Haematologica

A potent and manipulable graft-versus-leukemia effect underpins the increasingly important role of transplantation in acute myeloid leukemia

Charles Craddock — Wed, 01 Jul 2026 00:00:00 +0000

Stable, thus in critical condition: m6A-methylated fusion transcripts in B-cell acute lymphoblastic leukemia

Jonas De Kesel, Panagiotis Ntziachristos — Thu, 12 Feb 2026 00:00:00 +0000

Exploiting metabolic dependencies in acute myeloid leukemia: DHODH inhibition meets lipid and cholesterol metabolism

Nataly Cruz-Rodriguez — Thu, 26 Feb 2026 00:00:00 +0000

Genomic proximity mapping: a promising nextgeneration cytogenomic assay for comprehensive assessment of acute myeloid leukemia

Lianqun Qiu — Thu, 12 Feb 2026 00:00:00 +0000

Haploidentical transplantation in sickle cell disease: toward donor availability for all patients

Valeria Maria Pinto, Emanuele Angelucci — Thu, 26 Feb 2026 00:00:00 +0000

The patient voice: measuring what matters in lower-risk myelodysplastic syndromes treated with imetelstat

Kelly S. Chien, Amy E. DeZern — Thu, 26 Feb 2026 00:00:00 +0000

Metformin: interferon’s new dancing partner?

Hans C. Hasselbalch — Thu, 19 Feb 2026 00:00:00 +0000

CML-like biology: BCR::ABL1 and beyond

Jan Zuna — Thu, 30 Oct 2025 00:00:00 +0000

Introduction to the Review Series. Chronic myeloid leukemia in 2026

Jerald Radich — Wed, 01 Jul 2026 00:00:00 +0000

Prognostic factors in chronic myeloid leukemia: at diagnosis and for treatment-free remission

Delphine Rea — Thu, 04 Dec 2025 00:00:00 +0000

Although chronic myeloid leukemia (CML) is defined by the sole presence of the BCR::ABL1 fusion gene – the genetic event underlying the genesis of the disease – the diversity of clinical outcomes, even in the tyrosine kinase inhibitor (TKI) era, reveals that its apparent biological homogeneity is, in fact, misleading, both between and within individuals. Increasing knowledge of biological diversity through advances in cellular analytical tools and expansion of the TKI arsenal to address this heterogeneity are key factors in the path to better disease control and ultimately cure. In this review, we focus on well-established and novel modifiable and non-modifiable prognostic factors of CML at diagnosis and for treatment-free remission, with particular emphasis on those that are easy to use in clinical practice. We discuss how these factors may help shape therapeutic choices. Finally, we highlight innovative research avenues aiming at improving prognostication of CML.

Is there a best frontline therapy in chronic myeloid leukemia?

Akriti G. Jain, Mark Dalgetty, Jorge E. Cortes — Thu, 11 Dec 2025 00:00:00 +0000

The management of chronic myeloid leukemia in chronic phase (CML-CP) was transfigured with the introduction of imatinib in 2001. Since then, four other tyrosine kinase inhibitors (TKI), dasatinib, nilotinib, bosutinib and most recently asciminib, have garnered approval for frontline management of CML-CP. The second generation TKI (2G-TKI) and asciminib have all been shown to be significantly superior to imatinib in attaining molecular responses, and asciminib possibly superior to 2G-TKI. With limited prospective comparisons between the 2G-TKI and similar survival outcomes with imatinib compared to 2G-TKI, the selection of a TKI for patients with newly diagnosed CML-CP must be individualized to the needs of that specific patient. Important factors to consider when choosing a drug include patient-related factors (age, co-morbidities, lifestyle considerations, quality of life, patient preferences, shared-decision making and whether treatment-free remission is a goal), disease-related factors (risk stratification, transcript type, presence of high-risk gene mutations such as ASXL1) and drug-related factors (major molecular response rates with each TKI, adverse events, rates of treatment discontinuation and treatment-free remission rates).

Understanding drug resistance in chronic myeloid leukemia through the lens of leukemic stem cell states: insights from single-cell analyses

Vaidehi Krishnan, Pavithra Shyamsunder, Tiong S. Ong — Thu, 09 Apr 2026 00:00:00 +0000

Despite the advent of potent tyrosine kinase inhibitors (TKI), resistance and disease persistence remain significant clinical challenges in chronic myeloid leukemia. This review aims to synthesize concepts derived from recent advances in single-cell and multi-omics analyses, which have revealed profound heterogeneity among leukemic stem cells (LSC). These findings augment traditional models that focus solely on clonal selection and resistance-conferring mutations. We discuss how LSC, like normal hematopoietic stem cells, exist in a spectrum of transcriptionally and epigenetically defined cell states, each governed by distinct gene regulatory networks (GRN) that confer unique lineage biases and responses to therapy. Incorporating recent insights from single-cell analyses, our review highlights evidence for a conserved chronic phase LSC state characterized by lineage skewing, altered metabolic and environmental responsiveness, and epigenetic dysregulation, features that are likely to be underpinned by specific GRN configurations that collectively contribute to intrinsic TKI resistance. We explore how both intrinsic factors (such as germline polymorphisms and lineage bias) and extrinsic cues (including microenvironmental signals, immune interactions, and hypoxia) are likely to modulate GRN activity and LSC states, thereby affecting apoptotic thresholds, primary resistance, and the potential for treatment-free remission. Emerging data support the concept of GRN-defined LSC states at diagnosis that are predictive of TKI responses. Furthermore, multiple studies suggest that blast crisis converges on a common high-risk transcriptomic and GRN state that is agnostic to mutational diversity, and driven by polycomb and DNA methylation-dependent epigenetic reprogramming. Given that BCR::ABL1-independent mechanisms, regulated at the level of GRN, may contribute to resistance and LSC persistence, these observations support placing greater emphasis in the management of chronic myeloid leukemia on addressing GRN-defined cell-state vulnerabilities, with the goal of lowering the risk of blast crisis in high-risk patients and improving control of therapy-resistant chronic phase LSC.

Intrinsic cellular resistance to BCR::ABL1 inhibitors

Nataly Cruz-Rodriguez, Yulieth Torres-Llanos, Michael W. Deininger — Thu, 12 Feb 2026 00:00:00 +0000

The clinical implementation of BCR::ABL1 tyrosine kinase inhibitors (TKI) for the treatment of chronic myeloid leukemia (CML) represents one of the big successes of mechanism-based cancer therapy. In 2025, the survival of patients who start TKI therapy while in the chronic phase is approaching that of age-matched controls. Despite this paradigm shift, significant challenges remain. Some patients still develop overt TKI resistance and progress to blast phase, and the majority continue to harbor residual leukemia and require life-long TKI therapy. Growth and survival signals arising from the microenvironment or from within the leukemia cells confer various degrees of resistance to support a spectrum of leukemic activity ranging from overt acute leukemia in blast phase to persistence of minimal residual disease in patients with a deep molecular response. Here we review cell-intrinsic resistance, covering both reactivation of BCR::ABL1 kinase activity and the less well-defined mechanisms underlying BCR::ABL1-independent TKI resistance. We propose that the pathways used by CML to escape TKI effects reflect the potential and the constraints of BCR::ABL1-driven reprogramming of hematopoietic stem and progenitor cells and that the role of BCR::ABL1 functions other than kinase activity may be underappreciated, providing a rationale for the clinical development of BCR::ABL1 degraders.

Management of chronic myeloid leukemia with tyrosine kinase inhibitors: adverse events, toxicities and therapy dosing

Vivian G. Oehler, Ellin Berman, Ivan J. Huang — Thu, 12 Mar 2026 00:00:00 +0000

Targeted therapies have made a near-normal lifespan an attainable goal for many patients with chronic phase chronic myeloid leukemia. Most patients require years of therapy and not everyone may be able to discontinue treatment permanently without recurrence of the leukemia. BCR::ABL1 targeted tyrosine kinase inhibitors, including ATP binding site and allosteric inhibitors that bind to the myristoyl pocket, are associated with treatment-emergent adverse events that may compromise quality of life and well-being. Although alternative treatment options exist, side effects may persist, or new ones occur after a therapy switch. Using a case-based approach, this review examines the incidence of non-hematologic and hematologic treatment-emergent adverse events with specific therapies, provides guidance on adverse event management, and describes the impact of therapy dose reduction on efficacy and tolerability.

Improving quality of life for patients with chronic myeloid leukemia through supportive care, low-dose therapy, switching, and treatment-free remission

Kathryn E. Flynn, Ehab Atallah — Thu, 11 Dec 2025 00:00:00 +0000

Chronic myeloid leukemia (CML) is a hematologic malignancy that has become a largely manageable condition when treated with tyrosine kinase inhibitors (TKI). However, the lifelong treatment course required for most patients is associated with side effects and toxicities that can impact patients’ health-related quality of life (HRQOL). This review synthesizes current evidence on strategies to optimize HRQOL for patients on TKI. This can be achieved through supportive care to manage TKI-related symptoms, dose adjustments, switching to a different TKI, or treatment discontinuation for select patients. We examine the clinical rationale and empirical support for each approach. Emphasis is placed on the importance of clear patient-physician communication and authentic shared decision-making and individualized care to address the needs and experiences of patients and to improve HRQOL.

Chromosomal rearrangement-enhanced mRNA stability drives the oncogenic potential of fusion genes in pediatric leukemia

Thu, 13 Nov 2025 00:00:00 +0000

Acute lymphoblastic leukemia (ALL), the most common type of pediatric leukemia, is frequently driven by fusion genes generated by chromosomal rearrangements. Compared with wild-type genes, many oncogenic fusions show increased expression and sustained functional activity that drives tumorigenesis. However, the mechanisms by which chromosomal rearrangements lead to functional enhancement remain largely elusive. In addition, although large-scale sequencing has identified numerous fusion events, the functional significance of most remains unclear. Here, we demonstrate that enhanced mRNA stability represents an important tumorigenic mechanism for oncogenic fusions, including classical PAX5 fusions. Based on this mechanism, we characterize a novel oncogenic fusion, STK38-PXT1, which exhibits upregulated STK38 mRNA levels and drives the development of ALL. Mechanistically, the increased mRNA stability results primarily from enhanced N6-methyladenosine modification of oncogenic fusions, which is attributable to “gene truncation” (as in PAX5 fusions) and “partner collaboration” (as in STK38-PXT1). Furthermore, the m6A reader IGF2BP3 is crucial for maintaining the high mRNA stability of oncogenic fusions. We further propose venetoclax as an innovative and clinically available therapy for ALL driven by these oncogenic fusions characterized by high mRNA stability. Our study not only highlights mRNA stabilization as a crucial mechanism by which oncogenic fusions drive tumorigenesis, but also presents a promising therapeutic strategy for patients with ALL.

