Bruton Tyrosine Kinase Inhibitor Therapy Research Articles

Pirtobrutinib monotherapy in Bruton tyrosine kinase inhibitor-intolerant patients with B-cell malignancies: results of the phase I/II BRUIN trial.

Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment of B-cell malignancies, but intolerance has often led to their discontinuation. The phase 1/2 BRUIN study evaluated pirtobrutinib, a highly selective non-covalent (reversible) BTKi, in patients with R/R B-cell malignancies (NCT03740529). Pirtobrutinib was investigated in 127 patients with intolerance to at least one prior BTKi therapy in the absence of progressive disease. The most common adverse event (AE) leading to BTKi discontinuation was cardiac disorders (n=40, 31.5%), specifically atrial fibrillation (n=30, 23.6%). The median follow-up was 17.4 months and the median time on pirtobrutinib was 15.3 months. The most common reasons for pirtobrutinib discontinuation were progressive disease (26.8%), AE (10.2%), or death (5.5%). The most frequent treatment-emergent AEs were fatigue (39.4%) and neutropenia (37.0%). Among patients who discontinued a prior BTKi for a cardiac issue, 75% had no recurrence of their cardiac AE. No patient discontinued pirtobrutinib for the same AE that led to discontinuation of the prior BTKi. In 78 CLL/SLL and 21 MCL patients intolerant to prior BTKi, ORR to pirtobrutinib was 76.9% and 81.0%, respectively. Median PFS for CLL/SLL was 28.4 months and was not estimable for MCL. These results suggest that pirtobrutinib was safe, well-tolerated, and an efficacious option in patients with prior BTKi-intolerance.

Pre-existing cardiovascular disease is associated with an increased risk of cardiovascular events during Bruton tyrosine kinase inhibitor therapy.

The association between pre-existing cardiovascular disease (CVD) and the development of cardiovascular adverse events (CVAE) during Bruton tyrosine kinase inhibitor (BTKi) therapy is not well established. We compared the rate of CVAE, such as new onset or worsening atrial fibrillation (AF), supraventricular tachycardia, ventricular tachycardia, hypertension, myocardial infarction, and sudden cardiac death, between individuals with and without pre-existing CVD, during BTKi treatment. Secondary objectives were to compare the outcomes of patients treated with first generation BTKi versus second generation BTKi and characterize management decisions. A single-center retrospective review was conducted on patients treated with BTKi from 2013 to 2022 at Beth Israel Deaconess Medical Center. Adjusted logistic regression analyses were performed to evaluate the association between pre-existing CVD and CVAE. In this cohort, 11 out of 54 patients (20.4%) with pre-existing CVD developed CVAE, compared to 11 out of 135 patients (8.1%) without pre-existing CVD [age- and sex-adjusted OR 2.79; 95% CI (1.09, 7.25), P = .03]. Patients with pre-existing CVD had higher odds of developing new or worsening AF [age- and sex-adjusted OR 3.36; 95% CI (1.09, 10.71), P = .03]. Results remained robust after furtheradjustment of comorbidities, type of BTKi, and baseline medications. These results highlight the need for standardized approaches to prevent and promptly detect CVAE during BTKi treatment, particularly in patients with pre-existing CVD.

Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in patients with B-cell malignancies: analysis of the Richter transformation subgroup from the multicentre, open-label, phase 1/2 BRUIN study

Richter transformation usually presents as an aggressive diffuse large B-cell lymphoma, occurs in up to 10% of patients with chronic lymphocytic leukaemia, has no approved therapies, and is associated with a poor prognosis. Pirtobrutinib has shown promising efficacy and tolerability in patients with relapsed or refractory B-cell malignancies, including those who progress on covalent Bruton tyrosine kinase (BTK) inhibitors. This study aims to report the safety and activity of pirtobrutinib monotherapy in a subgroup of patients with Richter transformation from the multicentre, open-label, phase 1/2 BRUIN study. This analysis included adult patients (aged ≥18 years) with histologically confirmed Richter transformation, an Eastern Cooperative Oncology Group performance status score of 0-2, and no limit of previous therapies, with patients receiving first-line treatment added in a protocol amendment (version 9.0, Dec 15, 2021). Pirtobrutinib 200 mg was administered orally once a day in 28-day cycles. The primary endpoint of phase 1 of the BRUIN trial as a whole, which has been previously reported, was to establish the recommended phase 2 dose for pirtobrutinib monotherapy and the phase 2 primary endpoint was overall response rate. Safety and activity were measured in all patients who received at least one dose of pirtobrutinib monotherapy. This BRUIN phase 1/2 trial was registered with ClinicalTrials.gov and is closed to enrolment (NCT03740529). Between Dec 26, 2019, and July 22, 2022, 82 patients were enrolled, of whom five were enrolled during phase 1 and 77 during phase 2. All but one patient received a starting dose of 200 mg pirtobrutinib once a day as the recommended phase 2 dose. The remaining patient received 150 mg pirtobrutinib once a day, which was not escalated to 200 mg. The median age of patients was 67 years (IQR 59-72). 55 (67%) of 82 patients were male and 27 (33%) were female. Most patients were White (65 [79%] of 82). 74 (90%) of 82 patients received at least one previous Richter transformation-directed therapy. Most patients (61 [74%] of 82) had received previous covalent BTK inhibitor therapy for chronic lymphocytic leukaemia or Richter transformation. The overall response rate was 50·0% (95% CI 38·7-61·3). 11 (13%) of 82 patients had a complete response and 30 (37%) of 82 patients had a partial response. Eight patients with ongoing response electively discontinued pirtobrutinib to undergo stem-cell transplantation. The most common grade 3 or worse adverse event was neutropenia (n=19). There were no treatment-related deaths. Pirtobrutinib shows promising safety and activity among patients with Richter transformation, most of whom received previous Richter transformation-directed therapy, including covalent BTK inhibitors. These data suggest that further investigation is warranted of pirtobrutinib as a treatment option for patients with relapsed or refractory Richter transformation after treatment with a covalent BTK inhibitor. Loxo Oncology.

