Han F, Zhong Y, Tong C
… +8 more, Wang C, Liu Y, Yang Q, Guo Y, Zhang Y, Wu Z, Han W, Wang Y
Am J Hematol
· 2026 Jun · PMID 41804087
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In this single-arm, single-center, registrational phase 2 trial, tandem CD19/CD20 chimeric antigen receptor (CAR) T cell (TanCAR7) therapy showed promising efficacy and safety in patients with relapsed/refractory non-Hod...In this single-arm, single-center, registrational phase 2 trial, tandem CD19/CD20 chimeric antigen receptor (CAR) T cell (TanCAR7) therapy showed promising efficacy and safety in patients with relapsed/refractory non-Hodgkin's lymphoma (r/r NHL). Here, we report 5-year follow-up results, including assessments of durable response, survival, and safety. We also investigated risk factors and biomarkers associated with treatment resistance or relapse and evaluated salvage therapies after CAR-T cell failure. Among 87 patients with r/r NHL treated with TanCAR7, the objective response rate was 78% (complete remission rate, 70%) with a median follow-up of 63.4 months. At data cut-off, 40% of patients remained in remission. Median overall survival (OS) was not reached, with an estimated 5-year OS rate of 60.1% and median progression-free survival (PFS) of 33 months. No new or unexpected TanCAR7-related serious adverse events or deaths were observed. High tumor burden and systemic inflammation were risk factors for resistance and relapse. In addition to CAR-T cell expansion in peripheral blood, high levels of endogenous CD8 + T cells and total lymphocytes after infusion correlated with treatment benefit. Salvage chemotherapy post TanCAR7 failure showed limited efficacy, whereas targeted therapy or secondary CAR-T cell therapy achieved clinical responses in a subset of patients. This first-ever 5-year follow-up analysis of a dual-targeted CAR T-cell therapy shows long-term remission potential and no new safety signals in patients with r/r NHL. Trial Registration: ClinicalTrials.gov: NCT03097770.
Manakov D, Klanova M, Kolar M
… +12 more, Ivanek R, Geier F, Roux J, Zikmund T, Winkowska L, Kriegova E, Manakova J, Tuskova L, Spanikova S, Scasna A, Trneny M, Klener P
Am J Hematol
· 2026 May · PMID 41802856
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Mantle cell lymphoma (MCL) is a B-cell malignancy with a chronically relapsing clinical course and pronounced genetic heterogeneity. To investigate the clonal dynamics underlying early disease relapse, we performed singl...Mantle cell lymphoma (MCL) is a B-cell malignancy with a chronically relapsing clinical course and pronounced genetic heterogeneity. To investigate the clonal dynamics underlying early disease relapse, we performed single-cell RNA sequencing of paired tumor samples collected at diagnosis and at first relapse. Inference of copy number variants (CNVs) identified multiple subclonal clusters at both time points. In all cases, a minor subclone present at diagnosis harbored a CNV profile highly concordant with that of the dominant relapse clone, indicating the pre-existence of therapy-resistant subclones at diagnosis. Gene set enrichment analysis comparing therapy-resistant and therapy-sensitive clones revealed substantial inter-patient heterogeneity in resistance-associated transcriptional programs. Despite this heterogeneity, convergent dysregulation of cell-cycle control pathways emerged as a shared feature across patients. Furthermore, we investigated a case of SOX11-negative indolent MCL (iMCL) with late relapse characterized by extensive extranodal dissemination, including peripheral blood leukemization and intestinal tumor masses. While bone marrow- and peripheral blood-derived MCL cells maintained SOX11 negativity and a largely conserved transcriptomic state, intestinal MCL cells displayed blastoid morphology, expression of SOX11, a profoundly remodeled CNV landscape, and the acquisition of multiple additional driver mutations. Collectively, these findings indicate that early relapse in MCL originates from minor therapy-resistant subclones present at diagnosis and subsequently selected under therapeutic pressure. Moreover, disease progression in iMCL may be driven by spatially restricted clonal evolution, with the emergence of aggressive molecular features in distinct anatomical compartments. These results provide mechanistic insight into MCL clonal evolution and relapse biology.