Interleukin signaling mitigates the inhibitory effects of combined Src/BCR-ABL1 blockade on T-cell activity in Philadelphia chromosome-positive acute lymphoblastic leukemia

Farnaz Naeemikia, Joshua Reynolds, Cheng Dong, Justin R. Pritchard — Thu, 05 Feb 2026 00:00:00 +0000

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), driven by the BCR-ABL1 fusion gene, remains a high-risk malignancy despite therapeutic advances. Tyrosine kinase inhibitors (TKI) targeting BCR-ABL1 have significantly improved outcomes, but resistance and relapse persist, necessitating novel strategies such as combining TKI with bispecific T-cell engagers (BiTE) like blinatumomab. Blinatumomab redirects T cells to eliminate CD19+ leukemia cells and has shown impressive clinical activity in Ph+ ALL when combined with SrcBCR-ABL1 TKI. However, this contrasts with preclinical observations reporting that Src kinase inhibition by Src/BCR-ABL1 TKI antagonizes blinatumomab-mediated T-cell activation. Consistent with prior preclinical studies, we demonstrate that dasatinib and ponatinib, unlike SRC-sparing TKI (imatinib, nilotinib), antagonize blinatumomab’s T-cell engaging efficacy by potently inhibiting LCK Y394 phosphorylation, a critical step in proximal TCR signaling. This inhibition impairs T-cell proliferation, cytokine production, and NFAT activation. To reconcile this in vitro antagonism with favorable clinical combination outcomes, we confirmed that the mechanism of SRC inhibition is T-cell intrinsic, and we explored the impact of interleukins. We show that TKI-induced T-cell suppression and antagonism can be significantly improved by supplementing co-cultures with common γ-chain cytokines, particularly IL-7. IL-7 robustly enhances human T-cell proliferation, reduces exhaustion, and significantly improves blinatumomab’s cytotoxic efficacy in the presence of Src/BCR-ABL1 TKI.

Potent synergy of DHODH and SREBP inhibition in acute myeloid leukemia via disruption of cholesterol and lipid metabolism

Thu, 11 Dec 2025 00:00:00 +0000

Acute myeloid leukemia (AML) remains difficult to cure, in part related to strong genetic and functional heterogeneity between and within individual patients. Metabolic reprogramming is emerging as an important feature of AML cells, allowing exploration of alternative treatment strategies. Here, we describe a novel DHODH inhibitor, JNJ-74856665, that showed strong efficacy in a subset of AML samples. In a multi-omics approach, by combining label-free quantitative proteome data with drug sensitivity data in bone marrow stromal co-cultures in a large cohort of primary AML patient samples we identified that sensitivity to DHODH inhibition (DHODHi) is linked to cholesterol and lipid metabolism. DHODHi resulted in an accumulation of cholesterol, mitochondrial reactive oxygen species (ROS) and lipid peroxidation. LC-MS/ MS-based lipidomics studies revealed that DHODHi resulted in a strong increase in polyunsaturated fatty acids and triglycerides, which are the primary lipid species stored in lipid droplets (LD). We hypothesized that this might be the consequence of increased ROS and lipid peroxidation levels, prompting the cell to detoxify such toxic lipid species by storing them in LD. Indeed, we could observe a marked increase in LD formation upon DHODHi. The transcriptional regulator SREBF2, known to control cholesterol and lipid metabolism, was up-regulated in DHODHi sensitive AML, and a strong synergy was observed between the combination of both DHODHi and the SREBP inhibitor dipyridamole. Our data indicate that it would be interesting to further explore combined DHODH and SREBP inhibition as a therapeutic target option in AML.

Evaluation of acute myeloid leukemia using genomic proximity mapping-based next generation cytogenomics

Thu, 15 Jan 2026 00:00:00 +0000

Cytogenetic analysis encompasses a suite of standard-of-care diagnostic testing methods that is applied routinely in cases of acute myeloid leukemia (AML) to assess chromosomal changes that are clinically relevant for risk classification and treatment decisions. In this study, we assess the use of Genomic Proximity Mapping® (GPM) for cytogenomic analysis of AML diagnostic specimens for detection of cytogenetic risk variants included in the European Leukemia Network (ELN) risk stratification guidelines. Archival patients’ samples (N=48) from the Fred Hutchinson Cancer Center Leukemia Bank with historical clinical cytogenetic data were processed for GPM and analyzed with the CytoTerra cloud-based analysis platform. GPM showed 100% concordance for all specific variants that have associated impacts on risk stratification as defined by ELN 2022 criteria and 78% concordance when considering all variants reported by the Cytogenetics Laboratory at Fred Hutchinson Cancer Center. Notably, the percentage of blasts (ranging from 5–96%) did not have a clear effect on the ability to detect these variants. In two cases, GPM identified a recurrent inv(9)(p13.3p13.1). These findings demonstrate GPM’s effectiveness for the evaluation of known AML-associated risk variants and a source for biomarker discovery.

