Second-generation Bruton's Tyrosine Kinase Inhibitor Research Articles

Assessment of the Efficacy and Safety of Acalabrutinib in Chronic Lymphocytic Leukemia (CLL): A Systematic Review and Meta‑Analysis .

Chronic lymphoid leukemia (CLL) is a common adult leukemia that has been treated with chemoimmunotherapy, which has significant toxicity among patients. Advances in CLL understanding have led to targeted therapies, such as Bruton's tyrosine kinase (BTK) inhibitors. Acalabrutinib is one of the second-generation BTK inhibitors and offers improved selectivity, reducing off-target effects. This systematic review and meta-analysis analyze data from multiple clinical trials to assess acalabrutinib efficacy and safety among patients with CLL. A literature search was carried out in PubMed, Cochrane Controlled Register of Trials (CENTRAL), MEDLINE (Medical Literature Analysis and Retrieval System Online), and Ovid databases for articles published until 2024. The outcomes included the overall response rate (ORR), complete response rate(CRR), 24-month progression-free survival rate, and grade ≥3 adverse events (AEs). Meta-analysis was performed using jamovi software. The search strategy yielded 823 records. After assessing the eligibility of the retrieved studies, the systematic review finally included six clinical trials, including 808 patients. The findings demonstrated significant efficacy of acalabrutinib, with a pooled ORR (P < 0.001) and a pooled CRR (P = 0.001). The pooled 24-month progression-free survival (PFS) rate showed a significant improvement in maintaining patient safety and treatment effectiveness (P <0.001). However, hematological AEs such as neutropenia, anemia, and thrombocytopenia were reported across studies. The pooled grade ≥ 3 AEs rate was 0.51 (95% CI: 0.21-0.81, I² = 98.21%, P <0.001), indicating a notable incidence of severe side effects. Acalabrutinib is an active drug in treating CLL that induces significant clinical benefits concerning response rates and PFS. However, acalabrutinib should be managed carefully to mitigate the risk of severe AEs. Further trials should be focused on assessing and modulating the safety of acalabrutinib.

Efficacy and safety of first- versus second-generation Bruton tyrosine kinase inhibitors in chronic lymphocytic leukemia: a systematic review and meta-analysis.

We conducted this first systematic review and meta-analysis to assess the competitive advantage of 2nd-generation Bruton tyrosine kinase inhibitors (BTKi) compared to 1st-generation BTKi in chronic lymphocytic leukemia (CLL). The literature search was conducted from PubMed, Web of Science, Embase databases, and hematology annual conferences. Data of over response rate (ORR), progression-free survival (PFS), and overall survival (OS) were extracted to a pool meta-analysis of efficacy; adverse events (AEs) were also extracted to a pool meta-analysis of safety. Bias risk assessment and meta-analysis were performed by Review Manager 5.3 and STATA 14 software. A total of 3649 patients from 29 cohorts were included. The results showed that the benefits of ORR and 24-month PFS in 2nd-generation BTKi compared to 1st-generation BTKi were not significant in the whole population but only in the relapsed or refractory (R/R) CLL patient subgroup (ORR: 86.4% vs. 76.2%, p = 0.013; 24-month PFS: 76.9% vs. 67.9%, p = 0.004). Any-grade AEs were comparable between 1st- and 2nd-generation BTKi, but grade 3 or higher AEs were significantly less frequent with 2nd-generation BTKi versus 1st-generation BTKi (grade 3 or higher: 53.1% vs. 72.5%; p = 0.002). Headache was more frequent with 2nd-generation BTKi, while diarrhea and atrial fibrillation were more frequent with 1st-generation BTKi. Only for patients with relapsed or refractory CLL did 2nd-generation BTKi have a competitive advantage, while adverse effects still need to be considered. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, Identifier 42022342488.

Evaluation of second-generation Bruton's tyrosine kinase inhibitors for the treatment of mantle cell lymphoma.

Second-generation Bruton's tyrosine kinase (BTK) inhibitors, acalabrutinib and zanubrutinib, are preferred agents for the treatment of relapsed and/or refractory mantle cell lymphoma (MCL) over first-generation BTK inhibitor, ibrutinib. The comparative safety and efficacy of these two agents have not been studied. Currently, the decision between using one second-generation BTK inhibitor over the other is largely dependent on provider preference, cost, organ dysfunction, presence of drug-drug interactions, adherence considerations, and theorized differences in safety outcomes due to the lack of head-to-head trials in MCL. This retrospective, observational study seeks to provide real-world data on the safety and efficacy of second-generation BTK inhibitors in the setting of relapsed and/or refractory MCL. Thirty-eight patients treated with a second-generation BTK inhibitor were evaluated. Ten percent of patients experienced a select adverse drug event (ADE) in the acalabrutinib group that included hypertension and major hemorrhage with no patients experiencing a select ADE in the zanubrutinib group. Results support historical data that acalabrutinib and zanubrutinib have a more favorable safety profile compared to ibrutinib in MCL.

A review of Bruton's tyrosine kinase inhibitors in multiple sclerosis.

Bruton's tyrosine kinase (BTK) inhibitors are an emerging class of therapeutics in multiple sclerosis (MS). BTK is expressed in B-cells and myeloid cells, key progenitors of which include dendritic cells, microglia and macrophages, integral effectors of MS pathogenesis, along with mast cells, establishing the relevance of BTK inhibitors to diverse autoimmune conditions. First-generation BTK inhibitors are currently utilized in the treatment of B-cell malignancies and show efficacy in B-cell modulation. B-cell depleting therapies have shown success as disease-modifying treatments (DMTs) in MS, highlighting the potential of BTK inhibitors for this indication; however, first-generation BTK inhibitors exhibit a challenging safety profile that is unsuitable for chronic use, as required for MS DMTs. A second generation of highly selective BTK inhibitors has shown efficacy in modulating MS-relevant mechanisms of pathogenesis in preclinical as well as clinical studies. Six of these BTK inhibitors are undergoing clinical development for MS, three of which are also under investigation for chronic spontaneous urticaria (CSU), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Phase II trials of selected BTK inhibitors for MS showed reductions in new gadolinium-enhancing lesions on magnetic resonance imaging scans; however, the safety profile is yet to be ascertained in chronic use. Understanding of the safety profile is developing by combining safety insights from the ongoing phase II and III trials of second-generation BTK inhibitors for MS, CSU, RA and SLE. This narrative review investigates the potential of BTK inhibitors as an MS DMT, the improved selectivity of second-generation inhibitors, comparative safety insights established thus far through clinical development programmes and proposed implications in female reproductive health and in long-term administration.

