RARE DISEASE
Chronic myelomonocytic leukemia
Chronic myelomonocytic leukemia
Chronic myelomonocytic leukemia
Synonyms: CMML
Synonyms: CMML
Synonyms: CMML
Drug discovery
5
drugs
With orphan designations
Overview
Chronic myelomonocytic leukemia (CMML) is a rare clonal hematopoietic malignancy classified as a myelodysplastic/myeloproliferative neoplasm, characterized by persistent peripheral monocytosis (≥1×10⁹/L), dysplasia, and variable risk of progression to acute myeloid leukemia (15-30%) [1][5][20]. Pathogenesis involves mutations in epigenetic regulators (TET2, ASXL1), spliceosome components (SRSF2), and signaling pathways, driving both proliferative and dysplastic features [5][15][17]. Diagnosis requires exclusion of BCR::ABL1 and other MPNs [20].
Burden
Global ASIR: 0.31/100,000 (2017), with higher mortality in low-SDI regions [4][9]
Median survival: 12-36 months; 5-year OS <20% in advanced stages [11][17]
Economic impact: High costs of tyrosine kinase inhibitors and HSCT contribute to healthcare disparities, particularly in resource-limited settings [4][9]
Key challenges include frequent transfusion dependence (24% at diagnosis) and limited durable responses to non-transplant therapies [17][18].
Therapies
Risk-adapted approach: Hypomethylating agents (azacitidine) for high-blast/cytopenic subtypes; hydroxyurea for proliferative phenotypes (WBC ≥13×10⁹/L) [3][8][13]
Curative intent: Allogeneic stem cell transplant (limited to younger, fit patients) [13][16]
Supportive care: Transfusions, erythropoiesis-stimulating agents, and infection prophylaxis [3][6][18]
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
875 drug discovery papers about Chronic myelomonocytic leukemia, with 1 first-in-class and 13 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
875 drug discovery papers about Chronic myelomonocytic leukemia, with 1 first-in-class and 13 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-27 | [Effects of HMA and HU/BSC on prognosis in patients with intermediate-and high-risk chronic myelomonocytic leukemia, and characteristics of clonal evolution and inflammatory cytokines in progressive cases after HMA treatment].
Objective: To explore the prognostic impact of hypomethylating agents (HMA) versus hydroxyurea plus best supportive care (HU/BSC) in patients with intermediate-and high-risk chronic myelomonocytic leukemia (CMML), and to analyze the patterns of clonal evolution and dynamic changes of inflammatory cytokines in patients with disease progression before and after HMA treatment. Methods: A total of 63 patients diagnosed with intermediate-and high-risk CMML admitted to the Department of Hematology, the Second Hospital of Tianjin Medical University between October 20 2017 and May 8 2025 were retrospectively enrolled. All patients were followed up every 3 months via outpatient and inpatient visits after discharge, with the last follow-up conducted on February 28, 2026. According to treatment regimens, the patients were divided into HMA group (n=31) and HU/BSC group (n=32). Treatment response, disease progression and survival outcomes were compared between the 2 groups. The Kaplan-Meier method was used to plot the survival curves of overall survival (OS) and progression-free survival (PFS). Bone marrow DNA was collected from patients with disease progression before and after treatment with HMA (n=20) and HU/BSC (n=13). Next-generation sequencing was used to detect 325 mutated genes related to hematological malignancies, and the clonal evolution of gene mutations in patients receiving the 2 treatment regimens before and after disease progression was investigated. Bone marrow supernatant specimens were collected from patients with disease progression treated with HMAs (n=8) and HU/BSC (n=8), and enzyme-linked immunosorbent assay (ELISA) was used to measure the expression levels of 21 inflammatory cytokines including IL-6 and IFN-γ. The differences in inflammatory cytokine expression before and after disease progression were compared. Results: The median follow-up duration for all patients [M(Q1,Q3)] was 21 (10, 40) months. The median OS was 22.0 months (95%CI: 11.8-32.2) in the HMA group and 36.0 months (95%CI: 23.6-48.4) in the HU/BSC group, with no statistically significant difference between groups (P=0.208). The median PFS was 18.0 months (95%CI: 10.8-25.2) and 26.0 months (95%CI: 19.9-21.1) respectively, and the difference was also not statistically significant (P=0.108). Among patients with disease progression after HMA treatment, newly acquired mutations were predominantly enriched in RAS pathway genes, accounting for 25% (5/20). Clonal expansion of SF3B1, TP53 and RUNX1 was observed, and the mutational burden of each gene accounted for 10% (2/20). Compared with baseline levels, the concentrations of TNF-α [113.6 (104.1, 147.1) pg/ml vs 25.7 (20.2, 41.3) pg/ml, P<0.001] and IL-8 [77.5 (54.6, 115.8) pg/ml vs 7.0 (2.6, 9.2) pg/ml, P=0.003] were significantly increased after disease progression, while the level of IFN-γ [341.5 (221.2, 460.7) pg/ml vs 732.7 (389.0, 852.4) pg/ml, P=0.013] was markedly decreased. Conclusions: Compared with HU/BSC regimen, HMA failed to significantly improve OS and PFS in patients with intermediate-and high-risk CMML. Disease progression after HMA treatment may be closely associated with newly emerging mutations in the RAS pathway, clonal expansion of pre-existing mutations such as TP53, as well as the upregulation of TNF-α and IL-8 and downregulation of IFN-γ.
2026-07-22 | Dose schedule modifications of 5-azacitidine monotherapy in myelodysplastic neoplasias and chronic myelomonocytic leukaemia.
5-azacitidine (5-AZA) is the first hypomethylating agent synthetized and the cornerstone treatment for high-risk myelodysplastic neoplasms (MDS) and chronic myelomonocytic leukaemia (CMML). Although the validated schedule is 75 mg/m2 for 7 days (7-0-0), alternative schedules have been studied in terms of efficacy, complications and survival. The 7-0-0 shows an overall survival (OS) between 21 and 25 months in prospective and 16.5-27 months in retrospective studies and complete response (CR) rates between 7% and 18%. Alternative schedules, mostly 5-day (5-0-0) or 7-day with weekend pause (5-2-2) at 75 mg/m2, perform equally in terms of OS and CR with the 7-0-0, with a slight superiority for the 5-2-2, although direct comparisons are rare and almost always non-significant. Similarly, transfusion independence, time to leukaemia transformation and toxicities did not differ significantly across studies. For more intensive schedules, using 100 mg/m2 for 5 days, literature is limited, but response rates, survival and safety seem to be comparable to the 75 mg/m2 dose. In CMML, 5-AZA monotherapy yields satisfying overall response rates of 40% or more, with myelodysplastic subtype responding better than myeloproliferative. In all, alternative 5-AZA schedules seem non-inferior in terms of efficacy and toxicities and can be used as an alternative according to local protocols and patient choice.
2026-07-16 | Incidence, molecular and clinical characteristics of donor-derived hematologic malignancies after allogeneic stem cell transplantation for myeloid malignancies.
Allogeneic stem cell transplantation (allo-SCT) is the only potentially curative approach for several high-risk hematologic malignancies, but high relapse rates remain a challenge. Most relapses derive from the original malignant clone or its descendants. Occasionally, secondary blood cancers arise from transplanted donor cells and are referred to as donor-derived malignancies (DDMs). To assess the incidence of DDM at our center we performed a retrospective observational study on all evaluable patients allo-transplanted for myeloid malignancies in the Dept. of SCT of UMC Hamburg-Eppendorf between 1990 and 2024. Until the end of the observation (12/2025), we observed 791 relapses after 2827 allo-SCTs (28%). For 751 (94.9%) of the relapses, material was available for detailed molecular analysis. Three myeloid malignancies (CMML, MDS, AML) were unambiguously identified as DDMs (two from matched related, one from an unrelated donor) corresponding to low frequencies of 0.1% of all transplants and 0.4% of analyzed relapses. Notably, in no case we found mutations in typical germline predisposition genes (DDX41, RUNX1, GATA2, CEBPA), whereas mutations associated with CHIP (ASXL1, TET2, DNMT3A, CBL, U2AF1) were detected in all DDMs. In conclusion, comprehensive data from this - to our knowledge largest - single-center study covering almost 3,000 consecutive transplants over a period of 35 years supports a low overall incidence of DDMs and a potential role of donor-derived clonal hematopoiesis in their development.
2026-07-08 | Inflammatory signatures in the spectrum of myeloid diseases.
Dysregulated innate immunity contributes to clonal cytopenias and myeloid neoplasms, but its extent across disease stages and clinical relevance remain incompletely defined. We analyzed plasma ASC/NLRP3 double-positive (DP) specks, ASC single-positive (SP) specks, and 45 cytokines in 223 patients with idiopathic cytopenias of undetermined significance (ICUS)/clonal cytopenias of undetermined significance (CCUS), myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML) and 39 matched non-inflammatory controls using adjusted regression, survival modeling, and paired longitudinal analyses. Inflammasome activation and cytokine perturbations were evident across the disease spectrum. DP-ASC specks were elevated in MDS and CMML, whereas SP-ASC specks were increased across all groups, indicating activation of ASC-containing inflammasomes beyond NLRP3. Cytokines followed a graded ICUS → MDS → CMML pattern, with widespread upregulation of interleukins and chemokines (including IL-7, IL-8, IL-11/CXCL11, and CCL7) alongside suppression of stem and progenitor support factors such as CSF3, FLT3LG, TRAIL, and TWEAK. At baseline, elevated IL-15 and MMP1 predicted progression to acute myeloid Leukaemia, while higher IL-10, CXCL8, and IL-18 were associated with reduced survival; ASC specks were not independently prognostic. Longitudinal increases in selected cytokines distinguished progressors (area under the curve 0.82; 95% CI: 0.49-1.0). Cytokine patterns correlated with mutation categories, with the isolated SF3B1 mutation associated with higher DP-ASC specks. These findings define early and progressive inflammasome engagement and nominate dynamic cytokine panels and the inflammasome-IL-1 axis as actionable biomarkers and therapeutic targets.
