ABSTRACT Pirtobrutinib, a highly selective, non‐covalent Bruton tyrosine kinase inhibitor (BTKi) previously demonstrated durable efficacy and tolerable safety following covalent (c) BTKi therapy in heavily pretreated relapsed/refractory (R/R) mantle cell lymphoma (MCL). Here, we report final results from the global Phase 1/2 BRUIN trial evaluating pirtobrutinib in patients with R/R MCL, with and without prior cBTKi exposure. Endpoints included overall response rate (ORR), duration of response (DOR), progression‐free survival (PFS), overall survival (OS), and safety. BRUIN enrolled 166 patients with R/R MCL (data cutoff: 27Jan2025). In the cBTKi‐exposed cohort ( n = 152), median study follow‐up time was 16.1 months (range, 0.5–69.6). The ORR was 49.3% (95% CI, 41.1–57.6). Median DOR was 21.6 months (95% CI, 9.2–27.2). Median PFS was 5.6 months (95% CI, 5.3–9.2; 36‐month rate, 19.9%). Median OS was 23.9 months (95% CI, 17.3–51.5; 36‐month rate, 43.2%). In the cBTKi‐naïve cohort ( n = 14), median study follow‐up time was 44.5 months (range, 1.6–67.1). The ORR was 85.7% (95% CI, 57.2–98.2). Median DOR was 42.7 months (95% CI, 25.8–not estimable [NE]). Median PFS was 44.6 months (95% CI, 16.7–NE; 36‐month rate, 58.7%). Median OS was NE (36‐month rate, 76.2%). The most frequent any‐grade treatment‐emergent adverse events (TEAEs) were infections (44.0%), fatigue (31.9%), and diarrhea (22.9%); the most frequent grade ≥ 3 TEAEs were infections (21.1%) and neutropenia (15.1%). Grade ≥ 3 hemorrhage (3.0%) and any‐grade atrial fibrillation/flutter (3.6%) were infrequent. With extended follow‐up, pirtobrutinib continued to demonstrate efficacy and favorable safety in cBTKi‐exposed and ‐naïve R/R MCL. Trial Registration: ClinicalTrials.gov identifier: NCT03740529
ABSTRACT Background Follicular lymphoma (FL) is the most common indolent lymphoma and has widely variable disease trajectories. While patients with a durable response to initial therapy have expected survival comparable to the general population, patients with early or recurrent relapses, or with transformation to large cell lymphoma, are at serious risk of lymphoma‐associated death. Summary This review discusses the biological and clinical characteristics of FL as well as diagnostic assessment, prognostic tools, and treatment options. Conclusion Targeted therapies, bispecific antibodies, and CAR‐T cell therapies offer exciting new options for historically difficult‐to‐treat disease. Sequencing of novel therapies and their use earlier in treatment are areas of ongoing investigation. Recent data suggest FL may be cured in a portion of patients treated with chemoimmunotherapy. Minimal residual disease testing is a highly predictive test for progression and may have a role in FL management in the future.
ABSTRACT The 2022 ELN recommendations reclassified fms‐like tyrosine kinase‐3 ( FLT3 )‐ITD mutated acute myeloid leukemia (AML) as intermediate‐risk, irrespective of allelic ratio (AR), and designated capillary electrophoresis (CE) as the preferred detection method. However, CE requires substantial expertise, particularly to identify FLT3 ‐ITD microclones ( FLT3 ‐ITD m ; AR < 0.05), whose clinical significance remains uncertain. Herein, we investigated diagnostic aspects and the prognostic impact of FLT3 ‐ITD m . An initial methodological study performed on 48 FLT3 ‐ITD+ samples, with AR 0.001–6.00, showed overall concordance between CE and next‐generation sequencing (NGS) results ( p < 0.001), with only three microclones (AR: 0.002, 0.001, and 0.008) identified by CE and not by NGS. We next analyzed 658 AML patients diagnosed with a FLT3 ‐ITD+ AML ( n = 446 with AR ≥ 0.05, and n = 212 with a microclone) between 2017 and 2022. Patients with FLT3 ‐ITD m , as compared to patients with AR ≥ 0.05, were older, more often had secondary‐type AML, and displayed a higher prevalence of myelodysplasia‐related gene mutations, while NPM1 ‐mutation frequency was similar in the two groups. Complete remission rates were lower in FLT3 ‐ITD m (74%) than in patients with AR ≥ 0.05 (88%) treated with intensive chemotherapy without FLT3‐inhibitors (FLT3i). In the intensively treated subgroup, multivariate analyses demonstrated that age, NPM1 mutation, and allogeneic stem cell transplantation, rather than FLT3 ‐ITD AR, were independent predictors of disease‐free survival. At relapse, 15 of 33 (45%) evaluable patients remained FLT3 ‐ITD+, with 10 expanding the original microclone. In conclusion, FLT3 ‐ITD m are associated with older age, secondary AML, and with expansion of the FLT3 ‐ITD clone upon relapse, thereby providing a rationale for the evaluation of FLT3i in randomized clinical trials.
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy characterized by acute neurological manifestations and long-term sequelae related to microvascular brain injury. Cerebral small vessel disease (cSVD), detectable on MRI through lacunes, microbleeds, white matter hyperintensities, and enlarged perivascular spaces, is a risk factor for stroke and cognitive decline, but its prevalence and evolution in iTTP are unknown. We conducted a prospective study of consecutive patients with acute iTTP and age-matched controls to assess the prevalence and one-year progression of cSVD. Brain MRI was performed at enrollment and repeated after 12-18 months in clinical remission. cSVD burden was quantified using a standardized 0-4 score based on four MRI markers. Twenty-five patients (median age 56 years; 60% women) were enrolled. Acute focal ischemic lesions were detected in 13 (52%). cSVD was present in 48% of patients versus 27% of controls, while moderate burden (score >= 2) occurred in 24% versus none. Ordinal logistic regression showed an association between iTTP and higher cSVD scores (OR 3.19, 95% CI 1.00-10.14), independent of traditional cardiovascular risk factors. Follow-up MRI was available in 22 patients (88%). In paired analyses, cSVD prevalence increased from 50% to 64%, moderate-to-high burden from 27% to 41%, and six patients (27%) showed score progression. At 1 year, patients had higher odds of greater cSVD burden than controls (age- and sex-adjusted ordinal OR 7.00, 95% CI 1.65-29.74). These findings indicate that cSVD is common during acute iTTP and progresses during the first year despite hematological remission.