Real-World Treatment Patterns, Discontinuation and Clinical Outcomes in Patients with B-Cell Lymphoproliferative Diseases Treated with BTK Inhibitors in China

Bruton tyrosine kinase inhibitor (BTKi) has demonstrated substantial efficacy in treating B-cell lymphoproliferative diseases (BLPD). Nonetheless, the significant discontinuation rates due to toxicity or financial reasons cannot be overlooked. In China, empirical evidence on the usage of BTKi remains scarce. To address this, a retrospective cohort study was conducted focused on 673 Chinese patients with BLPD who underwent at least one month of BTKi therapy. Median age at BTKi initiation was 60 years. The median duration on BTKi treatment of the whole cohort was 36.4 months. The median post-BTK survival was not reach. BTKi-based treatment was permanently discontinued in 288 (43.8%) patients during follow-up, mostly attributed to progressive disease. Within the first 6 months of BTKi treatment, 76 patients (26.3%) had early treatment discontinuation. Patients with early discontinuation had extreme worse outcome with a median post-discontinuation survival of only 6.9 months. On multivariate analysis, withdrawal BTKi by toxicity and withdrawal BTKi within 6 months retained to be independent predictors of post-BTK survival, after taking account of the response depth, lines of therapy and baseline cytogenetics including 17p deletion. The decision between BTKi monotherapy and combination therapy, along with the preference for first or second-generation BTKi, exerted no significant impact on survival. These observations contribute valuable real-world insights into the utilization of BTKi in China. We concluded that BTKi is an effective and well-tolerated treatment for long-term use in Chinese patient population. However, it is imperative to stress that a proportion of patients discontinue BTKi early, leading to suboptimal outcomes. This study underscores the importance of adherence to BTKi therapy for improved clinical outcomes in real-world patients.

Epic: A Second Interim Analysis of the Non-Interventional, Observational Multi-Centre Cohort Study of Patients with Chronic Lymphocytic Leukaemia Treated with First-Line Acalabrutinib through the UK Early Access Programme

Background: Acalabrutinib, a second-generation Bruton Tyrosine Kinase inhibitor (BTKi), has shown an acceptable safety profile and high response rates in clinical trials of treatment naïve patients with chronic lymphocytic leukaemia (CLL). However, real-world data detailing the safety and effectiveness of first-line acalabrutinib treatment for CLL is limited. Here we present a second interim analysis (IA) of patients with CLL who were initiated on first-line acalabrutinib within the UK Early Access Programme (EAP). Methods: This is an ongoing observational multi-centre cohort study involving retrospective data collection from medical records (ClinicalTrials.gov: NCT05557695). Treatment-naïve patients with CLL from 9 UK clinical centres who initiated acalabrutinib as part of the UK EAP between 1 st April 2020 - 1 st April 2021 were eligible to participate. Patients will be followed for up to 60 months from the date of acalabrutinib initiation (index). Collected data for this IA (data cut-off 31 st May 2023) includes baseline demographics, clinical characteristics, and treatment patterns. Results: 101 patients were included in this IA. Median (interquartile range (IQR)) age at index was 73.8 (66.1-78.4) years; 56% (n=57/101) of patients were male; 89% (n=83/93) of patients were White British, 6% (n=6/93) were White other, 3% (n=3/93) were Asian and 1% (n=1/93) were of Mixed ethnicity (missing data n=8). Median (IQR) duration of follow-up was 32.4 (29.2-35.4) months; 89% (n=90/101) of patients had a follow-up duration of ≥1 year and 84% (n=85/101) ≥2 years. 88% (n=52/59) of patients had an Eastern Cooperative Oncology Group performance status (PS) of 0-1, 10% (n=6/59) had a PS of 2 and 2% (n=1/59) had a PS of 3 (missing n=42). 50% (n=40/80) of patients had a creatinine clearance &amp;lt;60 mL/min at index. 5% (n=5/101) of patients had a confirmed ATM mutation and no patients had a confirmed 17p13.1 deletion. 5% (n=5/101) had a confirmed TP53 mutation and of 10 patients with confirmed IgHV mutational status, 20% (2/10) had mutated IgHV (91 unknown). Median (IQR) time between CLL diagnosis and index was 2.8 (1.2-5.4) years. At index, 100 patients received 100 mg of acalabrutinib twice a day, 1 patient received 100 mg daily. The continuation rate (n=100) at 12 and 24 months was 81.0% (95% confidence interval [CI], 73.7%-89.1%) and 74.0% (95% CI, 65.9%-83.1%), respectively (1 patient not recorded). 68% (n=69/101) of patients remained on treatment at the time of data cut. Of those patients reporting reasons for treatment discontinuation, 48% (n=15/31) were due to adverse events (AEs; of the 14/15 patients reporting type of AEs resulting in discontinuation, 14% (2/14) was reported for each of the following AEs; cardiovascular, haematoma, headache and urinary tract infection), 6% (n=2/31) due to disease progression, 3% (n=1/31) due to patients' decision and 42% (n=13/31) other reasons (1 unknown). Of 39 patients with treatment interruptions, 72% (n=28/39) patients had interruptions due to AEs, 15% (n=6/39) due to a minor operation and/or procedure and 21% (n=8/39) other reasons. Of the 22/28 patients reporting type of AE resulting in treatment interruption, the most common AEs were upper respiratory tract infection (23%, n=5/22) and thrombocytopenia (18%, n=4/22). Of those with relevant medical records, 62% (n=40/65) had a recorded COVID-19 diagnosis; of these, 93% (n=37/40) diagnoses were confirmed via test. Sotrovimab was the most common treatment received for COVID-19 (20% of patients, n=8/40). COVID-19 vaccination and biannual boosters is offered to all patients with CLL as per UK guidelines, available data from 58 patients showed that 72% (n=42/58) of patients had received ≥4 COVID-19 vaccination doses and 28% (n=16/58) had received &amp;lt;4 doses at the time of datacut (missing n=43). Conclusion: This IA reports 12 and 24-month real-world acalabrutinib continuation rates of 81.0% (95% CI, 73.7%-89.1%, n=100) and 74.0% (95% CI, 65.9%-83.1%, n=100), respectively, in treatment naïve patients with CLL in UK. These findings provide clinical decision makers with valuable insights into acalabrutinib use in the real-world as well as highlighting the importance of BTKi AE management in a real-world clinical setting. Further IAs are planned.