Guidance of Preventing and Managing Cardiovascular Complications of Bruton Tyrosine Kinase Inhibitor Therapy: Findings of a White Paper Document From Roundtable Multidisciplinary Discussion

Guidance of Preventing and Managing Cardiovascular Complications of Bruton Tyrosine Kinase Inhibitor Therapy: Findings of a White Paper Document From Roundtable Multidisciplinary Discussion

SARS-CoV-2 Polymerase Chain Reaction Cycle Threshold Trends in Patients Who Are Immunocompromised and Implications for Isolation Precautions.

Among 495 patients who were immunocompromised and tested positive for SARS-CoV-2, polymerase chain reaction cycle thresholds remained <33 beyond 20 days more frequently in patients with hematologic malignancies, particularly those receiving B-cell-depleting or Bruton tyrosine kinase inhibitor therapy, as compared with those with solid organ malignancy (26% vs 5%).

Fixed-duration pirtobrutinib plus venetoclax with or without rituximab in relapsed/refractory CLL: the phase 1b BRUIN trial

AbstractPirtobrutinib is a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). Patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) were treated with fixed-duration pirtobrutinib plus venetoclax (PV) or pirtobrutinib plus venetoclax and rituximab (PVR) in this phase 1b trial. Prior covalent BTKi therapy was allowed, but not prior treatment with venetoclax. Patients were assigned to receive PV (n = 15) or PVR (n = 10) for 25 cycles. Most patients (68%) had received prior covalent BTKi therapy. At the data cutoff date, the median time on study was 27.0 months for PV and 23.3 months for PVR. Overall response rates were 93.3% (95% confidence interval [CI], 68.1-99.8) for PV and 100% (95% CI, 69.2-100.0) for PVR, with 10 complete responses (PV: 7; PVR: 3). After 12 cycles of treatment, 85.7% (95% CI, 57.2-98.2) of PV and 90.0% (95% CI, 55.5-99.7) of PVR patients achieved undetectable minimal residual disease (<10-4) in peripheral blood. Progression-free survival at 18 months was 92.9% (95% CI, 59.1-99.0) for PV patients and 80.0% (95% CI, 40.9-94.6) for PVR patients. No dose-limiting toxicities were observed during the 5-week assessment period. The most common grade ≥3 adverse events (AEs) for all patients included neutropenia (52%) and anemia (16%). AEs led to dose reduction in 3 patients and discontinuation in 2. In conclusion, fixed-duration PV or PVR was well tolerated and had promising efficacy in patients with R/R CLL, including patients previously treated with a covalent BTKi. This trial was registered at www.clinicaltrials.gov as #NCT03740529.

Navigating the complex terrain of hepatitis B virus reactivation in the era of Bruton tyrosine kinase inhibitors

In this editorial, we offer a summary of the risk associated with hepatitis B reactivation (HBVr) in the setting of both solid and hematologic malignancies treated with Bruton tyrosine kinase (BTK) inhibitors, with insights derived from current studies. Furthermore, we emphasize the critical need for a framework regarding robust risk evaluation in patients undergoing such treatments. This framework is essential for identifying those at increased risk of HBVr, enabling healthcare providers to implement proactive measures to prevent reactivation and ensure the safe administration of BTK inhibitor therapy.

BGB-11417-203: An ongoing, phase 2 study of sonrotoclax (BGB-11417), a next-generation BCL2 inhibitor, in patients with Waldenström macroglobulinemia.

TPS7090 Background: Bruton tyrosine kinase (BTK) inhibitors and anti-CD20 antibody-based systemic therapy are included within the preferred treatment algorithms for Waldenström macroglobulinemia (WM). However, to date, no treatments have been approved for patients with WM that is refractory to both BTK inhibitors and anti-CD20 therapy. Venetoclax, the first-generation BCL2 inhibitor, has demonstrated clinical activity in patients with relapsed/refractory (R/R) WM (Castillo et al. J Clin Oncol. 2022), but it has no regulatory approvals in WM. Sonrotoclax, a next generation BCL2 inhibitor, is more selective and a more pharmacologically potent inhibitor of BCL2 than venetoclax. In a phase 1 trial, sonrotoclax monotherapy was well tolerated at all dose levels tested up to 640 mg and showed promising evidence of antitumor activity in patients with R/R WM (Soumerai et al. Blood. 2022). Based on the data from these earlier studies, a phase 2 study of sonrotoclax monotherapy in patients with WM has been initiated and is currently recruiting. Methods: BGB-11417-203 (NCT05952037) is an open-label, international, phase 2 study. Eligible patients have histologically confirmed WM that is R/R to both BTK inhibitor therapy and anti-CD20–based systemic therapy combined with chemotherapy or a proteasome inhibitor (PI; Cohort 1); R/R to anti-CD20–based systemic therapy combined with chemotherapy or a PI and who are intolerant to BTK inhibitor therapy (Cohort 2); or R/R to a BTK inhibitor and who are unsuitable for chemoimmunotherapy (Cohort 3). Patients who have received previous treatment with a BCL2 inhibitor are ineligible. Approximately 85 patients will be enrolled across cohorts and will receive sonrotoclax until disease progression, death, unacceptable toxicity, patient withdrawal, loss to follow-up, or study termination. The primary endpoint is major response rate (MRR; defined as partial response or better) in Cohort 1 per IWWM-11 criteria, as assessed by independent review committee (IRC). Key secondary endpoints include MRR assessed by investigator (INV) in Cohort 1 and by IRC and INV in both Cohorts 2 and 3; overall response rate, duration of response, and progression-free survival by IRC and INV; overall survival; and safety and tolerability. Patient recruitment is ongoing in Australia, the US, China, and Europe. Clinical trial information: NCT05952037 .

