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:
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.
2026-07-25 | 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.
2026-07-22 | 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.
2026-07-27 | [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.
2026-07-25 | 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.
2026-07-22 | 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.
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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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