Elevate-TN: Impact of First-Year Dose Modifications in Patients with Treatment-Naive Chronic Lymphocytic Leukemia Treated with Acalabrutinib

Background: Acalabrutinib (acala), a second-generation Bruton tyrosine kinase inhibitor (BTKi), with or without obinutuzumab (obin), demonstrated superior progression-free survival (PFS) compared with obin plus chlorambucil in patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL) in the phase 3 ELEVATE-TN (NCT02475681) trial. Despite the long-term benefits observed with acala therapy, data from real-world studies in patients with CLL demonstrate that 22% of patients discontinue acala treatment for any reason in the first year of treatment across therapy lines (Roeker et al. Blood. 2022). To assess the impact on survival outcomes of acala discontinuation and dose modifications occurring in the first year of treatment, we conducted a post hoc analysis in patients treated in the acala-containing arms of ELEVATE-TN. Methods: Patients who received acala 100 mg twice daily with or without obin (fixed duration, up to 6 cycles) with at least 1 year of follow-up were included in this analysis. The impact of dose reductions, treatment breaks, or treatment discontinuations in the first year on overall survival (OS) was assessed. Protocol-specified dose-modification guidelines that included dose reductions, breaks, and discontinuations depending on severity and frequency were applied to patients with apparent treatment-related toxicity. To assess the impact of dose reductions, breaks, or discontinuations, patients were divided into 4 dose-modification subgroups: 1) patients with no dose reductions/breaks &amp;gt;14 days during the first year; 2) patients with dose reductions &amp;gt;14 days, but no breaks &amp;gt;14 days during the first year; 3) patients with breaks &amp;gt;14 days, but who continued treatment in the first year; and 4) patients who discontinued treatment during the first year. Results: With a median follow-up of 60 months, 358 patients (n=179, acala monotherapy; n=179, acala-obin) with ≥1 year of follow-up were included in this analysis. In the first year, 269 (75%) patients had no dose reductions/breaks &amp;gt;14 days, 11 (3%) patients had dose reductions &amp;gt;14 days but no breaks &amp;gt;14 days, 32 (9%) patients had breaks &amp;gt;14 days but continued treatment, and 46 (13%) patients discontinued treatment. Reasons for treatment discontinuation during the first year were adverse events (n=26), disease progression (n=7), physician decision (n=5), consent withdrawn (n=3), death (n=2), loss to follow-up (n=1), and other (n=2). Patients who discontinued treatment within the first year had inferior OS compared with patients who did not require dose reductions or breaks (OS hazard ratio [HR]: 8.39, 95% confidence interval [CI]: 3.96-17.8, P&amp;lt;0.0001; Figure 1). In contrast, patients who had dose reductions or breaks &amp;gt;14 days but did not discontinue treatment had statistically similar OS to patients who did not require dose reductions or breaks. Within the group that had no dose reductions or treatment breaks &amp;gt;14 days, there was no difference in the proportion of patients treated with acala monotherapy (n=133) and acala-obin (n=136). However, OS outcomes in this subgroup of patients with no treatment modifications were superior in patients treated with acala-obin compared with those treated with acala monotherapy (HR: 0.37, 95% CI 0.15-0.87, P=0.0183; Figure 2). Conclusions: This post hoc analysis of acala-treated patients with TN CLL in ELEVATE-TN demonstrated superior OS in patients who did not have dose reductions or breaks compared with patients who discontinued treatment within the first year. OS outcomes in patients who required dose reductions or breaks but did not discontinue treatment in the first year were similar to those in patients who did not require dose modification. Accepting the limitations of retrospective analysis, these data suggest that patients who are unable to tolerate standard-dose acala or who require treatment breaks may benefit from continuing or resuming treatment at a reduced dose rather than stopping treatment altogether. For patients who do not require dose modifications, ongoing follow-up of the ELEVATE-TN trial suggests durable and incrementally improved OS benefit from the addition of obin to acala.

Acrue: A Phase 2, Open-Label Study of Acalabrutinib in Combination with Rituximab in Elderly and/or Frail Patients with Treatment-Naive Diffuse Large B-Cell Lymphoma

Background and Significance: Patients aged ≥80 years with diffuse large B-cell lymphoma (DLBCL) account for approximately 18% of DLBCL cases in the United States (Morrison et al. Future Oncol. 2018). Standard-of-care chemoimmunotherapy (CIT) regimens such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), including reduced doses of CHOP (R-miniCHOP), are not well tolerated in elderly and/or frail patients, leading to high treatment-related mortality rates (Boslooper et al. Leuk Lymphoma. 2014; Freudenberger et al. Ann Hematol. 2021; Peyrade et al. Lancet Oncol. 2011). Therefore, safe, effective, and convenient treatment alternatives to CIT are needed. Acalabrutinib is a highly selective, second-generation Bruton tyrosine kinase inhibitor approved for the treatment of patients with relapsed/refractory mantle cell lymphoma and in patients with chronic lymphocytic leukemia. Acalabrutinib monotherapy has demonstrated encouraging activity in patients with DLBCL in phase 1b (NCT02112526) and phase 2 (NCT04002947) studies (Strati et al. Haematologica. 2021; Roschewski et al. Blood. 2021). However, neither of these studies were conducted specifically in a population of elderly and/or frail patients. Study Design and Methods: ACRUE (NCT05952024) is a phase 2, open-label, single-arm, global, multicenter study of acalabrutinib plus rituximab in elderly and/or frail patients with treatment-naive (TN) DLBCL who are unable to tolerate standard CIT ( Figure). Eligible patients are aged ≥80 years or aged 65-79 years with impairment in ≥1 activity of daily living (ADL) or instrumental ADL (IADL), or with cardiac/renal/liver function impairment or other comorbidities that render them unable to tolerate CIT. Furthermore, patients must have histologically confirmed CD20-positiveDLBCL (not otherwise specified), according to WHO 2016 classification, an Ann Arbor classification of stage II, III, or IV disease, an Eastern Cooperative Oncology Group performance status of 0-2, and ≥1 measurable lesion. Patients with active central nervous system involvement by lymphoma, leptomeningeal disease, or spinal cord compression, or significant cardiovascular disease within 6 months of screening are excluded. Target enrollment is 80 patients. Patients will receive acalabrutinib plus rituximab combination for 8 cycles (acalabrutinib 100 mg orally twice daily beginning on day 1 of cycles 1-8; rituximab 375 mg/m 2 intravenously on C1D15, then 1400 mg subcutaneously, on day 1 of cycles 2-8; cycles 1-8 are 21 days/cycle), followed by acalabrutinib monotherapy until disease progression, unacceptable toxicity, or 24 months (cycles 9-28 are 28 days/cycle). The primary endpoint is the percentage of patients with grade 3-4 treatment-emergent adverse events. The key secondary endpoint is investigator-assessed objective response rate per Lugano 2014 criteria. Other secondary endpoints include progression-free survival, event-free survival, overall survival, duration of response, and Timed Up and Go test. Exploratory biomarker analyses may include genomic characterization of baseline samples to evaluate predictors of survival, and of progression samples to evaluate genomic resistance mechanisms. Descriptive safety and efficacy data will be summarized. If patients discontinue treatment prior to completing 28 cycles of therapy, they will be followed every 12 weeks after their last treatment dose for up to 2 years. Patients who are still on treatment at the end of the study and are deriving clinical benefit may receive continued treatment, with assessments reverting to standard of care. Enrollment is planned to begin Q4 of 2023 in approximately 40 sites from North and South America and Asia. Summary: This study will help determine if acalabrutinib plus rituximab combination therapy is tolerable and effective in elderly and/or frail patients with TN DLBCL who are unable to tolerate CIT.