2026-07-01 | A Phase Ib/II study of ceralasertib, a selective inhibitor of ATR, in patients with relapsed or refractory MDS and CMML.
Pre-mRNA splicing gene mutations are common in MDS and CMML and induce R-loops which trigger ATR activation. We studied ceralasertib, an orally bioavailable ATR inhibitor, in adult patients with R/R MDS or CMML in a phase Ib/II study including a safety run-in and expansion of 160mg BID during a 28-day cycle on two schedules: days 1-14 (14on/14off) or days 1-7 and 15- 21 (7on/7off). Response rates and survival were estimated. Forty-four evaluable patients were treated. Grade 3 or higher all-cause adverse events in 10% or more patients included thrombocytopenia (n=13), anemia (n=12), neutropenia (n=9), febrile neutropenia (n=9), pneumonia (n=6), and hypoxia (n=5). Thrombocytopenia requiring a platelet transfusion during the first cycle was reduced to 1 of 10 patients on 7on/7off compared to 8 of 16 patients on 14on/14off among patients with a baseline platelet count >50k (p=0.087). ORR was 29.5% (13 of 44 patients) and included one CR, 5 marrow CR (2 with HI-N), and 7 with HI (HI-E=4, HI-N=2, HI-P=1). Median PFS was 4.8mo and OS was 12 months (95%CI 11, 24). ORR (p=0.72), PFS (p=0.9) and OS (p=0.65) did not differ between schedules. While splicing factor mutation VAFs were stable, RUNX1 mutation VAFs typically increased at progression. Serum inflammatory cytokine levels including TNFRSF8 (CD30) and other TNF family members decreased during ceralasertib exposure; this effect was blunted in RUNX1 mutant samples. In conclusion, ceralasertib 160mg BID d1-7 and 15-21 was established as monotherapy dosing with a response rate of 30% in patients with R/R MDS and CMML. NCT03770429.
cell therapies
2026-07-25 | Risk-Adjusted Comparison of Survival in Chronic Myelomonocytic Leukemia With and Without Allogeneic Stem Cell Transplant: Mayo Clinic Experience in 775 Consecutive Patients.
The recently published BLAST clinical risk model for chronic myelomonocytic leukemia (CMML) and its molecular version (BLAST-Mol) differentiate low, intermediate, and high-risk groups. The objective of the current retrospective study was to examine the survival impact of allogeneic stem cell transplant (ASCT) in a consecutive series of Mayo Clinic patients (n = 775; 68% males, median age 71 years) with CMML, overall and adjusted for baseline BLAST/BLAST-Mol risk categories. At a median follow-up of 77 months, 151 (20%) patients underwent ASCT. Overall survival (OS) was longer in the ASCT compared to the non-ASCT cohorts (median 77 vs. 28 months; p < 0.01). The significant difference in OS between the ASCT and non-ASCT cohorts was retained after adjusting for BLAST clinical risk groups: high-risk (median 50 vs. 14 months; p < 0.01), intermediate-risk (81 vs. 28 months; p < 0.01), and low-risk (111 vs. 65 months; p = 0.04), respectively. The same was mostly the case when OS comparison was adjusted for BLAST-Mol with respective p values of < 0.01, < 0.01, and 0.08, respectively. Time-dependent cox models confirmed the favorable survival impact of ASCT in the BLAST/BLAST-Mol high- and intermediate-risk groups. The current study highlights the benefit of ASCT for BLAST/BLAST-Mol high- and intermediate-risk groups in CMML and its potential to overcome the adverse impact of some high risk cytogenetic or molecular abnormalities. These observations support the early use of ASCT in CMML, ideally before BT and regardless of genetic characteristics.
2026-06-08 | Comparative efficacy of donor lymphocyte infusions in augmenting graft-versus-leukemia effect after allogeneic hematopoietic stem cell transplantation for patients with myeloid malignancies.
The efficacy of donor lymphocyte infusions (DLI) among various myeloid malignancies (particularly, genetic subtypes) and the optimal timing of DLI initiation remains unclear. This was a retrospective study of 62 patients with myeloid malignancies treated with an alloHSCT and DLI from years 2001-2022. DLI indication was therapeutic 55 (89%), pre-emptive 6 (10%) and prophylactic 1 (2%) with complete remission (CR/CRi) in twenty patients with common diagnoses being 9 (45%) acute myeloid leukemia, 6 (30%) myelodysplastic syndromes, and 3 (15%) chronic myelomonocytic leukemia among others. Among patients who received therapeutic DLI (n=55), the best response was CR/CRi in 16 (29%) patients. At a median follow-up from the date of DLI of 75 (95% CI 35-121) months, there were 49 (79%) deaths with a median OS of 6 (95% CI 4-14) months, higher in patients in CR/CRi versus no CR/CRi (median 51 versus 4 months, P=0.008). Presence of cytogenetic abnormalities such as complex karyotype, deletions in chromosome 5, 7 and 17p, and mutations in TP53, KRAS, NRAS, RUNX1 or JAK2 were associated with adverse outcomes. DLI is an effective treatment strategy for post-transplant relapse of all myeloid malignancies, with specific genetic subtypes showing poorer outcomes and survival.
2026-04-09 | Survival benefit of allogeneic HSCT in CMML patients during the molecular stratification era.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option for chronic myelomonocytic leukemia (CMML), yet the population benefit from HSCT and the optimal timing of HSCT remain controversial. Current guidelines, largely based on older CPSS criteria and retrospective data, may not reflect recent advances in transplant techniques and molecular stratification systems. This multicenter retrospective analysis included 389 adult CMML patients from 14 Chinese centers (2015-2023), aiming to reassess the survival benefit of allo-HSCT in a large multicenter cohort within the molecular era. Among all patients, 145 (37.3%) underwent allo-HSCT, including 68.3% from haploidentical donors. Risk stratification was performed using CPSS, MDAPS, CPSS-mol, and MMM systems. Landmark analysis set at day 148 (median transplant interval) was used to assess the effect of time-dependent covariates on long-term survival. The entire cohort had 1-, 3-, and 5-year overall survival (OS) rates of 82.7%, 55.5%, and 46.1%, respectively. In patients ≤70 years, allo-HSCT was associated with significantly improved 3-year OS in CPSS intermediate-1 (63.4% vs. 45.4%, p = 0.038) and intermediate-2 (60.2% vs. 38.7%, p = 0.049), MDAPS intermediate-1 (69.5% vs. 47.4%, p = 0.004), intermediate-2 (60.6% vs. 30.4%, p = 0.029), and high-risk (51.4% vs. 45.0%, p = 0.022), CPSS-mol intermediate-2 (59.8% vs. 39.0%, p = 0.046), and MMM high-risk groups (65.5% vs. 10.5%, p < 0.001). Landmark analysis confirmed sustained benefit in these subgroups. Haploidentical HSCT yielded outcomes comparable to matched donors. Multivariable analysis identified HSCT as an independent favorable factor for survival (HR = 0.619, p = 0.031). These findings advocate expanding transplant eligibility through integration of molecular stratification and modern HSCT platforms, particularly haploidentical protocols.
2025-12-11 | Single-Cell Analysis of Cell-Cell Signaling Pathways as a Strategy for Targeted Immunotherapy in Chronic Myelomonocytic Leukemia.
Chronic myelomonocytic leukemia (CMML) is a rare hematological disorder characterized by abnormal levels of monocytes and blasts in the blood, which accumulate in the bone marrow and impair normal blood cell production. Complex intercellular signaling and pathway dysregulation in this disease must be understood in depth to devise novel therapeutic strategies targeting the immune system. This present study employed exploration of CMML tumor microenvironment at the single-cell resolution via single-cell RNA sequencing data analysis elucidating distinct cell types and role of their differentially expressed marker genes in dysregulation of pathways contributing to impaired immune response and enhanced inflammatory response. Moreover, the intercellular communications observed via CellChat package revealed significant interactions among these cell types. Results revealed identification of diverse immune cells, including pro-B cells, pre-B cells, progenitor cells, platelets, ISG-expressing immune cells, erythroid-like and erythroid precursor cells, and cancer cells. Interestingly, downregulation of immune system associated pathways such as interleukins, cytokines signaling, and CSF3 growth factor pathway among neutrophils, and progenitor cells may give rise to impaired immune cells leading to the onset of immunocompromised environment. Moreover, the intercellular signaling pathway and communication analyses unveiled erythroid-like and erythroid precursor cells as crucial influencers, conveying signals that contribute to complexity of tumor microenvironment through major pathways such as MIF, GALECTIN, ICAM, CD86, CD80, CD22, COMPLEMENT, VEGF, CSF, and CD23. Intriguingly, MIF along with CD74, CXCR4, and CD74 appeared as the most significant player of activation of downstream signaling pathways.