Real-world understanding of the unmet need for treatment of non-covalent BTKi in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

e19028 Background: Non-covalent (nc) Bruton Tyrosine Kinase inhibitors (BTKi) for the treatment of Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (CLL/SLL) provide patients with a new treatment option after resistance to on-target BTK mutations or PLCγ2 mutations that bypass BTK inhibition. Given the December 1, 2023 accelerated FDA approval for pirtobrutinib, a nc-BTKi, in the treatment of CLL/SLL for treatment of patients who have received at least two prior lines of therapy with a covalent (c) BTKi and a B-Cell Lymphoma 2 Protein Inhibitor (BCL2i), we sought to understand the addressable population for treatment with nc-BTKI therapy in a real-world database of CLL/SLL patients. Methods: We used the Integra Connect PrecisionQ real-world de-identified database of over 3 million cancer pts across 500 sites of care to identify CLL/SLL pts for the analysis. The CLL patients included for the analysis were on a treatment in 2023 and must have had either &gt;5 CLL/SLL diagnosed visits or more CLL/SLL visits than non-CLL/SLL visits if &lt;5 CLL/SLL diagnosed visits. Descriptive analyses were used for this study. Results: Of the 6,992 patients treated for CLL/SLL in 2023, the median age at treatment start was 71, 62% were male, 65% identified as White, 6% as African American, and 29% as Other. Of the pts, 12% received a c-BTKi and BCL2i, 64% received a c-BTKi only, and 12% received a BCL2i only. Of the 12% of pts who received a c-BTKi and BCL2i, 191 pts started a subsequent line of therapy. Among pts who received a c-BTKi and BCL2i, 79% received a BTKi therapy first, 10% received a BCL2i therapy first, and 12% had a line of therapy with both a BTKi and BCL2i. We found 59 pts who received nc-BTKi; among those pts, 51% received a c-BTKi and BCL2i prior to initiation of nc-BTKi. The median age at first treatment for CLL/SLL was 71.7 for those who received a c-BTKi, 71.1 for those who received a BCL2i, and 70.8 for those who received nc-BTKi. The median age at first diagnosis for CLL/SLL was 68 for those who received a c-BTKi, 66 for those who received a BCL2i, and 63 for those who received nc-BTKi. The median time to first treatment was 470 days for pts treated with a c-BTKi, 507 days for pts treated with BCL2i, and 587 days for pts treated with nc-BTKi. Conclusions: We found that among nearly 7,000 treated patients in the database, 12% were treated with both a c-BTKi and BCL2i; of those, just 23% started a subsequent treatment. Among patients who were treated with a nc-BTKi we found their median age at treatment start and diagnosis was lower than those who received a c-BTKi or BCL2i respectively.

Risk of hypertension in patients with CLL/SLL who participated in ALPINE: A post hoc analysis.

e19016 Background: Bruton tyrosine kinase (BTK) inhibitors are an important therapeutic option for patients with CLL/SLL. The first-generation BTK inhibitor, ibrutinib (ibru), is associated with an increased risk of hypertension. Zanubrutinib (zanu) is a next-generation BTK inhibitor designed to maximize BTK occupancy and minimize toxicity with fewer off-target effects. This analysis evaluated the risk of developing hypertension based on initiation of antihypertensives (anti-HTN) in ALPINE (NCT03734016). Methods: Anti-HTN use in the zanu (n=324) and ibru (n=324) treatment arms was assessed. The definition of anti-HTN was based on Standardized Drug Grouping; concomitant anti-HTN were adjudicated by an independent hypertension specialist blinded to BTK inhibitor assignment. Time to initiating new anti-HTN and time to adding a new class of anti-HTN were assessed using the Kaplan-Meier method. Comparisons of time-to-onset endpoints were analyzed based on the log-rank test. Results: At baseline, patient characteristics were generally balanced between zanu and ibru arms (median age, 66.7 vs 67.1 y; male, 65.1% vs 71.4%; history of hypertension, 50.9% vs 50.0%; type 2 diabetes mellitus, 10.1% vs 8.9%). Among patients not on anti-HTN at baseline, 20.7% (n=35/169) of zanu- and 28.7% (n=51/178) of ibru-treated patients initiated anti-HTN during the study. Among all patients, fewer patients in the zanu arm initiated new anti-HTN (28.4% [n=92/324] vs 32.4% [n=105/324]) and the anti-HTN were initiated later (hazard ratio [HR], 0.77; P-value=.071). Additionally, statistically fewer patients in the zanu arm compared with the ibru arm started anti-HTN in a new class (24.1% [n=78/324] vs 29.3% [n=95/324]) and the anti-HTN were started later (HR, 0.72; P-value=.034). The event rates for initiation of new anti-HTN or a new class of anti-HTN were consistently lower in the zanu vs ibru arm at each timepoint (Table). Conclusions: In ALPINE, initiation of new anti-HTN or a new class of anti-HTN occurred less frequently in the zanu arm vs the ibru arm in patients with CLL/SLL. Adoption of anti-HTN occurred sooner with ibru than zanu. These findings should be considered when initiating BTK inhibitor therapy in patients with CLL/SLL who have an elevated cardiovascular risk. Clinical trial information: NCT03734016 . [Table: see text]

Optimizing BTK Inhibition in Waldenström Macroglobulinemia.

Bruton tyrosine kinase (BTK) inhibitors have become a standard of care in the treatment of patients with Waldenström macroglobulinemia (WM) and are the only medications approved by the FDA to treat these patients. As more patients with WM are treated with BTK inhibitors in the United States and worldwide, it is essential to optimize this therapy by selecting the patients who are more likely to benefit from it, and by managing the unique adverse effects associated with these agents. Herein, we propose a genomic-driven approach to selecting patients with WM who are more likely to experience fast, deep, and durable responses to BTK inhibitors, and provide practical strategies for managing adverse effects, including BTK inhibitor dose reductions, switching to other BTK inhibitors, and abandoning BTK inhibitor therapy. Ongoing clinical trials are evaluating covalent and noncovalent BTK inhibitors alone and in combination, as well as BTK degraders, with exciting results, making the horizon for BTK-targeting therapies in WM bright and hopeful.

A prospective study of zanubrutinib, a Bruton tyrosine kinase inhibitor, in relapsed/refractory idiopathic multicentric Castleman disease.

