Haematologica

Modern treatment of acute promyelocytic leukemia

Nigel Russell — 2026-02-01

Beating the STATs: targeting the metabolome in acute myeloid leukemia

Boaz Nachmias — 2025-09-04

CCRL2 and who? An important driver in TP53-mutant myeloid leukemias

Olivia Arnold — 2025-09-11

When the first graft fails: a strategic approach to donor selection for second transplant

Piyanuch Kongtim — 2025-08-14

Advancing quality of life research in chronic myeloid leukemia: where do we stand?

Jeffrey H. Lipton — 2025-07-10

Lineage bias in hematopoietic stem cells: more niche or intrinsic factors?

Taha Bartu Hayal — 2025-10-09

Should we move past erythropoietin-stimulating agent monotherapy in lower-risk myelodysplastic syndromes?

Lee Mozessohn — 2025-06-26

Beyond somatic mutations: the role of next-generation sequencing in identifying germline predisposition in patients with acute myeloid leukemia

Sanam Loghavi — 2025-08-28

CHIP ahoy: charting a decade of discovery in clonal hematopoiesis

Casey K. Wong — 2025-09-04

Clonal hematopoiesis (CH) involves the expansion of hematopoietic stem cells with age-acquired mutations linked to myeloid malignancy. Advances in next-generation and single-cell sequencing, along with computational modeling, have expanded our ability to detect both common and rare CH drivers, including single-nucleotide variants and mosaic chromosomal alterations, with increasing sensitivity. While sequencing methods differ in accuracy, cost, and ability to detect low-frequency variants, they have deepened our understanding of CH biology. A growing body of evidence has identified both somatic drivers, such as variants in DNMT3A, TET2, and ASXL1, and germline genetic variants that modify CH risk, highlighting the complex interplay between acquired and inherited factors. These collective discoveries are guiding the development of targeted therapies and interventions, particularly for individuals at risk of progression to myeloid neoplasms or cardiovascular disease. Additionally, CH is emerging as a clinically relevant factor in the treatment of solid tumors, in which it may influence the tumor microenvironment, response to treatment and the risk of therapy-related complications. Risk stratification models are facilitating earlier identification and monitoring of high-risk individuals, enabling personalized treatment decisions. The scope of CH management continues to expand, from surveillance to intervention, with ongoing trials testing preventive strategies in high-risk populations. Emerging trial frameworks emphasize risk stratification, age-appropriateness, inclusive recruitment, decentralized trial models, and the use of traditional clinical and novel endpoints. Together, these advances reflect a shift from passive observation to proactive intervention, charting a course for early detection, precision treatment, and prevention in CH care.

Moving forward from spleen response as an endpoint in randomized controlled trials in myelofibrosis

Ruben Van Dijck — 2025-09-25

Anticancer drugs should make patients live longer and/or feel better. Ideally, endpoints of cancer randomized controlled trials (RCT) should demonstrate that a drug leads to an increase in overall survival and/or improvement in quality of life. With the aim of including smaller numbers of patients, running shorter trials and thus getting new drugs to patients faster, cancer RCT are increasingly using (putative) surrogate endpoints. However, changes in surrogate endpoints often do not reliably predict improvements in overall survival and/or quality of life. Furthermore, especially in later lines of cancer treatments or in cancer patients with a short life expectancy, use of surrogates hardly speeds up the availability of novel therapies but does increase the advent of costly toxic drugs with uncertain benefit, thereby harming both patients and society. In myelofibrosis, spleen response has extensively been used as a surrogate for clinical outcome. In this review we argue that there is no convincing evidence for the use of spleen response or other surrogate endpoints in myelofibrosis, and that the use of surrogate endpoints in RCT in myelofibrosis should be avoided altogether.