2025-11-13 | Differential impact of graft-versus-host disease on post-transplant outcomes of chronic myelomonocytic leukemia according to transplant procedures.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides curative outcomes for chronic myelomonocytic leukemia (CMML). We conducted a retrospective study to clarify the protective impact of acute and chronic graft-versus-host disease (aGVHD and cGVHD) on relapse by transplant procedures in 314 CMML patients. Interaction effects of conditioning intensity were observed with aGVHD (Pinteraction=0.181) and cGVHD (Pinteraction=0.256) for the cumulative incidence of relapse (CIR), whereas interaction effects of donor type were not detected with GVHD. In patients with the myeloablative conditioning regimens, the multivariate analysis showed that the development of aGVHD was not associated with overall survival (OS). The development of limited cGVHD correlated with better OS (HR [95 % CI], 0.34 [0.14-0.81]; P = 0.015); and that of extensive cGVHD correlated with better OS (HR, 0.44 [0.21-0.91]; P = 0.026) and lower CIR (HR, 0.28 [0.08-0.94]; P = 0.040). In patients with the reduced-intensity conditioning regimens, the development of grade I-II aGVHD correlated with better OS (HR, 0.39 [0.20-0.76]; P = 0.005) and lower CIR (HR, 0.30 [0.13-0.70]; P = 0.006). The development of extensive cGVHD correlated with better OS (HR, 0.44 [0.20-0.96]; P = 0.039). The present results suggest that the type and severity of GVHD mediating graft-versus-leukemia effects against relapse were influenced by conditioning intensity in CMML patients.
proteins
2026-04-07 | Pathogenic TET2 Variants and Autoinflammatory Manifestations in Myeloid Hematologic Malignancies: Case Report and Literature Review.
Emerging evidence suggests that somatic mutations in genes associated with innate immunity can trigger adult-onset autoinflammatory diseases. Notably, loss-of-function variants in the TET2 gene have been linked to both hematological malignancies and immune-mediated disorders. A case is presented of a 73-year-old woman with chronic myelomonocytic leukemia who developed severe pericardial effusion secondary to inflammatory serositis, associated with a pathogenic TET2 variant. Despite initial treatment with corticosteroids and diuretics, her condition worsened, which led to the need to implement treatment with colchicine and anakinra. This regimen led to significant clinical improvement and resolution of the effusion. This case reflects the importance of searching for pathogenic variants in TET2 in patients with hematological disorders, with the aim of early recognition of inflammatory manifestations associated with this genetic alteration. Treatment with colchicine and anti-interleukin-1 should be considered in these cases, as they are effective and avoid the unnecessary use of other immunosuppressants. Cite this article as: Porto Fuentes Ó, de Paz Arias R, Álvarez Troncoso J. Pathogenic TET2 variants and autoinflammatory manifestations in myeloid hematologic malignancies: case report and literature review. Eur J Rheumatol. 2026, 13(1), 0119, doi:10.5152/eurjrheum.2026.24119.
2025-09-08 | Tagraxofusp, a CD123-targeted therapy, for chronic myelomonocytic leukemia: final results of a phase 1/2 study.
Chronic myelomonocytic leukemia (CMML) is an aggressive hematologic neoplasm characterized by an expansion of CD123+ monocytes and plasmacytoid dendritic cells (pDCs). pDC bone marrow clusters in CMML have been associated with higher rates of acute myeloid leukemia transformation. We evaluated tagraxofusp, a CD123-targeted therapy, in a phase 1/2 trial for patients with CMML. There were no dose-limiting toxicities. At the recommended phase 2 dose of 12 μg/kg per day, 37 patients were treated: 15 were treatment naïve; 22 had relapsed/refractory disease (median number of previous therapies, 1 [range, 1-7]). Common nonhematologic treatment-emergent adverse events (AEs) included fatigue (49%), hypoalbuminemia (46%), nausea, hypokalemia, and decreased appetite (44% each). Capillary leak syndrome occurred in 9 patients (23%; grade 3-4, 13%), whereas tumor lysis syndrome was seen in 13%. Hematologic grade 3/4 treatment-related AEs included thrombocytopenia (28%), anemia (13%), leukocytosis (15%), and neutropenia (13%). No complete or partial responses were observed. One patient each in the treatment-naïve and relapsed/refractory groups achieved complete cytogenetic remission with marrow response. Stable disease and clinical benefit were achieved by 40% and 27% of treatment-naïve patients and by 59% and 23% of relapsed/refractory patients, respectively. After a median follow-up of 43.7 months, overall survival was 11.2 months in treatment-naïve and 15.6 months in relapsed/refractory patients. Exploratory analysis showed stable CD123+ blast frequency, mutational variant allele frequencies, and monocyte subsets with treatment. Tagraxofusp demonstrated a manageable safety profile with limited clinical efficacy in CMML. This trial was registered at www.ClinicalTrials.gov as #NCT02268253.
2025-05-28 | Updated results of a phase 2 study: Timdarpacept (IMM01) combined with azacitidine (AZA) as the first-line treatment in adults with chronic myelomonocytic leukemia (CMML).
6577 Background: Timdarpacept is a recombinant signal regulatory protein α (SIRPα) IgG1 fusion protein that exerts anti-tumor activity via blocking “Don’t eat me” signal and activating the “Eat me” signal to induce strong antibody-dependent cellular phagocytosis (ADCP). Methods: The study (NCT05140811) assessed the safety and efficacy of Timdarpacept combined with AZA as first-line treatment for newly diagnosed CMML patients. Timdarpacept was administered intravenously at a dosage of 2.0mg/kg/week, while subcutaneous AZA was given at a dosage of 75 mg/m 2 on D1-7 per 28-day cycle. Results: At the cut-off date on Dec 31, 2024, 24 patients, with a median age of 62, males 62.5%, and 75.0% ECOG≥1, were enrolled. 33.3% and 66.7% patients were and high risk (HR), respectively. Majority of patients had poor baseline of hematologic conditions with a median hemoglobin (Hb) level of 69.5 (32-132) g/L and a median platelet (PLT) count of 73.5 (5-667)×10 9 /L. The median duration of follow-up was 21.0 months (95%CI, 19.3-23.3). Among 22 efficacy evaluable patients, overall response rate (ORR) was 72.7%, including 27.3% complete response (CR), 13.6% marrow CR (mCR) with hematologic improvement (HI), 4.5% HI and 27.3% mCR alone. The median time to response (TTR) was 1.8 months and the median duration of response (DoR) was 16.9 months (95%Cl, 5.1-not reached [NR]). The median time to CR (TTCR) was 3.7 months and the median duration of CR (DoCR) was 13.6 months (95%Cl, 5.7-NR). The median of progression-free survival (PFS) was 17.8 months (95%Cl, 5.3-NR), with an estimated 12-month PFS of 59.0% (95%Cl, 33.4-77.6). Median OS has not been reached yet. The most common ≥Grade 3 TRAEs (≥10%) included lymphopenia (66.7%), leukopenia (62.5%), neutropenia (58.3%), thrombocytopenia (50.0%), anemia (29.2%) and pneumonia (16.7%). Without using of a low dose priming regimen, Grade ≥3 hemolysis occurred in 1 patient (4.2%). Conclusions: Timdarpacept, without a low-dose priming, combined with AZA, was well tolerated in 1L CMML. The combination, when compared to the historical data of AZA monotherapy, showed promising efficacy results for patients with treatment-naive CMML-1 and -2. Clinical trial information: NCT05140811 .
2024-10-17 | Experience with luspatercept therapy in patients with transfusion-dependent low-risk myelodysplastic syndromes in real-world clinical practice: exploring the positive effect of combination with erythropoietin alfa.
