Chronic myelomonocytic leukemia (CMML)

Current understanding

MDS/MPN overlap syndrome with persistent monocytosis. Distinct from classical MPNs but tracked here for related myeloid biology.

Evidence log

• 2026-07-15 — Phase I/II Clinical Trial of Axatilimab, a CSF1R Monoclonal Antibody, in Combination With Ruxolitinib as Therapy for Patients With Myelofibrosis (MF) and Chronic Myelomonocytic Leukemia (CMML): Phase I/II dose-finding trial evaluates axatilimab (anti-CSF-1R mAb) alone and with ruxolitinib in CMML — pairs CSF-1R blockade (mechanistically apt for monocytosis-defining CMML) with JAK inhibition, distinct from the parallel axatilimab ± azacitidine advanced-phase/high-risk CMML trial and adding a JAKi-combination axatilimab arm to the CMML pipeline (trial-early; novelty 3). (novelty: 3)
• 2026-07-16 — Study of Tagraxofusp for Post-Transplant Maintenance for Patients With CD 123+ AML, MDS, MF and CMML (HSCT 002): HSCT 002 phase trial evaluates multi-cycle tagraxofusp as post-alloHCT maintenance in CD123+ CMML — introduces a first-in-class CD123-directed cytotoxin into the CMML post-transplant maintenance pipeline alongside Inqovi, olutasidenib (IDH1-mutated), venetoclax+FluBu, preemptive CIML NK, and MRD-guided approaches (trial-early; novelty 3). (novelty: 3)
• 2026-06-16 — Final analysis of phase 2 clinical trial of ruxolitinib and azacitidine combination therapy in patients with myelodysplastic syndrome/myeloproliferative neoplasms.: Final phase 2 analysis of azacitidine + ruxolitinib in MDS/MPN (which typically includes CMML enrollment) reported 58% ORR, median OS 26.7 months, and encouraging survival after subsequent alloHCT — adds mature durable-response and OS data for the HMA + JAK-inhibitor doublet in the CMML-inclusive overlap population (trial-early; novelty 3). (novelty: 3)
• 2026-08-12 — Additional myelodysplasia-related gene mutations alter clinical presentation and worsen prognosis in patients with/co-mutated myeloid neoplasms.: Retrospective cohort in TET2-co-mutated myeloid neoplasms found that additional myelodysplasia-related gene mutations (most often ASXL1) reduce monocytosis, increase anemia, roughly halve overall survival, and raise the AML transformation rate in CMML — refining prognostic stratification within TET2-mutated CMML. (novelty: 3)
• 2026-07-01 — Ruxolitinib for the Treatment of Chronic Myelomonocytic Leukemia (CMML): A Phase 2 Expansion: Phase 2 expansion trial evaluates ruxolitinib in CMML — extends JAK inhibition (already tested via pacritinib vs hydroxyurea in proliferative CMML) into a dedicated ruxolitinib expansion cohort, further building the JAK-STAT-directed axis in this subtype’s pipeline alongside HMA, BCL-2, CSF-1R, LSD1, ERK, PLK1, and IL-1β strategies (trial-early; novelty 3). (novelty: 3)
• 2026-06-24 — Chimeric Antigen Receptor T Cell Therapy Redirected to CD4 (CD4CAR)as a Second Line Treatment for Chronic Myelomonocytic Leukemia, CMML.: Phase I 3+3 trial evaluates CD4-directed CAR-T (CD4CAR) as second-line therapy for relapsed/refractory CMML — first-in-class application of CAR-T immunotherapy in CMML, targeting CD4+ monocytic cells and introducing an adoptive cellular immunotherapy axis mechanistically distinct from HMA, BCL-2, JAK, CSF-1R, LSD1, ERK, PLK1, IDH1, FLT3, and IL-1β strategies populating the CMML salvage pipeline (trial-early; novelty 4). (novelty: 4)
• 2026-06-23 — A Pragmatic Clinical Trial to Prevent Relapse for Myeloid Malignancies With Measurable Disease Prior to Allogeneic Transplant: Pragmatic prospective trial assigns MRD-status-guided post-transplant maintenance in myeloid malignancies including CMML undergoing allo-HCT — extends the CMML post-alloHCT maintenance pipeline (Inqovi, olutasidenib for IDH1-mutated, venetoclax+FluBu) by introducing MRD-directed therapy selection as the operative principle for relapse prevention in a subtype where transplant is curative but relapse is common (trial-early; novelty 3). (novelty: 3)
• 2026-06-17 — A Study of E7820 in People With Bone Marrow (Myeloid) Cancers: Phase 1 trial of E7820 (splicing modulator) in relapsed/refractory CMML harboring splicing factor gene mutations (e.g., SRSF2, SF3B1, U2AF1) — introduces splicing factor inhibition as a novel mechanistic axis into the CMML salvage pipeline, genotype-directed at a mutation class highly prevalent in CMML and distinct from HMA, BCL-2, JAK, CSF-1R, LSD1, ERK, and PLK1 strategies (trial-early; novelty 3). (novelty: 3)
• 2026-06-16 — Lysozyme-Associated Nephropathy in Myeloid Neoplasms: A Clinicopathological and Mass Spectrometric Study of Two Cases.: Case report identifies lysozyme-associated nephropathy (LyN) in CMML, with first proteomic mass spectrometry of affected proximal tubules revealing lysosomal homeostasis disruption, altered lipid metabolism, and cellular stress responses — reinforcing renal injury as a monocytosis-driven complication mechanistically tied to the defining CMML phenotype (case-report; novelty 4). (novelty: 4)
• 2026-06-08 — Recombinant EphB4-HSA Fusion Protein and Azacitidine or Decitabine for Relapsed or Refractory Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia Patients Previously Treated With a Hypomethylating Agent: Trial of recombinant EphB4-HSA fusion protein + azacitidine or decitabine in HMA-refractory MDS/CMML/AML — introduces a first-in-class EphB4 receptor tyrosine kinase-targeting axis layered on HMA backbone for post-HMA-failure CMML, mechanistically distinct from BCL-2, IDH1, FLT3, CSF-1R, LSD1, PLK1, ERK, and IL-1β strategies already populating the CMML salvage pipeline (trial-early; novelty 4). (novelty: 4)
• 2026-06-11 — Venetoclax in Combination With ASTX727 for the Treatment of Treatment-Naive High-Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia: Phase I/II trial evaluates venetoclax + ASTX727 (oral cedazuridine/decitabine) specifically in treatment-naive high-risk MDS or CMML — extends the oral HMA + BCL-2 doublet into the frontline high-risk CMML setting, complementing the parallel CMML-and-MDS/MPN-EB ASTX727 ± venetoclax randomization and the AVENHIR (aza+ven) effort by anchoring this combination as upfront therapy (trial-early; novelty 3). (novelty: 3)
• 2026-06-05 — A Phase II Study of Cladribine and Low Dose Cytarabine in Combination With Venetoclax, Alternating With Azacitidine and Venetoclax, in Patients With Higher-risk Myeloproliferative Chronic Myelomonocytic Leukemia or Higher-risk Myelodysplastic Syndromes With Excess Blasts: Phase II trial evaluates cladribine + low-dose cytarabine + venetoclax alternating with azacitidine + venetoclax in higher-risk CMML and higher-risk MDS with excess blasts — introduces an AML-style alternating induction-intensity regimen layered with BCL-2 inhibition into the CMML pipeline, distinct from the standard HMA + venetoclax doublet (AVENHIR, ASTX727+ven) by adding purine analog + low-dose ara-C cycles (trial-early; novelty 3). (novelty: 3)
• 2026-06-05 — Eltrombopag as a Novel Therapeutic Approach for Low-risk MDS and CMML With TET2 Mutations: Eltrombopag is being evaluated in low-risk MDS and CMML with TET2 mutations as a TPO-RA repurposed for both count improvement and selective suppression of TET2-mutant clonal growth — introducing a mutation-selective cytoreductive rationale distinct from HMA, BCL-2, JAK, CSF-1R, and LSD1 axes already populating the CMML pipeline (trial-early; novelty 4). (novelty: 4)
