Vilcassim S, Pholngam N, Thubthed R
… +11 more, Nualkaew T, Svasti S, Chaichompoo P, Kysenius K, Crouch PJ, Dames S, Eisermann M, Martinez A, Schaeper U, Vadolas J, Grigoriadis G
Am J Hematol
· 2026 Jun · PMID 42240074
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Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, cytopenias, and an increased risk of progression to acute myeloid leukemia (AML). De...Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, cytopenias, and an increased risk of progression to acute myeloid leukemia (AML). Despite advances in supportive and targeted therapies, disease-modifying interventions remain limited. Iron overload is increasingly recognized as a key driver of disease progression, amplifying oxidative stress and inflammation while impairing hematopoietic function. However, the mechanisms by which sustained iron excess contributes to disease evolution remain poorly understood. Hepcidin, the master regulator of systemic iron homeostasis, is produced by hepatocytes in response to iron and inflammatory cues and is negatively regulated by transmembrane protease serine 6 (TMPRSS6). Targeting TMPRSS6 to increase endogenous hepcidin offers a promising strategy to restrict iron overload and its inflammatory consequences. Here, we investigated hepatocyte-targeted silencing of Tmprss6 using a GalNAc-conjugated siRNA (SLN124) in the NUP98-HOXD13 (NHD13) mouse model of MDS. MDS and wild-type mice received monthly subcutaneous SLN124 (3 mg/kg) or oral deferiprone (1.25 mg/mL). Iron burden in MDS mice strongly correlated with ASC-speck formation in CD45 hematopoietic cells, consistent with inflammasome activation. Both SLN124 and deferiprone reduced tissue iron deposition and ASC-speck abundance, with SLN124 producing the most pronounced effect. Long-term SLN124 treatment delayed disease progression and significantly prolonged survival, with 30% of treated mice surviving beyond 450 days compared with complete mortality by Day 420 in controls and deferiprone-treated mice. These findings demonstrate that Tmprss6 inhibition via SLN124 suppresses iron-driven inflammation, and mitigated disease progression in MDS mice, establishing TMPRSS6 silencing as a promising disease-modifying therapeutic approach.
Chen Z, Luan D, Kragh Jørgensen RR
… +20 more, Jakobsen L, Maurer MJ, El-Galaly TC, Nastoupil LJ, Cerhan JR, Flowers CR, Link BK, Lossos IS, Stephens DM, Cohen J, Habermann TM, Nowakowski G, Bartlett N, Friedberg JW, Kahl BS, Leonard JP, Brown P, Smedby KE, Jerkeman M, Martin P
Am J Hematol
· 2026 Jun · PMID 42240061
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One quarter of patients with diffuse large B-cell lymphoma (DLBCL) who achieve a complete response following front-line therapy will eventually experience disease relapse. Existing prognostic models use baseline factors...One quarter of patients with diffuse large B-cell lymphoma (DLBCL) who achieve a complete response following front-line therapy will eventually experience disease relapse. Existing prognostic models use baseline factors to predict outcomes from the start of initial therapy and are not intended for use following completion of treatment. We developed a conditional event-free survival (cEFS) tool that predicts a patient's risk of lymphoma recurrence after completing front-line therapy taking into consideration baseline risk characteristics plus the time the patient has been in remission. Model development used pooled and harmonized data from two observational cohorts and four randomized trials of patients with newly diagnosed DLBCL treated with immunochemotherapy and either achieving a complete response or not experiencing an event within 12 weeks of end of therapy. Cox proportional-hazards regression modeling with backwards stepwise selection was utilized for model development. External validation was performed using a large independent data registry. In total, data from 2757 patients were used for model development. The risk of experiencing an event at a time point after having survived a period of time could be computed parsimoniously using four basic predictors: age, ECOG performance status grade, Ann Arbor stage, and lactate dehydrogenase level. C-index in the model development cohort was 0.65 (95% CI, 0.63-0.68), compared to 0.64 (95% CI, 0.62-0.66) in the external validation cohort. We believe that this dynamic risk prediction tool will not only aid clinicians in providing data-driven recommendations for surveillance, but also assist patients themselves with key decisions, such as family planning.