Relapsed and refractory (R/R) idiopathic multicentric Castleman disease (iMCD) is a clinical challenge with no standard treatment. In this preliminary clinical trial, we investigated the efficacy and safety profiles of a Bruton tyrosine kinase inhibitor (BTKi), zanubrutinib, in patients with R/R iMCD. The primary endpoint was theoverall response rate at Week 12according to theCastleman Disease Collaborative Network (CDCN) response criteria. The trial was terminated early due to a lack of treatment response in the first enrolled 5 patients. Although 3 patients achieved symptomatic response, none of the 5 patients had an overall response by Week 12. One patient had progressive disease and the other 4 had stable disease. The study drug was well tolerated without grade 2 or higher adverse events. Our findings suggest that BTKi therapy is not effective for iMCD, and further attempts at single-agent therapy with zanubrutinib or other BTKis for iMCD should be consideredwith caution and probably avoided. This trial was registered at www.clinialtrials.gov as #NCT04743687.

Response to Subsequent Novel Therapies and Time to Second Progression-Free Survival Event in the MURANO Trial in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Previously Treated with Fixed-Dose Venetoclax Plus Rituximab

Background: The randomized Phase III MURANO trial (NCT02005471) assessed fixed-duration treatment with venetoclax (Ven) plus rituximab (R) in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Despite improved clinical outcomes (progression-free survival [PFS], overall survival [OS] and time-to-next-treatment [TTNT], as well as minimal residual disease conversion and progressive disease [PD] association [Seymour et al. Blood 2022]) for pts randomized to VenR compared with bendamustine-R (BR), most pts will ultimately require subsequent therapies. However, the efficacy of subsequent treatment after relapse remains largely unexplored. This study was conducted prior to the widespread availability of other targeted therapies, so pts were not previously exposed to targeted therapies prior to MURANO treatment allocation. Here we report response rates to follow-up therapy with Ven-based regimens, or Bruton tyrosine kinase inhibitor (BTKi) therapy, as well as time to the second PFS events from the final analysis of the MURANO trial. Methods: Overall, 389 pts were randomized to VenR (2 years of Ven, with R for the first 6 months) or 6 months of BR. Pts in either arm with PD were followed for disease response to any subsequent anti-CLL therapeutic regimens, PFS and OS. A sub-study, introduced in 2018, allowed pts who developed PD following treatment with VenR or BR to receive the MURANO VenR regimen. Pts who initiated new anti-CLL therapy without a response assessment reported by the investigator, were considered unevaluable. Results : At the final clinical cutoff date of August 3, 2022, all pts had ceased study-specified treatment and the median follow-up of the main study was 85.7 (range: 0-99.2) months. PFS and OS benefits were maintained at the 7-year follow-up (Kater et al. EHA 2023). Overall, 73/194 (37.6%) pts in the VenR arm had not received a next-line therapy at the final cutoff, and 26 pts had died without subsequent therapy. Median TTNT or death with VenR was 63.0 months vs 24.0 months with BR (hazard ratio: 0.30). Following PD, 95/194 (49.0%) pts randomized to VenR and 131/195 (67.2%) pts randomized to BR had received subsequent anti-CLL therapy; the median (range) time off therapy in these pts was 28.3 months (-0.1-68.6) and 17.9 months (0.7-82.4), respectively. Of the 95 VenR pts receiving subsequent anti-CLL therapy, 30 (32.3%) received BTKi therapy (ibrutinib [n=25], acalabrutinib [n=4] and zanubrutinib [n=1]), with 18 ongoing at the time of the final cutoff; 47 (51.6%) received Ven-based therapy, with 12 ongoing at the time of the final cutoff; and 16 (17.2%) received chemoimmunotherapy (CIT). Two pts received a non-CLL therapy for another malignancy so were excluded from the subsequent analysis. Of the 131 BR pts receiving subsequent therapy, 79 (60.3%) received BTKi therapy (ibrutinib [n=69], acalabrutinib [n=6] and zanubrutinib [n=4]), with 20 ongoing at the time of the final cutoff; 17 (13.0%) received Ven-based therapy, with 3 ongoing at the time of the final cutoff; 24 (18.3%) received CIT; and 11 (8.4%) received other novel agents. Median time from randomization to second PFS event was 85.9 months (95% confidence interval [CI]: 81.8-88.2) in pts randomized to VenR and 48.4 months (95% CI: 44.5-56.6) in pts randomized to BR; p&amp;lt;0.0001 ( Figure). Best overall response (BOR; defined as complete remission [CR], CR with incomplete count recovery, partial remission [PR] and nodular PR) rates to first subsequent anti-CLL therapy for pts with evaluable responses were 75/93 (80.6%) for VenR and 85/107 (79.4%) for BR. Among evaluable pts previously treated with VenR and BR, the BOR rate to subsequent BTKi therapy was 19/22 (86.4%) and 51/65 (78.5%), respectively, while BOR rate to subsequent Ven-based therapies was 32/42 (76.2%) and 15/17 (88.2%), respectively. Conclusions: Final data from MURANO demonstrate that, despite the majority of BR pts receiving novel therapies after relapse on MURANO, there was a significantly prolonged time to second PFS event observed in favor of the VenR arm. Pts who had relapsed and received retreatment or crossed over to Ven-based regimens or subsequent BTKi therapy also demonstrated high response rates. These results indicate that early intervention with fixed-duration VenR in R/R CLL is an effective approach and does not compromise subsequent therapy response.

