Atallah-Yunes, Albert

Summary Renal response (RenR) in light‐chain (AL) amyloidosis is associated with a lower risk of end‐stage kidney disease and improved survival. However, substantial variation exists in the time to and depth of RenR. We investigated variables associated with RenR in a retrospective study of newly diagnosed AL amyloidosis patients ( n = 350) assessable for RenR between 2010 and 2022. RenRs were recorded at 6, 12 and 24 months and best response. Deep RenR was defined as a ≥renal very good partial response (RenVGPR, >60% reduction in 24‐h proteinuria or ≤200 mg). Logistic regression and competing risk methods were used to examine variables associated with RenR. The median age was 64 years, and median follow‐up was 5.5 years. On multivariable logistic regression, obtaining ≥HemVGPR within 6 months, kappa isotype, high baseline difference between involved and uninvolved free light chains (dFLC ≥40 mg/dL), renal stage and autologous haematopoietic stem cell transplant (AHSCT) were significantly associated with deep RenR. Cumulative incidence rates for deep RenR, treating death or renal progression as a competing event, demonstrated that early HemR, first‐line AHSCT, lower renal stage and dFLC ≥40 mg/dL significantly increased the likelihood of deep RenR. Specific clonal plasma cell features, namely light‐chain isotype and baseline dFLC levels, independently influence the timing and depth of RenRs in AL amyloidosis following treatment, in addition to renal stage and HemR.

Summary Chimeric antigen receptor T cells directed against CD‐19 are highly effective therapies for various subtypes of B‐cell non‐Hodgkin lymphoma (NHL). We have studied the impact of patient‐specific lymphocyte growth kinetics after lymphoid depletion chemotherapy on both long‐term outcomes and toxicity in patients with diffuse large B‐cell non‐Hodgkin lymphoma (DLBCL). The growth of the lymphocyte populations early after chimeric antigen receptor T‐cell (CAR‐T) therapy is well described by an exponential function and the growth rate of the cells appears to be one of the most critical determinants of overall survival in these patients. The maximum lymphocyte peak and the area under curve for lymphocytes within the first 4 weeks after CAR‐T therapy had no impact on survival. Receiver operator characteristic analysis determined that a replication rate ≥0.3876/day is associated with superior rates of complete response and durable responses. This threshold is associated with higher grades of cytokine release syndrome and the need for tocilizumab. However, patients with this threshold have a median overall survival of 3.04 years compared to 1.035 years for patients with slower lymphocyte replication ( p = 0.0206). The major determinant of depth of response and durability of response to CAR‐T in NHL is the speed of lymphocyte expansion.

ABSTRACT Anaplastic lymphoma kinase‐positive large B‐cell lymphoma (ALK+ LBCL) is a rare, aggressive subtype of diffuse large B‐cell lymphoma with poor outcomes using standard chemotherapy. In this multi‐institutional retrospective study, we analyzed 39 cases of ALK+ LBCL identified at six US academic centers from 2002 to 2024, with treatment including conventional cytotoxic regimens in frontline and biologically informed and nonchemotherapy‐based strategies in the relapsed setting. Ninety‐two percent of patients received frontline anthracycline‐based chemotherapy; 43% received intensified regimens, and 15% underwent upfront autologous stem cell transplantation (ASCT). Despite these approaches, outcomes remained poor. At a median follow‐up of 5.4 years, median event‐free survival (EFS) was 0.6 years (95% CI, 0.4–0.9), and median overall survival (OS) was 1.5 years (95% CI, 1.3–NR). One‐ and five‐year EFS rates were 28% and 17%, while corresponding OS rates were 72% and 42%, respectively. Advanced stage and high IPI scores were associated with inferior outcomes. Twelve patients received ALK inhibitors, with alectinib showing more durable responses than crizotinib. Lenalidomide and immune checkpoint inhibitors also demonstrated activity, including durable complete responses. Five patients underwent allogeneic stem cell transplantation, with three achieving sustained remission. In conclusion, our findings highlight the limited benefit of chemotherapy, even when intensified or followed by ASCT, and support the integration of biologically targeted therapies, which may have contributed to improved OS in our cohort compared to historical outcomes. Prospective, collaborative studies are needed to better understand disease biology and define optimal use of modern therapies in this rare lymphoma.

