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High-dose melphalan is one of the main cytotoxic DNA alkylating agents and is used in many transplantation conditioning regimens. Studies have shown a wide range of drug exposure when a traditional weight-based dose of melphalan is used. The optimal melphalan dose in BEAM (carmustine, etoposide, cytarabine, and melphalan), which results in maximum efficacy with acceptable toxicity, is unknown. In this pharmacokinetic (PK) analysis of 105 patients with lymphoma undergoing treatment with BEAM and autologous hematopoietic cell transplantation, we initially estimated melphalan exposure as area under the curve (AUC) by a noncompartmental analysis and subsequently compared it with a newly developed 2-compartment population-PK model. The 2 models correlated closely with each other. We found that the traditional fixed weight-based dosing of propylene glycol-free (captisol-enabled) melphalan in BEAM results in a wide variation in exposure as estimated by both models. Higher melphalan exposure was significantly associated with increased metabolic toxicities but did not seem to impact progression-free survival. Although our study suggests a melphalan AUC of 8 mg·h/L as a potential target in BEAM, larger prospective studies using personalized PK-directed melphalan dosing are needed to determine the optimal melphalan exposure in lymphomas., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Older patients with advanced hematologic malignancies are increasingly considered for allogeneic hematopoietic cell transplantation (allo-HCT) yet their survival outcomes remain suboptimal. We and others have previously shown that pre-HCT multi-morbidity and functional limitation and post-HCT geriatric syndromes significantly impact outcomes. Sarcopenia, an accelerated loss of muscle mass and function, has been increasingly recognized in older cancer patients. We identified 146 lymphoma patients 50 years or older who were allografted from 2008 to 2018 at our institution and found that before allo-HCT, 80 (55%) patients were sarcopenic. Pre-HCT sarcopenia was significantly associated with overall survival, progression-free survival, and nonrelapse mortality independent of multi-morbidity and functional limitation. In 6-month landmark analysis, post-HCT sarcopenia remained significantly associated with survival. Our findings illustrate the high prevalence and profound impact of sarcopenia on survival. While requiring prospective confirmation, preemptive, longitudinal, and multidisciplinary interventions for sarcopenia are warranted to improve HCT outcomes for older patients.

Checkpoint inhibition improves surveillance by the immune system and therefore outcomes in some lymphoma subtypes. In this review, we examine the available evidence regarding checkpoint inhibition in lymphoma by line of therapy. Although most published studies are in the setting of relapsed/refractory disease, several ongoing trials are looking at therapy in the upfront and second-line settings. Nivolumab and pembrolizumab have been approved for patients with relapsed or refractory Hodgkin lymphoma, whereas other programmed death 1 and programmed death ligand 1 monoclonal antibodies remain under investigation as single agents or in combination. Strategies to exploit various targets along these pathways with new forms of therapy or with traditional therapies are being developed. Amplification of chromosome 9p23-24 and other biomarkers are important correlative endpoints in several studies that could further the personalization of therapy. Immune-related adverse events are frequent, and vigilance is required for their diagnosis and treatment. The use of checkpoint inhibitors before and after allogeneic transplant can yield impressive results but can also increase the risk for graft-versus-host disease, so that mitigation strategies are needed. Overall, these agents have achieved excellent response rates with durable remissions in many lymphoma subtypes. The results of ongoing trials will yield additional options for patients.