Incidence of Pneumonia Among Bruton Tyrosine Kinase Inhibitors in Chronic Lymphocytic Leukemia: A Systematic Review and Meta-Analysis of Clinical Trials

Introduction: Bruton tyrosine kinase (BTK) signaling is critical for the proliferation and survival of malignant B lymphocytes in chronic lymphocytic leukemia (CLL). BTK inhibitors (BTKi) are used in the front-line setting as well as for relapsed/refractory (R/R) CLL. Three BTKi are currently approved by the United States Food and Drug Administration (US FDA) for CLL - ibrutinib, acalabrutinib, and zanubrutinib. However, there are some uncertainties on the risk of infections, especially pneumonia, from BTKi due to its potential off-target effects and its immunomodulatory effects on innate and adaptive immune response. The newer second-generation BTKi, acalabrutinib and zanubrutinib, have attenuated off-target effects compared to ibrutinib. We hereby evaluate the incidence of pneumonia, including Pneumocystis jirovecii pneumonia (PJP) and other fungal pneumonia, from BTKi monotherapy in patients with treatment naïve as well as relapsed CLL and compare the incidence among different BTKi. Methods: This systematic review identified clinical trials from MEDLINE, Embase, and CENTRAL databases from the inception to 30 June 2023. The number of cases with any grade and at least grade 3 lung infection/pneumonia, PJP and other fungal pneumonia, along with the total number of patients in the arms with BTKi monotherapy were extracted from each trial per the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. The incidence meta-analysis was performed using “meta” package version 6.5-0 of R version 4.2.2, via random-effects model. Pooled incidence and its associated 95% confidence interval (CI) were reported for each outcome .I² statistic was used to determine the heterogeneity of the studies. Subgroup analyses by type of BTKi (ibrutinib, acalabrutinib, and zanubrutinib) and treatment history (treatment-naïve and R/R) were performed. Results: After two rounds of review, eighteen clinical trials containing twenty arms of BTKi monotherapy were eligible for the meta-analysis. Among these, four trials reported the incidences of PJP and three reported on fungal pneumonia. The pooled incidence of any grade pneumonia in patients with CLL on BTKi therapy was 0.13 (95% CI, 0.10-0.16, I2 = 80%) [Figure (Fig) 1a]. The pooled incidence of grade 3 or higher pneumonia was 0.08 (95% CI, 0.06-0.10, I2 = 68%) [Fig 1b]. There were no differences in the incidences of any grade (p = 0.61) or grade 3 and higher pneumonia (p = 0.30) among patients treated with ibrutinib, acalabrutinib, or zanubrutinib in the subgroup analyses [Fig 1c and 1d respectively]. However, the pooled incidences of any grade and grade 3 or higher pneumonia were greater in R/R CLL patients compared to those who were treatment-naïve (0.15 vs 0.07, p&amp;lt;0.01 and 0.10 vs 0.05, p = 0.04, respectively) [Fig 1e and 1f respectively]. The pooled incidences of PJP and other fungal pneumonia were 0.01 (95% CI, 0.00-0.02, I2 = 10%) and 0.01 (95% CI, 0.00-0.02, I2 = 0%), respectively. Conclusion: Our study showed no significant differences in the incidence of pneumonia of any grade or at least grade 3 among patients treated with newer second-generation BTKi vs first-generation BTKi. Risk of pneumonia should not be a factor to choose among BTKi. Of note, the incidence of pneumonia was higher in R/R CLL patients on BTKi therapy when compared to treatment naïve CLL. R/R CLL are likely to have increased infections due to complement dysfunction and progressive immunodeficiency (decreased IgG and IgA levels). Fungal pneumonia, including PJP, are uncommon in CLL, and the subgroup analyses were not able to distinguish any differences among different BTKi. PJP prophylaxis is still considered during BTKi therapy in treatment naïve and R/R CLL, but true risk vs benefit is unknown.

Impact of Real-World Treatment Sequencing Patterns on Time to Next Treatment among Patients with Chronic Lymphocytic Leukemia in the United States

Background: The treatment landscape for chronic lymphocytic leukemia (CLL) is evolving at a rapid pace, with development of several targeted therapies. The real-world applicability of clinical trial effectiveness is markedly influenced by treatment choices, the specific characteristics of patients' diseases, their overall health, and individual preferences. However, there is limited evidence to understand the impact of multiple treatment options on real-world effectiveness in CLL in routine clinical practice. This study aimed to characterize recent real-world treatment sequencing patterns and associated time to next treatment among patients with CLL in the United States. Methods: This retrospective observational study included patients diagnosed with CLL (≥18 years at diagnosis) from January 1, 2018, through January 1, 2023, who received ≥1 treatment after initial diagnosis. Patients were sourced from the ConcertAI RWD360 dataset, a real-world de-identified dataset &amp;gt;6 million patients from across the United States derived from various electronic health record systems and integrated with a large administrative open claims dataset. Patients were followed through the end of the record or death, whichever occurred first. Patients were classified into the following treatment categories: chemotherapy (including bendamustine-based and other chemotherapy), anti-CD20-based, Bruton tyrosine kinase inhibitor (BTKi)-based (ibrutinib, acalabrutinib, or zanubrutinib), and venetoclax-based therapy. Demographic and clinical characteristics, treatment sequencing pattern, and time to next treatment were examined across lines of therapy for each treatment category. Kaplan-Meier analysis was used to estimate median time to next treatment. Results: The study included 3,431 patients with CLL (median age: 69 years; male: 63.8%). There was a significant variation in average age among the 4 treatment groups ( P&amp;lt;0.0001). Compared with the overall population, patients who received anti-CD20-based therapy were slightly older (median age: 71 years), while patients who received venetoclax-based therapy were relatively younger (median age: 67 years). Patients were primarily treated in community rather than academic settings (76.4% vs 21.3%). First-line patients were most commonly treated with BTKi (60.1%), venetoclax (16.0%), and anti-CD20 (15.4%) regimens. Among patients who initiated BTKi therapies, zanubrutinib use (2.6%) was limited; this may be due to the recent approval date (January 2023). Among CLL patients, 35.0% received second-line treatment and BTKi stayed dominant (35.7%), followed by anti-CD20 (29.6%) and venetoclax (25.8%) therapies. From first- to second-line therapy, the prevailing sequencing pattern was from either one BTKi to another BTKi (23.5%), venetoclax to anti-CD20 (13.2%), or BTKi to an anti-CD20 (9.7%). From second- to third-line therapy, patients most frequently switched from anti-CD20 to venetoclax (24.6%), anti-CD20 to BTKi (13.3%), or one BTKi to another BTKi (12.6%). From third- to fourth-line therapy, the predominant sequencing pattern was from venetoclax to anti-CD20 (21.3%), anti-CD20 back to venetoclax (20.6%), or one BTKi to another BTKi (11.6%). Median time to next treatment in first line was significantly longest for patients receiving BTKi (53.9 months) and shortest for patients treated with venetoclax (7.7 months) ( P&amp;lt;0.0001) (Figure 1). Median time to next treatment in second line was not reached among patients using BTKi, while it was significantly shorter for those on venetoclax and anti-CD20 (10.4 months and 1.5 months, respectively; P&amp;lt;0.0001) (Figure 2). Conclusions: This studydemonstrated unique treatment sequencing patterns among patients with CLL in the real-world setting.As the most commonly used regimen, BTKi therapy was shown to have significantly improved time to next treatment compared with other treatment regimens in first and second lines of therapies. Future studies with extended follow-up are needed to allow for assessment of newer treatments and enable evaluation of long-term clinical outcomes.