Packard DG, Kumar SK, Dispenzieri A
… +26 more, Kapoor P, Janda G, Hellou T, Buadi FK, Dingli D, Zanwar S, Jevremovic D, Hayman SR, Leung N, Cook J, Abdallah N, Binder M, Muchtar E, Warsame R, Kourelis TV, Go RS, Siddiqui M, Christenson L, Hobbs M, Fonder A, Pak K, Lee LH, Lin Y, Gertz MA, Rajkumar SV, Gonsalves WI
Am J Hematol
· 2026 Jun · PMID 42237452
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Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell disorder with inferior outcomes compared with multiple myeloma (MM). However, studies describing outcomes after first progression and subsequent li...Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell disorder with inferior outcomes compared with multiple myeloma (MM). However, studies describing outcomes after first progression and subsequent lines of therapy remain limited. We retrospectively analyzed 104 patients with pPCL who progressed after first-line therapy treated at one comprehensive cancer center between 2006 and 2024. Clinical characteristics, treatments, time to next treatment (TTNT), and overall survival (OS) were assessed using Kaplan-Meier methods. All pPCL patients received novel agent-based induction. At the time of analysis, 63% had died; median OS was 39 months. High-risk cytogenetics were present in 71%. The median TTNT after first-line therapy was 10 months. Symptomatic progression occurred in 29% of patients and was associated with significantly inferior subsequent OS (13 vs. 34 months) compared with those experiencing asymptomatic biochemical progression. The TTNT progressively shortened with subsequent lines of therapy (3rd line: 6 months; 4th line: 4 months; 5th line: 3 months). Notable exceptions included pPCL patients with t(11;14) treated with anti-BCL-2-based regimens, who achieved a median TTNT of 13 months. Additionally, 24 patients received anti-BCMA CAR T-cell therapy. With a median follow-up of 21 months, their median TTNT was 32 months. pPCL is characterized by frequent disease progression and diminishing response duration with successive therapeutic lines. Symptomatic progression portends particularly poor outcomes. Anti-BCL-2-based therapy in t(11;14) disease and anti-BCMA CAR T-cell therapy appear to provide more durable disease control and represent important advances for the management of progressed pPCL.
Cooper N, Bussel J, Ghanima W
… +15 more, Provan D, Tomiyama Y, Hou M, Arnold DM, Santoro C, Zaja F, Lovrencic B, Morgan M, Winograd M, DiRaimo J, Boyle D, Rajkovic-Hooley O, Vendranas M, Frade S, Kruse C
Am J Hematol
· 2026 Aug · PMID 42237448
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Limited data exist on how patients and physicians perceive immune thrombocytopenia (ITP) symptoms and treatment-related burden. I-WISh (ITP World Impact Survey) 2.0 surveyed 1018 patients and 431 physicians in 15 countri...Limited data exist on how patients and physicians perceive immune thrombocytopenia (ITP) symptoms and treatment-related burden. I-WISh (ITP World Impact Survey) 2.0 surveyed 1018 patients and 431 physicians in 15 countries to characterize the impact of ITP and its treatments on patients. Approximately one-third of patients reported that ITP had a high impact on daily activities and family/social life, and 54% reported that it had a high impact on emotional wellbeing. Patients and physicians generally aligned on symptoms and treatment goals, but more patients (48%) than physicians (29%) reported fatigue as common and problematic. Ninety-seven percent of patients reported that they had received treatment for ITP, most commonly corticosteroids. Most patients and 54% of physicians were satisfied with available treatments, although patients reported treatment-related burdens. Twenty-eight percent confirmed they would have chosen a different treatment. Two-thirds of patients were in a stable, sustained remission, and most had never paused treatment (67%). Nevertheless, two-thirds of patients preferred limiting time on treatment and/or not being on lifelong treatment. I-WISh 2.0 emphasizes the extensive disease and treatment burden faced by patients living with ITP, especially the impact of fatigue. It also reminds us that shared decision-making is needed to ensure treatment goals are aligned with patient expectations, including health-related quality of life.
