BACKGROUND: Approval of hypomethylating agents in patients with chronic myelomonocytic leukaemia is based on trials done in patients with myelodysplastic syndromes. We aimed to investigate whether hypomethylating agents provide a benefit in subgroups of patients with chronic myelomonocytic leukaemia compared with other treatments. METHODS: For this retrospective cohort study, data were retrieved between Nov 30, 2017, and Jan 5, 2019, from 38 centres in the USA and Europe. We included non-selected, consecutive patients diagnosed with chronic myelomonocytic leukaemia, who received chronic myelomonocytic leukaemia-directed therapy. Patients with acute myeloid leukaemia according to 2016 WHO criteria at initial diagnosis (ie, ≥20% blasts in the bone marrow or peripheral blood) or with unavailability of treatment data were excluded. Outcomes assessed included overall survival, time to next treatment, and time to transformation to acute myeloid leukaemia. Analyses were adjusted by age, sex, platelet count, and Chronic myelomonocytic leukaemia-Specific Prognostic Scoring System (CPSS). Patients were grouped by first received treatment with either hydroxyurea, hypomethylating agents, or intensive chemotherapy, and stratified by risk according to blast count, French-American-British subtype, CPSS, WHO 2016 subtype, and the eligibility criteria of the DACOTA trial (NCT02214407). FINDINGS: 949 patients diagnosed with chronic myelomonocytic leukaemia between April 13, 1981, and Oct 26, 2018, were included. Median follow-up was 23·4 months (IQR 11·5-42·3) from diagnosis and 16·2 months (6·6-31·6) from start of first-line treatment. 412 (43%) of 949 patients received hypomethylating agents as first treatment, 391 (41%) hydroxyurea, and 83 (9%) intensive chemotherapy. Adjusted median overall survival for patients treated with hydroxyurea versus hypomethylating agents was 15·6 months (95% CI 13·1-17·3) versus 20·7 months (17·9-23·4); hazard ratio (HR) 1·39 (1·17-1·65; p=0·0002) and 14·0 months (9·8-17·2) versus 20·7 months (17·9-23·4; HR 1·55 [1·16-2·05]; p=0·0027) for those treated with intensive chemotherapy versus hypomethylating agents. In patients with myeloproliferative chronic myelomonocytic leukaemia (myeloproliferative CMML), median overall survival was 12·6 months (10·7-15·0) versus 17·6 months (14·8-21·5; HR 1·38 [1·12-1·70]; p=0·0027) for patients treated with hydroxyurea versus hypomethylating agents, and 12·3 months (8·4-16·6) versus 17·6 months (14·8-21·5; HR 1·44 [1·02-2·03]; p=0·040) for intensive chemotherapy versus hypomethylating agents. Hypomethylating agents did not confer an overall survival advantage for patients classified as having lower-risk disease (ie, myelodysplastic chronic myelomonocytic leukaemia with <10% blasts, CMML-0, or lower-risk CPSS). INTERPRETATION: These data suggest hypomethylating agents as the preferred therapy for patients with higher-risk chronic myelomonocytic leukaemia and those with myeloproliferative CMML. Our findings also suggest that CPSS is a valuable tool to identify patients who are most likely to benefit from hypomethylating agents. Further evidence from prospective cohorts would be desirable. FUNDING: The Austrian Group for Medical Tumor Therapy.

141st Department of Internal Medicine National and Kapodistrian University of Athens Laikon General Hospital Athens Greece

3rd Medical Department with Hematology Medical Oncology Rheumatology and Infectiology Paracelsus Medical University Salzburg Austria; Salzburg Cancer Research Institute Center for Clinical Cancer and Immunology Trials Salzburg Austria

5th Medical Department Hospital Hietzing Vienna Austria

Assign Data Management and Biostatistics Innsbruck Austria

Center for Hematology and Regenerative Medicine Department of Medicine Huddinge Karolinska Institute and Department of Hematology Karolinska University Hospital Stockholm Sweden

Department of Hematology and Central Hematology Laboratory Inselspital Bern University Hospital University of Bern Switzerland

Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA USA

Department of Hematology G GENNIMATAS General Hospital Athens Greece

Department of Hematology Hospital Universitario y Politécnico La Fe Valencia Spain

Department of Hematology Hospital Universitario y Politécnico La Fe Valencia Spain; Centro de Investigacion Biomedica en Red Cance Instituto Carlos 3 Madrid Spain

Department of Hematology Oncology and Clinical Immunology Heinrich Heine University Düsseldorf Germany

Department of Internal Medicine 4 Klinikum Wels Grieskirchen Wels Austria

Department of Internal Medicine Division of Hematology and Hemostaseology Medical University of Vienna Vienna Austria; Ludwig Boltzmann Institute for Hematology and Oncology Medical University of Vienna Vienna Austria

Hematology Department Hospital de la Santa Creu i Sant Pau Barcelona Spain

Hematology Department Hospital Universitario de Salamanca Salamanca Spain

Hematology Department Hospital Universitario Son Espases Palma Mallorca Spain

Hematology Department Vall d'Hebron Hospital Universitari Experimental Hematology Vall d'Hebron Institute of Oncology Vall d'Hebron Barcelona Hospital Campus Barcelona Spain

Hematology Division Department of Internal Medicine University of Patras Medical School Patras Greece

Hospital Clinico Universitario de Valencia Valencia Spain

Hospital da Luz Lisbon Portugal; Centro de Investigação Interdisciplinar em Saúde Universidade Católica Portuguesa de Lisboa Lisbon Portugal

Hospital Universitario Central Asturias Instituto de Investigación Sanitaria del Principado de Asturias University Institute of Oncology of Asturias Cajastur Social Programme Oviedo Spain

Institut Català d'Oncologia Hospital Duran y Reynals Hospitalet de Llobregat Barcelona Spain

Institut Català d'Oncologia Hospital Germans Trias i Pujol Josep Carreras Leukemia Research Institute Universitat Autònoma de Barcelona Badalona Spain

Institute of Hematology and Blood Transfusion Prague Czech Republic

Leukemia Program Department of Hematology and Medical Oncology Taussig Cancer Institute Cleveland Clinic Cleveland OH USA

Malignant Hematology H Lee Moffitt Cancer Center and Research Institute Tampa FL USA

Servicio de Hematología y Oncología Médica Hospital Universitario Morales Meseguer Centro Regional de Hemodonación Universidad de Murcia IMIB Murcia Spain

Lancet Haematol. 2021 Feb;8(2):e99-e101. doi: 10.1016/S2352-3026(20)30401-4. PubMed

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NCT02214407