Luspatercept, an inhibitor of the transforming growth factor beta (TGF-β) pathway, is a novel treatment for anemic patients with lower-risk myelodysplastic syndromes (MDS) with transfusion dependence (TD) who do not respond to erythropoiesis-stimulating agents (ESA) therapy or are not suitable candidates for this treatment. We present real-world experience with luspatercept therapy from two hematology centers in the Czech Republic. By January 2024, 54 MDS patients (33 men, 21 women) with a median age of 74 years (range, 55-95) were treated with luspatercept ± ESA at two Charles University hematology centers in Prague and Hradec Králové. According to the WHO 2016 classification, the cohort included 32 MDS-RS-MLD, seven MDS-MLD, two patients with 5q- + ring sideroblasts (RS), 12 RARS-T, and 1 patient with CMML-0 + RS. SF3B1 mutation data were available for 45 patients. All patients were in the IPSS-R and IPSS-M lower-risk groups (except four IPSS-M high). The median follow-up was 17 months (range, 1-54). All patients were transfusion-dependent. Thirty-five (64.8%) patients had a high transfusion burden (HTB) with ≥ 4 transfusion units (TU)/8 weeks, and 19 (35.2%) had a low transfusion burden (LTB) (< 4 TU/8 weeks). The median time between diagnosis and initiation of luspatercept was 27 months (range, 4-156). ESA were used prior to luspatercept in 45 patients, and luspatercept was used as first-line treatment in nine patients. Thirty-one (61%) patients were treated simultaneously with ESA. Only patients who received luspatercept for ≥ 8 weeks (51 patients) were assessed. We evaluated the achievement of transfusion independence (TI) lasting 8, 12, 16, and 24 weeks. Thirty-two (62.7%) patients achieved TI for ≥ 8 weeks, 31 (60.7%) for ≥ 12 weeks, 29 (56.8%) for ≥ 16 weeks, and 25 (49%) for ≥ 24 weeks. Hematologic improvement (HI) without TI was achieved in six patients (11.7%). Overall, HI + TI was achieved in 38 patients (74.5%). Epoetin alfa was used simultaneously in 31 patients (60.7%). In 21 (55.2%) of all responding patients, concomitant therapy with epoetin alfa led to an improved response, with 16 reaching TI. Thirteen (25.5%) patients were nonresponders. Eight (21%) patients experienced therapy failure and became transfusion-dependent again. Optimal response required a gradual increase in the luspatercept dose to 1.75 mg/kg in up to 35 patients, with 23 responders (TI + HI). Response rates varied by transfusion burden: 79% in LTB and 50% in HTB reached TI. Of RS+ patients, 70% reached TI, while only one out of five RS- patients achieved TI. Among 39 SF3B1-positive patients, 61.6% achieved TI. In the low and very low IPSS-M groups, 86% of patients responded (TI + HI), compared to 62% in the moderate-low group. Luspatercept was well-tolerated, with no adverse events higher than grade II toxicity. We have demonstrated in real-world clinical practice that luspatercept is a very effective agent, even in an unselected, pretreated, significantly TD MDS population. The effect was particularly high in the IPSS-M low and very low groups. We believe that the relatively high response rate in our patients was influenced by the frequent use of a higher dose (1.75 mg/kg) and especially by adding ESA to luspatercept in poorly responding patients.
2023-12-01 | NLRP3 inflammasome activation and symptom burden in KRAS-mutated CMML patients is reverted by IL-1 blocking therapy
Chronic myelomonocytic leukemia (CMML) is frequently associated with mutations in the rat sarcoma gene (RAS), leading to worse prognosis. RAS mutations result in active RAS-GTP proteins, favoring myeloid cell proliferation and survival and inducing the NLRP3 inflammasome together with the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which promote caspase-1 activation and interleukin (IL)-1β release. Here, we report, in a cohort of CMML patients with mutations in KRAS, a constitutive activation of the NLRP3 inflammasome in monocytes, evidenced by ASC oligomerization and IL-1β release, as well as a specific inflammatory cytokine signature. Treatment of a CMML patient with a KRASG12D mutation using the IL-1 receptor blocker anakinra inhibits NLRP3 inflammasome activation, reduces monocyte count, and improves the patient's clinical status, enabling a stem cell transplant. This reveals a basal inflammasome activation in RAS-mutated CMML patients and suggests potential therapeutic applications of NLRP3 and IL-1 blockers.
antibodies
2026-06-28 | Vibecotamab for measurable residual disease in acute myeloid leukemia and for myelodysplastic syndromes and chronic myelomonocytic leukemia after hypomethylating agent failure: a phase II study.
Acute myeloid leukemia (AML) with persistent measurable residual disease (MRD) and relapsed/refractory myelodysplastic syndromes (MDS) are low-blast myeloid diseases for which there are few effective therapeutic options. CD123 represents an attractive target in these diseases. Vibecotamab is a bispecific antibody that binds to CD123 on malignant blasts and to CD3 on T-cells, to recognize and eliminate CD123-positive malignant cells. This single-center phase II study evaluated the efficacy of vibecotamab in patients AML with detectable MRD (AML-MRD cohort) or with MDS or chronic myelomonocytic leukemia (CMML) after hypomethylating agent failure (MDS/CMML cohort). In cycle 1, patients received vibecotamab IV on day 1 (0.43 µg/kg), day 3 (0.75 µg/kg), day 5 (1.1 µg/kg), and days 8, 15 and 22 (1.7 µg/kg). In subsequent cycles, patients received vibecotamab IV on days 1, 8, 15, and 22 (1.7 µg/kg). The primary outcomes were MRD negativity rate (AML-MRD cohort) and overall response (MDS/CMML cohort). Between May 2022 and April 2025, 48 patients were enrolled (21 AML-MRD cohort, 27 MDS/CMML cohort). The median ages of the AML-MRD and the MDS/CMML cohorts were 70 and 76 years, respectively. In the AML-MRD cohort, the median MRD level by flow cytometry was 0.64% (range, 0.1-3.9%), and in the MDS/CMML, the median bone marrow blast percentage was 7% (range, 3-19%). The AML-MRD clearance rate was 19% (4/21; 95% CI 5-42%), and in the MDS/CMML cohort, the overall response rate was 67% (18/27; 95% CI 46-83%). The median overall survival was 13.1 months (95% CI 8.9-NR) for the AML-MRD cohort and 6.5 months (95% CI 4.2-10.3) for the MDS/CMML cohort. The most frequent adverse event was infusion reaction or cytokine relapse syndrome, which occurred in 29 patients (60%) overall, most of which were grade 1-2. Vibecotamab was active in low-blast myeloid diseases, although the durability of responses was modest. Additional studies of CD123-targeting bispecific antibodies, alone or in combination, are warranted for these diseases. Clinicaltrials.gov (NCT05285813).
2026-06-22 | CD69 blockade restores the bone marrow niche and delays leukemogenesis in a mouse model of Nras G12D-driven chronic myelomonocytic leukemia.
A subset of patients with chronic myelomonocytic leukemia (CMML) carries NRAS mutations, which are associated with shorter overall survival and an increased risk of transformation to acute myeloid leukemia. However, the effects of NRAS mutations on the bone marrow microenvironment (BME) remain unclear. We used a CMML mouse model driven by a single Nras G12D allele mutation to investigate alterations in the BME and the potential role of CD69 in immune suppression. Nras G12D-mutated CMML mice were treated with an anti-CD69 monoclonal antibody. Flow cytometry, hematoxylin-eosin staining, and RNA sequencing were performed to evaluate treatment-related changes. Nras G12D-mutated CMML mice showed increased infiltration of regulatory T (Treg) cells and CD69+ T cells in the BME, whereas CD69 expression on peripheral blood T cells remained lower than that on bone marrow T cells. Anti-CD69 monoclonal antibody treatment was associated with reduced generation of granulocyte-macrophage progenitor cells, prolonged survival, and decreased Treg accumulation in the BME. Our findings suggest that CD69 may serve as a biomarker of BME immunological dysfunction in CMML.
2026-06-11 | Data for: CD69 Blockade Restores the Bone Marrow Niche and Delays Leukemogenesis in a Mouse Model of NrasG12D-driven Chronic Myelomonocytic Leukemia.
This dataset contains the underlying files and supporting data for the manuscript titled "CD69 Blockade Restores the Bone Marrow Niche and Delays Leukemogenesis in a Mouse Model of Nras G12D -driven Chronic Myelomonocytic Leukemia".The data provided includes: Figure 1.xlsx, Figure 2.xlsx, Figure 3 and 4 gene_count.xlsx, Figure 3.xlsx, Figure 4.xlsx, supplementary Figure 1.xlsx, and supplementary Figure 3.xlsx. Contains the source data used to build the graphs and figures in the study.
2025-12-17 | A case of delayed-onset postoperative pyoderma gangrenosum complicated with chronic myelomonocytic leukemia treated with systemic corticosteroids and spesolimab
Pyoderma gangrenosum (PG) constitutes an uncommon form of neutrophilic dermatosis frequently linked to systemic diseases, notably hematologic malignancies. Chronic myelomonocytic leukemia (CMML) provides a distinctive framework for the pathogenesis of PG, attributable to the mutual dysregulation of myeloid cell function. This case report documenting the delayed emergence of PG in conjunction with CMML postsurgery underscores the pivotal role of inhibiting the interleukin 36 (IL-36) pathway in managing PG associated with CMML.
2025-12-13 | CD69 Blockade Restores the Bone Marrow Niche and Delays Leukemogenesis in a Mouse Model of NrasG12D-driven Chronic Myelomonocytic Leukemia
A subset of patients with chronic myelomonocytic leukemia (CMML) carry NRAS mutations, which are associated with shorter overall survival and higher risk of leukemic transformation. The precise impact of NRAS mutations on the bone marrow microenvironment (BME) remains unclear. In a mouse model of CMML induced by a single Nras G12D allele mutation, we observed increased infiltration of regulatory T (Treg) cells and CD69 + T cells within the BME, whereas CD69 expression on peripheral blood T cells remained low compared to T cells in the bone marrow. We administered an anti-CD69 monoclonal antibody to Nras G12D -mutated CMML mice to investigate whether CD69 caused BME immune suppression. Flow cytometry, hematoxylin-eosin staining, and RNA sequencing revealed that anti-CD69 monoclonal antibody treatment prevented granulocyte-macrophage progenitor cells generation, prolonged CMML mouse survival, and decreased BME Tregs. Our data indicate that CD69 may be a biomarker for BME immunological dysfunction in CMML.
other
2023-04-06 | A three-gene leukaemic stem cell signature score is robustly prognostic in chronic myelomonocytic leukaemia.