Similar Efficacy of Ibrutinib Arms across ALPINE and ELEVATE-RR Trials in Relapsed/Refractory Chronic Lymphocytic Leukemia: A Matching-Adjusted Indirect Comparison

Background: Bruton tyrosine kinase inhibitors (BTKi) are currently widely used for the treatment of patients with chronic lymphocytic leukemia (CLL). Ibrutinib, the first BTKi approved for the treatment of CLL, was followed by the second-generation BTKi, acalabrutinib, and recently the next-generation BTKi, zanubrutinib. Both zanubrutinib and acalabrutinib were compared to ibrutinib in phase 3 randomized controlled trials in relapsed/refractory (R/R) CLL. In the ALPINE trial (NCT03734016), zanubrutinib demonstrated a superior progression-free survival (PFS) when compared with ibrutinib in the all-comer R/R CLL population with hazard ratio (HR)=0.65, whereas the ELEVATE-RR trial (NCT02477696) showed noninferior PFS of acalabrutinib vs ibrutinib in R/R CLL patients with the presence of del(17p) or del(11q) with HR=1. Recent attempts to compare the efficacy results of the ibrutinib arm across trials omitted some patient characteristics that are critical for appropriate cross-trial comparisons. This study aimed to compare the efficacy of the ibrutinib control arm across ALPINE and ELEVATE-RR trials using a comprehensive matching-adjusted indirect comparison (MAIC). Methods: Individual patient data from the ibrutinib arm of ALPINE were adjusted to match the published population-level profile from the ibrutinib arm of ELEVATE-RR. To obtain comparable populations for MAIC, a subgroup of patients from ALPINE was included in the analysis. An unanchored MAIC was conducted to adjust for all relevant treatment effect modifiers (EM). The following were considered for population adjustment: IGHV status, del17p, del11q, TP53 status, serum β2-microglobulin, number of prior therapies, and Binet stage. Additional prognostic factors (PF) were also adjusted in sensitivity analyses. ALPINE data cutoff of August 2022 was used given the availability of both independent review committee (IRC) and investigator (INV) assessed data, and the possibility of a comparison vs other recently published MAICs (median follow-up: 29.6 months). Efficacy of ibrutinib in ALPINE was compared with efficacy of ibrutinib in ELEVATE-RR (median follow-up: 40.9 months). After population adjustment, HR obtained by weighted Cox proportional hazard model was applied to assess PFS and overall survival (OS) outcomes. PFS was analyzed as per IRC and INV. As the ALPINE trial was conducted during the COVID-19 pandemic and ELEVATE-RR was not, sensitivity analysis was conducted by adjusting the ALPINE PFS and OS for COVID-19 impact by censoring the patients who died due to COVID-19 at the most recent disease assessment prior to death or at the death due to COVID-19. Results: The high-risk population in ALPINE included 123 patients in the ibrutinib arm, which were matched against 265 patients in the ibrutinib arm of the ELEVATE-RR trial. After population adjustment, no statistically significant differences were observed in ALPINE-ibrutinib vs ELEVATE-ibrutinib with regards to PFS-IRC (HR=0.80 [0.49-1.28], P=0.3485) (Figure 1), PFS-INV (HR=1.18 [0.75-1.86], P=0.4827) (Figure 2), and OS (HR=0.91 [0.50-1.65], P=0.7539). Sensitivity analysis with COVID-19 adjustment yielded similar results as the main analysis. Scenarios matching for both EM and PF also generated results consistent with the main analysis. Conclusion: Using a comprehensive list of matching variables, this MAIC compares the performance of ibrutinib across ALPINE and ELEVATE-RR trials and demonstrates no evidence of a difference. Comparing the common comparator arms of 2 trials (ibrutinib vs ibrutinib) instead of the different investigational arms (zanubrutinib vs acalabrutinib) allows for eliminating some of the residual confounding that is inherent in MAICs. Despite decreased estimated sample size due to considering a comprehensive list of variables in the adjustment, results were consistent across multiple scenarios tested. While MAIC provides a basis for testing hypotheses with regards to treatment efficacy across trials, the ultimate evidence of relative efficacy must be sought within randomized controlled trials.

Cumulative Review of Hypertension in Patients with Chronic Lymphocytic Leukemia (CLL) and Other Hematologic Malignancies Treated with Acalabrutinib

Background: Patients (pts) with CLL have a high rate of comorbidities, including cardiovascular disease (CVD). Comorbid CVD is correlated with higher mortality in this pt population. Hypertension (HTN) is the most common concurrent CVD in pts with CLL and is associated with development of complications such as stroke and heart failure. The incidence of new or worsening HTN in treatment-naive CLL pts receiving placebo within the CLL12 trial was 8.3% over a 69.3-month observation period (Langerbeins et al. Hematol Oncol. 2023). New and/or worsening HTN has been observed in pts with CLL treated with Bruton tyrosine kinase inhibitor (BTKi) therapy. Studies have shown new or worsening HTN with ibrutinib (7−30%) and zanubrutinib (11−20%) (Christensen et al. Expert Rev Hematol. 2022). Acalabrutinib (acala), a selective, second-generation BTKi, demonstrated a lower rate of HTN (8.6%) vs ibrutinib (22.8%) in the head-to-head ELEVATE-RR study at a median follow-up of 40.9 months (Byrd et al. J Clin Oncol. 2021). Here, we performed a cumulative analysis of new or worsening HTN from the acala global development program and compared these data against real-world prevalence and incidence of HTN for pts with CLL prior to treatment initiation using claims data. Methods: Safety reports of new or worsening HTN were obtained from 11 clinical trials with acala (the safety database analysis comprised 2034 pts from studies in CLL [86.3%] and mantle cell lymphoma [6.1%], with the remainder from other B-cell malignancies). The clinical trials analyzed included therapy with acala (monotherapy or in combination with obinutuzumab) and active comparator groups (described in Table 1). Using the narrow Standardized MedDRA Query and the related MedDRA preferred terms for “HTN,” exposure-adjusted incidence rates in events/100 person-years were determined, and as a comparison, HTN prevalence was assessed at median treatment exposure for acala monotherapy. HTN prevalence (proportion of pts with HTN 6 months before treatment initiation) and incidence rates (number of new cases of HTN per 100 person-years during the 5 years before any treatment initiation) were also assessed based on ICD-10 codes from 3 adjudicated closed claims databases (Optum, MarketScan, and IQVIA). Results: In the claims database analysis, prevalence of HTN ranged from 47.3% to 66.1% in pts with TN CLL prior to treatment initiation. HTN prevalence with acala monotherapy at median treatment exposure (45.5 months) was 55.7%. Exposure-adjusted incidence rates of HTN were analyzed from 11 clinical trials; 1225 pts received acala monotherapy (947 pts with CLL), 223 pts received acala + obinutuzumab (all pts with CLL), 264 pts received ibrutinib as a comparator (all pts with CLL), and 322 pts received other comparators (all pts with CLL). Among the 1225 pts treated with acala monotherapy, 165 pts (147 with CLL) experienced a treatment-emergent adverse event of HTN (median age 66 years; 66.1% [n=109] male; 59.4% [n=98] with history of HTN at baseline). The exposure-adjusted incidence rates of HTN with acala monotherapy (3.844) and acala + obinutuzumab (3.926) were similar to that of other comparators (4.788 [excluding ibrutinib]) ( Table 1). In the ELEVATE-RR study specifically (subgroup of the current analysis), the exposure-adjusted incidence rate of HTN with acala (3.053) was approximately one-third that of ibrutinib (8.590). The exposure-adjusted incidence rate of HTN in pts treated with acala monotherapy without history of HTN was 3.239. Conclusions: Our data showed that HTN is a common comorbidity in pts with CLL as demonstrated in the claims database and clinical trial database analyses where 59.4% of pts who experienced HTN with acala monotherapy had history of HTN at baseline. The incidence rates of new or worsening HTN with acala monotherapy and acala + obinutuzumab were low (3.844 and 3.926, respectively). This is supported by similar incidence proportion of new or worsening HTN in pts receiving placebo (8.3%) from CLL12 (median follow-up 69.3 months) and acala monotherapy (8.9%) from ELEVATE-TN (median follow-up 58.2 months; Sharman et al. EHA. 2022), and similar HTN prevalence at median treatment exposure vs before treatment initiation in claims databases. Our analysis, conducted predominantly in patients with CLL, suggests that acala monotherapy did not worsen pre-existing HTN or increase the risk of new-onset HTN.