Hypomethylating agents plus venetoclax versus intensive chemotherapy in acute myeloid leukemia with chromosome 5 and 7 abnormalities

Thu, 29 Jan 2026 00:00:00 +0000

Abnormalities in chromosomes 5 and 7 are frequently identified in acute myeloid leukemia, are particularly enriched in therapy- and myelodysplasia-related disease, and confer an adverse prognosis. Given the high risk of relapse, allogeneic stem cell transplant (allo-SCT) is typically recommended for patients achieving complete remission following induction chemotherapy. We currently lack prospective data to decide whether intensive chemotherapy (IC) or a hypomethylating agent + venetoclax (HMA+ven) is the superior frontline treatment approach for these patients. Hence, we performed a retrospective study in a large cohort of patients with acute myeloid leukemia and deletion 7 (-7) and/or deletion 5 or 5q (-5/ del5q) comparing outcomes between patients treated with IC or HMA+ven. Remission rates after IC and HMA+ven were found to be comparable (43% vs. 52%, P=0.2). When adjusting for patient and disease characteristics in multivariable analysis, treatment with IC vs. HMA+ven did not significantly impact overall survival (hazard ratio [HR]=1.02, P=0.9202), while age at diagnosis (HR=1.02, P=0.0324), prior myeloid disease (HR=1.42, P=0.0266), monosomal karyotype (HR=1.48, P=0.029), complex karyotype (HR=1.61, P=0.0156), and KRAS mutations (HR=2.21, P=0.0063) were associated with inferior survival. There was also no difference in overall survival in patients age 60-75 years by treatment strategy (7.8 vs. 6.4 months, P=0.56), motivating future randomized trials of IC versus HMA+ven in this older population to inform optimal therapy. Importantly, overall survival was significantly improved in patients undergoing allo-SCT irrespective of frontline therapy, and allo-SCT consolidation was the most important predictor of long-term survival in multivariable analysis (HR=0.36, P<0.0001).

Selective lymphodepletion underlies the efficacy of horse anti-thymocyte globulin-based immunosuppressive therapy in aplastic anemia

Thu, 29 Jan 2026 00:00:00 +0000

Horse-derived anti-thymocyte globulin (ATGAM) in combination with long-term ciclosporin is the first-line treatment for most immune-mediated aplastic anemia (AA) patients. The exact impact of this immunosuppressive therapy (IST) on hematologic recovery and the immune landscape, however, remains poorly understood. We report a longitudinal analysis of the pharmacodynamic effects of ATGAM-based IST in a cohort of 44 AA patients. We used flow cytometry to quantify plasma levels of lymphocyte-binding ATGAM, which is believed to mediate the therapeutic effect. Population pharmacokinetic modeling revealed substantial between-patient variability in ATGAM exposure, with higher exposure levels associating with earlier hematologic recovery. ATGAM bound all lymphoid lineages and profoundly depleted T and natural killer cells at high plasma concentrations. Strikingly, ATGAM did not deplete B cells but instead induced an increase in CD27+ B cells. Deep immunophenotyping on series of peripheral blood samples collected up to three years after start of IST demonstrated that ATGAM induced rapid depletion of T cells, including KLRG1+ terminally differentiated CD8+ T cells and Th17-like CCR6+CD4+ T cells. Although naïve and pathogen-specific T cells were also depleted, they recovered quickly, indicating preservation of protective immunity. Notably, CCR6++ B cells, implicated in AA pathogenesis, escaped ATGAM depletion but reduced gradually over time along with residual potentially pathogenic T cells, including the CCR6+CD4+ T cells. This could explain the crucial contribution of long-term ciclosporin to successful IST. Collectively, our results identify ATGAM exposure as a factor influencing hematologic recovery and indicate that the therapeutic effect of IST goes beyond total lymphodepletion but is rather the result of selective depletion and suppression of key lymphocyte subpopulations.

Chronic graft-versus-host disease in the era of posttransplant cyclophosphamide

Thu, 22 Jan 2026 00:00:00 +0000

Chronic graft-versus-host disease (cGVHD) remains a leading cause of late morbidity after allogeneic hematopoietic cell transplantation (HCT), but its phenotype under modern prophylaxis with post-transplant cyclophosphamide (PTCy) is not well characterized. We conducted a prospective, single-center study of 600 consecutive adults undergoing HCT with PTCy- based prophylaxis to assess incidence, clinical manifestations, treatment response, prognostic factors, and outcomes. Donors included matched siblings (36%), matched unrelated (34%), haploidentical (24%), and mismatched unrelated (6%). The 1-year cumulative incidence of moderate-to-severe cGVHD was 22% (95% confidence interval [CI]: 19-26%). The mouth was the most frequently involved organ (64%), with lichen planus-like changes as the predominant diagnostic feature, whereas sclerotic forms were uncommon. Notably, 27% of moderate-to-severe cases were managed successfully without systemic corticosteroids. The cumulative incidence of systemic therapy requirement was 15% at 1 year, with risk significantly higher in donors ≥30 years and in female-to-male transplants. Among 105 patients requiring systemic steroids, 64% achieved complete response, 32% discontinued immunosuppression, yet 18% developed cGVHD-related sequelae. Mouth ulcers and erythema, as well as a lung score ≥2 at steroid initiation independently predicted shorter failure-free survival. At 2 years, overall survival, cGVHD-free relapse-free survival, and GVHD-free relapse-free survival were 76% (95% CI: 72-79), 63% (95% CI: 60-68), and 57% (95% CI: 53-62), respectively. In conclusion, after HCT with PTCy-based prophylaxis, systemic therapy was required in only a minority of patients, with risk influenced by donor age and sex mismatch rather than donor type. While corticosteroids were generally effective, a substantial subset required salvage therapy, underscoring the burden of refractory cGVHD and the need for steroid-sparing approaches and novel interventions.

