Paludo, Jonas

ABSTRACT 162 patients with relapsed secondary central nervous system lymphoma (R‐SCNSL) (median age, 65 years; male, 59.9%) including central nervous system (CNS)‐only ( n = 120) and concomitant CNS/systemic relapse ( n = 42) were retrospectively analyzed. Overall, 21.9% of patients were classified as high risk according to the CNS International Prognostic Index (CNS‐IPI). Several biological and clinical features were significantly associated with leptomeningeal involvement, including double‐ or triple‐hit (DHL/THL) status, MYC rearrangement, negative BCL6 expression by IHC, bone marrow involvement, and concomitant R‐SCNSL. Multivariable analysis showed that leptomeningeal involvement independently predicted inferior OS and was associated with a 98% increase in the hazard of death compared with parenchymal relapse (HR = 1.98, 95% CI: 1.20–3.26, p = 0.008). Based on anatomical localization, R‐SCNSL was classified into four subtypes: parenchymal‐only involvement (parenchymal‐CNS [P‐CNS], 68/42%) and parenchymal involvement plus systemic relapse (parenchymal‐concomitant [P‐concomitant], 17/10.5%); and leptomeningeal with or without parenchymal involvement (leptomeningeal‐CNS [LM‐CNS], 52/32.1%) and leptomeningeal with systemic relapse (leptomeningeal‐concomitant [LM‐concomitant], 25/15.4%). This anatomical classification significantly impacted OS and PFS ( p < 0.001). Two‐year OS and PFS were 58.2% and 29.1% for P‐CNS, 32.4% and 17.7% for P‐concomitant, 22% and 13.9% for LM‐CNS, and 7.1% and 0% for LM‐concomitant, respectively. ASCT showed a trend toward improved survival among patients with a response (CR/PR) in a 4‐month landmark analysis. These findings support the clinical application of the anatomical classification in the management of R‐SCNSL.

Abstract Waldenström macroglobulinemia (WM) is characterized by recurrent MYD88 and CXCR4 mutations, whose prognostic value in patients treated with chemoimmunotherapy remains unclear. Moreover, the typically prolonged progression-free survival (PFS) correlates inconsistently with overall survival (OS), underscoring the importance of examining other surrogates. Progression of disease within 24 months (POD24), an established early end point, delineates functionally high-risk patients in other indolent lymphomas. This international study evaluated 253 patients receiving frontline fixed-duration bendamustine-rituximab (BR), a common chemoimmunotherapy for WM. At a median follow-up of 5.9 years, 5-year PFS and OS were 65% and 87%, respectively; 5-year PFS was similar between MYD88L265P (90%) and MYD88wild-type (WT) subcohorts (64% each; P = .4). Among 89 patients with known CXCR4 status, the subcohort with CXCR4mutation (28%) had shorter PFS (median 3.3 vs 8.8 years; hazard ratio [HR], 2.8; P = .0036) and OS (HR, 2.6; P = .036) compared with CXCR4WT. POD24 occurred in 11.5% of patients who demonstrated inferior subsequent OS (5-year OS, 71% vs 86%; HR, 3.1; P = .005) and higher mortality (standardized mortality ratio [SMR], 3.7), unlike the non-POD24 group, whose mortality was comparable to the matched general population (SMR, 1.1). In conclusion, BR is effective irrespective of the MYD88 status, but CXCR4 mutations and POD24 portend worse outcomes. Patients without POD24 represent a cohort with distinctly favorable outcome.

Background: Ibrutinib is the only Bruton tyrosine kinase inhibitor (BTKi) with once-daily oral capsule, tablet, and oral suspension formulations approved in the United States across indications of chronic lymphocytic leukemia/small lymphocytic lymphoma, Waldenström macroglobulinemia, and previously treated chronic graft-versus-host disease, and for mantle cell lymphoma in Europe. Patients with difficulty swallowing capsules or tablets may require alternative formulations or administration options to optimize treatment. Objectives: To evaluate the relative bioavailability of ibrutinib oral suspension relative to capsule or tablet formulations and to examine compatibility for optimal administration methods. Methods: Relative bioavailability of ibrutinib oral suspension was evaluated in healthy volunteers or patients in comparison to capsule or tablet formulations. Dose recovery and delivery, presence of impurities, particle size, and hold time were evaluated after in vitro mock oral suspension administration via syringe and nasogastric and percutaneous endoscopic gastrostomy (PEG) tubes. Results: Clinical bioavailability was comparable for ibrutinib oral suspension and capsules (420 mg/day) under the fasted state in healthy volunteers. Dose-normalized pharmacokinetic values were similar across ibrutinib formulations in patient studies. All evaluated enteral tubes achieved 90%–110% ibrutinib dose recovery regardless of tube type or syringe after 2 × 3 mL water rinses. Oral suspension preservative may be adsorbed into enteral tubes after a 60-minute hold time. Conclusion: Ibrutinib oral suspension bioavailability was comparable with ibrutinib tablet and capsule formulations. When dosed via standard enteral tube administration methods, ibrutinib oral suspension is stable and compatible with polyurethane, silicone, or polyvinyl nasogastric or PEG tubes. To ensure full dose recovery and prevent drug preservative adsorption into tubes, ibrutinib oral suspension should be administered immediately and followed by two rinses of 3 mL of water each. Ibrutinib oral suspension is a viable BTKi treatment option for patients requiring or preferring alternatives to oral capsules and tablets.