Gene Panels for Intraocular Lymphoma Can Overcome Diagnostic Difficulties and Enable Precision Medicine

Background: Definitive diagnosis of intraocular lymphoma (IOL) is often challenging, at least partially due to limited accessibility to the lesion and the rarity of tumor cells, with pathologically false-negative results reportedly occurring in approximately 30% of cases. Delayed diagnosis is often an important clinical issue, and the average time to diagnosis is approximately 1.5 years.Because of delayed diagnosis, IOLs are often found only after central nervous system (CNS) invasion has occurred, possibly leading to worse treatment outcomes. In this study, we tried to overcome diagnostic difficulties by using gene panel diagnostics of IOL. Furthermore, genetic analysis of IOLs may be able to predict the risk of recurrence.in Japan, a second-generation Bruton's tyrosine kinase (BTK) inhibitor, tirabrutinib, has been approved for the treatment of relapsed/refractory CNS lympoma. Herein, we present a case of IOL and CNS lesion with MYD88 mutation treated with tirabrutinib as part of precision medicine. Methods: We have developed a digital polymerase chain reaction-based system for multiplex gene panel testing of cell-free DNA (cfDNA) obtained from intraocular liquid biopsies (patent number 7149000, 2022/9/30). Our system can detect specific gene mutations in minute cfDNA by amplifying specific gene loci in bubbles, even from an extremely small number of cells. Using this multiplex gene panel testing, we analyzed genetic mutations in nine regions of four genes, MYD88, CD79B, BTG2, and PIM1, using cfDNA obtained from intraocular liquid biopsies. The diagnostic performance of the novel system was evaluated in 86 samlpes of patients with IOL. We also retrospectively analyzed the prognostic potential of the genetic mutations for IOL. Lastly, in the case of CNS lymphoma and IOL, we presented the MYD88 mutation treated with tirabrutinib. Results: Among the four disease-specific genes, the MYD88 mutation was present in 55 of 86 cases (64%), and frequencies of the CD79B, BTG2, and PIM1 mutations were 47%, 38%, and 29%, respectively. At least one of these mutations was found in 83 of the 86 IOL cases examined (97%), making this assay highly sensitive (Fig. 1). The MYD88 mutation was not associated with recurrence in patients with recurrent and refractory CNS lymphoma and IOL. Conversely,patients with the CD79B mutation had high rates of relapse for CNS lymphoma: the 4-year rate of recurrence-free survival was 35%, compared to 79% in patients without the CD79B mutation (p=0.012). Patients with the BTG2 mutation also had high rates of relapse (Fig. 2). Furthermore, we present a case of CNS lynphoma and IOL. By testing IOL gene panel, only MYD88 mutation was detected in the vitreous sample of IOL patient. We have experienced this case in which the second-generation BTK inhibitor,tirabrutinib, was effective not only for central but also for intraocular lesions. Conclusion: Our panel enables rapid and accurate diagnosis of IOL with only a small sample of intraocular liquid. We believe that this multiplex gene panel testing may aid in the diagnosis of IOL in difficult-to-diagnose patients, including those with chronic uveitis, by preventing CNS invasion due to diagnostic delay. Moreover, genetic profiling panels of IOL can help to stratify clinical outcomes.CD79B and BTG2 mutation is a potent predictive marker for relapse. In the clinical setting, we experienced a case of IOL with MYD88 mutation in which tirabrutinib was effective. Potentially, tirabrutinib also penetrates directly into the eye in intraocular lesions. Oral drug, tirabrutinib as eye dripping drug, might be effective as a therapeutic option for IOL and should be assessed in future clinical trials of precision medicine for IOL.

A Matching-Adjusted Indirect Comparison of Acalabrutinib with and without Obinutuzumab Versus Zanubrutinib in Treatment-Naïve Chronic Lymphocytic Leukemia