• 2026-06-05 — Venetoclax and Azacitidine for the Treatment of Relapsed or Refractory High-Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia: Phase I/II trial evaluates venetoclax + azacitidine specifically in relapsed/refractory high-risk MDS or CMML — extends the HMA + BCL-2 doublet into the R/R salvage setting for CMML, complementing the frontline AVENHIR (aza+ven) and ASTX727+venetoclax efforts by focusing on the harder-to-treat post-HMA-failure population (trial-early; novelty 3). (novelty: 3)
• 2026-06-03 — Hyperbaric Oxygen Therapy and Allogeneic Peripheral Blood Stem Cell (PBSC) Transplant: Early-phase trial evaluates hyperbaric oxygen therapy (HBOT) as a peri-transplant adjunct in CMML patients undergoing allogeneic PBSC transplant — first-in-class application of HBOT in CMML alloHCT, targeting engraftment, GVHD, neutrophil recovery, and mucositis as a novel non-pharmacologic supportive-care axis distinct from JAKi, HMA, and BCL-2 strategies in this subtype’s transplant pipeline (trial-early; novelty 4). (novelty: 4)
• 2026-05-29 — Azacitidine With or Without Lenalidomide or Vorinostat in Treating Patients With Higher-Risk Myelodysplastic Syndromes or Chronic Myelomonocytic Leukemia: Randomized phase II/III trial evaluates azacitidine ± lenalidomide or vorinostat in higher-risk MDS/CMML — tests whether layering immunomodulatory (lenalidomide) or HDAC-inhibitor (vorinostat) agents onto the HMA backbone improves outcomes vs azacitidine alone in the CMML subset (trial-late; novelty 3). (novelty: 3)
• 2026-05-20 — A Phase 2 Study Evaluating Olutasidenib in Combination With Hypomethylating Agents in Patients With IDH1-mutated Higher-risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Advanced Myeloproliferative Neoplasm: Phase 2 trial evaluates olutasidenib (IDH1 inhibitor) + hypomethylating agent in IDH1-mutated higher-risk MDS, CMML, or advanced MPN — first prospective test of upfront (non-maintenance) IDH1 inhibitor + HMA combination in the IDH1-mutated CMML subset, complementing the post-alloHCT olutasidenib maintenance trial and extending the AML-validated IDH1i+HMA paradigm into CMML (trial-early; novelty 3). (novelty: 3)
• 2026-05-20 — Venetoclax Added to Fludarabine + Busulfan Prior to Transplant and to Maintenance Therapy for AML, MDS, and MDS/MPN: Phase I/II trial adds venetoclax to fludarabine/busulfan conditioning AND to post-transplant maintenance (with azacitidine or oral decitabine/cedazuridine) in AML/MDS/CMML/MDS-MPN-U undergoing alloHCT — first prospective test in CMML of BCL-2 inhibition layered into both the conditioning and maintenance phases of transplant, extending the HMA+venetoclax paradigm across the entire peri-transplant continuum and complementing the Inqovi-maintenance and olutasidenib-maintenance approaches already in the CMML pipeline (trial-early; novelty 3). (novelty: 3)
• 2026-05-15 — Chemotherapy (Decitabine in Combination With FLAG-Ida) and Total-Body Irradiation Followed by Donor Stem Cell Transplant for the Treatment of Adults With Myeloid Malignancies at High Risk of Relapse: Phase I/II trial evaluates decitabine + FLAG-Ida + TBI as a novel pre-allogeneic transplant conditioning regimen (vs FLAG-Ida + TBI alone) in high-risk myeloid malignancies including CMML — first prospective test of HMA-intensified myeloablative conditioning in CMML, complementing thiotepa-based and Inqovi-maintenance approaches in this subtype’s transplant pipeline (trial-early; novelty 3). (novelty: 3)
• 2026-05-15 — Prospective Single-Arm Clinical Study of Thiotepa-Containing Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Chronic Myelomonocytic Leukemia: Prospective single-arm trial evaluates a thiotepa + busulfan + fludarabine (± ATG) conditioning regimen for allo-HSCT in intermediate-2/high-risk CMML — addresses a notable evidence gap in CMML-specific transplant conditioning, complementing post-transplant maintenance approaches (olutasidenib for IDH1-mutated, ASTX727/Inqovi) being explored in this subtype (trial-early; novelty 3). (novelty: 3)