HLA-haploidentical hematopoietic stem cell transplantation in patients with sickle cell disease: results from the phase II DREP-HAPLO trial

Thu, 11 Dec 2025 00:00:00 +0000

We report the final analysis of the DREP-HAPLO multicenter phase II protocol, which evaluated haploidentical transplantation after a reduced-intensity conditioning regimen incorporating thiotepa, in children and adults with severe sickle cell disease (SCD). Twenty-two patients (median age, 17 years; range, 12-40) received a conditioning regimen consisting of 2 Gy total body irradiation, thymoglobulin, cyclophosphamide, fludarabine, and thiotepa, followed by T-cell–replete bone marrow infusion and graft-versus-host disease (GvHD) prophylaxis based on post-transplant cyclophosphamide. The primary endpoint, event-free survival, defined as survival without graft failure and without moderate-to-severe chronic GvHD, was 68.18% (95% confidence interval [95% CI]: 51.25%-90.70%) and 61.98% (95% CI: 44.07%-87.19%) at 1 and 4 years, respectively. Overall survival and rejection-free survival at 4 years were 90.15% (95% CI: 78.03%-100%) and 85.56% (95% CI: 71.63%- 100%), respectively. Six patients (27%) developed moderate-to-severe GVHD. In most cases (4/6) GvHD resolved, leaving only two patients (9%) with persistent moderate-to-severe GvHD at their last follow-up. Eighty-five grade 2 to 4 infectious episodes were reported in 21 patients during the 24 months of follow-up, most of which were bacterial (38 cases). These data strengthen existing evidence supporting the feasibility of haploidentical transplantation in both pediatric and adult patients with severe SCD, demonstrating a very low rejection rate when thiotepa is incorporated into the conditioning regimen. Future efforts should focus on reducing chronic GvHD and infection rates.

Imetelstat improves patient-reported outcomes and quality of life in lower-risk myelodysplastic syndromes: results from the phase III IMerge study

Thu, 22 Jan 2026 00:00:00 +0000

Red blood cell (RBC) transfusions for anemia associated with lower-risk myelodysplastic syndromes/neoplasms (LR-MDS) often contribute to reduced quality of life (QOL). Thus, reduction in RBC transfusion dependency (TD) is a primary therapeutic goal. Imetelstat is a first-in-class, competitive telomerase inhibitor approved to treat certain adult patients with LRMDS with RBC-TD anemia who have not responded to, have lost response to, or are ineligible for erythropoiesis-stimulating agents. In the phase III IMerge study (clinicaltrials.gov identifier: NCT02598661), treatment with imetelstat resulted in clinically meaningful, statistically significant increases in the primary endpoint of ≥8-week RBC transfusion independence (TI) versus placebo. Because patients with LR-MDS experience detrimental effects on numerous facets of QOL (physical, emotional, social, and functional), these exploratory analyses assessed patient-reported outcomes using the Functional Assessment of Chronic Illness Therapy-Fatigue, Quality of Life in Myelodysplasia Scale, and Functional Assessment of Cancer Therapy-Anemia questionnaires as part of the phase III IMerge study. Nominal P values were reported. Fewer imetelstat-treated patients experienced deterioration in fatigue levels and more imetelstat-treated patients experienced sustained improvement in fatigue levels and QOL versus placebo. In the imetelstat group, 8-week, 24-week, and 1-year RBC-TI responders had sustained improvements in predefined significance thresholds versus non-responders for fatigue (70%, 73%, and 88%, respectively, vs. 37%, 41%, and 44%, respectively; P<0.001, P=0.004, and P=0.002) and QOL across different measures of response (43-53% vs. 21-30%; P≤0.0126). These results suggest that treatment with imetelstat may be associated with improvement in QOL beyond fatigue while sustaining RBC-TI in patients with LR-MDS with RBC-TD anemia.

Metformin alleviates side effects and supports the resumption of interferon therapy in polycythemia vera and essential thrombocythemia

Thu, 27 Nov 2025 00:00:00 +0000

Interferon-α is emerging as the preferential cytoreductive therapy for polycythemia vera (PV) and essential thrombocythemia (ET) due to improved long-term outcomes over alternatives such as hydroxyurea. Historically, interferon-α therapy has been marked by high rates of adverse events and subsequently poor adherence. Long-acting formulations of interferon-α, i.e., ropeginterferon-α-2b (ropeg), improve tolerability. However, nearly half of ropeg-treated patients experience fatigue, arthralgias, or myalgias and 10-20% discontinue treatment or cannot tolerate maximal ropeg doses, due to adverse events. Herein, we report our retrospective experience of adjunct metformin therapy in 11 PV and ET patients who were intolerant of ropeg. Metformin improved ropeg-related fatigue and/or myalgias in ten of 11 patients. A complete hematologic response (CHR) was maintained in all six patients who had already achieved this prior to starting metformin, and a deepened hematologic response was observed in three of four patients after the addition of metformin. These encouraging results merit further evaluation in a randomized clinical study. Further, additional investigations are needed to elucidate the mechanism of interferon-α-mediated fatigue and myalgias and the mechanism of putative beneficial interaction between interferon-α and metformin.

