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Abstract Background Pirtobrutinib is a highly selective, non-covalent Bruton tyrosine kinase inhibitor (BTKi) approved for patients (pts) with relapsed/refractory (R/R) chronic lymphocytic lymphoma (CLL) who have previously received a covalent BTKi (cBTKi) and a BCL-2 inhibitor such as venetoclax. Pirtobrutinib monotherapy has demonstrated a median duration of response of 12.2 months in the BRUIN trial. Pirtobrutinib is increasingly being used as a second-line therapy after failure of a cBTK inhibitor without prior BCL-2 inhibitor exposure. We aim to characterize short-term survival outcomes and adverse events of pirtobrutinib in venetoclax-naïve versus venetoclax-exposed pts with R/R CLL. Methods We conducted a retrospective cohort study using TriNetX Global Collaborative Network, comprising data from 152 healthcare organizations. Adults (≥18 years) with R/R CLL who received pirtobrutinib after venetoclax were classified into the “V+P” cohort. Pts who received pirtobrutinib without prior venetoclax exposure were included in the “P” cohort. 1:1 propensity score matching (PSM) was performed, and the cohorts were balanced for gender and age. The primary outcome was all-cause mortality (ACM). Secondary outcomes assessed were anemia, neutropenia, sepsis, neutropenic fever, tumor lysis syndrome (TLS), and major adverse cardiovascular and cerebrovascular events (MACCE). Kaplan-Meier analysis and risk analysis were used to assess outcomes at 6 months and 1 year. Results We identified 200 pts in V+P and 172 pts in P, with 149 matched pts in each group after PSM. The mean age of pts in V+P and P was 72.4 +/- 8.6 years and 72.7 +/- 10.5 years, respectively. 6-month ACM was 15.5% in V+P, and 12.7% in P. However, the odds ratio of ACM at 6 months, in pts in V+P when compared to P was 1.259 (95% CI 0.654 to 2.425, p = 0.490) and was not statistically significant. At 6 months, the odds ratios of the secondary outcomes in the V+P pts were higher when compared to P pts, but were not statistically significant; anemia 1.614 (95% CI 0.617 to 4.225, p = 0.327), neutropenia 1.445 (95% CI 0.599 to 3.486, p = 0.411), sepsis 1.196 (95% CI 0.477 to 2.998, p = 0.703), neutropenic fever 1.353 (95% CI 0.573 to 3.195, p = 0.490), TLS 1.180 (95% CI 0.474 to 2.939, p = 0.722), and MACCE 1.046 (95% CI 0.541 to 2.024, p = 0.893). 1 year ACM was 18.75% in V+P vs. 10.55% in P (OR 1.96; 95% CI 1.03-3.71; p=0.038) and was statistically significant. However, the secondary outcomes were clinically significant but statistically insignificant in V+P pts when compared to P pts- anemia 1.614 (95% CI 0.617 to 4.225, p = 0.327), neutropenia 1.269 (95% CI 0.568 to 2.834, p = 0.561), sepsis 1.077 (95% CI 0.438 to 2.650, p = 0.872), neutropenic fever 1.24 (95% CI 0.589 to 2.607, p = 0.571), TLS 1.180 (95% CI 0.474 to 2.939, p = 0.722), and MACCE 1.338 (95% CI 0.724 to 2.472, p = 0.352). Conclusion Pirtobrutinib use in venetoclax-exposed pts was associated with a statistically significant higher odds of all-cause mortality at 1 year, which was not present at 6 months. Although adverse event rates of anemia, neutropenia, TLS, sepsis, and neutropenic fever were numerically higher in the venetoclax-exposed cohort, these differences did not reach statistical significance. These findings suggest early survival benefit of pirtobrutinib in venetoclax-naïve patients and aligns with existing evidence supporting its role as a second-line therapy following covalent BTK inhibitor failure, including results from the BRUIN trial. Prospective studies are needed to validate these preliminary observations.

