, SRC-family kinases). These drugs have been recently FDA-approved for relapsed or refractory mantle cell lymphoma. Although the overall incidence of their toxicities is expected to be more limited, acalubrutinib and zanubrutinib are associated with a range of dermatologic toxic effects that appear to be similar to those previously described with ibrutinib, including bruising and ecchymoses, panniculitis, human herpesvirus infections, cellulitis, and skin rash. In particular, both drugs induce skin bleeding events in more than 30% of patients treated. However, the available dermatological data are still rather limited and will have to be consolidated prospectively. This review article analyses the wide spectrum of dermatological toxicities that can be encountered with first- and second-generation BTK inhibitors. Finally, recommendations for appropriate treatment as well as a synthesis algorithm for management are also proposed.