Lisa Pleyer1, Michael Leisch2, Alexandra Kourakli3, Eric Padron4, Jaroslaw Pawel Maciejewski5, Blanca Xicoy Cirici6, Jennifer Kaivers7, Johanna Ungerstedt8, Sonja Heibl9, Peristera Patiou3, Anthony Michael Hunter10, Elvira Mora11, Klaus Geissler12, Maria Dimou13, Maria-José Jimenez Lorenzo6, Thomas Melchardt2, Alexander Egle2, Athina-Nora Viniou13, Bhumika Jayantibhai Patel5, Montserrat Arnan14, Peter Valent15, Christoforos Roubakis16, Teresa Bernal Del Castillo17, