Wagner-Ballon O, Lhoumeau AC, Raimbault A
… +22 more, Debord C, Vial JP, Soenen V, Pannetier M, Bonneville E, Bera E, Bret C, Chapuis N, Latger-Cannard V, Mayeur-Rousse C, Harrivel V, Vergez F, Loosveld M, Xuan JV, Mathis S, Socié G, de Fontbrune FS, de Latour RP, Drenou B, Debliquis A, Le Garff-Tavernier M, French PNH working group CytHem‐HPN
The clinical significance of PNH Type II white blood cells (WBCs) remains unclear. We assessed the relative percentage (rel%) of Type II neutrophils in 355 patients with a PNH clone ≥ 1% on neutrophils enrolled by 33 flo...The clinical significance of PNH Type II white blood cells (WBCs) remains unclear. We assessed the relative percentage (rel%) of Type II neutrophils in 355 patients with a PNH clone ≥ 1% on neutrophils enrolled by 33 flow cytometry laboratories in the 5-year French nation-wide multicenter prospective observational study. We first analyzed 127 of 133 patients with a major PNH clone (≥ 50%) and evaluable Type II neutrophil rel%. Using hemolysis data available for 107 patients, a threshold of 3% Type II neutrophils rel% distinguished two groups: 22 "high Type II" and 105 "low Type II" patients. Hemolysis was less frequent in the "high Type II" group. Thrombosis was more frequent at diagnosis and during cumulative long-term follow-up in this group. High neutrophil rel% ≥ 3% was independently associated with thrombotic events. Among 222 patients with smaller PNH clones (1%-50%), 207 displayed evaluable Type II neutrophil rel%, of which 87 were classified as "high Type II" and 120 as "low Type II". Although no thrombosis was present at diagnosis, two thrombotic events occurred during follow-up in the "high Type II" group, whereas none were observed in the "low Type II" group. Long-term follow-up showed no major changes in Type II neutrophil rel%, irrespective of variations in total clone size. These findings suggest that, regardless of the total PNH clone size, PNH Type II neutrophil rel% is a stable parameter and may represent a reliable predictor of thrombosis, potentially supporting earlier consideration of anticomplement therapy initiation.
van der Veen S, Biemond BJ, Cnossen MH
… +24 more, Bartolucci P, Boaro MP, Garcia BC, Colombatti R, D'Agnolo M, Fijnvandraat K, Gimbert AC, Idrizovic A, Kountouris P, Mañú-Pereira M, Mezzalira E, de Montalembert M, Nur E, D'Orengiani APHA, Sanavia T, Schols SEM, Traets MJM, Rab MAE, Reidel SI, Rijneveld AW, Zaouali Y, Verhoeven-Duif NM, Jans JJM, van Beers EJ
Hydroxyurea (HU) is the most widely prescribed disease-modifying treatment in sickle cell disease (SCD), though treatment responses vary due to metabolism and adherence. We examined HU blood levels and treatment response...Hydroxyurea (HU) is the most widely prescribed disease-modifying treatment in sickle cell disease (SCD), though treatment responses vary due to metabolism and adherence. We examined HU blood levels and treatment response in patients with homozygous sickle cell disease (HbSS). We measured HU in whole blood of 955 SCD patients enrolled in GenoMed4All using mass spectrometry. HU detection was defined as Z-score > 2.5 relative to untreated healthy controls. Among HbSS patients not receiving recent transfusion therapy (n = 539), HU was detected in 39% (143/369) of HU-prescribed patients ≥ 10 years (median age 31.8 [10.0-69.9]). In only 24% (23/109) of young patients (< 10 years, median age 5.9 [1.2-9.9]), HU was detected, despite comparable HU dosing (18.8 vs. 20.3 mg/kg/day). Detectable HU was associated with increased MCV (p < 0.001), and in patients ≥ 10 years also with increased HbF, despite low HbF (< 10%) in 25%. Neutropenia occurred in 8.0% of patients with detectable HU, 4.5% with undetected HU. Only one patient had severe neutropenia (< 0.5 × 10e9/l). In young patients, neutropenia occurred in 1.4% with undetected HU, and in 8.7% with detected HU. This is the largest study to date that reports data on HU levels in HbSS patients. Most HU-prescribed patients, particularly young patients, had undetectable HU levels. Low MCV, HbF, and absent toxicity in children and limited toxicity in adults suggest that treatment for patients with undetectable HU is suboptimal. These findings warrant the need to optimize dosing and adherence to improve treatment in SCD, especially in young patients.
DISEASE OVERVIEW: The myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML)....DISEASE OVERVIEW: The myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML). MDS occurs more frequently in older males and in individuals with prior exposure to cytotoxic therapy. DIAGNOSIS: Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry, and molecular genetics is usually complementary and may help refine diagnosis. Under the 2022 WHO classification of MDS, this entity is now termed myelodysplastic neoplasms. RISK-STRATIFICATION: Prognosis of patients with MDS can be calculated using a number of scoring systems. All these scores include analysis of peripheral cytopenias, percentage of blasts in the bone marrow, and cytogenetic characteristics. The most commonly used systems are the Revised International Prognostic Scoring System (IPSS-R) and the molecular IPSS-M. RISK-ADAPTED THERAPY: Therapy is selected based on risk, transfusion needs, percent of bone marrow blasts, cytogenetic and mutational profiles, comorbidities, potential for allogeneic stem cell transplantation (alloSCT), and prior exposure to hypomethylating agents (HMA). Goals of therapy are different in lower-risk patients than in higher-risk and in those with HMA failure. In lower risk, the goal is to decrease transfusion needs and transformation to higher-risk disease or AML, as well as to improve survival. In higher-risk, the goal is to prolong survival. In 2020, two agents were approved in the US for patients with MDS: luspatercept and oral decitabine/cedazuridine. Imetelstat was approved in 2024 for transfusion-dependent lower-risk MDS. Other available therapies include growth factors, lenalidomide, HMAs, intensive chemotherapy, and alloSCT. A number of combinations studies have been completed at the time of this report; none of them was superior to single-agent azacitidine. There are no approved interventions for patients with progressive or refractory disease, particularly after HMA-based therapy. AlloSCT still remains the only curative approach in MDS.
Frameshift mutations in exon 12 of nucleophosmin 1 (NPM1) are among the most common mutations in acute myeloid leukemia (AML) and have historically been considered favorable-risk in the absence of FLT3-ITD. In the Europe...Frameshift mutations in exon 12 of nucleophosmin 1 (NPM1) are among the most common mutations in acute myeloid leukemia (AML) and have historically been considered favorable-risk in the absence of FLT3-ITD. In the European LeukemiaNet (ELN) 2024 risk-classification for patients treated with hypomethylating agents plus venetoclax (HMA + VEN), NPM1 is not considered favorable when co-occurring with signaling gene (SG) mutations (i.e., FLT3-ITD, NRAS, KRAS). However, due to limited numbers in the original analysis, the prognostic impact of SG mutations in NPM1-mutant AML remains unclear. We evaluated the prognostic significance of NPM1 with and without SG mutations in two independent cohorts of patients ≥ 60 years with ELN 2024 favorable- or intermediate-risk AML treated with HMA + VEN. Cohort 1 included 322 patients treated in the academic setting. NPM1 (n = 61) was associated with a nonsignificantly longer overall survival (OS) compared to NPM1 wild-type (NPM1) (median, 53.05 vs. 17.03 months, p = 0.10). In multivariable analysis (MVA), SG mutations were not independently prognostic within the NPM1 subgroup. Cohort 2 included 816 patients from a real-world community-treated cohort. NPM1 (n = 124) had a longer OS compared with NPM1 (median, 15.3 vs. 14.4 months, p = 0.03). In MVA, NRAS, KRAS, and FLT3-ITD were independent unfavorable prognostic factors; NPM1 with, compared to without, SG co-mutation had a shorter OS (median, 9.4 vs. 31.6 months, p = 0.001). These findings suggest SG mutations negate the favorable impact of NPM1 in older patients treated with HMA + VEN. Prospective clinical trials are needed to investigate the use of combination therapies to improve outcomes in this high-risk subgroup.