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.

Real-World Switching Pattern, Persistence, and Associated Healthcare Resource Utilization of Bruton Tyrosine Kinase Inhibitors for the Treatment of Mantle Cell Lymphoma in the United States

Introduction: Mantle cell lymphoma (MCL) is an aggressive form of B-cell non-Hodgkin's lymphoma. While incurable, MCL can be controlled for a prolonged period of time, but typically becomes refractory or relapsed and requires additional treatment. Bruton tyrosine kinase inhibitors (BTKi) are approved for relapse/refractory MCL and recommended by the National Comprehensive Cancer Network (NCCN ®); However, it is unclear how BTKi are being utilized and switched in the real-world patient populations. This study aimed to examine treatment patterns, persistence, and associated healthcare resource utilization of BTKi use in patients with MCL in the US. Methods: A retrospective observational study was conducted using Symphony Integrated Dataverse (IDV ®), a comprehensive, longitudinal, open-claims database and integrated Electronic Medical Record (EMR) data. Patients aged ≥18 years with ≥1 diagnosis for MCL and initiated a BTKi between 1/1/20 and 12/31/22 were included in the study. Patients were required to be continuously enrolled for 365 days leading up to the index date and ≥90 days following the index date (date of BTKi initiation). The full patient history in the database was used to identify previous BTKi use and analyze switching patterns for each patient. Three mutually exclusive cohorts (ibrutinib, acalabrutinib, zanubrutinib) were developed based on first-initiated BTKi. Patients were followed until the end of the study period (3/31/23) or lost to follow-up. Treatment switching pattern, duration, persistence, time to discontinuation (TTD), and healthcare resource utilization (HCRU) were examined by each BTKi cohort. Treatment duration was defined as time from BTKi initiation to the end date of last BTKi prescription. TTD was defined as time from BTKi initiation to the end date of the BTKi prescription that had a gap of &amp;gt;60 days with a subsequent BTKi prescription. Treatment persistence was evaluated as the proportion of patients that were continually prescribed BTKi (≥80% proportion of days covered) across 30-day intervals. HCRU was measured by number of outpatient visits and inpatient services, per patient per month (PPPM), during the treatment regimen. Results: BTKi switching patterns were analyzed for the 1,674 patients that initiated any BTKi therapy during study period (acalabrutinib [n= 697]; ibrutinib [n=693]; zanubrutinib [n=284]). Switching rates were 23.8% for ibrutinib, 5.6% for acalabrutinib, and 2.8% for the zanubrutinib cohort. In the ibrutinib cohort, the majority of patients switched to acalabrutinib (72.7%). Of those who switched from acalabrutinib, more than half (59.9%) switched to zanubrutinib. Of those who switched in zanubrutinib cohort, they were equally switched to ibrutinib and acalabrutinib (Table 1). Mean outpatient visits PPPM were 1.39 for patients who initiated with ibrutinib then switched to zanubrutinib, and 1.49 for those who switched to acalabrutinib. Mean inpatient services PPPM were 0.39 for patients who switched from ibrutinib to zanubrutinib, and 0.59 for those who switched to acalabrutinib. The 3 BTKi cohorts were similar across sociodemographic characteristics. The zanubrutinib cohort had higher median TTD (days) (188.5) compared to ibrutinib (161.5) and acalabrutinib (179), as well as higher median treatment duration (200) compared to ibrutinib (171) and acalabrutinib (194). Among MCL patients continuously enrolled for ≥ 360 days, zanubrutinib patients consistently had higher persistence rates (p=0.0079. Figure 1). Persistence at 90-days was 66.9% for zanubrutinib compared to 56.3% for ibrutinib and 62.7% for acalabrutinib. After 360 days, zanubrutinib continued to have the highest persistence (16.9%) compared to ibrutinib (10.8%) or acalabrutinib (13.2%). Zanubrutinib had the least number of mean inpatient services PPPM (0.56) compared to ibrutinib (0.83) and acalabrutinib (0.71) and mean outpatient visits-zanubrutinib (1.53), ibrutinib (1.81), acalabrutinib (1.59). Conclusions: This real-world study suggested that US patients with MCL receiving zanubrutinib showed longer treatment persistence, treatment duration and TTD, as well as lower switching rates and HCRU compared to those receiving acalabrutinib and ibrutinib.

A CD5 Gene Signature Identifies Diffuse Large B-Cell Lymphomas Sensitive to Brutonʼs Tyrosine Kinase Inhibition