The STAT3-VDAC1 axis modulates mitochondrial function and plays a critical role in the survival of acute myeloid leukemia cells

Kellen B. Gil — 2025-06-19

Signal transducer and activator of transcription 3 (STAT3) is a well-described transcription factor that mediates oxidative phosphorylation and glutamine uptake in bulk acute myeloid leukemia cells and leukemic stem cells. STAT3 has also been shown to translocate to the mitochondria in acute myeloid leukemia cells, and phosphorylation at the serine 727 (pSTAT3 S727) residue has been shown to be especially important for the mitochondrial functions of STAT3. We demonstrate that inhibition of STAT3 results in impaired mitochondrial function and decreased leukemia cell viability. We discovered a novel interaction of STAT3 with voltage-dependent anion channel 1 (VDAC1) in the mitochondria which provides a mechanism through which STAT3 modulates mitochondrial function and cell survival. Through VDAC1, STAT3 regulates calcium and oxidative phosphorylation in the mitochondria. STAT3 and VDAC1 inhibition also results in significantly reduced engraftment potential of leukemia stem cells, including primary samples resistant to venetoclax. These results implicate STAT3 as a therapeutic target in acute myeloid leukemia.

C-C motif chemokine receptor-like 2 promotes the interferon-γ signaling response in myeloid neoplasms with erythroid differentiation and mutated TP53

Nour Sabiha Naji — 2025-08-28

Patients with myeloid neoplasms with loss-of-function TP53 mutations and erythroid differentiation have poor outcomes, and a better understanding of disease biology is required. Upregulation of interferon-γ (IFN-γ) signaling has been associated with acute myeloid leukemia (AML) progression, selection of TP53 mutated clones and chemotherapy resistance, but its drivers remain unclear. In this study, we found that the surface receptor C-C motif chemokine receptor-like 2 (CCRL2) is over-expressed in AML with erythroid differentiation and TP53 mutations compared to other AML subtypes and healthy hematopoietic cells. CCRL2 knockout (KO) suppressed erythroleukemia growth in vitro and in vivo. Further proteomics and transcriptomics analysis revealed IFN-γ signaling response as the top CCRL2-regulated pathway in erythroleukemia. Our mechanistic studies support direct CCRL2-driven IFN-γ signaling upregulation without a clear effect of exogenous IFN-γ, through phosphorylation of STAT1, which is partially mediated by JAK2. CCRL2/IFN-γ signaling is up-regulated in erythroid leukemias, and TP53 mutated AML and appears to be directly induced by TP53 KO. Finally, CCRL2/IFN-γ signaling is associated with the transformation of pre-leukemic single-hit TP53 clones to multi-hit TP53 mutated AML, increased resistance to venetoclax and worse survival in AML. Overall, our findings support the view that CCRL2 is an essential driver of cell-autonomous IFN-γ signaling response in myeloid neoplasms with erythroid differentiation and TP53 mutations, and highlight CCRL2 as a relevant novel target for these neoplasms.

Genetic risk classification in acute myeloid leukemia patients treated with hematopoietic cell transplantation and post-transplant cyclophosphamide

Marta Villalba — 2025-09-04

We analyzed the outcomes of 217 acute myeloid leukemia patients in complete remission who underwent allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning and post-transplant cyclophosphamide-based graftversus- host disease prophylaxis, aiming to assess the prognostic significance of genetic risk categories. In the overall cohort, the 2-year overall survival (OS) and event-free survival (EFS) were 77% (95% confidence interval [CI]: 71-83) and 72% (95% CI: 66-78), respectively. European LeukemiaNet (ELN)2022 risk stratification lacked prognostic value in HCT. Instead, we identified four risk categories with distinct impact on OS: standard risk (ELN2022 favorable/intermediate and adverse risk without high-risk genetic risk under the defined subcategories), intermediate risk (≥2 myelodysplasia-related gene mutations) (hazard ratio [HR]=2.23; 95% confidence interval [CI]: 1.14-4.92), adverse risk (complex karyotype, monosomal karyotype, inv(3)/t(3;3), KMT2A rearrangement) (HR=4.24; 95% CI: 2.00-9.02), and very adverse risk (TP53 mutations) (HR=6.81; 95% CI: 3.00-15.5). These categories demonstrated similar predictive power for EFS and cumulative incidence of relapse. Moreover, integrating pre-transplant measurable residual disease (MRD) refined risk stratification, identified MRD-negative patients with ≥2 myelodysplasia-related gene mutations whose OS and EFS were comparable to standard-risk patients. This refined classification improves the prognostic value of ELN2022 for acute myeloid leukemia patients undergoing allogeneic HCT with modern platform by integrating genetic features and MRD status to better guide post-transplant management.