Am J Hematol
· 2026 May · PMID 41796974
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Preclinical studies showed a synergistic antileukemia activity with combination of selective XPO1 inhibitor selinexor (SEL) and venetoclax (VEN), with potential to overcome VEN resistance by reducing the anti-apoptotic p...Preclinical studies showed a synergistic antileukemia activity with combination of selective XPO1 inhibitor selinexor (SEL) and venetoclax (VEN), with potential to overcome VEN resistance by reducing the anti-apoptotic protein MCL1. In an investigator-sponsored, open-label, phase Ib study (NCT03955783), adult patients with relapsed or refractory acute myeloid leukemia (R/R AML) were enrolled. After the dose-escalation phase, SEL 80 mg po weekly plus VEN 400 mg/day following ramp-up was deemed the recommended phase II dose. Responses were assessed with IWG2003 and ELN 2022 criteria. Nineteen patients with R/R AML were enrolled. Median age at enrollment was 67.2 (range, 21.1-83.8) years. Overall, patients received median of 3 (range, 1-5) prior lines of therapy. The most common grade 3-5 treatment emergent adverse events (TEAE) were anemia (39%), neutropenia (33%), febrile neutropenia (28%), and thrombocytopenia (28%). Overall, the response rate with SEL-VEN was 21%. Two (11%) patients, one with prior allo-HSCT and one with prior VEN and both treated with SEL 80 mg/week, experienced complete remissions, with duration of response of 7 and 9.1 months, respectively. After a median follow up of 3.0 (range, 0.6-15.4) months, median event-free survival was 2.4 (95% CI: 1.9-12.1) months and median overall survival was 6.4 (95% CI: 2.5-12.1) months. In conclusion, SEL-VEN was feasible and active in a heavily pretreated AML cohort, with no new toxicity signal, but survival outcomes remained poor. The second-generation XPO1-inhibitor eltanexor, combined with VEN may further improve outcomes in VEN resistant AML in an ongoing study (NCT06399640).
Lam BD, Ryu J, Jafari O
… +5 more, Kim RB, Ma S, Ranjan M, Jiang JY, Li A
Am J Hematol
· 2026 May · PMID 41796432
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Prior epidemiological studies on cancer-associated venous thromboembolism (VTE) were limited by homogenous patient populations. We leverage Cosmos, a collaborative dataset of Epic electronic health record systems, to con...Prior epidemiological studies on cancer-associated venous thromboembolism (VTE) were limited by homogenous patient populations. We leverage Cosmos, a collaborative dataset of Epic electronic health record systems, to conduct an updated evaluation of cancer-associated VTE in the United States (US). Cosmos includes patients from all 50 states, and the dataset is representative of the US census in terms of age, race, ethnicity, and insurance coverage. We included patients in the US with a new cancer diagnosis between 2018 and 2023. We computed the cumulative incidence of VTE at 6 and 12 months after the diagnosis date and used Cox regression to identify risk factors and examine the association between VTE type within the first year and mortality. We identified 1 628 626 patients, with a cumulative incidence of VTE at 6 months of 2.7% and at 12 months of 3.7%. Major risk factors included prior VTE, cancer type, advanced stage, and chemotherapy-based treatment regimens. The occurrence of VTE within the first year of cancer diagnosis was independently associated with increased mortality.
Röth A, Patriquin CJ, Szer J
… +6 more, Terriou L, Patel AS, Metzger J, Gustovic P, Nishimura JI, Brodsky RA
Am J Hematol
· 2026 May · PMID 41795103
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Ravulizumab, a second-generation complement component 5 inhibitor (C5i) derived from eculizumab, with improved pharmacokinetics, is the current standard-of-care treatment for patients with paroxysmal nocturnal hemoglobin...Ravulizumab, a second-generation complement component 5 inhibitor (C5i) derived from eculizumab, with improved pharmacokinetics, is the current standard-of-care treatment for patients with paroxysmal nocturnal hemoglobinuria (PNH), where available. Pivotal trials have demonstrated durable long-term efficacy, safety, and improved survival, and increasing real-world evidence is required. This analysis utilized data from the International PNH Registry (NCT01374360) to evaluate the real-world effectiveness and safety of ravulizumab, and to assess baseline characteristics at treatment initiation. Adults (aged 18-65 years) enrolled in the registry as of July 1, 2024, who were treated with ravulizumab for ≥ 6 months were included and stratified by prior eculizumab use (eculizumab-experienced and C5i-naive). Ravulizumab treatment outcomes were assessed for up to 24 months and included change in lactate dehydrogenase (LDH) ratio from baseline, transfusion avoidance, and adverse event rates. Data for 203 eculizumab-experienced and 23 C5i-naive patients were analyzed. During treatment, LDH ratio was maintained near normal (< 1.5 × the upper limit of normal in both groups); 86.8% of eculizumab-experienced and 76.5% of C5i-naive patients were transfusion-independent, and a low rate of major adverse vascular events was reported (eculizumab-experienced, 0.4 per 100 person-years; C5i-naive, no events). These findings reinforce the pivotal trial outcomes and demonstrate the effectiveness and safety of ravulizumab in the real-world setting, further supporting ravulizumab as the first-line treatment of choice for patients with PNH, where available. Trial Registration: International PNH Registry: NCT01374360.