Introduction: Diffuse large B-cell lymphomas (DLBCLs) with a non-germinal center B cell-like (non-GCB) cell-of-origin are frequently driven by genetic alterations that culminate in constitutive B-cell receptor (BCR) signaling, which has inspired the exploration of Bruton's tyrosine kinase inhibitors (BTKi) in these lymphomas. However, the phase III PHOENIX study that randomized untreated, non-GCB DLBCL patients to R-CHOP plus placebo or ibrutinib failed to meet its primary endpoint of event-free survival (Younes et al. 2019), which suggests that cell-of-origin alone is an insufficient biomarker to predict BTKi sensitivity in DLBCL. More recently, a DLBCL genetic classifier termed LymphGen has identified distinct subtypes (MCD and N1) of non-GCB DLBCL that benefit from the addition of BTKi to R-CHOP (Wilson et al. 2021). However, genetic classifiers are complex and difficult to implement in routine clinical settings and may fail to capture all DLBCLs that benefit from BTKi. Therefore, we sought to identify a straightforward biomarker of BTKi responsiveness in DLBCL with greater precision than cell-of-origin but with broader inclusivity than current genomic platforms, such as LymphGen. We hypothesized that CD5 - a surrogate marker of BCR activation - may effectively identify BCR-driven, non-GCB DLBCLs that are sensitive to BTKi therapy, and evaluated the extent to which CD5 protein expression and a transcriptionally defined CD5 gene signature could accurately identify BCR-activated DLBCLs with potential susceptibility to BTKi-based therapies. Methods: CD5 immunohistochemistry (IHC) was performed on a cohort of 406 diagnostic DLBCL samples, which were considered CD5+ if &amp;gt;=30% of lymphoma cells exhibited unequivocal membranous staining. A majority of DLBCL samples had available RNA-sequencing and targeted mutational sequencing data. A comparison of differentially expressed genes between CD5+ and CD5- DLBCLs was performed in order to construct a 60-gene CD5 signature (CD5sig), which was applied to large genomic DLBCL datasets, including pre-treatment biopsies from patients enrolled on PHOENIX (n = 584) to evaluate the utility of the CD5sig in identifying DLBCLs that benefitted from the addition of ibrutinib to R-CHOP. Results: Twenty-six of 406 DLBCLs were identified as CD5+ by IHC (6% of all DLBCLs; 12% of non-GCB DLBCLs). CD5 IHC+ DLBCLs were majority non-GCB cell-of-origin and were associated with inferior progression-free survival (PFS) to R-CHOP (50% 3-year PFS), compared with CD5 IHC- DLBCLs, consistent with previous reports. Gene set enrichment analysis revealed that CD5 IHC+ DLBCLs exhibited transcriptional features of BCR activation, and mutational analysis demonstrated that CD5 IHC+ DLBCLs were enriched for CD79B BCR-activating mutations known to correlate with BTKi sensitivity. Many CD5 IHC+ DLBCLs, however, lacked canonical BCR-activating mutations or were classified as “Other” by LymphGen. A CD5 gene signature (CD5sig; Figure 1A) was developed that recapitulated these findings in independent DLBCL datasets (NCI, Duke), where ~13% of non-GCB DLBCLs were classified as CD5sig+. Together, these results suggest that CD5 signature expression captures DLBCLs with both a genetic and non-genetic basis for BCR dependence. Supporting this notion, CD5sig+ DLBCL patients (&amp;lt; 60 years) derived a selective and striking event-free and overall survival advantage from the addition of ibrutinib to R-CHOP in the PHOENIX study ( Figure 1B), independent of LymphGen classification. Conclusions: We demonstrate that CD5 IHC and a novel CD5 gene signature identify high-risk, BCR-driven DLBCLs. Importantly, the CD5 signature also identifies DLBCL patients with a selective survival advantage to BTK inhibitor-based therapy, independent of LymphGen classification. In conclusion, the CD5 signature expands upon LymphGen classification as a biomarker of BTKi response by accurately identifying DLBCLs with both genetic and non-genetic bases for BTKi response. The CD5 signature and/or CD5 IHC should be prospectively evaluated in BTKi-based clinical trials for non-GCB DLBCLs.

A Single Center Real World Study of Outcome and Resistance of Bruton Tyrosine Kinase Inhibitors (BTKi) in Chinese Patients with Chronic Lymphocytic Leukeima/Small Lymphocytic Lymphoma

Introduction Acquired BTK/PLCG2 mutations remain to be the driver of Bruton Tyrosine Kinase inhibitor (BTKi) resistance. But the underlying mechanisms need to be further explored. In this study, we retrospectively analyzed clinical and biological characteristics of BTKi-treated CLL patients and report the outcome and resistance in our center (the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital). Method 262 patients treated with single BTKis continuously were collected and follow up the outcome in our center. Progression-free survival (PFS) was defined as from BTKi initiation to disease progression on BTKi. Next-generation sequencing (NGS) and High sensitivity droplet digital PCR (ddPCR) acquired at treatment initiation /or at the time of disease progression were used to describe mutational landscape. Kaplan-Meier method and the log-rank test were used for analysis. Results A total of 262 patients were enrolled from January 2014 to March 2023, and the median age was 63 (range 28-88) years. Ibrutinib, Zanubrutinib, Orelabrutinib were administered in 55.3%,18.3% and 17.9% of patients respectively, in addition to 6 patients with Acalabrutinib and one with Loxo-305, among them 47.7% (125/262) received BTKi as first line treatment. With a median follow up of 27.3 months, 208 patients were in durable remission while 54 patients relapsed, the median exposure of BTKi was 26.8 (range, 1-73.8) sand 27.7 (range, 3-69.8) months respectively. The median PFS was 5.8 years (5.0-NA, 95% CI) for the whole cohort. Clinical and biological characteristics of both cohorts at initiation of BTKi treatment were described and compared in Table 1. Higher proportion of bulky disease (50.0% vs 23.5%), IGHV unmutated status (84.3% vs 50.5%), del(17p) (44.7% vs 12.9%), TP53 mutation (37.8% vs 15.2%), TP53 aberrations (62.5% vs 24.3%) and complex karyotype (40.5% vs 21.1%) were shown in the BTKi relapsed cohort as compared to responsive cohort. Inferior PFS was observed in patients with TP53 aberration vs without TP53 aberration ( 45.6 mos vs not reached, p&amp;lt;0.0001), unmutated IGHV vs mutated IGHV (56.2 mos vs not reached, p=0.0005), with del(17p) vs without del(17p) (36.1 mos vs not reached, p&amp;lt;0.0001), with complex karyotype and without complex karyotype (69.8 mos vs not reached, p=0.0401), bulky disease vs no bulky disease (45.6 mos vs 69.8 mos, p=0.0006) and elevated LDH vs normal LDH (66.5 mos vs not reached, p=0.0083). Moreover, patients with del(11q) or BTKi given as second or greater line showed a tendency of inferior PFS ( p= 0.1963, p= 0.0735, respectively). Regarding the relapsed cohort, 43 patients displayed CLL progression while 11 patients displayed Richter transformation (RT, including 1 Hodgkin lymphoma [HL]) , the median time from initiation to progression were 33.7 months and 9.5 months, respectively（p&amp;lt;0.0001). BTK/PLCG2 mutations were the most common mutation at the timepoint of disease progression. By integrating NGS and ddPCR results, 54.9% (28/51) relapsed patients acquired BTK/PLCG2 mutation. BTKC481S mutation was the dominant hotspot mutation in all kinds of BTKi relapsed cases. Other mutations at the C481 site included C481R, C481Y, C481F. However, BTKT474 mutation was only detected in Orelabrutinib-resistant cases (Figure 1). 6 patients presented with multi-hit mutations. Treatment after disease progression on BTKis is still challenging. In our relapsed cohort, the median PFS was 5.7 months and poorer in RT as compared with CLL progression (3.0 months vs 6.7 months, p= 0.0874). Venetoclax-based regimen might be an effective salvage therapy which could showed a benefit trend in PFS as compared to other post BTKi therapy (10.1 months vs 3.1 months, p= 0.1818). Conclusion In our real world study, patients with IGHV unmutated status, TP53 aberrations, bulky disease and elevated LDH showed inferior PFS. Acquired BTK/PLCG2 mutations remained to be key drivers of BTKis resistance and BTKC481S mutation was the dominant mutation, while BTKT474 mutation was only detected in Orelabrutinib-resistant patients. The prognosis was rather poor for relapsed patients especially for RTs, treatment strategy after disease progression remains to be optimized.