Introduction The second-generation Bruton tyrosine kinase inhibitors acalabrutinib (acala) and zanubrutinib (zanu) have not been compared with each other in a head-to-head randomized controlled trial (RCT). Acala with and without obinutuzumab (obin) was evaluated in the ELEVATE-TN RCT in treatment-naïve patients with chronic lymphocytic leukemia (CLL). Zanu was evaluated in treatment-naïve patients with CLL/small lymphocytic leukemia (SLL) in cohorts 1 and 2 of the SEQUOIA RCT. We used an unanchored matching-adjusted indirect comparison (MAIC) to compare the efficacy and safety of acala ± obin versus zanu in patients with treatment-naïve CLL/SLL without del(17p). Datasets were derived from comprehensive individual patient data (IPD) from ELEVATE-TN and published aggregate data from cohort 1 in SEQUOIA. Methods In this unanchored MAIC, we weighted IPD for the acala + obin and acala monotherapy arms from ELEVATE-TN to match zanu baseline data from SEQUOIA. We excluded patients with del(17p) in ELEVATE-TN to match cohort 1 in SEQUOIA, which excluded patients with del(17p). Patients were matched based on variables considered prognostic and/or predictive of investigator-assessed progression-free survival (INV-PFS) in an exploratory multivariate Cox-regression analysis of ELEVATE-TN. These were age, ECOG status, Binet stage, bulky disease, B2 microglobulin, cytopenia, del(11q), trisomy 12, IGHV status,and TP53 mutation. The efficacy analysis assessed INV-PFS in randomized patients (acala + obin, n = 162; acala monotherapy, n = 163; zanu, n = 241) using the Oct 2021 data cut-off (DCO) for ELEVATE-TN and the Oct 2022 DCO for SEQUOIA (median follow-up 58 versus 44 months). Pseudo-IPD for INV-PFS for zanu were obtained from Kaplan-Meier curves. The safety analysis assessed the incidence of adverse events (AEs) and reported the odds ratios (ORs) of AEs in treated patients (acala + obin, n = 162; acala monotherapy, n = 162; zanu, n = 240). To compare the incidence of AEs, the ELEVATE-TN Sep 2020 DCO was used to match the median follow-up from the SEQUOIA Oct 2022 DCO (47 versus 44 months). Results In the efficacy analysis, the acala + obin and acala monotherapy effective sample sizes (ESSs) post-matching were 124 (76%) and 105 (64%), respectively. Matching had little impact on acala + obin and acala monotherapy INV-PFS (Figure 1). Post-matching, 36-month INV-PFS was higher with acala + obin (95%; 95% CI: 90-97) than with zanu (84%; 95% CI: 79-88). The MAIC-weighted Cox hazard ratio (HR) found INV-PFS to be superior with acala + obin versus zanu (HR: 0.41; 95% CI: 0.23-0.74; Figure 1). No evidence of a difference between acala monotherapy post-matching and zanu was found when looking at 36-month INV-PFS (86%; 95% CI: 78-91 versus 84%; 95% CI: 79-88; HR: 0.91; 95% CI: 0.53-1.56). In the safety analysis, the acala + obin and acala monotherapy ESSs post-matching were 123 (76%) and 103 (64%), respectively. There were no significant differences in the odds of having most types of AE with acala + obin versus zanu, except for higher odds of having any grade neutropenia (OR: 2.19; 95% CI: 1.33-3.60) and arthralgia (OR: 2.33; 95% CI: 1.37-3.96). Acala monotherapy showed lower odds of having any grade hypertension (OR: 0.44, 95% CI: 0.20-0.99; Figure 2) and no significant differences in the odds of having other types of AEs versus zanu. Conclusions In this MAIC of ELEVATE-TN and SEQUOIA evaluating patients with treatment-naïve CLL/SLL without del(17p), acala + obin had a longer INV-PFS versus zanu, while there was no evidence of a difference between acala monotherapy and zanu. Acala + obin and acala monotherapy generally had similar safety profiles to zanu. However, acala monotherapy was associated with lower odds of any grade hypertension versus zanu, while acala + obin was associated with higher odds of any grade neutropenia and arthralgia versus zanu. Although the results of MAIC analyses can only be hypothesis-generating, these results address an important data gap by systematically comparing these two commonly used regimens where randomized, prospective data are not available.

Traverse: A Phase 2, Open-Label, Randomized Study of Acalabrutinib in Combination with Venetoclax and Rituximab in Patients with Treatment-Naive Mantle Cell Lymphoma

Background and Significance: Despite advances in treatment for mantle cell lymphoma (MCL), no curative option exists. Currently, the majority of patients with treatment-naive (TN) MCL receive chemoimmunotherapy, which can result in prolonged remissions, but is associated with significant toxicity. Almost all patients inevitably relapse, and therefore, frontline chemotherapy-free options are being increasingly explored. Acalabrutinib is a highly selective, second-generation Bruton tyrosine kinase inhibitor (BTKi) approved for the treatment of adult patients with relapsed/refractory (R/R) MCL. In a phase 1b study in patients with TN MCL, acalabrutinib in combination with venetoclax and rituximab (AVR) demonstrated high rates of clinical and molecular response with an acceptable toxicity profile, supporting its continued development as a chemotherapy-free treatment option (Wang et al. Blood. 2021; Wang et al. Blood. 2022). Furthermore, the occurrence of complete responses (CRs) with clearance of minimal residual disease (MRD) in MCL clinical trials suggests that treatment may be stopped in these patients, as observed in patients with chronic lymphocytic leukemia who received combination therapy with venetoclax and rituximab. Study Design and Methods: TrAVeRse (NCT#05951959) is a phase 2, open-label, randomized, multicenter, international study of AVR in patients with TN MCL. Patients aged ≥18 years with an Eastern Cooperative Oncology Group performance status of 0-2 (3 if due to lymphoma), and Ann Arbor stage II, III, or IV disease are eligible. Key exclusion criteria are active central nervous system involvement by lymphoma or leptomeningeal disease, severe/life-threatening illness or medical condition, clinically significant cardiovascular disease, stroke, or intracranial hemorrhage within 6 months of enrollment, and any active uncontrolled infection. Approximately 125 patients will be screened to achieve a study population of 100 patients. During the induction phase, patients will receive oral acalabrutinib 100 mg twice daily (BID) in 28-day cycles for 13 cycles, starting at cycle 1; oral venetoclax once daily, starting at cycle 2 at a dose of 20 mg daily, with ramp-up to a maximum of 400 mg daily over 5 weeks for a total of 12 cycles; and intravenous rituximab 375 mg/m 2 on day 1 of every cycle for 12 cycles, starting at cycle 1. Patients who complete 13 cycles of AVR induction will be centrally tested for MRD status and continue to receive acalabrutinib 100 mg BID for 1 additional cycle (cycle 14) while awaiting disease response assessment and MRD results. Patients who achieve an MRD-negative CR (in peripheral blood at a threshold of 10 -5) at the end of induction will be randomly assigned in a 1:1 ratio to either continue to receive acalabrutinib 100 mg BID or to observation from cycle 15. Randomization will be stratified according to the simplified MCL International Prognostic Index [sMIPI] score (low [score, 0-3] and intermediate risk [4-5] vs high risk [6-11]), histologic features (blastoid or pleomorphic vs classical histology), and TP53 status (mutated vs unmutated). Those with an MRD-positive CR, partial response (PR), or stable disease (SD) at end of induction will continue to receive acalabrutinib 100 mg BID until disease progression, death, or unacceptable toxicity. Patients who progress during observation may be retreated with acalabrutinib 100 mg BID at relapse. The primary endpoint of this study is the MRD-negative CR rate at the end of AVR induction (ie, end of cycle 13). Secondary endpoints include MRD-negative CR rate at any point during the study, objective response rate and CR rate, duration of response, time to next treatment, progression-free survival, event-free survival, overall survival, safety, and tolerability. The study will also assess the feasibility of response-adapted treatment cessation for those who achieve MRD-negative CR after AVR induction and the efficacy of acalabrutinib retreatment in the subgroup of patients randomized to observation who subsequently relapse. Patients will be followed for 36 months post last patient randomized. Enrollment is planned to begin Q3 of 2023 including sites in North America, Australia, and Europe. Summary: This study will evaluate the efficacy of AVR, a chemotherapy-free triplet combination therapy, in patients with TN MCL.