Immunomodulatory role of megakaryocytes in the hematopoietic niche of myeloproliferative neoplasms

Xiaoxi Yang, Sandy Lee, Kyla Masarik, Tameena Ahmed, Lei Zheng, Huichun Zhan — Thu, 22 Jan 2026 00:00:00 +0000

Myeloproliferative neoplasms (MPN) are clonal stem cell disorders characterized by dysregulated megakaryopoiesis and expansion of neoplastic hematopoietic stem cells (HSC). Megakaryocytes (MK) not only regulate HSC function, but also shape immune responses within the marrow niche. Using an aging murine model of MPN with MK-restricted JAK2V617F expression, we investigated the immunomodulatory roles of mutant MK. Compared to wild-type MK, aged mutant MK exhibit enhanced antigen uptake and MHC I presentation, secretion of pro-inflammatory cytokines (PF4, TGFβ, IL-1β), and induction of T-cell dysregulation in the marrow niche. In chimeric murine models with co-existing wild-type and JAK2^V617F mutant hematopoietic cells, enhanced MK immune activity correlates with mutant cell expansion and MPN development. Single-cell RNA sequencing revealed that aging amplifies JAK2V617F MK–driven immune remodeling. Notably, aged mutant MK showed marked upregulation of long-interspersed element-1 (LINE-1) retrotransposon transcripts alongside elevated innate immune sensors cyclic GMP–AMP synthase (cGAS) and stimulator of interferon genes (STING), implicating retrotransposon activity in niche inflammation. In human MPN marrow, immunohistochemistry detected LINE-1–encoded protein ORF1p in MK from 12 of 13 MPN patients, but not in orthopedic controls (N=5). These findings identify MK as active immune regulators in MPN, with JAK2^V617F mutation and aging synergizing to reprogram MK into inflammatory, immune-modulatory niche cells. LINE-1 activation emerges as a potential driver of chronic marrow inflammation, and a targetable mechanism in clonal hematopoiesis and MPN progression.

Metabolic syndrome and risk of monoclonal gammopathy of undetermined significance: a large Korean cohort study

Thu, 29 Jan 2026 00:00:00 +0000

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell disorder with a risk of progression to multiple myeloma. Metabolic syndrome (MetS) is implicated in cancer development, yet its association with MGUS remains unclear. We examined MetS as a risk factor for MGUS in a large Korean cohort. In a retrospective cohort study using the National Health Information Database, we analyzed 4,453,504 adults undergoing health checkups in 2012, followed through up to 2022. MetS was defined by NCEP-ATP III criteria. Over a median 9.3-year follow-up, 1,241 MGUS cases were identified. MetS was associated with a 28% increased MGUS risk (hazard ratio [HR]=1.28; 95% confidence interval [CI]: 1.14- 1.44). Risk escalated with more MetS components, peaking at 76% for five components (HR=1.76; 95% CI: 1.35-2.30). Low high-density lipoprotein cholesterol, hypertension, and central obesity were key risk factors, with higher risks in males and younger adults (range, 20-39 years). Longitudinal analysis showed MetS onset (HR=1.25; 95% CI: 1.06-1.47) or persistence (HR=1.25; 95% CI: 1.06-1.48) increased MGUS risk compared to persistent MetS absence, whereas MetS resolution showed no significant risk increase over persistent MetS absence. MetS increases MGUS risk, particularly in males and younger individuals. Resolving MetS may mitigate MGUS risk, supporting targeted metabolic interventions.

Increasing daily step counts improves physical fitness, and reduces pain and arterial stiffness in sickle cell patients

Thu, 05 Feb 2026 00:00:00 +0000

Patients with sickle cell anemia (SCA) have long been discouraged from physical activity (PA). The aim of the present study was to assess the impact of increasing daily step counts on physical fitness, pain and vascular function in patients with SCA. Thirty-eight patients with SCA were recruited and equipped with a Fitbit wrist-worn accelerometer-based PA tracker for five weeks to objectively quantify their baseline daily step counts. Patients were then randomly assigned to one of three groups: 1) control group - no specific information regarding PA was given for eight weeks (N=12); 2) PA1 group - daily step counts increased by 25% of baseline for eight weeks (N=12); 3) PA2 group - daily step counts increased by 25% for four weeks, then by 50% for an additional four weeks (N=14). Pain intensity and frequency decreased after the intervention in the PA1 and PA2 groups. In addition, patients from these two groups increased the distance walked in six minutes. Arterial stiffness decreased in both PA1 and PA2 groups, without any change in the autonomic nervous system activity. Several inflammatory markers slightly decreased in the PA2 group. Incubation of cultured endothelial cells with patient plasma showed a decrease in the percentage of ICAM-1 positive cells in the PA2 group. This study is the first to show that adopting a simple approach to increase daily PA (i.e., increasing daily step count by 25-50%) for eight weeks is sufficient to decrease pain, and improve physical condition and vascular function of patients with SCA.

Incidence and outcomes of treatment-associated hepatotoxicity during pediatric acute lymphoblastic leukemia induction therapy: a Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium report

Thu, 22 Jan 2026 00:00:00 +0000

Abrupt ferritin increases as a marker of cancer in transfusion-dependent thalassemia

Thu, 15 Jan 2026 00:00:00 +0000

IDH1-mutated B-cell acute lymphoblastic leukemia characterized by oncogenic reprogramming of lipid metabolism

Thu, 08 Jan 2026 00:00:00 +0000

Hematologic complications in patients exposed to poly- ADP ribose polymerase inhibitors

Thu, 29 Jan 2026 00:00:00 +0000

De novo mutations in antithrombin deficiency: high frequency and heterogeneous mechanisms

Thu, 29 Jan 2026 00:00:00 +0000

Myelodysplastic syndrome with cryptic 5q deletions in young male patients showing sustained response to lenalidomide