Strategies for identifying NUP98 rearrangements in adult myeloid neoplasms

Lisa D. Yuen — 2025-08-14

Nucleoporin 98 rearrangements (NUP98r) are recurrent in myeloid neoplasms and are subtype-defining for acute myeloid leukemia (AML) in the World Health Organization Classification 5th edition (WHO5) and the International Consensus Classification (ICC). Identification of NUP98r is essential given the frequency of treatment resistance and possibility of sensitivity to targeted therapies. However, NUP98r is often cryptic on karyotype and has over 40 described partners. Therefore, it is underdiagnosed in the absence of dedicated testing that is not always routine practice, e.g., RNA-based next generation sequencing (NGS), NUP98 break-apart fluorescence in situ hybridization, or real-time-quantitative polymerase chain reaction for specific NUP98 fusions. Historically, AML with NUP98r has received the most attention in pediatric AML, where its incidence is highest, but has been increasingly characterized in adult AML. By contrast, the incidence and behavior of NUP98 fusions in myelodysplastic syndromes (MDS) is less understood and based predominantly on case reports. In this study, we describe our adult institutional experience with a clinically validated anchored multiplex PCR RNA-based targeted NGS assay, explore strategies for rational use of specific testing for NUP98r including a proof-of-principle based on WT1 and FLT3- ITD mutational status, and integrate our results with a review of the literature. In total, we identified 3 MDS and 15 AML patients with NUP98r as the genetic driver, including two novel fusion partners (FGF14 and LAMC3), thus highlighting the utility of NGS testing to detect NUP98 fusions. Recognition of NUP98r in myeloid neoplasms is crucial for accurate diagnosis and prognosis, with significant implications for therapy or enrollment in clinical trials.

Anti-HLA class I IgG subclasses skew platelet activation mechanisms in transfusion refractoriness

Adèle Couvidou — 2025-09-18

Patients requiring recurrent platelet transfusions are subject to platelet transfusion refractoriness (PTR), a therapeutic failure due to rapid clearance of transfused platelets from the circulation. One major cause of PTR is the presence in the recipient of multiple immunoglobulin (Ig)G directed against allogeneic HLA class-I (HLA-I) molecules expressed by the donor platelets. Strikingly, the presence of anti-HLA-I IgG does not necessarily correlate with PTR, thus questioning the role of the antibody properties themselves. Using blood of HLA-I allo-immunized patients with or without PTR, we identified the subclasses of their anti-HLA-I IgG. We found the distribution of these subclasses to be different in patients, with IgG1 being predominant in non-PTR patients while IgG1 in combination with IgG2 or IgG3 were detected in PTR patients. To understand the mechanisms associated with PTR, we used human chimeric pan-HLA-I IgG1, IgG2, or IgG3 antibodies and assessed the functional implications of these human IgG subclasses on platelet activation. We showed that each subclass led to platelet aggregation, P-selectin exposure and Annexin V binding. However, we found that the mechanisms of platelet activation differed between subclasses. Specifically, we discovered that pan-HLA-I hIgG2-induced platelet activation was CD32a dependent, while hIgG1- and hIgG3-induced platelet activation relied on complement recruitment. Hence, this study may have direct implications for hierarchizing pathogenic anti-HLA-I alloantibodies in highly poly-immunized patients and be a valuable aid in selecting suitable treatments, particularly by streamlining the search for functionally compatible platelet components (clinicaltrials gov. Identifier: NCT05399693).

Post-transplant cyclophosphamide improves survival compared to antithymocyte globulin in HLA-mismatched unrelated donor stem cell transplantation

Jonathan Bordat — 2025-08-28

Allogeneic hematopoietic stem cell transplantation (alloHSCT) from mismatched unrelated donors (MMUD) carries high risks of non-relapse mortality (NRM) and graft-versus-host disease (GvHD). Post-transplant cyclophosphamide (PTCY) has emerged as an alternative to antithymocyte globulin (ATG) for GvHD prophylaxis. This single-center retrospective study compared PTCY (N=41) to high-dose ATG and low-dose ATG in 155 MMUD alloHSCT recipients. PTCY was associated with better overall survival with a 1-year overall survival of 78.7% versus 56.5% in the PTCY and high-dose ATG groups (P=0.007) and 64.8% in the low-dose ATG group (P=0.059), driven by a significant reduction in NRM (P=0.008), with a 1-year NRM in the PTCY group of 7.7% versus 24.4% in the high-dose ATG group (P=0.031) and 29.8% in the low-dose group (P=0.026). The relapse incidence was similar between the groups (17.5% vs. 25.7% and 16.2% for the PTCY, high-dose ATG and low-dose ATG groups, respectively; P=0.830), despite a better progression-free survival in the PTCY group (P=0.034) with 1-year progression-free survival being 78.4% compared with 50.0% in the high-dose ATG group (P=0.002) and 54.0% in the low-dose group (P=0.041). Day-100 grade II-IV and grade III-IV acute GvHD, as well as 1-year chronic GvHD and moderate/severe chronic GvHD were not significantly different. However, 1-year GvHD-related mortality was lower in the PTCY group (2.6% vs. 14.4% and 14.9% in the high- and low-dose ATG groups, respectively; P=0.018). Infection-related mortality was similar across groups, but cytomegalovirus and Epstein-Barr virus infections were less frequent with PTCY, a finding potentially linked to differences in immune reconstitution. Compared to high-dose and low-dose ATG, PTCY prophylaxis was associated with improved overall survival and progression-free survival as well as lower NRM in MMUD alloHSCT.

Changing donors improves outcomes of second transplantation in patients who experienced graft failure after first allogeneic stem cell transplantation

Rui Ma — 2025-07-17

A second transplantation is almost the only salvage for patients encountering graft failure (GF) following first allogeneic stem cell transplantation. However, there were no standard protocols for second transplantations, and the role of changing donors remained controversial. We retrospectively studied 272 consecutive patients from 18 Chinese centers undergoing second transplantations due to GF, aiming to assess the impact of changing donors and the factors affecting second transplantation outcomes. The primary endpoint was neutrophil engraftment. Other endpoints included platelet engraftment, graft-versushost disease (GvHD), transplant-related mortality (TRM), relapse, and survival. Of the 272 patients, 193 (71.0%) patients experienced primary GF, and 70.6% (192) used a different second donor. Neutrophil engraftment was achieved in 218 (86.3%) patients by day (d)28, and platelet engraftment was achieved in 164 (70.0%) patients by d100. The 3-year cumulative incidence of acute GvHD, chronic GvHD, relapse, and TRM were 43.5%, 27.8%, 15.6%, and 44.6%, respectively. The 1-year and 3-year overall survival (OS) were 56.1% and 49.5%, respectively. Compared to using the same donor, changing donors significantly improved neutrophil engraftment (92.4% vs. 71.4%, P<0.001) and platelet engraftment (76.9% vs. 51.8%, P<0.001), 1-year TRM (34.8% vs. 56.3%, P<0.001), and OS (61.9% vs. 42.7%, P<0.001). Subgroup analysis confirmed engraftment benefit of changing donor in primary GF (P<0.001), but not in secondary GF (P=0.346). This is the largest multicenter study of second transplantations for GF, suggesting that changing donors might be critical for engraftment and survival after second transplantation.

IGLV3-21^R110-directed bispecific antibodies activate T cells and promote killing in a high-risk subset of chronic lymphocytic leukemia

Claudia Fischer — 2025-09-11

We previously used a disease-specific B cell receptor (BCR) point mutation (IGLV3-21^R110) for selective targeting of a highrisk subset of chronic lymphocytic leukemia (CLL) with chimeric antigen receptor (CAR) T cells. Since CLL is a disease of the elderly and a significant fraction of patients is not able to physically tolerate CAR T-cell treatment, we explored bispecific antibodies as an alternative for precision targeting of this tumor mutation. Heterodimeric IgG1-based antibodies consisting of a fragment crystallizable region (Fc) attached to both an anti-IGLV3-21^R110 Fab and an anti-CD3 (UCHT1) single chain variable fragment (R110-bsAb) selectively killed cell lines engineered to express high levels of the neoepitope as well as primary CLL cells using healthy donor and CLL patient-derived T cells as effectors. R110-bsAb spared polyclonal human B cells (as opposed to CD19-targeting blinatumomab) as well as CD34⁺ human stem cells. Yet, R110-bsAb induced lower T-cell activation than blinatumomab with primary CLL cells likely due to lower expression of target antigen. In vivo, R110- bsAb specifically killed IGLV3-21^R110-expressing cell lines and CLL cells while sparing peripheral blood mononuclear cells. These findings highlight bispecific antibodies as a potential off-the-shelf immunotherapy for high-risk CLL patients, offering selective targeting while preserving healthy B cells.

Early cytokine and chemokine signals shape the anti-AML activity of bispecific engager-secreting T cells

Natalie J. Holl — 2025-09-11

Immunotherapies, including cell therapies, are effective anti-cancer agents. However, cellular product persistence can be limiting with short functional duration of activity contributing to disease relapse. A variety of manufacturing protocols are used to generate therapeutic engineered T cells; these differ in techniques used for T-cell isolation, activation, genetic modification, and other methodology. We sought to determine how pre-selection affected the phenotype of T cells engineered to secrete a CD123xCD3 bispecific engager (ENG-T). These cells were designed to treat acute myeloid leukemia (AML). We evaluated the effect of T-cell selection on transduction efficiency, T-cell activation, short- and long-term anti-AML cytotoxicity, and gene transcription. Unselected, CD4, CD8, and CD4/CD8 pre-selected ENG-T cells have minor differences in T-cell subset components, equivalent activation, and equal cytotoxicity in short-term assays. While unselected and CD4/ CD8-selected ENG-T cells have identical CD4:CD8 composition prior to target cell exposure, serial stimulation in vitro showed CD4/CD8 pre-selection supports ENG-T-cell survival and long-term activity. Likewise, CD4 and CD4/CD8 pre-selected ENG-T cells display superior anti-tumor efficacy and prolong murine survival in AML xenografts. Unselected ENG-T cells are exposed to cytokines during early manufacture that imprint upregulation of intracellular inflammatory pathways. This early activation likely underpins long-term observed functional differences. Pre-selection of T cells from banked patient biospecimens decreased blast contamination, exposure to inflammatory cytokines, and may improve T-cell expansion during manufacture. Pre-selection of T-cell products should continue to be performed to enhance the quality of clinical cellular therapeutics.

Improving chronic myeloid leukemia management and quality of life: patient and physician survey on unmet needs from the CML SUN survey

Fabian Lang — 2025-07-10

For patients with chronic myeloid leukemia in chronic phase (CML-CP), disease management, treatment experiences, and decisions around switching therapies due to resistance or intolerance can have significant impacts on their lives. Experiences and perspectives regarding the roles of patients and treating physicians in shared decision-making are poorly understood. The CML Survey on Unmet Needs (CML SUN), the largest CML survey to date, was initiated to gather insights from patients with CML-CP and physicians on disease management, including treatment goals, decision-making, satisfaction, tolerability, and the impact of CML on daily life. The survey was deployed in 11 countries with 361 patient and 198 physician participants and comprised separate questionnaires for each group. Results indicated that nearly three-quarters of physicians saw themselves as the ultimate initial treatment decision-makers; only a quarter of patients reported that these decisions were discussed and decided together with their physician. Nearly half of physicians reported making treatment decisions across all lines of therapy with little to no input from the patient. Disparities between patient and physician opinions were observed regarding treatment goals, especially the balance between efficacy and tolerability. The CML SUN highlights the need for improvements in communication about treatment options and the importance of shared treatment decision-making to unify treatment goals.

Genetic determinants of clinical variability in type 2 von Willebrand disease: bridging genotype and phenotype

Omid Seidizadeh — 2025-08-14

The clinical and genetic features of type 2 von Willebrand disease (VWD) have been described, but genotype-phenotype correlations in large cohorts remain incompletely understood. We investigated the relationship between von Willebrand factor gene (VWF) variants and bleeding severity in a large, well-characterized cohort of type 2 VWD patients, aiming to identify genetic determinants underlying clinical variability. Comprehensive laboratory evaluation, VWF molecular testing, in silico analyses, and bleeding assessment using the ISTH bleeding assessment tool (ISTH-BAT) were performed. Among 371 genetically confirmed cases, ISTH-BAT scores were available for 274 individuals: 83 with type 2A, 69 with 2B, 106 with 2M, and 16 with 2N. The highest bleeding scores were observed in type 2A (median 7), followed by 2B (5), 2M (4), and 2N (4). A total of 67 distinct VWF variants were identified. Notably, we observed substantial variability in bleeding severity both across different variants causing the same VWD phenotypes and among individuals carrying the same VWF variant. ISTH-BAT scores were significantly higher in females than in males, and in adults compared to children. Among adults, but not children, bleeding scores differed significantly between some subtypes. No significant differences were observed between patients with blood group O and non-O. While certain mucocutaneous bleeding symptoms such as menorrhagia, cutaneous, and epistaxis were commonly observed across all type 2 subtypes, our data highlight important subtype-specific differences in bleeding phenotype profiles. This study provides one of the largest genotype-phenotype datasets in type 2 VWD, revealing marked variability in bleeding severity both across type 2 VWD subtypes and among patients with the same genetic variants.