Lim MY, Gangaraju R, Jafari O
… +9 more, Yang Z, Tiong JWT, Chiang ECL, Ma S, Jiang JY, Ryu J, Lam BD, Ranjan M, Li A
Am J Hematol
· 2026 Jun · PMID 42237094
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Cancer care is often complicated by coagulopathy leading to thrombosis and bleeding. While venous thromboembolism (VTE) has been extensively studied, bleeding remains an underestimated threat. To address this knowledge g...Cancer care is often complicated by coagulopathy leading to thrombosis and bleeding. While venous thromboembolism (VTE) has been extensively studied, bleeding remains an underestimated threat. To address this knowledge gap, we leveraged the Epic Cosmos database to determine the impact of cancer-associated clinically relevant bleeding (CRB) in 2 455 332 individuals with incident cancer encounters from 215 US health systems between 2018 and 2024. In the 12 months leading up to the cancer diagnosis, the period prevalence of CRB was 5.3% in the overall cohort, highlighting CRB as a common early presentation preceding cancer diagnosis. In the 12-month window after cancer diagnosis, the cumulative incidence of CRB was 6.3% in the overall cohort, 7.0% in those receiving systemic antineoplastic therapy, and up to 15.0% among individuals on certain baseline anticoagulants. In addition to age, sex, and race, factors appreciably associated with CRB on multivariable analysis included cancer types, metastatic disease, systemic therapy, anticoagulant or antiplatelet use, higher comorbidity index, recent hospitalization, recent history of bleeding or VTE, and selective laboratory features (hemoglobin, platelets, albumin, eGFR). Furthermore, the onset of CRB as a time varying covariate was independently associated with mortality in multivariable adjusted analysis: intracranial hemorrhage (HR 4.17, 95% CI 4.11-4.24); gastrointestinal bleeding (HR 2.52, 95% CI 2.50-2.55); other bleeding (HR 2.46, 95% CI 2.44-2.49). Together, these findings reveal a substantial and overlooked risk of bleeding in cancer care and underscore a need for validated bleeding risk models that can be integrated alongside VTE prediction tools to guide personalized thromboprophylaxis decisions.
Lam BD, Ito S, Ryu J
… +16 more, O'Sullivan K, Potnis K, Lu R, Bidikian A, Ng DQ, Singh R, Deter A, Carfagnini C, Bechara S, Kandula M, Do N, Fillmore N, Freed JA, Patell R, La J, Goshua G
Am J Hematol
· 2026 Jun · PMID 42227164
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Bernaudin F, Verlhac S, Ducros-Miralles E
… +38 more, Arnaud C, Genty I, Petras M, Paillard C, De Luna G, Meunier B, Thuret I, Kamdem A, Pondarré C, Cannas G, Chantalat-Auger C, Firah N, Pertuisel S, Joseph L, Missud F, de Montalembert M, Guitton C, Pluchart C, Brousse V, Elmaleh M, Gajdos V, Leveillé E, Belozertseva E, Gaba M, Poirot C, Barraud-Lange V, Chadebech P, Pirenne F, Bernaudin M, Neven B, Frange P, Angoso M, Yakouben K, Bruno B, Dhédin N, Dalle JH, Delatour RP, Jung C
Am J Hematol
· 2026 Aug · PMID 42210447
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Management of cerebral vasculopathy in sickle cell anemia (SCA) includes standard-care, that is, chronic transfusion (CT) or hydroxyurea, and hematopoietic cell transplantation (HCT). DREPAGREFFE-1 (December 2010/June 20...Management of cerebral vasculopathy in sickle cell anemia (SCA) includes standard-care, that is, chronic transfusion (CT) or hydroxyurea, and hematopoietic cell transplantation (HCT). DREPAGREFFE-1 (December 2010/June 2013), a French multicenter trial, was the first prospective trial comparing standard-care to match sibling donor (MSD)-HCT in 67 (35F/32M) SCA children (5-15 year) on