Leukaemic stem cell (LSC) gene expression has recently been linked to prognosis in patients with acute myeloid leukaemia (17-gene LSC score, LSC-17) and myelodysplastic syndromes. Although chronic myelomonocytic leukaemia (CMML) is regarded as a stem cell disorder, the clinical and biological impact of LSCs on CMML patients remains elusive. Making use of multiple independent validation cohorts, we here describe a concise three-gene expression signature (LSC-3, derived from the LSC-17 score) as an independent and robust prognostic factor for leukaemia-free and overall survival in CMML. We propose that LSC-3 could be used to supplement existing risk stratification systems, to improve prognostic performance and guide management decisions.
small molecules
2026-07-27 | [Effects of HMA and HU/BSC on prognosis in patients with intermediate-and high-risk chronic myelomonocytic leukemia, and characteristics of clonal evolution and inflammatory cytokines in progressive cases after HMA treatment].
Objective: To explore the prognostic impact of hypomethylating agents (HMA) versus hydroxyurea plus best supportive care (HU/BSC) in patients with intermediate-and high-risk chronic myelomonocytic leukemia (CMML), and to analyze the patterns of clonal evolution and dynamic changes of inflammatory cytokines in patients with disease progression before and after HMA treatment. Methods: A total of 63 patients diagnosed with intermediate-and high-risk CMML admitted to the Department of Hematology, the Second Hospital of Tianjin Medical University between October 20 2017 and May 8 2025 were retrospectively enrolled. All patients were followed up every 3 months via outpatient and inpatient visits after discharge, with the last follow-up conducted on February 28, 2026. According to treatment regimens, the patients were divided into HMA group (n=31) and HU/BSC group (n=32). Treatment response, disease progression and survival outcomes were compared between the 2 groups. The Kaplan-Meier method was used to plot the survival curves of overall survival (OS) and progression-free survival (PFS). Bone marrow DNA was collected from patients with disease progression before and after treatment with HMA (n=20) and HU/BSC (n=13). Next-generation sequencing was used to detect 325 mutated genes related to hematological malignancies, and the clonal evolution of gene mutations in patients receiving the 2 treatment regimens before and after disease progression was investigated. Bone marrow supernatant specimens were collected from patients with disease progression treated with HMAs (n=8) and HU/BSC (n=8), and enzyme-linked immunosorbent assay (ELISA) was used to measure the expression levels of 21 inflammatory cytokines including IL-6 and IFN-γ. The differences in inflammatory cytokine expression before and after disease progression were compared. Results: The median follow-up duration for all patients [M(Q1,Q3)] was 21 (10, 40) months. The median OS was 22.0 months (95%CI: 11.8-32.2) in the HMA group and 36.0 months (95%CI: 23.6-48.4) in the HU/BSC group, with no statistically significant difference between groups (P=0.208). The median PFS was 18.0 months (95%CI: 10.8-25.2) and 26.0 months (95%CI: 19.9-21.1) respectively, and the difference was also not statistically significant (P=0.108). Among patients with disease progression after HMA treatment, newly acquired mutations were predominantly enriched in RAS pathway genes, accounting for 25% (5/20). Clonal expansion of SF3B1, TP53 and RUNX1 was observed, and the mutational burden of each gene accounted for 10% (2/20). Compared with baseline levels, the concentrations of TNF-α [113.6 (104.1, 147.1) pg/ml vs 25.7 (20.2, 41.3) pg/ml, P<0.001] and IL-8 [77.5 (54.6, 115.8) pg/ml vs 7.0 (2.6, 9.2) pg/ml, P=0.003] were significantly increased after disease progression, while the level of IFN-γ [341.5 (221.2, 460.7) pg/ml vs 732.7 (389.0, 852.4) pg/ml, P=0.013] was markedly decreased. Conclusions: Compared with HU/BSC regimen, HMA failed to significantly improve OS and PFS in patients with intermediate-and high-risk CMML. Disease progression after HMA treatment may be closely associated with newly emerging mutations in the RAS pathway, clonal expansion of pre-existing mutations such as TP53, as well as the upregulation of TNF-α and IL-8 and downregulation of IFN-γ.
2026-07-22 | Dose schedule modifications of 5-azacitidine monotherapy in myelodysplastic neoplasias and chronic myelomonocytic leukaemia.
5-azacitidine (5-AZA) is the first hypomethylating agent synthetized and the cornerstone treatment for high-risk myelodysplastic neoplasms (MDS) and chronic myelomonocytic leukaemia (CMML). Although the validated schedule is 75 mg/m2 for 7 days (7-0-0), alternative schedules have been studied in terms of efficacy, complications and survival. The 7-0-0 shows an overall survival (OS) between 21 and 25 months in prospective and 16.5-27 months in retrospective studies and complete response (CR) rates between 7% and 18%. Alternative schedules, mostly 5-day (5-0-0) or 7-day with weekend pause (5-2-2) at 75 mg/m2, perform equally in terms of OS and CR with the 7-0-0, with a slight superiority for the 5-2-2, although direct comparisons are rare and almost always non-significant. Similarly, transfusion independence, time to leukaemia transformation and toxicities did not differ significantly across studies. For more intensive schedules, using 100 mg/m2 for 5 days, literature is limited, but response rates, survival and safety seem to be comparable to the 75 mg/m2 dose. In CMML, 5-AZA monotherapy yields satisfying overall response rates of 40% or more, with myelodysplastic subtype responding better than myeloproliferative. In all, alternative 5-AZA schedules seem non-inferior in terms of efficacy and toxicities and can be used as an alternative according to local protocols and patient choice.
2026-07-16 | Incidence, molecular and clinical characteristics of donor-derived hematologic malignancies after allogeneic stem cell transplantation for myeloid malignancies.
Allogeneic stem cell transplantation (allo-SCT) is the only potentially curative approach for several high-risk hematologic malignancies, but high relapse rates remain a challenge. Most relapses derive from the original malignant clone or its descendants. Occasionally, secondary blood cancers arise from transplanted donor cells and are referred to as donor-derived malignancies (DDMs). To assess the incidence of DDM at our center we performed a retrospective observational study on all evaluable patients allo-transplanted for myeloid malignancies in the Dept. of SCT of UMC Hamburg-Eppendorf between 1990 and 2024. Until the end of the observation (12/2025), we observed 791 relapses after 2827 allo-SCTs (28%). For 751 (94.9%) of the relapses, material was available for detailed molecular analysis. Three myeloid malignancies (CMML, MDS, AML) were unambiguously identified as DDMs (two from matched related, one from an unrelated donor) corresponding to low frequencies of 0.1% of all transplants and 0.4% of analyzed relapses. Notably, in no case we found mutations in typical germline predisposition genes (DDX41, RUNX1, GATA2, CEBPA), whereas mutations associated with CHIP (ASXL1, TET2, DNMT3A, CBL, U2AF1) were detected in all DDMs. In conclusion, comprehensive data from this - to our knowledge largest - single-center study covering almost 3,000 consecutive transplants over a period of 35 years supports a low overall incidence of DDMs and a potential role of donor-derived clonal hematopoiesis in their development.
2026-07-08 | Inflammatory signatures in the spectrum of myeloid diseases.
Dysregulated innate immunity contributes to clonal cytopenias and myeloid neoplasms, but its extent across disease stages and clinical relevance remain incompletely defined. We analyzed plasma ASC/NLRP3 double-positive (DP) specks, ASC single-positive (SP) specks, and 45 cytokines in 223 patients with idiopathic cytopenias of undetermined significance (ICUS)/clonal cytopenias of undetermined significance (CCUS), myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML) and 39 matched non-inflammatory controls using adjusted regression, survival modeling, and paired longitudinal analyses. Inflammasome activation and cytokine perturbations were evident across the disease spectrum. DP-ASC specks were elevated in MDS and CMML, whereas SP-ASC specks were increased across all groups, indicating activation of ASC-containing inflammasomes beyond NLRP3. Cytokines followed a graded ICUS → MDS → CMML pattern, with widespread upregulation of interleukins and chemokines (including IL-7, IL-8, IL-11/CXCL11, and CCL7) alongside suppression of stem and progenitor support factors such as CSF3, FLT3LG, TRAIL, and TWEAK. At baseline, elevated IL-15 and MMP1 predicted progression to acute myeloid Leukaemia, while higher IL-10, CXCL8, and IL-18 were associated with reduced survival; ASC specks were not independently prognostic. Longitudinal increases in selected cytokines distinguished progressors (area under the curve 0.82; 95% CI: 0.49-1.0). Cytokine patterns correlated with mutation categories, with the isolated SF3B1 mutation associated with higher DP-ASC specks. These findings define early and progressive inflammasome engagement and nominate dynamic cytokine panels and the inflammasome-IL-1 axis as actionable biomarkers and therapeutic targets.
2026-07-01 | A Phase Ib/II study of ceralasertib, a selective inhibitor of ATR, in patients with relapsed or refractory MDS and CMML.