Abstract Monomorphic posttransplant lymphoproliferative disorders (PTLDs) beyond diffuse large B-cell lymphoma (DLBCL) are rare, biologically heterogeneous entities with limited prospective data to guide treatment. DLBCL-PTLD, which comprises most cases, is managed using approaches informed by prospective phase 2 studies, including reduction in immunosuppression and a risk-adapted sequential immunochemotherapy approach. In contrast, non-DLBCL subtypes such as Burkitt lymphoma, PTLDs of T/NK-cell origin, and plasmacytic variants are less common and are typically treated using strategies extrapolated from established treatment algorithms used in immunocompetent patients and sporadic case reports. Classic Hodgkin lymphoma PTLD, although not classified as monomorphic, represents another distinct and clinically relevant subtype. This review summarizes the epidemiology, clinical features, treatment strategies, and outcomes associated with these less common PTLDs, aiming to provide a practical framework for their management.

Abstract The treatment patterns and clinical outcomes for patients experiencing progression of disease (POD) following CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) mantle cell lymphoma (MCL) are undefined. We identified all patients who received CD19-directed CAR T-cell therapy for R/R MCL therapy across 15 international centers, and studied those experiencing POD post–CAR T-cell therapy in detail. We extracted clinical/treatment/pathologic variables, and associated these features with survival outcomes. In total, 384 patients received CAR T-cell therapy, and 135 (35%) experienced POD. POD occurred at a median of 6 months following CAR T-cell therapy infusion, and most (64%) patients with POD had complete response as best response to CAR T-cell therapy. Tumor features at POD included blastoid/pleomorphic morphology in 29 of 78 (37%) patients, and TP53 mutation in 21 of 41 (51%) patients. Following POD, 17 patients received no further therapy, 13 underwent local therapy, and 105 received systemic therapy. The most common first-line systemic therapies were chemo(immuno)therapy (22 patients; overall response rate [ORR], 40%), pirtobrutinib (17 patients; ORR, 36%), and bispecific antibodies (13 patients; ORR, 67%). Among patients experiencing POD, the median progression-free survival and overall survival (OS) were 2.5 months and 5.4 months, respectively, from POD. Lack of response to CAR T-cell therapy and short time from CAR T-cell therapy infusion to POD (<3 vs 3-6 vs >6 months), among other factors, were associated with inferior OS after POD. In conclusion, we confirm the challenging prognosis for patients experiencing POD following CD19 CAR T-cell therapy for R/R MCL, and establish a benchmark for future investigations in this patient population.

SummaryMultiagent chemoimmunotherapy remains the standard of care treatment for Burkitt lymphoma leading to a cure in the majority of cases. However, frontline treatment regimens are associated with a significant risk of treatment related toxicity especially in elderly and immunocompromised patients. Additionally, prognosis remains dismal in refractory/relapsed Burkitt lymphoma. Thus, novel therapies are required to not only improve outcomes in relapsed/refractory Burkitt lymphoma but also minimize frontline treatment related toxicities. Recurrent genomic changes and signalling pathway alterations that have been implicated in the Burkitt lymphomagenesis include cell cycle dysregulation, cell proliferation, inhibition of apoptosis, epigenetic dysregulation and tonic B‐cell receptor‐phosphatidylinositol 3‐kinase (BCR‐PI3K) signalling. Here, we will discuss novel targeted therapy approaches using small molecule inhibitors that could pave the way to the future treatment landscape based on the understanding of recurrent genomic changes and signalling pathway alterations in the lymphomagenesis of adult Burkitt lymphoma.