Thu, 29 Jan 2026 00:00:00 +0000

Clinical and sociodemographic predictors of intensive care unit admission following chemotherapy in acute myeloid leukemia

Thu, 15 Jan 2026 00:00:00 +0000

Performance of commonly used risk triage tools in predicting clinical deterioration among hospitalized hematopoietic stem cell transplant recipients

Brenna Park-Egan, Catherine L. Hough, Patrick G. Lyons, Laura F. Newell — Thu, 15 Jan 2026 00:00:00 +0000

National-level dietary patterns and acute myeloid leukemia: a global ecological analysis

Thu, 29 Jan 2026 00:00:00 +0000

Thrombophilia screening in patients with autoimmune hemolytic anemia: a single-center analysis

Thu, 22 Jan 2026 00:00:00 +0000

Real-world effectiveness and safety of belantamab mafodotin monotherapy in patients with relapsed/ refractory multiple myeloma treated in Europe

Thu, 22 Jan 2026 00:00:00 +0000

Recombinant von Willebrand Factor (vonicog alfa) reduces platelet inhibition caused by antiplatelet drugs and has potential as an acute haemostatic agent

Thu, 22 Jan 2026 00:00:00 +0000

Lactoferrin reduces febrile neutropenia in children receiving chemotherapy for hematologic malignancies: a randomized, placebo-controlled trial

Thu, 29 Jan 2026 00:00:00 +0000

Diabetes mellitus and diabetes-related complications are common in patients with myelodysplastic syndromes but Hemoglobin A1C is an inadequate marker

Thu, 29 Jan 2026 00:00:00 +0000

First-line tagraxofusp leads to durable responses and prolonged survival in adults with blastic plasmacytoid dendritic cell neoplasm regardless of fitness level

Thu, 15 Jan 2026 00:00:00 +0000

Frontline ponatinib plus hyper-CVAD over imatinib in adults with Ph-positive acute lymphoblastic leukemia: realworld efficacy and risks of early ponatinib dose reduction

Thu, 29 Jan 2026 00:00:00 +0000

A lower-intensity, venetoclax-containing protocol is effective in adults with newly diagnosed mixedphenotype acute leukemia

Thu, 12 Feb 2026 00:00:00 +0000

Second primary malignancy in multiple myeloma: does a prior malignancy matter?

Thu, 05 Feb 2026 00:00:00 +0000

Multilineage involvement in ABL-class fusion–positive pediatric B-cell acute lymphoblastic leukemia: CML-like biology

Thu, 28 Aug 2025 00:00:00 +0000

Clonal origin tracing and integrated biomarker analysis in a JAK2^V617F-positive essential thrombocythemia patient progressing to T-cell acute lymphoblastic leukemia

Yewei Wang, Doudou Tang, Zhao Cheng, Lingyan Ding, Yang Zhang, Guangsen Zhang — Thu, 26 Feb 2026 00:00:00 +0000

Relapsing, steroid-refractory ICANS after CAR T-cell therapy: diagnostic work-up and response to delayed repeated intrathecal chemotherapy

Thu, 05 Mar 2026 00:00:00 +0000

Treatment of leukemic ocular infiltrations with intraarterial chemotherapy in very early mixed relapse of B-cell acute lymphoblastic leukemia

Thu, 07 May 2026 00:00:00 +0000

Response to Comment on: “Clinical interrogation of TP53 aberrations and its impact on survival in patients with myeloid neoplasms”

Jayastu Senapati, Naval G. Daver — Thu, 09 Oct 2025 00:00:00 +0000

Comment on: “Clinical interrogation of TP53 aberrations and its impact on survival in patients with myeloid neoplasms”

Hamza Sajid — Thu, 09 Oct 2025 00:00:00 +0000

HLA matching in the PTCy era: the locus still matters. Comment on: “Selection of unrelated donors for allogeneic transplantation using post-transplant cyclophosphamide in acute lymphoblastic leukemia: an analysis by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation”

Nihar Desai, Jonas Mattsson — Thu, 11 Sep 2025 00:00:00 +0000

Response to Comment on: “Selection of unrelated donors for allogeneic transplantation using post-transplant cyclophosphamide in acute lymphoblastic leukemia: an analysis by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation”

Jaime Sanz, Mohamad Mohty, Fabio Ciceri — Thu, 18 Sep 2025 00:00:00 +0000

Erratum to: “Isatuximab plus bortezomib, lenalidomide, and dexamethasone for transplant-ineligible newly diagnosed multiple myeloma patients: a frailty subgroup analysis of the IMROZ trial”

Wed, 01 Jul 2026 00:00:00 +0000

Haematologica

A potent and manipulable graft-versus-leukemia effect underpins the increasingly important role of transplantation in acute myeloid leukemia

Stable, thus in critical condition: m6A-methylated fusion transcripts in B-cell acute lymphoblastic leukemia

Exploiting metabolic dependencies in acute myeloid leukemia: DHODH inhibition meets lipid and cholesterol metabolism

Genomic proximity mapping: a promising nextgeneration cytogenomic assay for comprehensive assessment of acute myeloid leukemia

Haploidentical transplantation in sickle cell disease: toward donor availability for all patients

The patient voice: measuring what matters in lower-risk myelodysplastic syndromes treated with imetelstat

Metformin: interferon’s new dancing partner?

CML-like biology: BCR::ABL1 and beyond

Introduction to the Review Series. Chronic myeloid leukemia in 2026

Prognostic factors in chronic myeloid leukemia: at diagnosis and for treatment-free remission

Is there a best frontline therapy in chronic myeloid leukemia?