Zhou X, Mu Q, Chen H
… +16 more, Chen Y, Wang H, Zhang Y, Cao P, Ma X, Chen J, Chen X, Fang J, Ouyang G, Chen Q, Sun H, Ma X, Wang F, Zhang Z, Zhao J, Liu H
Am J Hematol
· 2026 May · PMID 41794651
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Guijosa A, Tsakamaklis N, Kobs M
… +10 more, Kofides A, Budano N, Nguyen J, Eurell A, Meid K, Guerrera ML, Hunter ZR, Treon SP, Sarosiek S, Castillo JJ
Am J Hematol
· 2026 May · PMID 41793242
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Venetoclax and pirtobrutinib have emerged as two chemotherapy-free options for relapsed or refractory Waldenström macroglobulinemia (WM). However, evidence to guide treatment sequencing or identify molecular subsets most...Venetoclax and pirtobrutinib have emerged as two chemotherapy-free options for relapsed or refractory Waldenström macroglobulinemia (WM). However, evidence to guide treatment sequencing or identify molecular subsets most likely to benefit from each agent remains limited. We retrospectively evaluated consecutive WM patients treated with venetoclax or pirtobrutinib. Major response rate (MRR) and progression-free survival (PFS) were assessed for each agent, with predictors of response and PFS analyzed using logistic and Cox regression. Comparative efficacy was examined in unmatched analyses and in a 1:1 matched cohort. Among 91 treatment exposures (64 venetoclax and 27 pirtobrutinib) across 80 unique patients, treatment discontinuation due to adverse effects occurred in 12 of 64 patients (19%) treated with venetoclax and in none treated with pirtobrutinib. In the venetoclax cohort, TP53 alterations were associated with shorter PFS (10.0 vs. 35.6 months; p < 0.001). In the pirtobrutinib cohort, CXCR4 mutations predicted lower MRR (40% vs. 91%; p = 0.01) and shorter PFS (8.3 months vs. not reached; p = 0.02). When transitioning from a cBTKi, IgM rebound occurred in 62% (8/13) of patients initiating venetoclax without overlap, whereas no rebound was observed with cBTKi-venetoclax overlap (0/5) or with pirtobrutinib initiation (0/15). In the matched cohort (n = 42), venetoclax and pirtobrutinib demonstrated comparable outcomes for MRR (p = 0.91) and PFS (p = 0.83). Despite the retrospective design and limited sample size, these findings indicate comparable efficacy between venetoclax and pirtobrutinib with distinct molecular vulnerabilities and support consideration of pirtobrutinib sequencing when transitioning from a cBTKi, as well as further exploration of combination strategies that may exploit complementary vulnerabilities.
Mellgard GS, Bazarbachi AH, Zanwar S
… +22 more, Hegenbart U, Bodanapu G, Bhutani D, Chen G, D'Souza A, Dispenzieri A, Gertz M, Kumar S, Lentzsch S, Milani P, Muchtar E, Palladini G, Trajanova D, Patwari A, Sanchorawala V, Mohty M, Wang S, Kastritis E, Theodorakakou F, Schönland S, Chakraborty R, Cowan AJ
Systemic AL amyloidosis is a clonal plasma cell dyscrasia, where toxic free light chains (FLCs) lead to vital organ damage, with risk of early mortality despite effective therapies. Notably, there is a paucity of data on...Systemic AL amyloidosis is a clonal plasma cell dyscrasia, where toxic free light chains (FLCs) lead to vital organ damage, with risk of early mortality despite effective therapies. Notably, there is a paucity of data on the incidence and predictors of early mortality in the daratumumab (Dara) era. We conducted a multi-center retrospective cohort study to develop and validate a risk-prediction model for early mortality (all-cause death within 6 months) in patients treated with Dara-based frontline regimens. We used univariate analysis to identify covariates for a logistic regression model predictive of 6-month mortality and generated a clinical risk score. Among 339 patients across eight centers, 36 (10.6%) experienced early mortality. Multivariate analysis identified four independent predictors: NT-proBNP > 5300 pg/mL (odds ratio [OR] 3.83, p = 0.006), Age > 75 years (OR 2.96, p = 0.073), absence of t(11;14) on Cytogenetics (OR 3.0, p = 0.022), and ECOG performance status (OR 1.72 per unit increase, p = 0.044). The resulting PACE score stratified patients into three risk groups with a 6-month mortality of 1.2% (low-risk), 11.7% (intermediate-risk), and 50.0% (high-risk). The PACE score demonstrated superior discrimination (C-index 0.78) for early mortality compared to Mayo 2004 (0.69) and Mayo 2012 (0.55) staging systems. External validation confirmed robust discrimination (C-index 0.73) with corresponding 6-month mortality rates of 4.2%, 15.25%, and 37.04% across respective risk groups. The PACE score provides a clinically applicable tool for early mortality risk stratification in AL amyloidosis patients receiving Dara-based therapy, and will enable improved patient counseling, clinical trial design, and identification of ultra-high-risk patients requiring intensive monitoring and novel therapies.