Effectivness and Safety of Orelabrutinib in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Retrospective, Real-World Study in China

Introduction: Orelabrutinib is a second-generation Bruton tyrosine kinase inhibitor (BTKi) with high kinase selectivity. Clinical studies have demonstrated that orelabrutinib achieved a high complete response rate of 26.3% in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), showing promising efficacy and acceptable safety profile. However, the real-world data of Orelabrutinib are not available. This study aimed to evaluate the effectiveness and safety of orelabrutinib-containing regimens for the treatment of patients (pts) with CLL/SLL in a real-world setting. Methods: This was a retrospective, multi-center, real-world study conducted. Pts (aged 18 years or older) with CLL/SLL who received at least 3 months of orelabrutinib-containing regimens between December 2020 and March 2023 were analyzed. Efficacy was evaluated by hematologic response rate (HRR), defined as the proportion of pts who met at least 1 of the following hematologic response criteria: hemoglobin response (pts having a recovery of hemoglobin value or ≥50% increase from baseline), platelet response (pts having a recovery of platelet count or ≥50% increase from baseline), or lymphocyte response (pts having a recovery of lymphocyte count or ≥50% reduction from baseline). Safety was assessed by adverse events (AEs) as per NCI-CTCAE 5.0. Results: 24 pts with CLL/SLL (12 males; 22 CLL) were included, with a median age of 62.5 years (range: 38-82). Most pts had an Eastern Cooperative Oncology Group score of 0-1 (17/24, 70.8%) and Rai stage III or IV disease (16/18, 88.9%). 7 pts with hypertension, of which 2 with very high-risk hypertension. 3 pts have previously received other BTKi. A total of 9 pts(37.5%) performed del(17p), TP53, or IGHV testing. Among them, pts received orelabrutinib 100 mg (2/24,) or 150 mg (22/24,) once daily. As of the cut-off date (July 13, 2023), the median follow-up was 10.67 (range, 2.73-25.77) months. 18 pts (16 CLL, 2 SLL) with abnormal hemoglobin value, platelet count, or lymphocyte count at baseline were evaluable for hematologic response. Hematologic response was achieved in 11 (61.1%) of 18 evaluable pts. Pts aged &amp;lt;65 years had a higher HRR versus pts aged ≥65 years (87.5% vs. 40.0%, p=0.040). HRR was 56.3% in CLL versus 100.0% in SLL pts, and 60.0% in pts with hypertension versus 61.5% without hypertension . Four of 11 responders had a hematologic response in at least two criteria (CLL, n=3; SLL, n=1), of which 3 pts had a hemoglobin response (Figure 1). The most commonly reported AEs included hemoglobin decreased (16.7%) and platelet count decreased (16.7%). Grade ≥3 AEs were white blood cell count decreased (4.2%), platelet count decreased (4.2%), and lymphocyte count decreased (4.2%). No pts experienced severe AEs. No cardiovascular AEs were reported during treatment in 7 pts with hypertension at baseline. Conclusions: This real-world study assessed the preliminary characteristics and clinical outcome of patients receiving orelabrutinib-containing regimens under routine clinical practice conditions in China. The orelabrutinib-containing regimens in this study furnished beneficial evidence for the treatment of CLL/SLL and is essential for determining the best treatment option, future data with a larger sample and longer follow-up will be updated.

Real-World Effectiveness and Safety Outcomes of Acalabrutinib Treatment By Line of Therapy in Patients with Chronic Lymphocytic Leukemia and/or Small Lymphocytic Lymphoma

Background: Acalabrutinib is a second-generation Bruton tyrosine kinase inhibitor (BTKi) approved by the Food and Drug Administration for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Data from phase 3, randomized, controlled trials of acalabrutinib, as monotherapy or in combination with obinutuzumab, in patients with treatment-naive (TN) and relapsed/refractory (R/R) CLL with long-term follow-up, including ELEVATE-TN, ELEVATE-RR, and ASCEND, have demonstrated sustained improvement vs comparators in progression-free survival and overall survival (OS) with cardiovascular (CV) and bleeding events consistent with previous reports (Sharman et al. J Clin Oncol. 2021; Byrd et al. J Clin Oncol. 2021; Ghia et al. Blood. 2022). As real-world evidence of the acalabrutinib effectiveness and safety profile is limited in CLL/SLL patients, this study aimed to describe time to next treatment (TTNT), OS, and CV and bleeding events in patients receiving first-line (1L) and later-line (2L+) acalabrutinib for the treatment of CLL/SLL in the real-world setting. Methods: A retrospective, observational analysis was conducted utilizing the Optum Clinformatics © Data Mart claims and electronic medical record database to identify patients aged ≥18 years with TN or R/R CLL/SLL who initiated acalabrutinib in any line of therapy (LoT) on or after November 21, 2019 (FDA approval date for acalabrutinib). Patients with CLL/SLL were required to have ≥6 months of continuous enrollment in the Optum database system prior to acalabrutinib treatment initiation. Patients were followed until the earliest of last day of data availability, death, or end of study period (September 30, 2022). Treatment effectiveness was described as TTNT (time from acalabrutinib initiation to next LoT or death of any cause) and OS (time from acalabrutinib initiation to date of death from any cause or end of study period). The Kaplan-Meier (KM) method was used to estimate TTNT and OS. Patients who continued treatment at the last follow-up were censored. CV and bleeding events were assessed in all patients who initiated acalabrutinib. All outcomes were evaluated in patients who received 1L or 2L+ acalabrutinib therapy. Results: A total of 530 patients were identified and included in the analysis. Of these patients, 63% (n=334) received 1L acalabrutinib and 37% (n=196) received 2L+ acalabrutinib. At acalabrutinib initiation, the mean age was 72.8 years in the 1L cohort and 74.2 years in the 2L+ cohort; 61.7% (121/196) of patients treated with 2L+ acalabrutinib had prior BTKi therapy prior to acalabrutinib initiation (ibrutinib, n=120; zanubrutinib, n=1). Distributions of gender and race were similar between the cohorts. At baseline, 18.1%, 75.3%, and 16.0% of patients had atrial fibrillation/flutter, hypertension, and bleeding episodes, respectively. With a median follow-up of 8.9 months in the 1L cohort and 12.4 months in the 2L+ cohort, the median TTNT and OS were not reached in either cohort. At 18 months, the proportion of patients remaining on treatment was 82% in the 1L cohort and 78% in the 2L+ cohort ( Figure 1). Of the patients that progressed, the median TTNT was 4.0 months in the 1L cohort (n=33) and 4.2 months in the 2L cohort (n=31). The 18-month OS rate was 90% and 85% for the 1L and 2L+ cohorts, respectively ( Figure 2). After initiation of acalabrutinib treatment, the incidence rates of atrial fibrillation/flutter, hypertension, and bleeding events were 2.7%, 8.9%, and 2.7% of patients in the 1L cohort and 7.4%, 2.4%, and 3.3% of patients in the 2L+ cohort, respectively, who had no history of these events prior to treatment with acalabrutinib. Conclusions: This is the first study demonstrating real-world effectiveness (OS and TTNT) and safety data of acalabrutinib treatment in first-line and later-line therapy. While clinical trial and clinical practice settings may differ, overall, the survival findings in this study were similar to those of acalabrutinib trials. The observed incidence rates of CV and bleeding events were not inconsistent with those observed in published acalabrutinib trials.