Understanding drug resistance in chronic myeloid leukemia through the lens of leukemic stem cell states: insights from single-cell analyses

Intrinsic cellular resistance to BCR::ABL1 inhibitors

Management of chronic myeloid leukemia with tyrosine kinase inhibitors: adverse events, toxicities and therapy dosing

Improving quality of life for patients with chronic myeloid leukemia through supportive care, low-dose therapy, switching, and treatment-free remission

Chromosomal rearrangement-enhanced mRNA stability drives the oncogenic potential of fusion genes in pediatric leukemia

Interleukin signaling mitigates the inhibitory effects of combined Src/BCR-ABL1 blockade on T-cell activity in Philadelphia chromosome-positive acute lymphoblastic leukemia

Potent synergy of DHODH and SREBP inhibition in acute myeloid leukemia via disruption of cholesterol and lipid metabolism

Evaluation of acute myeloid leukemia using genomic proximity mapping-based next generation cytogenomics

Hypomethylating agents plus venetoclax versus intensive chemotherapy in acute myeloid leukemia with chromosome 5 and 7 abnormalities

Selective lymphodepletion underlies the efficacy of horse anti-thymocyte globulin-based immunosuppressive therapy in aplastic anemia

Chronic graft-versus-host disease in the era of posttransplant cyclophosphamide

HLA-haploidentical hematopoietic stem cell transplantation in patients with sickle cell disease: results from the phase II DREP-HAPLO trial

Imetelstat improves patient-reported outcomes and quality of life in lower-risk myelodysplastic syndromes: results from the phase III IMerge study

Metformin alleviates side effects and supports the resumption of interferon therapy in polycythemia vera and essential thrombocythemia

Immunomodulatory role of megakaryocytes in the hematopoietic niche of myeloproliferative neoplasms

Metabolic syndrome and risk of monoclonal gammopathy of undetermined significance: a large Korean cohort study

Increasing daily step counts improves physical fitness, and reduces pain and arterial stiffness in sickle cell patients

Incidence and outcomes of treatment-associated hepatotoxicity during pediatric acute lymphoblastic leukemia induction therapy: a Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium report

Abrupt ferritin increases as a marker of cancer in transfusion-dependent thalassemia

IDH1-mutated B-cell acute lymphoblastic leukemia characterized by oncogenic reprogramming of lipid metabolism

Hematologic complications in patients exposed to poly- ADP ribose polymerase inhibitors

De novo mutations in antithrombin deficiency: high frequency and heterogeneous mechanisms

Myelodysplastic syndrome with cryptic 5q deletions in young male patients showing sustained response to lenalidomide

Clinical and sociodemographic predictors of intensive care unit admission following chemotherapy in acute myeloid leukemia

Performance of commonly used risk triage tools in predicting clinical deterioration among hospitalized hematopoietic stem cell transplant recipients

National-level dietary patterns and acute myeloid leukemia: a global ecological analysis

Thrombophilia screening in patients with autoimmune hemolytic anemia: a single-center analysis

Real-world effectiveness and safety of belantamab mafodotin monotherapy in patients with relapsed/ refractory multiple myeloma treated in Europe

Recombinant von Willebrand Factor (vonicog alfa) reduces platelet inhibition caused by antiplatelet drugs and has potential as an acute haemostatic agent

Lactoferrin reduces febrile neutropenia in children receiving chemotherapy for hematologic malignancies: a randomized, placebo-controlled trial

Diabetes mellitus and diabetes-related complications are common in patients with myelodysplastic syndromes but Hemoglobin A1C is an inadequate marker

First-line tagraxofusp leads to durable responses and prolonged survival in adults with blastic plasmacytoid dendritic cell neoplasm regardless of fitness level

Frontline ponatinib plus hyper-CVAD over imatinib in adults with Ph-positive acute lymphoblastic leukemia: realworld efficacy and risks of early ponatinib dose reduction

A lower-intensity, venetoclax-containing protocol is effective in adults with newly diagnosed mixedphenotype acute leukemia

Second primary malignancy in multiple myeloma: does a prior malignancy matter?

Multilineage involvement in ABL-class fusion–positive pediatric B-cell acute lymphoblastic leukemia: CML-like biology

Clonal origin tracing and integrated biomarker analysis in a JAK2V617F-positive essential thrombocythemia patient progressing to T-cell acute lymphoblastic leukemia

Relapsing, steroid-refractory ICANS after CAR T-cell therapy: diagnostic work-up and response to delayed repeated intrathecal chemotherapy

Treatment of leukemic ocular infiltrations with intraarterial chemotherapy in very early mixed relapse of B-cell acute lymphoblastic leukemia

Response to Comment on: “Clinical interrogation of TP53 aberrations and its impact on survival in patients with myeloid neoplasms”

Comment on: “Clinical interrogation of TP53 aberrations and its impact on survival in patients with myeloid neoplasms”

Response to Comment on: “Selection of unrelated donors for allogeneic transplantation using post-transplant cyclophosphamide in acute lymphoblastic leukemia: an analysis by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation”

Erratum to: “Isatuximab plus bortezomib, lenalidomide, and dexamethasone for transplant-ineligible newly diagnosed multiple myeloma patients: a frailty subgroup analysis of the IMROZ trial”

Clonal origin tracing and integrated biomarker analysis in a JAK2^V617F-positive essential thrombocythemia patient progressing to T-cell acute lymphoblastic leukemia