Vitamin B12 deficiency causes megaloblastic anemia and ineffective hematopoiesis. While intramuscular administration remains standard, intravenous and intranasal alternatives are increasingly used. Rigorous comparative d...Vitamin B12 deficiency causes megaloblastic anemia and ineffective hematopoiesis. While intramuscular administration remains standard, intravenous and intranasal alternatives are increasingly used. Rigorous comparative data on hematological efficacy across routes remain limited. We thus aimed to compare intranasal, intramuscular, and intravenous vitamin B12 therapy for hematological recovery in vitamin B12 deficiency anemia, and to identify independent predictors of treatment response. In this prospective randomized controlled trial (IEC/2024/450; CTRI/2024/10/075521), 153 adults with vitamin B12 deficiency were randomized to intranasal (n = 55), intravenous (n = 56), or intramuscular (n = 42) administration. Hemoglobin (Hb), mean corpuscular volume (MCV), reticulocyte count, and lactate dehydrogenase (LDH) were assessed at baseline and on Days 7, 14, and 28. Inter-group comparisons used the Kruskal-Wallis test; covariate-adjusted analyzes employed ANCOVA and multiple linear regression. All three routes produced significant hematological recovery (all within-group p < 0.001). Mean ΔHb was +2.48, +1.80, and +2.18 g/dL for intranasal, intravenous, and intramuscular groups. Although the unadjusted analysis detected an intergroup difference (H = 7.23, p = 0.027), ANCOVA abolished the significance (all p > 0.06). MCV reduction was equivalent (Kruskal-Wallis p = 0.948). LDH normalization was greater with parenteral routes (H = 8.17, p = 0.017); intramuscular therapy produced the most pronounced reticulocytosis (H = 13.93, p = 0.001). In multivariate regression (adj. R = 0.575), baseline Hb (β = -0.298, p < 0.001), vegan diet (β = +1.30, p = 0.001), and age (β = -0.013/year, p = 0.039) were independent predictors; route was not. All three routes produce hemoglobin recovery at 28 days with no statistically significant adjusted differences. Intranasal vitamin B12 is a safe, effective, noninvasive alternative suitable for long-term maintenance and resource-limited settings. All conclusions are restricted to short-term hematological outcomes. Trial Registration: CTRI/2024/10/075521.
Despite significant progress in chronic GVHD therapies, challenges remain in understanding pleomorphic phenotypes and varying responses to treatment. The aim of this study was to identify predictors of treatment response...Despite significant progress in chronic GVHD therapies, challenges remain in understanding pleomorphic phenotypes and varying responses to treatment. The aim of this study was to identify predictors of treatment response. We conducted a prospective, observational cohort study of patients beginning first-, second-, or third-line systemic therapy for chronic GVHD with defined agents. We describe best and 6-month response rates, failure-free survival (FFS), and clinical predictors of response. Best response rates were 60%-70% to index therapies, which subsequently declined to 40% at 6 months. Similarly, failure-free survival at 6 months was 66%, but dropped to 41% at 18 months and did not vary based on agent or line of therapy. No clear clinical predictors of FFS or survival were identified. Patient-reported fatigue was associated with NIH response, but we did not find any other clinical predictors of response. Six-month responders were associated with higher FFS at 1 year. When patients were responding to therapy, more than one organ improved. Conversely, one organ usually accounted for patients progressing. In the contemporary era, we demonstrate high but not durable responses across all agents and the first three lines of therapy. There remain large variations in practice, and no specific patterns of agents used, organ responsiveness, or overall responsiveness were identified. Additional study is needed to identify clinical and biologic phenotypes and define predictors of treatment response. Trial Registration: clinicaltrials.gov identifier: NCT04431479.