Pre-mRNA splicing gene mutations are common in MDS and CMML and induce R-loops which trigger ATR activation. We studied ceralasertib, an orally bioavailable ATR inhibitor, in adult patients with R/R MDS or CMML in a phase Ib/II study including a safety run-in and expansion of 160mg BID during a 28-day cycle on two schedules: days 1-14 (14on/14off) or days 1-7 and 15- 21 (7on/7off). Response rates and survival were estimated. Forty-four evaluable patients were treated. Grade 3 or higher all-cause adverse events in 10% or more patients included thrombocytopenia (n=13), anemia (n=12), neutropenia (n=9), febrile neutropenia (n=9), pneumonia (n=6), and hypoxia (n=5). Thrombocytopenia requiring a platelet transfusion during the first cycle was reduced to 1 of 10 patients on 7on/7off compared to 8 of 16 patients on 14on/14off among patients with a baseline platelet count >50k (p=0.087). ORR was 29.5% (13 of 44 patients) and included one CR, 5 marrow CR (2 with HI-N), and 7 with HI (HI-E=4, HI-N=2, HI-P=1). Median PFS was 4.8mo and OS was 12 months (95%CI 11, 24). ORR (p=0.72), PFS (p=0.9) and OS (p=0.65) did not differ between schedules. While splicing factor mutation VAFs were stable, RUNX1 mutation VAFs typically increased at progression. Serum inflammatory cytokine levels including TNFRSF8 (CD30) and other TNF family members decreased during ceralasertib exposure; this effect was blunted in RUNX1 mutant samples. In conclusion, ceralasertib 160mg BID d1-7 and 15-21 was established as monotherapy dosing with a response rate of 30% in patients with R/R MDS and CMML. NCT03770429.
cell therapies
2026-07-25 | Risk-Adjusted Comparison of Survival in Chronic Myelomonocytic Leukemia With and Without Allogeneic Stem Cell Transplant: Mayo Clinic Experience in 775 Consecutive Patients.
The recently published BLAST clinical risk model for chronic myelomonocytic leukemia (CMML) and its molecular version (BLAST-Mol) differentiate low, intermediate, and high-risk groups. The objective of the current retrospective study was to examine the survival impact of allogeneic stem cell transplant (ASCT) in a consecutive series of Mayo Clinic patients (n = 775; 68% males, median age 71 years) with CMML, overall and adjusted for baseline BLAST/BLAST-Mol risk categories. At a median follow-up of 77 months, 151 (20%) patients underwent ASCT. Overall survival (OS) was longer in the ASCT compared to the non-ASCT cohorts (median 77 vs. 28 months; p < 0.01). The significant difference in OS between the ASCT and non-ASCT cohorts was retained after adjusting for BLAST clinical risk groups: high-risk (median 50 vs. 14 months; p < 0.01), intermediate-risk (81 vs. 28 months; p < 0.01), and low-risk (111 vs. 65 months; p = 0.04), respectively. The same was mostly the case when OS comparison was adjusted for BLAST-Mol with respective p values of < 0.01, < 0.01, and 0.08, respectively. Time-dependent cox models confirmed the favorable survival impact of ASCT in the BLAST/BLAST-Mol high- and intermediate-risk groups. The current study highlights the benefit of ASCT for BLAST/BLAST-Mol high- and intermediate-risk groups in CMML and its potential to overcome the adverse impact of some high risk cytogenetic or molecular abnormalities. These observations support the early use of ASCT in CMML, ideally before BT and regardless of genetic characteristics.
2026-06-08 | Comparative efficacy of donor lymphocyte infusions in augmenting graft-versus-leukemia effect after allogeneic hematopoietic stem cell transplantation for patients with myeloid malignancies.
The efficacy of donor lymphocyte infusions (DLI) among various myeloid malignancies (particularly, genetic subtypes) and the optimal timing of DLI initiation remains unclear. This was a retrospective study of 62 patients with myeloid malignancies treated with an alloHSCT and DLI from years 2001-2022. DLI indication was therapeutic 55 (89%), pre-emptive 6 (10%) and prophylactic 1 (2%) with complete remission (CR/CRi) in twenty patients with common diagnoses being 9 (45%) acute myeloid leukemia, 6 (30%) myelodysplastic syndromes, and 3 (15%) chronic myelomonocytic leukemia among others. Among patients who received therapeutic DLI (n=55), the best response was CR/CRi in 16 (29%) patients. At a median follow-up from the date of DLI of 75 (95% CI 35-121) months, there were 49 (79%) deaths with a median OS of 6 (95% CI 4-14) months, higher in patients in CR/CRi versus no CR/CRi (median 51 versus 4 months, P=0.008). Presence of cytogenetic abnormalities such as complex karyotype, deletions in chromosome 5, 7 and 17p, and mutations in TP53, KRAS, NRAS, RUNX1 or JAK2 were associated with adverse outcomes. DLI is an effective treatment strategy for post-transplant relapse of all myeloid malignancies, with specific genetic subtypes showing poorer outcomes and survival.
2026-04-09 | Survival benefit of allogeneic HSCT in CMML patients during the molecular stratification era.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option for chronic myelomonocytic leukemia (CMML), yet the population benefit from HSCT and the optimal timing of HSCT remain controversial. Current guidelines, largely based on older CPSS criteria and retrospective data, may not reflect recent advances in transplant techniques and molecular stratification systems. This multicenter retrospective analysis included 389 adult CMML patients from 14 Chinese centers (2015-2023), aiming to reassess the survival benefit of allo-HSCT in a large multicenter cohort within the molecular era. Among all patients, 145 (37.3%) underwent allo-HSCT, including 68.3% from haploidentical donors. Risk stratification was performed using CPSS, MDAPS, CPSS-mol, and MMM systems. Landmark analysis set at day 148 (median transplant interval) was used to assess the effect of time-dependent covariates on long-term survival. The entire cohort had 1-, 3-, and 5-year overall survival (OS) rates of 82.7%, 55.5%, and 46.1%, respectively. In patients ≤70 years, allo-HSCT was associated with significantly improved 3-year OS in CPSS intermediate-1 (63.4% vs. 45.4%, p = 0.038) and intermediate-2 (60.2% vs. 38.7%, p = 0.049), MDAPS intermediate-1 (69.5% vs. 47.4%, p = 0.004), intermediate-2 (60.6% vs. 30.4%, p = 0.029), and high-risk (51.4% vs. 45.0%, p = 0.022), CPSS-mol intermediate-2 (59.8% vs. 39.0%, p = 0.046), and MMM high-risk groups (65.5% vs. 10.5%, p < 0.001). Landmark analysis confirmed sustained benefit in these subgroups. Haploidentical HSCT yielded outcomes comparable to matched donors. Multivariable analysis identified HSCT as an independent favorable factor for survival (HR = 0.619, p = 0.031). These findings advocate expanding transplant eligibility through integration of molecular stratification and modern HSCT platforms, particularly haploidentical protocols.
2025-12-11 | Single-Cell Analysis of Cell-Cell Signaling Pathways as a Strategy for Targeted Immunotherapy in Chronic Myelomonocytic Leukemia.
Chronic myelomonocytic leukemia (CMML) is a rare hematological disorder characterized by abnormal levels of monocytes and blasts in the blood, which accumulate in the bone marrow and impair normal blood cell production. Complex intercellular signaling and pathway dysregulation in this disease must be understood in depth to devise novel therapeutic strategies targeting the immune system. This present study employed exploration of CMML tumor microenvironment at the single-cell resolution via single-cell RNA sequencing data analysis elucidating distinct cell types and role of their differentially expressed marker genes in dysregulation of pathways contributing to impaired immune response and enhanced inflammatory response. Moreover, the intercellular communications observed via CellChat package revealed significant interactions among these cell types. Results revealed identification of diverse immune cells, including pro-B cells, pre-B cells, progenitor cells, platelets, ISG-expressing immune cells, erythroid-like and erythroid precursor cells, and cancer cells. Interestingly, downregulation of immune system associated pathways such as interleukins, cytokines signaling, and CSF3 growth factor pathway among neutrophils, and progenitor cells may give rise to impaired immune cells leading to the onset of immunocompromised environment. Moreover, the intercellular signaling pathway and communication analyses unveiled erythroid-like and erythroid precursor cells as crucial influencers, conveying signals that contribute to complexity of tumor microenvironment through major pathways such as MIF, GALECTIN, ICAM, CD86, CD80, CD22, COMPLEMENT, VEGF, CSF, and CD23. Intriguingly, MIF along with CD74, CXCR4, and CD74 appeared as the most significant player of activation of downstream signaling pathways.
2025-11-13 | Differential impact of graft-versus-host disease on post-transplant outcomes of chronic myelomonocytic leukemia according to transplant procedures.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides curative outcomes for chronic myelomonocytic leukemia (CMML). We conducted a retrospective study to clarify the protective impact of acute and chronic graft-versus-host disease (aGVHD and cGVHD) on relapse by transplant procedures in 314 CMML patients. Interaction effects of conditioning intensity were observed with aGVHD (Pinteraction=0.181) and cGVHD (Pinteraction=0.256) for the cumulative incidence of relapse (CIR), whereas interaction effects of donor type were not detected with GVHD. In patients with the myeloablative conditioning regimens, the multivariate analysis showed that the development of aGVHD was not associated with overall survival (OS). The development of limited cGVHD correlated with better OS (HR [95 % CI], 0.34 [0.14-0.81]; P = 0.015); and that of extensive cGVHD correlated with better OS (HR, 0.44 [0.21-0.91]; P = 0.026) and lower CIR (HR, 0.28 [0.08-0.94]; P = 0.040). In patients with the reduced-intensity conditioning regimens, the development of grade I-II aGVHD correlated with better OS (HR, 0.39 [0.20-0.76]; P = 0.005) and lower CIR (HR, 0.30 [0.13-0.70]; P = 0.006). The development of extensive cGVHD correlated with better OS (HR, 0.44 [0.20-0.96]; P = 0.039). The present results suggest that the type and severity of GVHD mediating graft-versus-leukemia effects against relapse were influenced by conditioning intensity in CMML patients.
proteins
2026-04-07 | Pathogenic TET2 Variants and Autoinflammatory Manifestations in Myeloid Hematologic Malignancies: Case Report and Literature Review.