CT for abnormal time-averaged mean maximum velocities (TAMMV ≥ 200 cm/s). Seven had a stroke history. We reported that MSD-HCT reduced the highest TAMMVs at 1- and 3-year (p < 0.001) and improved quality of life (QoL) for physical and school functioning. In stroke-free patients, the 3-year stenosis score was lower (p = 0.010). Nevertheless, no significant difference was observed for silent cerebral infarcts (SCI) and cognitive performance. This prompted us to initiate DREPAGREFFE-2 to reevaluate the outcomes at 10 years (September 2022/August 2024) with the same 67 SCA children. No death or stroke occurred in either arm. No rejection or chronic-GvHD arose in the MSD-HCT group (n = 32). In the standard-care group (n = 35), 16 were on hydroxyurea, and 16 on CT at Year 10, and 3 received haploidentical-HCT. After MSD-HCT, the QoL was better, even for social functioning, and the number of hospitalizations, hospitalized days (p < 0.001), and crises (p = 0.001) was lower than on standard-care. In stroke-free patients, stenosis (p = 0.027) and SCI scores (p = 0.041) decreased significantly more after MSD-HCT than on standard-care; working memory (p = 0.016) and processing speed (p = 0.011) improved significantly after MSD-HCT, but worsened on standard-care. These effects were not previously detected with shorter follow-up. This supports earlier consideration of HCT for SCA children with MSD to preserve neurologic function and QoL for a more productive future.
Pan J, Fu C, Ling Q
… +28 more, Lu Y, Shi Y, Zhang Y, Wang S, Ji C, Qian S, Huang Z, Ge Z, Zhang J, Ouyang G, Jin C, Lu Q, Huang L, Kong H, Zhu Y, Yan Z, Liu D, Jiang H, Chen N, Lin X, Zhou Y, Zhang Y, Li X, Tong H, Jin J, Chen S, Wang H, East China Leukemia Alliance
Am J Hematol
· 2026 Aug · PMID 42187108
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Acute myeloid leukemia (AML) harboring KMT2A rearrangement (KMT2Ar) was generally associated with poor prognosis. We enrolled 490 patients with KMT2Ar from the East China Leukemia Alliance between March 2013 and August 2...Acute myeloid leukemia (AML) harboring KMT2A rearrangement (KMT2Ar) was generally associated with poor prognosis. We enrolled 490 patients with KMT2Ar from the East China Leukemia Alliance between March 2013 and August 2025. KMT2A::MLLT3 was the most frequent KMT2Ar (31.6%), followed by KMT2A::MLLT4 (25.1%), KMT2A::ELL (20%), and KMT2A::MLLT10 (12.7%). KMT2A::MLLT4 showed an inferior prognosis. The most co-occurring gene mutations were KRAS (20.1%), NRAS (19.0%), TET2 (10.2%), WT1 (8.6%), and PTPN11 (7.4%). Trisomy 8 was more common in patients < 60 years, while FLT3-ITD was only detected in patients < 60 years. With a median follow-up time of 42.6 months, the median overall survival (OS) of all patients was 30.9 months, and the 3-year OS rate was 49.9%. Patients treated with venetoclax plus intensive chemotherapy (Ven+IC) showed the best composite complete remission (CRc) rate and OS compared to intensive chemotherapy, venetoclax plus reduced-intensive chemotherapy, and reduced-intensive chemotherapy (CRc rate: 89.5% vs. 62.4% vs. 57.3% vs. 61.4%; median OS: not reached vs. 39.9 months vs. 34.8 months vs. 12.7 months). Multivariate analysis identified multiparameter flow cytometry minimal residual disease negativity post-induction therapy, allogeneic hematopoietic stem cell transplantation, and Ven+IC as independent favorable prognostic factors for event-free survival (EFS), and KMT2A::MLLT4 fusion, EVI1 overexpression were independent unfavorable prognostic factors for EFS. In summary, our study showed characteristics and prognostic implications in newly diagnosed KMT2Ar AML in China.