Ananth S, Agarwal N, Sahaf B
… +10 more, Jacob A, Lee LW, Simmons H, Kirsch I, Bharadwaj S, Weng WK, Smith M, Dahiya S, Miklos D, Frank MJ
Am J Hematol
· 2026 Aug · PMID 42077190
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CD19-directed chimeric antigen receptor (CAR) T-cell therapy has transformed outcomes for patients with relapsed or refractory (r/r) mantle cell lymphoma (MCL), yet more than 40% relapse within one year. Early identifica...CD19-directed chimeric antigen receptor (CAR) T-cell therapy has transformed outcomes for patients with relapsed or refractory (r/r) mantle cell lymphoma (MCL), yet more than 40% relapse within one year. Early identification of patients at risk for progression could inform post CAR-T surveillance and consolidation strategies. Measurable residual disease (MRD) has emerged as a powerful prognostic biomarker in frontline MCL, but its role after CAR T-cell therapy remains incompletely defined. We retrospectively analyzed 37 patients with r/r MCL treated with brexucabtagene autoleucel (brexu-cel). MRD was assessed using next-generation immunoglobulin high-throughput sequencing (Ig-HTS) of peripheral blood mononuclear cells obtained before lymphodepletion, at 1- and 3-months post-infusion, and every 3 months thereafter. Clonotype identification was successful in 36 of 37 patients. Pre-lymphodepletion MRD levels were lower in patients receiving bridging therapy (337 [0-198 449] vs. 21 213 [1-788 251]; p = 0.04), and MRD undetectability trended toward improved progression-free survival (PFS; unreached vs. 28.5 months; HR 5.2; p = 0.07). Post-infusion, patients with detectable Day 28 MRD had inferior PFS compared with those with undetectable MRD (10.9 vs. 51.5 months; HR 3.99; p = 0.002), whereas Day 28 PET-CT response did not correlate with PFS (p = 0.35; HR 1.8). Longitudinal MRD monitoring identified relapse a median of 6.5 months before PET/CT in most relapsing patients (15 out of 18). Early and serial MRD monitoring is thus a sensitive prognostic and surveillance tool in brexu-cel treated MCL, with Day 28 MRD serving as an early predictor of long-term outcomes.
Kanack AJ, Splinter NP, Mauch EE
… +23 more, Tefera L, Gil MR, Jasra S, Goodwin A, Smock KJ, Ahmad H, Ashrani A, Robinson NL, Casanegra AI, Jones CG, Pechauer SM, Yttre E, Aster RH, Kohlhagen MC, Leger RR, Johns G, Murray DL, Zhou L, Wang D, Wen R, Chen D, Pruthi RK, Padmanabhan A
Am J Hematol
· 2026 Aug · PMID 42068120
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BACKGROUND: Platelet factor 4-polyanion enzyme-linked immunosorbent assays (ELISAs) are considered highly sensitive for diagnosing heparin-induced thrombocytopenia (HIT), such that current practice guidelines recommend u...BACKGROUND: Platelet factor 4-polyanion enzyme-linked immunosorbent assays (ELISAs) are considered highly sensitive for diagnosing heparin-induced thrombocytopenia (HIT), such that current practice guidelines recommend use of ELISA-negative results to exclude HIT. Once HIT is ruled out, alternative, non-heparin-based anticoagulant treatments are ceased, and heparin reintroduction frequently occurs. METHODS: Antigen-based and PF4-dependent functional testing were used to study PF4/polyvinylsulfonate ELISA-negative platelet-activating antibodies in HIT-suspected patients. RESULTS: Three patients with clinical presentations consistent with HIT tested negative in an ELISA using PF4-polyvinylsulfonate (PF4/PVS), an antigenic target very commonly used for HIT antibody screening. All three patients demonstrated PF4-dependent platelet activation in functional testing that was sensitive to blockade of platelet FcγRIIa receptors and inhibited by high concentrations of heparin, consistent with pathogenic HIT antibodies. Functional testing-based screening of 500 ELISA-negative patients identified three additional patients whose sera activated platelets in a PF4- and FcγRIIa-dependent manner and had clinical histories consistent with HIT. Five of the six ELISA-negative HIT patients were re-exposed to heparin, which precipitated a decrease in platelet counts in all re-exposed patients, and one patient developed a new thrombus. CONCLUSIONS: Recognition of ELISA-negative HIT is critical to avoid harm due to the cessation of alternative anticoagulation therapy and re-exposure of these patients to heparin.