• 2026-05-13 — Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloproliferative Neoplasm: Phase II trial randomizes ASTX727 (oral decitabine/cedazuridine) ± venetoclax in CMML and MDS/MPN with excess blasts — directly tests whether adding BCL-2 inhibition to an oral HMA backbone improves disease-burden reduction in CMML, complementing the AVENHIR (azacitidine + venetoclax) effort by using the oral HMA partner instead (trial-early; novelty 3). (novelty: 3)
• 2026-02-23 — Onvansertib for the Treatment of Recurrent or Refractory Chronic Myelomonocytic Leukemia and Myelodysplastic Syndrome/MPN Overlap Neoplasms: Phase I trial evaluates onvansertib (first-in-class PLK1 inhibitor) for safety, dosing, and efficacy in recurrent/refractory CMML — introduces mitotic kinase (PLK1) inhibition as a novel mechanistic axis into the CMML salvage pipeline, distinct from HMA, BCL-2, JAK, FLT3, ERK, LSD1, and CSF-1R-directed approaches (trial-early; novelty 4). (novelty: 4)
• 2026-04-13 — A Phase II, Open-Label, Study of Subcutaneous Canakinumab, an Anti-IL-1β Human Monoclonal Antibody, for Patients With Low or Int-1 Risk IPSS/IPSS-R Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: Phase II trial evaluates subcutaneous canakinumab (anti-IL-1β monoclonal antibody) in low/Int-1 risk MDS and CMML — first clinical test of IL-1β-directed inflammatory cytokine blockade in lower-risk CMML, introducing an inflammation-targeted therapeutic axis distinct from HMA, JAK, and BCL-2 strategies (trial-early; novelty 3). (novelty: 3)
• 2026-01-29 — Guadecitabine and Atezolizumab in Treating Patients With Advanced Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia That Is Refractory or Relapsed: Phase I/II trial evaluates guadecitabine (next-generation HMA) + atezolizumab (anti-PD-L1) in relapsed/refractory MDS or CMML — first prospective test of HMA + checkpoint inhibitor combination in CMML, leveraging epigenetic-immunotherapy synergy in a refractory population with limited salvage options (trial-early; novelty 3). (novelty: 3)
• 2026-03-18 — Study of NMS-03592088 in Patients With Relapsed or Refractory AML or CMML: Phase I first-in-human study evaluates NMS-03592088 (novel investigational agent, mechanism not specified in abstract) for safety, MTD, and antitumor activity in relapsed/refractory AML or CMML — adds another early-phase candidate to the CMML salvage pipeline alongside STX-0712. (novelty: 3)
• 2026-03-13 — Axatilimab With or Without Azacitidine for the Treatment of Patients With Advanced Phase Myeloproliferative Neoplasms, Myeloproliferative Neoplasm/Myelodysplastic Syndrome Overlap or High Risk Chronic Myelomonocytic Leukemia: Phase Ib/II trial evaluates axatilimab (anti-CSF-1R monoclonal antibody) ± azacitidine in high-risk CMML — first-in-class CSF-1R-directed targeting of monocyte/macrophage biology, mechanistically apt for the monocytosis-defining CMML subtype (trial-early; novelty 4). (novelty: 4)
• 2026-03-05 — Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia: Randomized trial compares pacritinib (BID) vs hydroxyurea over 48 weeks in advanced proliferative CMML — first head-to-head test of a JAK2/IRAK1 inhibitor against the standard cytoreductive backbone in this subtype, potentially redefining first-line control for the proliferative CMML phenotype (trial-early; novelty 3). (novelty: 3)
• 2026-02-13 — Phase I/II Study of a Combination of Decitabine and Cedazuridine (ASTX727) and ASTX029, an ERK Inhibitor, for Patients With RAS Pathway Mutant Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms: ASTX029 + ASTX727 phase I/II trial is relevant to CMML, where RAS pathway mutations (NRAS, KRAS, CBL, PTPN11, NF1) are highly prevalent — introducing the first ERK inhibitor + oral HMA combination as a genotype-directed strategy for this subtype (trial-early; novelty 4). (novelty: 4)