Dental plaque microbiota following allogeneic hematopoietic cell transplantation and risk of chronic graft-versus-host disease

Hakan Gem — 2025-09-04

Microbiota disruptions have been associated with short-term complications after allogeneic hematopoietic cell transplantation (alloHCT). However, only a few studies have examined the relationship between dysbiosis and chronic graft-versus-host disease (cGvHD), the main long-term immunologic toxicity of alloHCT. Considering the role of oral microbiota in systemic inflammatory diseases, we evaluated whether oral microbiota at day 28 post HCT corresponding to clinical recovery from the acute events after transplantation is associated with subsequent cGvHD. Shotgun metagenomic sequencing of 207 saliva and supragingival plaque samples collected longitudinally at baseline (pre-conditioning), day +28, and day +84 from 37 patients (11 with subsequent moderate/severe cGvHD) revealed a significant association between day +28 plaque microbiota composition and cGvHD. Two orthogonal statistical approaches demonstrated Streptococcus sanguinis and Prevotella loescheii in day +28 plaque to be associated with cGvHD. Metagenome-based functional analysis identified 4 microbial metabolic pathways associated with future cGvHD, 2 of which were highly attributed to S. sanguinis. These pathways – ethanolamine utilization and glycerol metabolism – increase bacterial fitness by providing an alternative carbon/nitrogen source and improving survival in inflamed tissues. Our findings propose a novel mechanism by which the early post-transplant dental biofilm may contribute to cGvHD months later, offering a potential target for early prophylactic intervention.

Comparative single-cell lineage bias in human and murine hematopoietic stem cells

Isaac Shamie — 2025-07-17

The commitment of hematopoietic stem cells (HSC) to myeloid, erythroid, and lymphoid lineages is influenced by microenvironmental cues, and governed by cell-intrinsic and epigenetic characteristics that are unique to the HSC population. To investigate the nature of lineage commitment bias in human HSC, mitochondrial single-cell assay for transposase-accessible chromatin (ATAC)-sequencing was used to identify somatic mutations in mitochondrial DNA to act as natural genetic barcodes for tracking the ex vivo differentiation potential of HSC to mature cells. Clonal lineages of human CD34+ cells and their mature progeny were normally distributed across the hematopoietic lineage tree without evidence of significant skewing. To investigate commitment bias in vivo, mice were transplanted with limited numbers of long-term HSC (LT-HSC). Variation in the ratio of myeloid and lymphoid cells between donors was suggestive of a skewed output but was not altered by increasing numbers of LT-HSC. These data suggest that the variation in myeloid and lymphoid engraftment is a stochastic process dominated by the irradiated recipient niche with minor contributions from cell-intrinsic lineage biases of LT-HSC.

Recombinant human erythropoietin plus all-trans retinoic acid and testosterone undecanoate for the treatment of anemia in patients with lower-risk myelodysplastic syndromes: a multicenter, single-arm, prospective trial