Segolene G, Richard L, François L
… +11 more, Muriel F, Stéphanie G, Sylvain LJ, Christelle C, Constance G, Johanna O, Laurent G, Louis A, Giovanna M, Anoosha H, Armand MD
Am J Hematol
· 2026 Aug · PMID 42057377
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Liu H, Sun M, Wang C
… +16 more, Tang X, Sheng L, Ma J, Lu X, Huang H, Shi J, Li R, Zhang J, Chen M, Cao L, Shen H, Li J, Wang W, Zhao X, Ding K, Fan L
Although programmed cell death 1 inhibitors (PD1i) are recommended in guidelines for relapsed/refractory extranodal NK/T-cell lymphoma (ENKTL), their role in frontline therapy remains unclear. In this retrospective, mult...Although programmed cell death 1 inhibitors (PD1i) are recommended in guidelines for relapsed/refractory extranodal NK/T-cell lymphoma (ENKTL), their role in frontline therapy remains unclear. In this retrospective, multi-center study of 755 newly diagnosed ENKTL patients, 17.9% received first-line PD1i. Despite harboring more adverse risk features, the PD1i group showed significantly improved progression-free survival (hazard ratio = 0.62, p = 0.007) and overall survival (hazard ratio = 0.55, p = 0.027) after a median follow-up of 32.9 months. The benefit was also observed in key subgroups (non-upper aerodigestive tract, advanced stage, intermediate/high-risk). Conventional multivariate Cox regression before propensity score matching, robust multivariate Cox analysis after matching, and the time-varying Cox model employed in landmark analysis consistently demonstrated that PD1i therapy served as an independent favorable prognostic factor for both progression-free survival and overall survival. The random forest algorithm revealed enhanced efficacy with PD1i-asparaginase combination therapy, showing about a 50% reduction in event probability, particularly in advanced-stage and intermediate/high-risk patients. Multi-state survival modeling indicated PD1i primarily delays disease progression rather than post-progression survival. Safety data showed that adding PD1i to asparaginase-based chemotherapy resulted in an expected increase in hematologic toxicities, but with a reduced risk of severe/fatal infections and rare severe immune-related adverse events, demonstrating a favorable risk-benefit profile. Overall, in this study, frontline PD1i, particularly in combination with asparaginase, yielded significantly improved outcomes and demonstrated a manageable safety profile in intermediate-/high-risk and advanced ENKTL. This evidence supports its incorporation into first-line treatment and underscores the need for prospective randomized trials.
Therapeutic options for relapsed/refractory (R/R) primary CNS lymphoma (PCNSL) are limited, and the clinical activity and central nervous system (CNS) pharmacology of CD20 × CD3 bispecific antibody glofitamab remain poor...Therapeutic options for relapsed/refractory (R/R) primary CNS lymphoma (PCNSL) are limited, and the clinical activity and central nervous system (CNS) pharmacology of CD20 × CD3 bispecific antibody glofitamab remain poorly defined. This multicenter real-world study evaluated the efficacy, CNS penetration, and molecular response dynamics of glofitamab in 16 adults with R/R PCNSL treated with glofitamab monotherapy. Paired plasma and cerebrospinal fluid (CSF) samples were analyzed to assess CNS drug penetration. Serial CSF circulating tumor DNA (ctDNA) profiling was performed during glofitamab monotherapy, and chimeric antigen receptor T (CAR-T) cell kinetics were examined in patients receiving CAR-T consolidation. Glofitamab monotherapy achieved an interim overall response rate of 75%, including 50% complete responses. Median progression-free survival was 15.4 months, and median overall survival was not reached. In several patients, glofitamab was used as a bridge to subsequent CAR-T and/or autologous stem cell transplantation (ASCT), which may have influenced long-term outcomes. Glofitamab was detectable in the CSF of 60% of patients, with CSF/plasma ratios up to 0.44%. Longitudinal ctDNA analysis demonstrated that early molecular clearance was associated with radiographic response, while persistent or re-emergent ctDNA preceded clinical progression. The safety profile of glofitamab monotherapy was manageable, with most adverse events being Grade 1-2. Two patients (11%) experienced Grade ≥ 3 neurotoxicity and recovered after corticosteroid treatment. Two additional patients developed fatal immune effector cell-associated neurotoxicity syndrome following CAR-T consolidation. Glofitamab demonstrates early clinical activity and measurable CNS penetration in R/R PCNSL. Serial CSF ctDNA profiling may aid treatment monitoring, warranting prospective validation.