Emerging evidence suggests that somatic mutations in genes associated with innate immunity can trigger adult-onset autoinflammatory diseases. Notably, loss-of-function variants in the TET2 gene have been linked to both hematological malignancies and immune-mediated disorders. A case is presented of a 73-year-old woman with chronic myelomonocytic leukemia who developed severe pericardial effusion secondary to inflammatory serositis, associated with a pathogenic TET2 variant. Despite initial treatment with corticosteroids and diuretics, her condition worsened, which led to the need to implement treatment with colchicine and anakinra. This regimen led to significant clinical improvement and resolution of the effusion. This case reflects the importance of searching for pathogenic variants in TET2 in patients with hematological disorders, with the aim of early recognition of inflammatory manifestations associated with this genetic alteration. Treatment with colchicine and anti-interleukin-1 should be considered in these cases, as they are effective and avoid the unnecessary use of other immunosuppressants. Cite this article as: Porto Fuentes Ó, de Paz Arias R, Álvarez Troncoso J. Pathogenic TET2 variants and autoinflammatory manifestations in myeloid hematologic malignancies: case report and literature review. Eur J Rheumatol. 2026, 13(1), 0119, doi:10.5152/eurjrheum.2026.24119.
2025-09-08 | Tagraxofusp, a CD123-targeted therapy, for chronic myelomonocytic leukemia: final results of a phase 1/2 study.
Chronic myelomonocytic leukemia (CMML) is an aggressive hematologic neoplasm characterized by an expansion of CD123+ monocytes and plasmacytoid dendritic cells (pDCs). pDC bone marrow clusters in CMML have been associated with higher rates of acute myeloid leukemia transformation. We evaluated tagraxofusp, a CD123-targeted therapy, in a phase 1/2 trial for patients with CMML. There were no dose-limiting toxicities. At the recommended phase 2 dose of 12 μg/kg per day, 37 patients were treated: 15 were treatment naïve; 22 had relapsed/refractory disease (median number of previous therapies, 1 [range, 1-7]). Common nonhematologic treatment-emergent adverse events (AEs) included fatigue (49%), hypoalbuminemia (46%), nausea, hypokalemia, and decreased appetite (44% each). Capillary leak syndrome occurred in 9 patients (23%; grade 3-4, 13%), whereas tumor lysis syndrome was seen in 13%. Hematologic grade 3/4 treatment-related AEs included thrombocytopenia (28%), anemia (13%), leukocytosis (15%), and neutropenia (13%). No complete or partial responses were observed. One patient each in the treatment-naïve and relapsed/refractory groups achieved complete cytogenetic remission with marrow response. Stable disease and clinical benefit were achieved by 40% and 27% of treatment-naïve patients and by 59% and 23% of relapsed/refractory patients, respectively. After a median follow-up of 43.7 months, overall survival was 11.2 months in treatment-naïve and 15.6 months in relapsed/refractory patients. Exploratory analysis showed stable CD123+ blast frequency, mutational variant allele frequencies, and monocyte subsets with treatment. Tagraxofusp demonstrated a manageable safety profile with limited clinical efficacy in CMML. This trial was registered at www.ClinicalTrials.gov as #NCT02268253.
2025-05-28 | Updated results of a phase 2 study: Timdarpacept (IMM01) combined with azacitidine (AZA) as the first-line treatment in adults with chronic myelomonocytic leukemia (CMML).
6577 Background: Timdarpacept is a recombinant signal regulatory protein α (SIRPα) IgG1 fusion protein that exerts anti-tumor activity via blocking “Don’t eat me” signal and activating the “Eat me” signal to induce strong antibody-dependent cellular phagocytosis (ADCP). Methods: The study (NCT05140811) assessed the safety and efficacy of Timdarpacept combined with AZA as first-line treatment for newly diagnosed CMML patients. Timdarpacept was administered intravenously at a dosage of 2.0mg/kg/week, while subcutaneous AZA was given at a dosage of 75 mg/m 2 on D1-7 per 28-day cycle. Results: At the cut-off date on Dec 31, 2024, 24 patients, with a median age of 62, males 62.5%, and 75.0% ECOG≥1, were enrolled. 33.3% and 66.7% patients were and high risk (HR), respectively. Majority of patients had poor baseline of hematologic conditions with a median hemoglobin (Hb) level of 69.5 (32-132) g/L and a median platelet (PLT) count of 73.5 (5-667)×10 9 /L. The median duration of follow-up was 21.0 months (95%CI, 19.3-23.3). Among 22 efficacy evaluable patients, overall response rate (ORR) was 72.7%, including 27.3% complete response (CR), 13.6% marrow CR (mCR) with hematologic improvement (HI), 4.5% HI and 27.3% mCR alone. The median time to response (TTR) was 1.8 months and the median duration of response (DoR) was 16.9 months (95%Cl, 5.1-not reached [NR]). The median time to CR (TTCR) was 3.7 months and the median duration of CR (DoCR) was 13.6 months (95%Cl, 5.7-NR). The median of progression-free survival (PFS) was 17.8 months (95%Cl, 5.3-NR), with an estimated 12-month PFS of 59.0% (95%Cl, 33.4-77.6). Median OS has not been reached yet. The most common ≥Grade 3 TRAEs (≥10%) included lymphopenia (66.7%), leukopenia (62.5%), neutropenia (58.3%), thrombocytopenia (50.0%), anemia (29.2%) and pneumonia (16.7%). Without using of a low dose priming regimen, Grade ≥3 hemolysis occurred in 1 patient (4.2%). Conclusions: Timdarpacept, without a low-dose priming, combined with AZA, was well tolerated in 1L CMML. The combination, when compared to the historical data of AZA monotherapy, showed promising efficacy results for patients with treatment-naive CMML-1 and -2. Clinical trial information: NCT05140811 .
2024-10-17 | Experience with luspatercept therapy in patients with transfusion-dependent low-risk myelodysplastic syndromes in real-world clinical practice: exploring the positive effect of combination with erythropoietin alfa.
Luspatercept, an inhibitor of the transforming growth factor beta (TGF-β) pathway, is a novel treatment for anemic patients with lower-risk myelodysplastic syndromes (MDS) with transfusion dependence (TD) who do not respond to erythropoiesis-stimulating agents (ESA) therapy or are not suitable candidates for this treatment. We present real-world experience with luspatercept therapy from two hematology centers in the Czech Republic. By January 2024, 54 MDS patients (33 men, 21 women) with a median age of 74 years (range, 55-95) were treated with luspatercept ± ESA at two Charles University hematology centers in Prague and Hradec Králové. According to the WHO 2016 classification, the cohort included 32 MDS-RS-MLD, seven MDS-MLD, two patients with 5q- + ring sideroblasts (RS), 12 RARS-T, and 1 patient with CMML-0 + RS. SF3B1 mutation data were available for 45 patients. All patients were in the IPSS-R and IPSS-M lower-risk groups (except four IPSS-M high). The median follow-up was 17 months (range, 1-54). All patients were transfusion-dependent. Thirty-five (64.8%) patients had a high transfusion burden (HTB) with ≥ 4 transfusion units (TU)/8 weeks, and 19 (35.2%) had a low transfusion burden (LTB) (< 4 TU/8 weeks). The median time between diagnosis and initiation of luspatercept was 27 months (range, 4-156). ESA were used prior to luspatercept in 45 patients, and luspatercept was used as first-line treatment in nine patients. Thirty-one (61%) patients were treated simultaneously with ESA. Only patients who received luspatercept for ≥ 8 weeks (51 patients) were assessed. We evaluated the achievement of transfusion independence (TI) lasting 8, 12, 16, and 24 weeks. Thirty-two (62.7%) patients achieved TI for ≥ 8 weeks, 31 (60.7%) for ≥ 12 weeks, 29 (56.8%) for ≥ 16 weeks, and 25 (49%) for ≥ 24 weeks. Hematologic improvement (HI) without TI was achieved in six patients (11.7%). Overall, HI + TI was achieved in 38 patients (74.5%). Epoetin alfa was used simultaneously in 31 patients (60.7%). In 21 (55.2%) of all responding patients, concomitant therapy with epoetin alfa led to an improved response, with 16 reaching TI. Thirteen (25.5%) patients were nonresponders. Eight (21%) patients experienced therapy failure and became transfusion-dependent again. Optimal response required a gradual increase in the luspatercept dose to 1.75 mg/kg in up to 35 patients, with 23 responders (TI + HI). Response rates varied by transfusion burden: 79% in LTB and 50% in HTB reached TI. Of RS+ patients, 70% reached TI, while only one out of five RS- patients achieved TI. Among 39 SF3B1-positive patients, 61.6% achieved TI. In the low and very low IPSS-M groups, 86% of patients responded (TI + HI), compared to 62% in the moderate-low group. Luspatercept was well-tolerated, with no adverse events higher than grade II toxicity. We have demonstrated in real-world clinical practice that luspatercept is a very effective agent, even in an unselected, pretreated, significantly TD MDS population. The effect was particularly high in the IPSS-M low and very low groups. We believe that the relatively high response rate in our patients was influenced by the frequent use of a higher dose (1.75 mg/kg) and especially by adding ESA to luspatercept in poorly responding patients.