MAHOGANY: Will it Establish Zanbrutinib, a Second-generation Bruton Tyrosine Kinase Inhibitor, as a Preferred Targeted Therapy for Relapsed/Refractory Follicular and Marginal Zone Lymphomas?

MAHOGANY: Will it Establish Zanbrutinib, a Second-generation Bruton Tyrosine Kinase Inhibitor, as a Preferred Targeted Therapy for Relapsed/Refractory Follicular and Marginal Zone Lymphomas?

Structure of BTK kinase domain with the second-generation inhibitors acalabrutinib and tirabrutinib.

Bruton's tyrosine kinase (BTK) is the target of the therapeutic agent, Ibrutinib, that treats chronic lymphocyte leukemia (CLL), mantle cell lymphoma (MCL) and other B cell malignancies. Ibrutinib is a first in class, covalent BTK inhibitor that limits B-cell survival and proliferation. Designing new inhibitors of BTK has been an important objective for advancing development of improved therapeutic agents against cancer and autoimmune disorders. Based on the success of Ibrutinib, several second-generation irreversible BTK inhibitors have been developed that exhibit fewer off-target effects. However, the binding-mode and their interaction with Btk have not been experimentally determined and evaluated at atomic resolution. Here we determined the first crystal structure of the BTK kinase domain in complex with acalabrutinib. In addition, we report a structure of the BTK/tirabrutinib complex and compare these structures with previously solved structures. The structures provide insight in the superior selectivity reported for acalabrutinb and guide future BTK inhibitor development.

Zanubrutinib Ameliorates Cardiac Fibrosis and Inflammation Induced by Chronic Sympathetic Activation.

(1) Background: Heart failure (HF) is the final stage of multiple cardiac diseases, which have now become a severe public health problem worldwide. β-Adrenergic receptor (β-AR) overactivation is a major pathological factor associated with multiple cardiac diseases and mediates cardiac fibrosis and inflammation. Previous research has demonstrated that Bruton's tyrosine kinase (BTK) mediated cardiac fibrosis by TGF-β related signal pathways, indicating that BTK was a potential drug target for cardiac fibrosis. Zanubrutinib, a second-generation BTK inhibitor, has shown anti-fibrosis effects in previous research. However, it is unclear whether Zanubrutinib can alleviate cardiac fibrosis induced by β-AR overactivation; (2) Methods: In vivo: Male C57BL/6J mice were treated with or without the β-AR agonist isoproterenol (ISO) to establish a cardiac fibrosis animal model; (3) Results: In vivo: Results showed that the BTK inhibitor Zanubrutinib (ZB) had a great effect on cardiac fibrosis and inflammation induced by β-AR. In vitro: Results showed that ZB alleviated β-AR-induced cardiac fibroblast activation and macrophage pro-inflammatory cytokine production. Further mechanism studies demonstrated that ZB inhibited β-AR-induced cardiac fibrosis and inflammation by the BTK, STAT3, NF-κB, and PI3K/Akt signal pathways both in vivo and in vitro; (4) Conclusions: our research provides evidence that ZB ameliorates β-AR-induced cardiac fibrosis and inflammation.

Hepatitis B Virus Reactivation in Patients Receiving Bruton Tyrosine Kinase Inhibitors.

Bruton tyrosine kinase (BTK) inhibitors are used to treat B-cell hematologic malignancies. Ibrutinib has been associated with hepatitis B virus (HBV) reactivation. We sought to identify patients with hematologic malignancies who developed HBV reactivation after receiving first-generation (ibrutinib) or second-generation (acalabrutinib and zanubrutinib) BTK inhibitors. We retrospectively studied all consecutive patients with hematologic malignancies with past HBV infection (HBV surface antigen [HBsAg] negative and hepatitis B core antibody [anti-HBc] positive) or chronic HBV infection (HBsAg positive and anti-HBc positive) treated with BTK inhibitors at our institution from November 1, 2015, through November 1, 2022. Of 82 patients initially identified, 53 were excluded (11 because of false-positive anti-HBc results, and 42 because they were receiving anti-HBV prophylaxis owing to recent receipt of anti-CD20 monoclonal antibodies). The 29 remaining patients were further analyzed and 3 (10%; 2/28 with past and 1/1 with chronic HBV infection) were found to have HBV reactivation. One patient received ibrutinib, and 2 received acalabrutinib. All developed HBV-associated hepatitis requiring anti-HBV therapy and survived. One patient continued receiving acalarutinib. Among the patients with past HBV infection, 13 received ibrutinib and 1 (8%) had HBV reactivation; 14 received acalabrutinib and 1 (7%) had HBV reactivation (P=1.0). HBV reactivation risk is intermediate in patients with past HBV infection who receive BTK inhibitors. For patients with past HBV infection who received BTK inhibitors, data are insufficient to recommend universal anti-HBV prophylaxis, but monitoring for HBV reactivation is warranted.

Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option.

Ibrutinib, the first-in-class Bruton's tyrosine kinase inhibitor (BTKi), is a commonly deployed therapeutic option for previously untreated and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia (CLL). The use of ibrutinib is, however, partially limited by off-target side effects. Zanubrutinib (zanu) is a second-generation BTKi with enhanced target selectivity and occupancy of the kinase binding site. The SEQUOIA study showed that zanu significantly prolonged progression-free survival (PFS) when compared to bendamustine-rituximab (BR) in treatment-naive CLL patients. More recently, data from the phase III ALPINE trial, which directly compared zanu with ibrutinib, demonstrated that zanu's advantages include an improved safety profile as well as enhanced clinical efficacy. Based on the results of the SEQUOIA and ALPINE pivotal trials, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) licensed zanu for the treatment of patients with CLL or small lymphocytic lymphoma (SLL) in January 2023. The updated (v2.2023) National Comprehensive Cancer Network (NCCN) guidelines and the most recent German CLL algorithm suggest that zanu may replace first-generation BTKis as a preferred therapeutic option for patients with CLL/SLL due to its increased selectivity for the kinase binding site, improved therapeutic efficacy, and favorable toxicity profile. Some drug class-related characteristics such as drug resistance, low complete remission (CR) rates, and indefinite treatment duration still remain with zanu, and the results from recently completed and ongoing fixed-duration clinical trials, combining zanu with an anti-BCL2 agent, are eagerly awaited with the possible promise of a reduced treatment duration and lower financial burden.