Chen Mei — 2025-06-12

Erythropoiesis-stimulating agents (ESA) achieve hematological improvement-erythroid (HI-E) in only 30% of ESA-naïve lower- risk myelodysplastic syndrome (LR-MDS) patients with anemia, highlighting the need for developing novel drugs or new treatment strategies to improve the outcome of these patients. We conducted this multicenter, single-arm trial to investigate the efficacy and safety of a triple regimen consisting of recombinant human erythropoietin (rhEPO), all-trans retinoic acid (ATRA) and testosterone undecanoate in patients with anemia due to lower-risk MDS based on Revised International Prognostic Scoring System. Eligible patients received rhEPO 10,000 IU/day, oral ATRA 25 mg/m2/day and oral testosterone undecanoate 80 mg twice daily for 12 weeks. The primary endpoint was the proportion of patients achieving HI-E during 12 weeks of treatment. Of 52 eligible patients, 32 (61.5%, 95% confidence interval [CI]: 48.0-73.5%) achieved HI-E, meeting the primary endpoint. Fifteen patients (65.2% [15/23]) with baseline serum erythropoietin (EPO) ≤500 IU/L had HI-E versus 58.6% of those (17/29) with baseline serum EPO >500 IU/L. More patients with very low or low risk had HI-E than those with intermediate risk (73.3% vs. 45.5%; P=0.041) and fewer patients with mutated ASXL1 had HI-E than those with wild-type ASXL1 (33.3% vs. 70.0%; P=0.040). The regimen had an acceptable safety profile compatible with individual agents. In conclusion, the triple regimen of rhEPO combined with ATRA and testosterone undecanoate attained HI-E in approximately 61.5% of patients regardless of baseline serum EPO levels, supporting further development of this regimen for LR-MDS patients with anemia. This study was registered at http://www.chictr.org.cn (Identifier: ChiCTR2000032845).

Infection risk in 158 patients with relapsed/refractory multiple myeloma treated with bispecific antibodies: a single-center experience

Lorenzo Cani — 2025-09-04

Four bispecific antibodies (BsAb) are approved for the treatment of relapsed refractory multiple myeloma (RRMM), but their use is associated with infection risks, requiring mitigation strategies. This single-center retrospective study evaluated the incidence, etiology, and risk factors for infections in 158 RRMM patients treated with BsAb. A total of 101 patients received BCMAxCD3 BsAb (teclistamab and elranatamab), and 57 GPRC5DxCD3 BsAb (talquetamab). Prophylactic measures included herpes zoster and Pneumocystis jirovecii coverage, along with monthly intravenous immunoglobulin (IVIG) as primary prophylaxis. Tocilizumab was used for the prevention of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, and BsAb frequency was reduced in responding patients. Cytomegalovirus (CMV) viral load was assessed monthly. Median follow-up was 6.1 versus 4.5 months for anti-BCMA versus anti-GPRC5D group. The cumulative incidence of the first any-grade infection at 5 and 10 months was 38.6% and 47.9% in the anti-BCMA group, and 28.1% and 30.3% in the anti-GPRC5D group (P=0.06). IVIG administration significantly reduced the risk of grade ≥3 infections in multivariate analysis (hazard ratio =0.38; P<0.01). Most infections were viral (60%), mainly upper respiratory (38%). The cumulative incidence of CMV infections at 5 and 10 months was 45.1% and 48% in the anti-BCMA group, versus 27.3% at both time points in the anti-GPRC5D group (P=0.03). With the limitation of a short follow-up, our results showed a higher incidence of anygrade infections in patients receiving anti-BCMA BsAb. Primary IVIG prophylaxis reduced severe infections. CMV infections were more frequent in patients treated with anti-BCMA agents.

Belantamab mafodotin does not induce B-cell maturation antigen loss or systemic immune dysfunction in multiple myeloma

Hanny Musa — 2025-08-28

Various drug classes target B-cell maturation antigen (BCMA) including chimeric antigen receptor T-cell (CAR T) therapies, bispecific antibodies (bsAb), and antibody-drug conjugates (ADC). Outcomes with CAR T and bsAb therapies in multiple myeloma (MM) have been affected by T-cell exhaustion, and abrogated expression/mutation of the BCMA target has been observed with anti-BCMA therapies. Optimal anti-BCMA sequencing strategies are needed to improve long-term clinical outcomes. We used data from multiple clinical studies of the ADC belantamab mafodotin (as monotherapy and combination regimens) to explore its impact on BCMA levels and binding (using electrochemiluminescence methodology) and T-cell/ natural killer (NK) cell fitness (including cell counts, expression of functional markers), to determine whether belantamab mafodotin could be sequenced ahead of other BCMA-targeting therapies for MM. Levels of free soluble BCMA (sBCMA), measured at the best-confirmed response (BCR) and at progression, dropped at BCR but returned to near baseline at time of disease progression. There was no apparent impact on the binding epitope of BCMA, as indicated by the retention of belantamab mafodotin binding to sBCMA. No significant changes in cell counts or expression of T-cell exhaustion markers (PD-1, TIGIT, TIM-3 [except NK cells], or CTLA-4) and co-stimulatory markers (ICOS [except CD4+ T cells], OX40, 4-1BB) were observed at relevant time points (up to 4 or 21+ months depending on the marker). No negative impact was observed on expression of proliferation (Ki67) and antitumor activity (granzyme B, CD107a) markers. Pending confirmatory studies, our results indicate potential for utilizing belantamab mafodotin ahead of other anti-BCMA therapies in MM.