Jabbour E, Goulart H, Sasaki K
… +17 more, Rausch CR, Jain N, Kadia TM, DiNardo C, Daver N, Pemmaraju N, Ravandi F, Montalban-Bravo G, Garcia-Manero G, Hammond D, Swaminathan M, Hachem M, Khouri R, Ohanian M, Garris R, Short NJ, Kantarjian HM
Kadia TM, Bataller A, Bazinet A
… +27 more, Borthakur G, Daver N, Short NJ, DiNardo C, Jabbour E, Rausch CR, Issa GC, Pemmaraju N, Ohanian M, Maiti A, Montalban-Bravo G, Sasaki K, Bouligny IM, Yilmaz M, Haddad FG, Masarova L, Chien K, Alvarado Y, Jain N, Popat U, Shpall E, Loghavi S, Qiao W, Wang X, Garcia-Manero G, Ravandi F, Kantarjian HM
Venetoclax-based low-intensity regimens have improved the outcomes of older or unfit patients with acute myeloid leukemia (AML). This phase II study investigated the combination of cladribine plus low-dose cytarabine and...Venetoclax-based low-intensity regimens have improved the outcomes of older or unfit patients with acute myeloid leukemia (AML). This phase II study investigated the combination of cladribine plus low-dose cytarabine and venetoclax alternating with azacitidine plus venetoclax for older or unfit patients with newly diagnosed AML. A total of 190 patients were included; the median age was 68 years (range, 47-84 years; 13% ≥ 75 years). By the European LeukemiaNet 2022 classification, 16%, 20%, and 64% were stratified as favorable, intermediate, and adverse risk, respectively. The rates of complete remission (CR)/CR with incomplete blood count recovery (CRi) and minimal residual disease (MRD) negative CR/CRi were 84% and 75% overall and 91% and 77% among patients with TP53-wild type AML, respectively. The 4- and 8-week mortality rates were 1% and 3%, respectively. Among responders, 44% proceeded to allogeneic hematopoietic stem cell transplantation. The median overall survival (OS) and event free survival (EFS) were 52 and 50 months, respectively. The 2- and 5-year OS rates were 60% and 45%, respectively. The 2-and 5-year EFS rates were 56% and 43%, respectively. Patients achieving MRD-negative CR had a median OS not reached and a 2-year OS rate of 70%. The median time to absolute neutrophil count recovery (> 1 × 10/L) and platelet count recovery (> 100 × 10/L) after induction was 27 and 24 days, respectively. Overall, the treatment was safe and most grade 3 and 4 adverse events were infectious complications. The combination produced a high rate of remissions, translating into favorable outcomes for older patients with newly diagnosed AML. Trial Registration: ClinicalTrials.gov idetifier: NCT03586609.
Anemia results from imbalanced hemoglobin or red blood cell production and clearance. Hemolytic anemia, caused by premature red blood cell removal, can be intravascular (in blood) or extravascular (erythrophagocytosis)....Anemia results from imbalanced hemoglobin or red blood cell production and clearance. Hemolytic anemia, caused by premature red blood cell removal, can be intravascular (in blood) or extravascular (erythrophagocytosis). Hemolysis is common in Sickle Cell Disease (SCD) and Beta-Thalassemia anemia (β-thalassemia), the most prevalent inherited hemolytic anemias. Hemolysis severity is primarily assessed by measuring indirect serum biomarkers such as lactate dehydrogenase, released by cytolysis, bilirubin and haptoglobin. However, these markers do not directly indicate either the cause or the primary site of hemolysis. We introduced a novel plasma heme assay that quantifies all heme-related species in plasma, including hemoglobin, methemoglobin, heme, and hemopexin. Our findings revealed a more profound intravascular red blood cell destruction in SCD compared to β-thalassemia as demonstrated by higher values of plasma hemoglobin, respectively 6.20 and 2.52 μM (p < 0.001), with significant inter-individual variability. In contrast, β-thalassemia patients exhibited higher plasma heme values (11.00 μM vs. 1.51 μM; p < 0.0001) reflecting a probable mixed origin (dyserythropoiesis and hemolysis). Plasma hemopexin was negatively correlated with plasma heme in all patients. Plasma heme exceeded hemopexin scavenging capability in 72% of β-thalassemia and 36% of SCD patients. In β-thalassemia, plasma heme levels were significantly higher in transfusion-dependent compared to non-transfusion-dependent patients, indicating that excess heme reflects clinical severity. In SCD, elevated concentration of excess heme was associated with a significant increased risk of mortality compared to LDH or reticulocytes%. This novel spectral assay offered significant benefits for diagnosis, treatment, and patient management.