Marvin-Peek J, Kantarjian H, Jen WY
… +17 more, Daver N, Short N, Borthakur G, Bazinet A, Maiti A, Abbas H, Yilmaz M, Issa G, Macfarland M, Alvarado Y, Garcia-Manero G, Alousi A, Popat U, Shpall E, Ravandi F, DiNardo C, Kadia TM
Raiola AM, Contini P, Gambella M
… +17 more, Barabino L, Bregante S, di Grazia C, Dominietto A, Ghiso A, Guastalla A, Marri L, Serio A, Luchetti S, Varaldo R, Laudisi A, Francia G, Passannante M, Ivaldi F, Bo A, De Palma R, Angelucci E
Am J Hematol
· 2026 May · PMID 41780993
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Cryopreservation of allogeneic peripheral blood stem cells was widely adopted during the SARS-CoV-2 pandemic. We evaluated transplant-related complications and graft product composition in a retrospective (n = 62) and pr...Cryopreservation of allogeneic peripheral blood stem cells was widely adopted during the SARS-CoV-2 pandemic. We evaluated transplant-related complications and graft product composition in a retrospective (n = 62) and prospective (n = 47) series of patients transplanted from an HLA-identical donor comparing cryopreserved (n = 50) versus fresh (n = 59) peripheral blood stem cell grafts. Primary endpoints were hematological reconstitution and cumulative incidence of grade II-IV acute graft versus host disease. Median times to neutrophil and platelet recovery were longer in the cryopreserved group compared with the fresh group: 18 vs. 16 days (p < 0.001) and 20 vs. 14 days (p < 0.001), respectively. The cumulative incidence of grade II-IV acute graft versus host disease at day 100 and of poor graft function at 1 year was significantly higher in the cryopreserved group: 34% vs. 10.1%, (p = 0.0017) and 20% vs. 1.6% (p < 0.001), respectively. To characterize immune cell profiles in fresh and cryopreserved samples, a representative subset was analyzed by mass cytometry, revealing a higher number of T-cell populations known to modulate immune responses and promote graft engraftment in fresh samples. Thus, cryopreservation of allogeneic peripheral blood stem cells is associated with increased incidence of acute graft versus host disease and poor graft function.
Mizuno S, Takami A, Kawamura K
… +21 more, Harada K, Masuko M, Nakasone H, Toubai T, Doki N, Tanaka M, Yoshihara S, Onizuka M, Miyakoshi S, Katayama Y, Uchida N, Fukuda T, Eto T, Ishikawa J, Nakamae H, Asada N, Sawa M, Kanda Y, Atsuta Y, Konuma T, Yanada M
Using data from a nationwide Japanese registry, we evaluated the impact of the total body irradiation (TBI) dose in reduced-intensity conditioning (RIC) for allogeneic hematopoietic cell transplantation (allo-HCT) in pat...Using data from a nationwide Japanese registry, we evaluated the impact of the total body irradiation (TBI) dose in reduced-intensity conditioning (RIC) for allogeneic hematopoietic cell transplantation (allo-HCT) in patients with acute myeloid leukemia (AML). Adults undergoing their first allo-HCT with RIC between 2010 and 2021 were classified into three groups: non-TBI, low-TBI (2 to < 4 Gy), or moderate-TBI (4-8 Gy). Outcomes were analyzed separately for patients in complete remission (CR, n = 1949) and those in the non-CR group (n = 1484). Non-TBI was associated with higher overall mortality than low-TBI (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.03-1.56 in CR; HR, 1.19; 95% CI, 1.00-1.42 in non-CR). Moderate-TBI showed no significant difference in overall mortality compared to low-TBI (HR, 0.96; 95% CI, 0.80-1.15 in CR; HR, 0.89; 95% CI, 0.77-1.05 in non-CR). Among patients in the CR group with matched sibling donors, moderate-TBI reduced overall mortality (HR, 0.33; 95% CI, 0.17-0.64) and relapse (HR, 0.29; 95% CI, 0.12-0.69). In cord blood transplantation, non-TBI increased relapse in CR (HR, 2.73; 95% CI, 1.48-5.06) and overall mortality in non-CR (HR, 1.62; 95% CI, 1.19-2.19). In haploidentical transplants, non-TBI increased relapse (HR, 5.52; 95% CI, 1.72-17.72 in CR; HR, 1.54; 95% CI, 1.04-2.30 in non-CR). The incidence of secondary primary malignancies did not differ according to the use or dose of TBI. In conclusion, adding low- or moderate-TBI to RIC may improve disease control and survival without increasing non-relapse mortality.