Abstract Background In patients with myelofibrosis (MF) undergoing allogeneic hematopoietic cell transplantation (allo-HCT), graft-versus-host disease (GVHD) prophylaxis has traditionally included a calcineurin inhibitor (CNI) plus methotrexate (MTX). We conducted a retrospective study comparing the safety and efficacy of post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis to CNI-based regimens. Methods This study was approved by the Mayo Clinic IRB. Patients with myelofibrosis who underwent allo-HCT after 2016 at Mayo Clinic in Arizona and Florida were included. Categorical variables were compared using Chi-square or Fisher's exact tests. Overall survival (OS) was defined from transplant to death, and progression-free survival (PFS) from transplant to relapse or death. OS and PFS were estimated using Kaplan-Meier methods; univariate differences were assessed with log-rank tests. The cumulative incidence of acute and chronic GVHD and time to neutrophil and platelet engraftment were analyzed using competing risk models, with death as a competing event; differences were tested using Gray's test. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs). Results A total of 110 patients were included. 53 patients received PTCy-based prophylaxis (43 PTCy/Tac/MMF, 1 PTCy/CSA/MMF, 9 PTCy/Siro/MMF), while 57 received non-PTCy regimens (54 Tac/MTX +/- 39 T-cell depletion, 2 CSA/MMF, 1 Tac/MMF). Median age at transplant was 63 (range: PTCy 40-76; others 38-74) years in both groups; 59 were male (58.5% PTCy vs 49.1% others). Median Karnofsky Performance Status (KPS) and HCT–Comorbidity Index (HCT-CI) in patients receiving PTCy vs non-PTCy were 90 vs 80 and 1 vs 3, respectively. Conditioning intensity was similar: 22.6% myeloablative vs 21.7%, and 77.4% reduced-intensity vs 76.7% in PTCy and non-PTCy, respectively (p=1.000). Stem cell source was peripheral blood in all patients except one in the non-PTCy group who received bone marrow. 58 patients had primary MF (54.7% PTCy vs 50.9% others), and 52 had secondary MF (45.3% PTCy vs 49.1% others), including essential thrombocythemia (28.3% PTCy vs 31.6% others), polycythemia vera (17.0% vs 15.8%), and MPN-NOS (0% vs 1.8%). Median follow-up was 26.2 months (95% CI: 20.7-52.7) in the PTCy and 60.6 months (95% CI: 53.1-70.6) in the non-PTCy cohort. CD3 and CD33 donor chimerism ≥95% at day +100 was 66.7% and 86.7% in PTCy vs 63.6% and 92.7% in others, respectively (p=0.50); day +100 driver molecular mutations were present in 32.1% of PTCy and 32.0% of others (p>0.99). Rates of acute GVHD grades ≥2 and ≥3 were not statistically significant, in the PTCy group (37.7% vs 49.1% p=0.229 and 17.0% vs 22.8% p=0.445, respectively). Chronic GVHD (any grade) occurred in 42.3% of PTCy vs 38.2% of others (p=0.664), while moderate-to-severe cGVHD was lower with PTCy (21.2% vs 27.3% p=0.461). Platelet engraftment was significantly delayed in the PTCy group (median 33 vs 21 days, p=0.030). Median time to neutrophil engraftment was also delayed in the PTCy group (20 vs 17 days, adjusted p=0.025). Age-adjusted HR for time to platelet engraftment was 0.60 (95% CI: 0.41–0.90; p=0.014), and for neutrophil engraftment 0.65 (95% CI: 0.44–0.95; p=0.025), indicating significantly delayed hematopoietic recovery with PTCy. Graft failure occurred in 9.4% vs 5.3% (p = 0.48); primary 7.5% vs 3.5%, secondary 1.9% vs 1.8% in PTCy vs non-PTCy groups, respectively. Relapse or progression occurred in 11.3% of PTCy vs 17.5% of others (p=0.355); four patients in the non-PTCy group progressed to AML post-transplant, versus none in the PTCy group (p=0.119). 1-year TRM was 22.6% in the PTCy group and 14.0% in the non-PTCy group, p = 0.324. Median OS was 72.8 months in the PTCy group (95% CI: 49.9 months, upper limit not estimable [NE]) and 93.4 months in the non-PTCy group (95% CI: 48.5 months, upper limit NE), although the difference was not statistically significant (p=0.739). After adjusting for age and HCT-CI, there were no significant differences in PFS (adjusted HR 1.37; 95% CI: 0.73–2.56; p=0.331) or OS (adjusted HR 1.27; 95% CI: 0.64–2.51; p=0.498). Conclusions In myelofibrosis patients undergoing allo-HCT, PTCy-based GVHD prophylaxis showed similar rates of grade ≥2 acute and moderate-severe chronic GVHD compared to non-PTCy regimens. Engraftment was significantly delayed, while OS and PFS were comparable. PTCy appears to be a safe and viable alternative to CNI-based prophylaxis.