• 2026-03-30 — Inqovi Maintenance Therapy in Myeloid Neoplasms: Prospective trial evaluates oral decitabine/cedazuridine (ASTX727/Inqovi) as post-alloHCT maintenance in MDS and CMML — first study of oral HMA maintenance in CMML aimed at reducing post-transplant relapse, complementing the IDH1-targeted olutasidenib maintenance approach in molecularly defined subsets (trial-early; novelty 3). (novelty: 3)
• 2026-04-02 — Seclidemstat and Azacitidine for the Treatment of Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia: Phase I/II trial evaluates seclidemstat (LSD1/KDM1A inhibitor) + azacitidine in MDS or CMML — first combination of an LSD1 inhibitor with HMA backbone in CMML, introducing epigenetic LSD1 targeting into the CMML therapeutic pipeline (trial-early; novelty 3). (novelty: 3)
• 2026-02-09 — A Phase 1 Study of STX-0712 in Patients With Advanced Hematological Malignancies (CMML and AML): 2026 — A Phase 1 Study of STX-0712 in Patients With Advanced Hematological Malignancies: First-in-human Phase 1 dose-escalation of STX-0712 (novel investigational agent, potentially first-in-class) in advanced CMML and AML who have exhausted standard options — introduces a new mechanistic class into the CMML therapeutic pipeline for treatment-refractory disease (trial-early; novelty 4). (novelty: 4)
• 2026-03-05 — Olutasidenib for the Treatment of Patients With IDH1 Mutated AML, MDS or CMML After Donor Hematopoietic Cell Transplant: Phase I trial evaluates olutasidenib (IDH1 inhibitor) as post-allogeneic HCT maintenance in IDH1-mutated AML, MDS, or CMML — first prospective study extending IDH1 inhibition into the post-transplant maintenance setting for the IDH1-mutated CMML subset, addressing relapse risk in a molecularly defined slice where targeted maintenance options are otherwise absent (trial-early; novelty 3). (novelty: 3)
• 2026-03-05 — Azacitidine Combined With Venetoclax in Patients With Higher-risk Chronic Myelomonocytic Leukemia (AVENHIR): AVENHIR phase II single-arm multicenter trial evaluates azacitidine + venetoclax in higher-risk CMML — applies the established AML doublet to a CMML-specific higher-risk population with limited treatment options, complementing the FLT3-mutated triplet study and helping define the role of BCL-2 inhibition in CMML. (novelty: 3)
• 2026-04-16 — Azacitidine, Venetoclax, and Gilteritinib in Treating Patients With Recurrent/Refractory FLT3-Mutated Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, or High-Risk Myelodysplastic Syndrome/Myeloproliferative Neoplasm: Phase I/II trial evaluates azacitidine + venetoclax + gilteritinib triplet in R/R FLT3-mutated AML, CMML, and high-risk MDS/MPN — extends triplet HMA/BCL-2/FLT3-inhibitor strategy into the FLT3-mutated CMML subset, a rare but molecularly defined slice of this population. (novelty: 3)
• 2026-04-13 — Topotecan Hydrochloride and Carboplatin With or Without Veliparib in Treating Advanced Myeloproliferative Disorders and Acute Myeloid Leukemia or Chronic Myelomonocytic Leukemia: Phase II trial evaluates topotecan + carboplatin ± veliparib (PARP inhibitor) in advanced MPNs, AML, and CMML — first PARP inhibitor combination tested in CMML, leveraging DNA-damage repair vulnerability in this refractory population (trial-early; novelty 3). (novelty: 3)
• April 28, — Fedratinib Shows Promise in MDS/MPN Overlap Syndromes and CNL: cross-connection with mds-mpn-overlap: CMML is the prototypical MDS/MPN overlap entity excluded from this trial’s MDS/MPN-U/RS-T/aCML cohort, but the fedratinib rationale (JAK-STAT activation) is conceptually relevant to CMML biology. (novelty: 4)

Open questions

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