It is an exciting era in leukemia owing to the development of novel targeted therapies and advances in genomics, pathophysiology, prognostication, and monitoring (e.g., highly sensitive measurable residual disease assays...It is an exciting era in leukemia owing to the development of novel targeted therapies and advances in genomics, pathophysiology, prognostication, and monitoring (e.g., highly sensitive measurable residual disease assays). Currently, most leukemias are effectively treated with immunotherapies (highly effective monoclonal antibodies targeting CD19 [blinatumomab], or CD22 [inotuzumab ozogamicin]), BCR::ABL1 tyrosine kinase inhibitors (TKIs; e.g., dasatinib, ponatinib), Bruton TKIs (e.g., ibrutinib, acalabrutinib), BCL-2 inhibitors (venetoclax), IDH1/2 inhibitors (ivosidenib, olutasidenib, and enasidenib), FLT3 inhibitors (e.g., midostaurin, quizartinib, and gilteritinib), menin inhibitors (revumenib, ziftomenib), and chimeric antigen receptor T-cell therapies. These novel agents and their judicious use in combination strategies have transformed the treatment landscape across all leukemias, significantly increased survival and quality of life for patients, and attenuated the need for intensive chemotherapy and hematopoietic stem cell transplantation. Leukemia subtypes, such as Philadelphia-positive acute lymphoblastic leukemia (incurable before 2000) and chronic lymphocytic leukemia (previously considered incurable) with historically dire prognoses were recently transformed to favorable leukemias with 5- and 10-year survival rates of 80+% and 90+%, respectively. The BCR::ABL1 TKIs resulted in normal life expectancy in chronic myeloid leukemia. Notable advances have also been made in AML with targeted therapies, although some subsets (older/unfit patients for intensive chemotherapy, complex karyotype, TP53-mutated, KMT2A-rearranged, and treated secondary AML) still have unfavorable outcomes. Herein, we provide a high-level overview of prominent clinical developments across all leukemias. In contemporary times, harnessing the benefits of novel targeted therapies and the evolving treatment landscape bolster the optimistic view that most, if not all, leukemias are curable.
El Aouhel S, Bellegarde V, Da Silva Faria S
… +8 more, St-Laurent T, Lecluze E, Pham Hung d'Alexandry d'Orengiani AL, Galactéros F, Bartolucci P, Legault MA, Lettre G, Pincez T
Am J Hematol
· 2026 May · PMID 41757739
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Acute chest syndrome (ACS) is a severe complication of sickle cell disease (SCD) occurring in ~50% of patients, some presenting frequent episodes. We lack tools to identify patients at high risk of ACS occurrence or freq...Acute chest syndrome (ACS) is a severe complication of sickle cell disease (SCD) occurring in ~50% of patients, some presenting frequent episodes. We lack tools to identify patients at high risk of ACS occurrence or frequent episodes. Epidemiological studies have found an association between asthma and ACS, but whether this link is causal is unclear. We used polygenic scores (PGS) to analyze whether the genetic propensity for asthma was associated with ACS and could be used to stratify the risk of ACS. We identified that PGS for asthma (PGS) was associated with ACS rate (number of episodes per year), but not ACS occurrence, in both the CSSCD (n = 1278) and the GEN-MOD (n = 406) prospective SCD cohorts, independently of fetal hemoglobin (HbF) (β = 0.17, standard error = 0.06, p = 0.006). This effect was most pronounced in patients with low HbF levels. Combining PGS and HbF identified a population at high risk of frequent ACS after a first episode: individuals within the highest PGS quintile and the lowest HbF quintile. Finally, we found that the genetic correlation between these two conditions only partially overlapped. This suggests that genetically determined asthma is not the unique contributor to the genetic propensity for ACS and that other genetic determinants may also play a role. In sum, our results suggest that patients with a high genetic propensity for asthma are prone to frequent ACS if not protected by high HbF levels. Combining PGS and HbF may allow identifying patients at high risk of frequent ACS after a first episode for personalized management.