Real-World Outcomes Among 2L+ Patients with Chronic Lymphocytic Leukemia (CLL) By Line of Therapy (LOT)

Introduction: The chronic lymphocytic leukemia (CLL) treatment landscape is rapidly evolving, and real-world (rw) outcomes of patients receiving 2L+ therapy in the current treatment paradigm are incompletely understood. This study examined the rw outcomes of patients with CLL/ small lymphocytic lymphoma (SLL) receiving 2 or more lines of therapy (LOTs) using a large, contemporary rw dataset. Methods: Patients meeting the study criteria were identified in the COTA real-world, clinical database: Aged ≥ 18 years at diagnosis with CLL/SLL who initiated 2L therapy between January 1, 2014 and June 30, 2021. The initial index date for the study was the date of 2L initiation and was updated to the start of each subsequent LOT for LOT-specific analyses. The following time to event outcomes were evaluated for the study population and by LOT using the Kaplan-Meier method: time to next treatment (TTNT: time from index to the initiation of the next LOT or death), time to treatment discontinuation (TTD: time from index to treatment discontinuation for any reason, including end of therapy as prescribed/indicated), rw duration of response (rwDOR: time from the first clinician-documented CR or PR to the first assessment of progressive disease or the initiation of next LOT among responders), rw progression-free survival (rwPFS), and rw overall survival (rwOS). For all time-to-event endpoints, patients were censored at the date of last visit. Rw overall response rate (rwORR) was the proportion of patients who had a clinician-documented PR or CR as the best response to a LOT among all patients who received that LOT. Results: A population of 1,102 patients was identified from the COTA database meeting the study criteria. Key patient and clinical characteristics included: median age at diagnosis of 64 years, 60.9% male, 88.1% treated in a community setting, 74.1% diagnosed in 2014 or earlier, 9.3% positive for TP53 mutation (55.0% unknown), and 7.8% with del(17p) mutation (66.2% unknown). Median TTNT among patients who received 2L (n=1102) was 29.3 months (95% CI: 27.3, 32.6), and median DOR to 2L (n=863) was 31.9 months (95% CI: 27.5, 36.4). Generally, median TTNT and DOR decreased across LOT 2-4. Median TTNT from 3L (n=468) and 4L (n=201) initiation were 21.4 (95% CI: 18.2, 25.1) and 15.1 months (95% CI: 11.5, 20.2), respectively, and median DOR among 3L (n=333) and 4L (n=130) responders were 22.6 (95% CI: 18.3, 26.2) and 15.1 months (95% CI: 11.7, 22.9), respectively. More than three-quarters (78.3%) of 2L patients experienced a physician-documented CR or PR, and rwORR decreased over subsequent LOTs (71.2% in 3L and 64.7% in 4L). Median TTD varied by treatment type. Patients who received continuous therapy with Bruton's Tyrosine Kinase inhibitors (BTKis) experienced longer median TTD, while patients who received fixed-duration therapies experienced shorter median TTD. Median TTD among patients who received ibrutinib (n=391), acalabrutinib (n=54), or venetoclax + rituximab (n=48) in 2L was 24.8, 32.6, or 23.5 months, respectively, while median TTD among patients who received BR (n=194) or rituximab monotherapy (n=67) was 4.0 or 0.9 months, respectively. Finally, median rwPFS and rwOS decreased by LOT for patients who received 2L-4L. Median rwPFS for 2L, 3L, and 4L were 31.4 (95% CI: 28.6, 35.5), 22.8 (95% CI: 19.1, 26.4), and 16.5 (95% CI: 13.6, 22.6) months, respectively, and median rwOS were 79.0 (95% CI: 68.9, 85.3), 56.3 (95% CI: 51.6, 64.5), and 51.9 months (95% CI: 33.8, Not Reached), respectively. Conclusions: In this real-world, contemporary database analysis, median TTNT and DOR exceeded 2 years among 2L patients. Although the adoption of novel therapies has changed the CLL/SLL treatment paradigm and patients who received 2L BTKi therapy experienced numerically greater TTD relative to those who received other treatment types, patients with relapsed/refractory (R/R) disease continue to experience poor rwPFS and rwOS relative to patients in clinical trials. This study demonstrates the continued unmet need for this rw patient population and highlights the need for continued innovation, namely new therapeutic agents leveraging novel mechanisms of action, to improve rw outcomes for patients with R/R CLL/SLL.