This study systematically analyzed relapse patterns in pediatric B-cell acute lymphoblastic leukemia (B-ALL) across 2930 patients from the TARGET and MP2PRT cohorts, with an additional 2972 patients from four independent...This study systematically analyzed relapse patterns in pediatric B-cell acute lymphoblastic leukemia (B-ALL) across 2930 patients from the TARGET and MP2PRT cohorts, with an additional 2972 patients from four independent external validation cohorts, to define clinically relevant prognostic thresholds. Monthly landmark-based Cox analyses identified 13 months as the time point with the peak hazard ratio (HR = 31.97) and 27 months as the time point with the maximum -log10P value (158.08); given the small differences from 12 and 24 months and their greater clinical practicality, POD12 (progression of disease within 12 months) and POD24 (progression of disease within 24 months) were selected as clinically practical landmarks for subsequent analyses. In the TARGET and MP2PRT cohorts, POD12 occurred in 2.56% of patients and POD24 in 8.67%. Patients with POD12 had a 5-year overall survival (OS) of 11.13% versus 90.89% in non-POD12 patients, whereas patients with POD24 had a 5-year OS of 36.19% versus 93.62% in non-POD24 patients. In all four external validation cohorts, POD12 and POD24 were likewise associated with significantly inferior OS compared with their respective non-POD groups. In univariate analyses, E2A-PBX1 and MLL rearrangements were associated with increased risk of POD12 and POD24. These findings support POD12 and POD24 as clinically practical, data-driven landmarks for identifying patients with adverse survival outcomes. They may also inform the exploratory evaluation of 1-year and 2-year progression-free survival as hypothesis-generating candidate early trial endpoints, pending prospective validation.
Bernal T, Zambrano Márquez J, Rodríguez-Veiga R
… +27 more, Rodríguez-Arbolí E, Bergua-Burgués JM, Vives S, Arnán M, Martínez Sánchez P, Herrera-Puente P, Serrano-López J, Rubio V, Marchante-Cepillo I, Cervera-Calvo M, Novo García A, Fernández Martín R, Gil Cortés C, Rodríguez-Medina C, Noriega-Concepción V, Alfonso-Piérola A, Loredo C, Antuña-Casal M, Boluda B, Cano-Ferri I, Acuña-Cruz E, Torres-Miñana L, Sánchez-García J, Bilbao C, Gómez-Casares MT, Martínez Cuadrón D, Montesinos P
Am J Hematol
· 2026 Jun · PMID 42374628
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Quizartinib is a tyrosine kinase inhibitor with single agent activity in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) and has demonstrated efficacy in first-line therapy when combined with inte...Quizartinib is a tyrosine kinase inhibitor with single agent activity in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) and has demonstrated efficacy in first-line therapy when combined with intensive chemotherapy in both FLT3 ITD-negative and positive AML. The FLAG-QUIDA trial was a multicenter phase 1/2 study of quizartinib combined with FLAG-IDA in adult patients with first R/R AML. The primary objectives were to determine the recommended phase 2 dose (RP2D) in phase 1 and to establish the complete remission (CR) and CR with incomplete hematologic recovery (CRi) rates in phase 2. Nine patients were included in phase 1 and 52 in phase 2. Eighteen out of 61 (30%) patients were FLT3-ITD-positive. The RP2D of quizartinib was established at 60 mg/day for 14 days per 28-day cycle. Overall, the CR/CRi rate was 56% (n = 34), and the CR/CRi plus morphologic leukemia free state (MLFS) rate was 66% (n = 40), without differences across genetic subgroups. Measurable residual disease negativity was achieved in 38% (n = 13) of CR/CRi patients. Thirty-one patients (51%) were bridged to allogeneic stem cell transplantation after FLAG-QUIDA, 28 in CR/CRi and 3 in MLFS. Median relapse-free survival was 17 months as compared to 7.6 months in a cohort of matched patients treated with FLAG-IDA without quizartinib (p = 0.028), and median overall survival was 15.8 months in the FLAG-QUIDA cohort and 8.6 months in the matched cohort (p = 0.09). No safety concerns were raised. FLAG-IDA with quizartinib demonstrated promising efficacy in R/R AML, supporting future investigations. Trial Registration: EudraCT number: 2019-001976-12; ClinicalTrials.gov identifier: NCT04112589.