2023-12-01 | NLRP3 inflammasome activation and symptom burden in KRAS-mutated CMML patients is reverted by IL-1 blocking therapy
Chronic myelomonocytic leukemia (CMML) is frequently associated with mutations in the rat sarcoma gene (RAS), leading to worse prognosis. RAS mutations result in active RAS-GTP proteins, favoring myeloid cell proliferation and survival and inducing the NLRP3 inflammasome together with the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which promote caspase-1 activation and interleukin (IL)-1β release. Here, we report, in a cohort of CMML patients with mutations in KRAS, a constitutive activation of the NLRP3 inflammasome in monocytes, evidenced by ASC oligomerization and IL-1β release, as well as a specific inflammatory cytokine signature. Treatment of a CMML patient with a KRASG12D mutation using the IL-1 receptor blocker anakinra inhibits NLRP3 inflammasome activation, reduces monocyte count, and improves the patient's clinical status, enabling a stem cell transplant. This reveals a basal inflammasome activation in RAS-mutated CMML patients and suggests potential therapeutic applications of NLRP3 and IL-1 blockers.
antibodies
2026-06-28 | Vibecotamab for measurable residual disease in acute myeloid leukemia and for myelodysplastic syndromes and chronic myelomonocytic leukemia after hypomethylating agent failure: a phase II study.
Acute myeloid leukemia (AML) with persistent measurable residual disease (MRD) and relapsed/refractory myelodysplastic syndromes (MDS) are low-blast myeloid diseases for which there are few effective therapeutic options. CD123 represents an attractive target in these diseases. Vibecotamab is a bispecific antibody that binds to CD123 on malignant blasts and to CD3 on T-cells, to recognize and eliminate CD123-positive malignant cells. This single-center phase II study evaluated the efficacy of vibecotamab in patients AML with detectable MRD (AML-MRD cohort) or with MDS or chronic myelomonocytic leukemia (CMML) after hypomethylating agent failure (MDS/CMML cohort). In cycle 1, patients received vibecotamab IV on day 1 (0.43 µg/kg), day 3 (0.75 µg/kg), day 5 (1.1 µg/kg), and days 8, 15 and 22 (1.7 µg/kg). In subsequent cycles, patients received vibecotamab IV on days 1, 8, 15, and 22 (1.7 µg/kg). The primary outcomes were MRD negativity rate (AML-MRD cohort) and overall response (MDS/CMML cohort). Between May 2022 and April 2025, 48 patients were enrolled (21 AML-MRD cohort, 27 MDS/CMML cohort). The median ages of the AML-MRD and the MDS/CMML cohorts were 70 and 76 years, respectively. In the AML-MRD cohort, the median MRD level by flow cytometry was 0.64% (range, 0.1-3.9%), and in the MDS/CMML, the median bone marrow blast percentage was 7% (range, 3-19%). The AML-MRD clearance rate was 19% (4/21; 95% CI 5-42%), and in the MDS/CMML cohort, the overall response rate was 67% (18/27; 95% CI 46-83%). The median overall survival was 13.1 months (95% CI 8.9-NR) for the AML-MRD cohort and 6.5 months (95% CI 4.2-10.3) for the MDS/CMML cohort. The most frequent adverse event was infusion reaction or cytokine relapse syndrome, which occurred in 29 patients (60%) overall, most of which were grade 1-2. Vibecotamab was active in low-blast myeloid diseases, although the durability of responses was modest. Additional studies of CD123-targeting bispecific antibodies, alone or in combination, are warranted for these diseases. Clinicaltrials.gov (NCT05285813).
2026-06-22 | CD69 blockade restores the bone marrow niche and delays leukemogenesis in a mouse model of Nras G12D-driven chronic myelomonocytic leukemia.
A subset of patients with chronic myelomonocytic leukemia (CMML) carries NRAS mutations, which are associated with shorter overall survival and an increased risk of transformation to acute myeloid leukemia. However, the effects of NRAS mutations on the bone marrow microenvironment (BME) remain unclear. We used a CMML mouse model driven by a single Nras G12D allele mutation to investigate alterations in the BME and the potential role of CD69 in immune suppression. Nras G12D-mutated CMML mice were treated with an anti-CD69 monoclonal antibody. Flow cytometry, hematoxylin-eosin staining, and RNA sequencing were performed to evaluate treatment-related changes. Nras G12D-mutated CMML mice showed increased infiltration of regulatory T (Treg) cells and CD69+ T cells in the BME, whereas CD69 expression on peripheral blood T cells remained lower than that on bone marrow T cells. Anti-CD69 monoclonal antibody treatment was associated with reduced generation of granulocyte-macrophage progenitor cells, prolonged survival, and decreased Treg accumulation in the BME. Our findings suggest that CD69 may serve as a biomarker of BME immunological dysfunction in CMML.
2026-06-11 | Data for: CD69 Blockade Restores the Bone Marrow Niche and Delays Leukemogenesis in a Mouse Model of NrasG12D-driven Chronic Myelomonocytic Leukemia.
This dataset contains the underlying files and supporting data for the manuscript titled "CD69 Blockade Restores the Bone Marrow Niche and Delays Leukemogenesis in a Mouse Model of Nras G12D -driven Chronic Myelomonocytic Leukemia".The data provided includes: Figure 1.xlsx, Figure 2.xlsx, Figure 3 and 4 gene_count.xlsx, Figure 3.xlsx, Figure 4.xlsx, supplementary Figure 1.xlsx, and supplementary Figure 3.xlsx. Contains the source data used to build the graphs and figures in the study.
2025-12-17 | A case of delayed-onset postoperative pyoderma gangrenosum complicated with chronic myelomonocytic leukemia treated with systemic corticosteroids and spesolimab
Pyoderma gangrenosum (PG) constitutes an uncommon form of neutrophilic dermatosis frequently linked to systemic diseases, notably hematologic malignancies. Chronic myelomonocytic leukemia (CMML) provides a distinctive framework for the pathogenesis of PG, attributable to the mutual dysregulation of myeloid cell function. This case report documenting the delayed emergence of PG in conjunction with CMML postsurgery underscores the pivotal role of inhibiting the interleukin 36 (IL-36) pathway in managing PG associated with CMML.
2025-12-13 | CD69 Blockade Restores the Bone Marrow Niche and Delays Leukemogenesis in a Mouse Model of NrasG12D-driven Chronic Myelomonocytic Leukemia
A subset of patients with chronic myelomonocytic leukemia (CMML) carry NRAS mutations, which are associated with shorter overall survival and higher risk of leukemic transformation. The precise impact of NRAS mutations on the bone marrow microenvironment (BME) remains unclear. In a mouse model of CMML induced by a single Nras G12D allele mutation, we observed increased infiltration of regulatory T (Treg) cells and CD69 + T cells within the BME, whereas CD69 expression on peripheral blood T cells remained low compared to T cells in the bone marrow. We administered an anti-CD69 monoclonal antibody to Nras G12D -mutated CMML mice to investigate whether CD69 caused BME immune suppression. Flow cytometry, hematoxylin-eosin staining, and RNA sequencing revealed that anti-CD69 monoclonal antibody treatment prevented granulocyte-macrophage progenitor cells generation, prolonged CMML mouse survival, and decreased BME Tregs. Our data indicate that CD69 may be a biomarker for BME immunological dysfunction in CMML.
other
2023-04-06 | A three-gene leukaemic stem cell signature score is robustly prognostic in chronic myelomonocytic leukaemia.
Leukaemic stem cell (LSC) gene expression has recently been linked to prognosis in patients with acute myeloid leukaemia (17-gene LSC score, LSC-17) and myelodysplastic syndromes. Although chronic myelomonocytic leukaemia (CMML) is regarded as a stem cell disorder, the clinical and biological impact of LSCs on CMML patients remains elusive. Making use of multiple independent validation cohorts, we here describe a concise three-gene expression signature (LSC-3, derived from the LSC-17 score) as an independent and robust prognostic factor for leukaemia-free and overall survival in CMML. We propose that LSC-3 could be used to supplement existing risk stratification systems, to improve prognostic performance and guide management decisions.
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Drug Discovery Landscape
5 orphan drug designations for Chronic myelomonocytic leukemia.
5 orphan drug designations for Chronic myelomonocytic leukemia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
co-packaged combination of azacitidine and cedazuridine | small molecules | FDA | 2025-02-25 | — | Taiho Oncology, Inc. |
small molecule inhibitor of bcr-abl tyrosine kinase | — | FDA | 2024-11-22 | — | Enliven Therapeutics, Inc. |
recombinant, humanized immunoglobulin G1 monoclonal antibody that targets the leukocyte immunoglobulin-like receptor subfamily B4 | antibodies | FDA | 2024-02-08 | — | Immune-Onc Therapeutics |
Recombinant human signal regulating protein alpha (SIRPalpha) fragment crystallizable (Fc)-fusion protein | proteins | FDA | 2023-11-07 | — | ImmuneOnco Biopharmaceuticals (Shanghai) Inc. |
(2S,3S,4E,6S,7R,10R)-7,10-Dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6R)-6-(pyridin-2-yl)hepta-2,4-dien-2-yl]oxacyclododec-4-en-6-yl 4-methylpiperazine-1-carboxylate | small molecules | FDA | 2017-06-22 | — | Eisai Inc. |
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