The glutaminase activity of ASNS fuels glutamine metabolism in leukemia

Wai-Kin Chan — 2025-09-11

Genomic ancestry, F8 variants, and immune tolerance in hemophilia A patients with inhibitors: exome sequencing insights

Hanaisa Sant’Anna — 2025-05-15

Use of upfront autologous stem cell transplantation in myeloma patients aged >65 years: a population-based study by the Nordic Myeloma Study Group

Kari Lenita Falck Moore — 2025-09-04

Variables influencing the in vitro measurement of spontaneous aggregation of human platelets

Claudia Ghali — 2025-08-14

Racial differences in the proportion of myeloma cases attributable to excess body weight and diabetes mellitus in the United States

Aishwarya Anuraj — 2025-08-21

Structural and functional insights into γ-glutamyl carboxylase-factor IX interaction: implications for vitamin K-dependent bleeding disorders

Kang Liu — 2025-08-21

The invisible divide: the impact of racial and geographic disparities on multiple myeloma outcomes - insights from a single-site study

Michael A. Bauer — 2025-09-04

Serial next-generation sequencing for detecting germline predisposition in acute myeloid leukemia

Jae-Sook Ahn — 2025-07-03

A novel p.C1130S mutation in a Finnish family with a complex phenotype of von Willebrand disease

Bas Calcoen — 2025-08-28

Assessing the benefit of incorporating an anti-CD38 monoclonal antibody into second- or third-line systemic treatment for patients with relapsed/refractory multiple myeloma: results from the French real-world EMMY study

Thomas Chalopin — 2025-08-28

Benchmarking prophylaxis with factor concentrates: reference data on annualized bleeding rates in children with severe hemophilia

Susanna Ranta — 2025-08-28

CXCR2 deficiency with myelokathexis caused by a novel variant: correction via CRISPR/Cas9

Daniëla M. Hinke — 2025-08-28

Safety and efficacy of BCMA CAR-T vs. bispecific antibodies in patients with relapsed multiple myeloma: a systematic review and meta-analysis

Hayley Vandenboom — 2025-08-14

The immunophenotypic and genetic characterization of pediatric T-lymphoblastic leukemia with a mature immunophenotype

Mahsa Khanlari — 2025-08-28

Infectious complications in acquired hemophilia A: insights from the Spanish registry (AHASR)

Maria-Eva Mingot-Castellano — 2025-08-14

Lenalidomide-associated reversible TP53-mutated clonal hematopoiesis in plasma cell neoplasms

Christian B. Gocke — 2025-10-16

Primary asciminib resistance in a chronic myeloid leukemia patient with the atypical BCR::ABL1 e13a3 transcript: a case study

Birte Kristin Jung — 2025-10-16

β-thalassemia trait and iron overload: is it time to consider oral iron chelators? Comment on: “A case series of patients with β-thalassemia trait and iron overload: from multifactorial hepcidin suppression to treatment with mini-phlebotomies”

Alberto Piperno — 2025-08-28

Response to Comment on: “A case series of patients with β-thalassemia trait and iron overload: from multifactorial hepcidin suppression to treatment with miniphlebotomies”

Fabiana Busti — 2025-09-11

Do high-volume centers really save more lives? A call for scientific rigor and transparency. Comment on: “Does size matter? Center-specific characteristics and survival after allogeneic hematopoietic cell transplantation for acute myeloid leukemia: an analysis of the German Registry for Stem Cell Transplantation and Cell Therapy”

Dries Deeren — 2025-08-14

Response to Comment on: “Does size matter? Centerspecific characteristics and survival after allogeneic hematopoietic cell transplantation for acute myeloid leukemia: an analysis of the German Registry for Stem Cell Transplantation and Cell Therapy”

Wolfgang Bethge — 2025-09-11