Bhatt VR, Wichman CS, Bouska A
… +6 more, Ellithi M, Haddadin M, Iqbal J, Talmadge JE, Maness LJ, Gundabolu K
Am J Hematol
· 2026 Jun · PMID 42359621
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Dordaviprone is a first-in-class small-molecule imipridone. In preclinical studies, it is active against leukemia cells harboring a TP53 mutation or complex karyotype and leukemia stem cells while sparing normal bone mar...Dordaviprone is a first-in-class small-molecule imipridone. In preclinical studies, it is active against leukemia cells harboring a TP53 mutation or complex karyotype and leukemia stem cells while sparing normal bone marrow cells. This study aimed to determine the safety of dordaviprone maintenance after allogeneic hematopoietic cell transplantation (HCT) for high-risk acute myeloid leukemia (AML) and myelodysplastic neoplasm (MDS). In a Phase I trial (n = 20), adults with high-risk AML or MDS received escalating doses of oral dordaviprone administered weekly for up to 13 four-weekly cycles (ClinicalTrials.gov ID: NCT03932643). The primary objective was to determine the rate of dose-limiting toxicities (DLTs) and grade ≥ 3 adverse events (AEs). Participants' characteristics included a median age of 68 years (range: 39-75 years) and high-risk features such as adverse-risk AML (50%) or very poor-risk MDS (75%), TP53 mutations (36%), or measurable residual disease before HCT (41% of AML). A total of 10 patients (one unevaluable) received 250-500 mg weekly doses, whereas the remaining 10 patients received 625 mg weekly doses. Patients received a median of 8.5 cycles (range: 1-13) of dordaviprone. No DLTs or graft failures were noted. Grades 3-4 acute GVHD was noted in 5%. Grade ≥ 3 AEs occurred in 45% (15% related). Grade 3-4 cytopenias were infrequent: anemia (15%), neutropenia (10%), and thrombocytopenia (15%). At 2 years, relapse-free survival and overall survival were 60% (95% confidence interval [CI]: 42%-86%) and 70% (95% CI: 53%-93%), respectively. Posttransplant dordaviprone maintenance was determined to be safe with low rates of cytopenias and promising efficacy in this high-risk population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03932643.
Lim KJC, Kumar S, Parrondo R
… +22 more, Chhabra S, Tan M, Dooley K, Corraes AMS, Gertz M, Hwa L, Stephens H, Kapoor P, Kourelis T, Warsame R, Cook J, Binder M, Abdallah N, Bergsagel PL, Yadav U, Wiedmeier-Nutor JE, Geyer S, Rajkumar SV, Ailawadhi S, Fonseca R, Lin Y, Zanwar S
Am J Hematol
· 2026 Jun · PMID 42351384
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Ciltacabtagene autoleucel (cilta-cel) has demonstrated excellent efficacy and long-term disease control in patients with relapsed/refractory multiple myeloma (RRMM). However, a proportion of patients experience early tre...Ciltacabtagene autoleucel (cilta-cel) has demonstrated excellent efficacy and long-term disease control in patients with relapsed/refractory multiple myeloma (RRMM). However, a proportion of patients experience early treatment failures. We investigated clinical factors associated with early progression or death (within 12 months) in patients with RRMM receiving standard-of-care cilta-cel across the three Mayo clinic centers. Patients with a follow-up of at least 12 months or progression or death within 12 months from infusion were included. Of the patients with early treatment failure (n = 52), 69% had progressive disease and 31% had a non-relapse mortality (NRM) event. In patients without early treatment failure (n = 164), 13% of events were NRM. Among pretreatment factors, prior BCMA-directed therapy, presence of extramedullary disease and a CAR-HEMATOTOX score of ≥ 2 were independent predictors of early progression or death. The utilization of cilta-cel in earlier lines of treatment (1-3 vs. 4 or more) demonstrated comparable PFS (12-month PFS 73% vs. 77%, p = 0.94). Measurable residual disease positivity in the bone marrow at 3 months (11/197 patients) identified a small but high-risk group with an increased risk of early treatment failure (OR 5.68; p = 0.012). Patients with less than a complete response on a FDG PET/CT at 3 months also had an increased risk of early treatment failure (OR 11.8; p < 0.0001). Our findings may help identify patients at high-risk for early adverse outcomes despite receiving highly effective therapy, and support consideration of novel therapeutic strategies within a clinical trial setting.