In a large multicenter real-world cohort, we aimed to evaluate outcomes of FLAG-Ida salvage therapy for relapsed/refractory (R/R) acute myeloid leukemia (AML) and validated the SALFLAGE prognostic score. We analyzed 1079...In a large multicenter real-world cohort, we aimed to evaluate outcomes of FLAG-Ida salvage therapy for relapsed/refractory (R/R) acute myeloid leukemia (AML) and validated the SALFLAGE prognostic score. We analyzed 1079 adults with R/R AML treated across 112 PETHEMA institutions over 26 years (1998-2024), including patients with primary refractory disease (36.9%) and first relapse episode (63.1%), with a median age of 52 years. Complete remission composite (CRc) was achieved 56.8%, including complete remission (CR) in 51.0%, CR with incomplete recovery in 4.0%, and morphological-free-state in 1.8%, enabling 35.2% of patients and 62% of responders to proceed to allogeneic transplantation without morphological disease. With median follow-up of 50.9 months, median overall survival (OS) was 10.2 months, with 5-year OS rate of 21.6%. Prior allogeneic transplantation (HR 0.54; p < 0.001) and relapse-free interval ≥ 1 year (HR 0.75; p = 0.024) independently predicted improved OS, whereas modified high-risk cytogenetics including t(8; 21) (HR 3.58; p < 0.001), FLT3-ITD mutation at primary diagnosis (HR 1.61; p < 0.001), and age ≥ 60 (HR 1.43; p < 0.001) conferred inferior OS. Validation of the SALFLAGE score demonstrated moderate discrimination (C-index 0.67), with 5-year survival of 38.4%, 27.2%, and 12.7% across risk categories (p < 0.001). Outcomes improved over periods (1998-2005 vs. 2006-2016 vs. 2017-2024): 30-day mortality was 6.9% vs. 9.3% vs. 5.0%, respectively (p = 0.030), and median OS was 7.8 versus 9.4 versus 11.1 months, respectively (p = 0.16). We confirm FLAG-Ida as a reference salvage regimen in fit R/R AML and validate the SALFLAGE score in this setting.
Chari A, Costello C, Krishnan A
… +13 more, Patel K, Banerjee R, Berdeja JG, Biran N, Callander N, Costa LJ, Dhakal B, Gasparetto C, Hansen DK, Kumar A, Nooka AK, Pan D, Richard S
The rapid expansion of therapeutic options for multiple myeloma (MM) has created uncertainty regarding optimal sequencing and clinical application. To address gaps in evidence, the 2025 Bridging the Gaps Consensus Confer...The rapid expansion of therapeutic options for multiple myeloma (MM) has created uncertainty regarding optimal sequencing and clinical application. To address gaps in evidence, the 2025 Bridging the Gaps Consensus Conference convened 16 US MM experts who reviewed data, debated controversies, and voted on 51 questions that were developed using a modified Delphi approach. Eleven consensus recommendations were developed spanning smoldering MM, frontline therapy, transplant, maintenance, and relapsed/refractory disease. Key themes included integration of quadruplet induction, individualized maintenance, and early referral for CAR-T therapy. These expert-derived recommendations provide practical guidance while highlighting areas requiring further investigation.
Survival has improved substantially for patients with Hodgkin lymphoma (HL), but long-term quality of life (QoL) remains incompletely understood. This was a Danish, nationwide, cross-sectional study of QoL among persons...Survival has improved substantially for patients with Hodgkin lymphoma (HL), but long-term quality of life (QoL) remains incompletely understood. This was a Danish, nationwide, cross-sectional study of QoL among persons with a diagnosis of HL matched 1:10 to general population comparators. Questionnaires included the HeartQoL, the European Organization for Research and Treatment of Cancer Quality of Life Core-30 (QLQ-C30), the Short Form-36 (SF-36), and the EuroQoL Health Questionnaire (EQ-5D). Mean differences (MD) were estimated using linear regression adjusted for sex and age, and stratified by time since diagnosis (0-5, > 5-10, and > 10 years). Overall, 1777 patients with HL (42% of 4156 invited) and 6166 matched comparators (14% of 41 558 invited) responded, and median age was similar (HL: 59, comparators: 61). Most had classical HL (92%). HL groups had consistently and significantly lower QoL than their respective comparators, with 0-5, > 5-10, and > 10 years post-diagnosis MDs of -0.27, -0.28, and -0.24 for the HeartQoL, -7.4, -7.6, and -5.6 points for the QLQ-C30 summary score, -4.5, -4.9, and -4.2 points for the SF-36 physical component summary, and -0.05, -0.05, and -0.04 for the EQ-5D index. The relative difference between the HL group and comparators decreased from baseline to > 10 years post-diagnosis, but differences remained clinically important. The most pronounced symptoms were fatigue and dyspnea. To summarize, persons with HL experience reductions in QoL compared with the general population, even > 10 years post-diagnosis. The observed differences were clinically relevant within several domains and emphasize the need for a multidisciplinary approach to survivorship care.