Pirtobrutinib 100mg tablets

AbstractThe epidemiology of invasive fungal infections (IFIs) among patients receiving Bruton tyrosine kinase inhibitors (BTKIs) remains incompletely characterized. We conducted a systematic review and meta-analysis of 88 studies including 23 737 patients to evaluate the prevalence and risk factors for IFIs in this population. Among 16 studies that applied the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium consensus definitions of IFIs, the pooled prevalence of proven/probable IFIs was 2.83% (95% confidence interval [CI], 1.97-4.06), with the highest prevalence observed in patients with central nervous system lymphoma (9.02%). Aspergillosis was the most frequently reported IFI (1.76%), followed by pneumocystosis, candidiasis, and cryptococcosis. The risk factors significantly associated with proven/probable IFIs were concurrent corticosteroid use (odds ratio [OR], 5.03; 95% CI, 2.31-10.92) and ≥3 previous lines of therapy (OR, 3.26; 95% CI, 1.54-6.88). Across clinical trials, the prevalence of fungal infections varied across BTKI agents, ranging from 2.50% with tirabrutinib, to 0.62% with pirtobrutinib. Data on antifungal and Pneumocystis jirovecii pneumonia prophylaxis were limited and inconclusive. Among clinical trials that reported fungal infections as adverse events, the prevalence of IFI was the highest in patients treated with tirabrutinib (2.50%), followed by zanubrutinib (2.13%), ibrutinib (1.75%), acalabrutinib (1.31%), orelabrutinib (1.08%), and pirtobrutinib (0.62%). Although some findings suggest a potential benefit in selected patients, current evidence remains insufficient to support broad prophylaxis recommendations. These results underscore the need for individualized risk assessment and further research to inform prevention strategies.

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BackgroundRichter's transformation (RT) is an aggressive progression of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), most commonly to diffuse large B-cell lymphoma (DLBCL). Therapeutic options are limited, and outcomes are poor, particularly in relapsed or refractory cases. Bruton's tyrosine kinase (BTK) inhibitors have transformed the treatment landscape of CLL, but their role in RT is less well defined.MethodsWe conducted a systematic review in accordance with PRISMA guidelines to evaluate the efficacy and safety of BTK inhibitor-based therapies in patients with RT. PubMed, EMBASE, and ClinicalTrials.gov were searched through January 1, 2025. Clinical trials reporting outcomes such as overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) in RT patients treated with BTK inhibitors were included.ResultsSeven studies (six clinical trials and one case series) comprising 220 patients were included. Monotherapy with pirtobrutinib and acalabrutinib showed ORRs of 50% and 40%, respectively. Combination regimens such as zanubrutinib plus tislelizumab and ibrutinib plus nivolumab demonstrated ORRs ranging from 41.6% to 65%, with improved outcomes in treatment-naïve patients. Safety profiles were generally manageable, though grade ≥3 AEs, particularly cytopenias and infections, were common. Risk of bias was moderate to serious across studies due to non-randomized designs and small sample sizes.ConclusionBTK inhibitor-based therapies show promising efficacy in patients with RT, particularly in combination with immunotherapeutic agents. While monotherapy may offer a tolerable option for frail patients, combination regimens may improve outcomes in select populations. Larger, randomized controlled trials are needed to better define the role of BTK inhibition in this high-risk disease.

Abstract licence: CC BY

PurposeBRUIN CLL-313 is a randomized, open-label, global phase III study comparing the efficacy and safety of pirtobrutinib, a highly selective, noncovalent Bruton tyrosine kinase inhibitor (BTKi), against bendamustine plus rituximab (BendaR), a common frontline chemoimmunotherapy, in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).MethodsPatients with previously untreated CLL/SLL without del(17p) were randomly assigned 1:1 to continuous pirtobrutinib monotherapy or BendaR, stratified by immunoglobulin heavy chain gene mutation status and Rai stage. The primary end point was independent review committee (IRC)-assessed progression-free survival (PFS); secondary end points included overall survival (OS), investigator (INV)-assessed PFS, safety, and tolerability.ResultsOverall, 282 patients were randomly assigned to receive pirtobrutinib (n = 141) or BendaR (n = 141). IRC-assessed PFS was significantly improved with pirtobrutinib versus BendaR (hazard ratio [HR], 0.199 [95% CI, 0.107 to 0.367]; P ConclusionPirtobrutinib demonstrated superiority over BendaR in IRC-assessed PFS in treatment-naïve CLL/SLL. OS trends favored pirtobrutinib despite the study design allowing for crossover. Pirtobrutinib was well tolerated, consistent with its known safety profile, and more favorable than BendaR.

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Background: Pirtobrutinib has recently emerged as a promising first-line treatment option for chronic lymphocytic leukemia (CLL). Unlike currently established regimens, which are generally based on doublet combinations, pirtobrutinib can be administered as monotherapy. Because no head-to-head trials comparing pirtobrutinib with contemporary first-line combinations are currently available, indirect comparative evidence may help define its potential role. Methods: A non-anchored indirect comparison based on reconstructed individual patient data (IPD) was conducted using published Kaplan-Meier curves from randomized controlled trials evaluating first-line treatments for CLL. Progression-free survival (PFS) was the endpoint of interest. Reconstructed IPD were generated using WebPlotDigitizer and the IPDfromKM algorithm. Pirtobrutinib monotherapy was compared indirectly with acalabrutinib plus obinutuzumab, venetoclax plus obinutuzumab, and venetoclax plus ibrutinib. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using univariate Cox models. Results: The analysis included four randomized trials. Compared with pirtobrutinib monotherapy, HRs for PFS were 0.5544 (95%CI, 0.2696-1.1397) versus venetoclax plus obinutuzumab, 0.4583 (95%CI, 0.2066-1.0200) versus venetoclax plus ibrutinib, and 1.4453 (95%CI, 0.6684-3.1240) versus acalabrutinib plus obinutuzumab. Confidence intervals were wide and crossed unity in all comparisons, indicating substantial statistical uncertainty. Visual inspection of reconstructed Kaplan-Meier curves did not suggest inferior PFS for pirtobrutinib relative to established doublet regimens. Conclusions: This exploratory non-anchored analysis suggests that pirtobrutinib monotherapy may provide PFS outcomes broadly comparable to current first-line combination regimens for CLL. Given the methodological limitations inherent to indirect comparisons, prospective head-to-head studies are needed to clarify the optimal positioning of pirtobrutinib in treatment-naïve CLL.

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