Ortega Perez R, Domínguez Rodríguez LM, Ferrer-Marín F
… +17 more, Cuevas Ruíz B, Martínez Valverde C, Vélez Tenza P, Mata Vázquez MI, Segura Díaz A, Fox ML, Mora E, Pérez Encinas MM, Gasior Kabat M, Carreño-Tarragona G, Del Orbe RA, Caballero-Navarro G, Magro Mazo E, Pardo Sanz A, Zamorano Gómez JL, Álvarez Larrán A, Garcia-Gutierrez V
Am J Hematol
· 2026 Jun · PMID 42340052
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Li J, Yu C, Wang J
… +28 more, An N, Dong Y, Chen L, Luo J, Wang S, Lu Q, Jiang S, Zhang J, Zou Y, Shou L, Shen L, Chen J, Zhang L, Lu X, Feng J, Zhang H, Jiang H, Zhou J, Xu T, Wang W, Yang Y, Zhou F, Xie W, Shen X, Yang Y, Lai P, Li C, Liu P
Am J Hematol
· 2026 Jun · PMID 42333973
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This national, multicenter, retrospective study analyzed 1070 patients with newly diagnosed systemic light-chain (AL) amyloidosis in China (2008-2025). Findings reveal increasing annual diagnoses and a marked shift in fi...This national, multicenter, retrospective study analyzed 1070 patients with newly diagnosed systemic light-chain (AL) amyloidosis in China (2008-2025). Findings reveal increasing annual diagnoses and a marked shift in first-line therapy from proteasome inhibitor (PI)-based regimens to predominantly daratumumab-based regimens since 2024. Monthly kinetic assessments demonstrated that daratumumab-based induction produced deeper and faster hematologic responses than PI-based therapy [≥ very good hematologic partial response (HemVGPR): 80.3% vs. 70.8%, p = 0.012; median time to ≥ HemVGPR: 1.2 vs. 1.8 months, p = 0.001], with significantly superior cardiac overall response (63.1% vs. 53.3%, p = 0.030). Early mortality rates at 1, 3, and 6 months were 5.5%, 13.2%, and 16.2%, respectively, with daratumumab-based therapy identified as an independent protective factor for 6-month mortality. Median event-free survival (EFS) was 44.4 months, while median overall survival (OS) was not reached. Achievement of hematologic complete response (HemCR) conferred superior EFS and OS over HemVGPR (both p < 0.001), with minimal residual disease negativity further improving EFS in HemCR patients (p = 0.043). Concurrent hepatic and cardiac involvement defined a high-risk subgroup with poor outcomes (median EFS 12.8 months, OS 51.0 months). Multivariable analysis confirmed Eastern Cooperative Oncology Group (ECOG) performance status (PS) > 2, liver involvement, and gain1q as adverse prognostic factors for EFS, whereas ≥ HemVGPR was protective. For OS, liver involvement, concomitant multiple myeloma, and ECOG PS > 2 were independent risk factors, while ≥ HemVGPR and cardiac response predicted improved survival. This study establishes a contemporary benchmark for AL amyloidosis management in China, confirming the superior real-world efficacy of daratumumab-based frontline therapy.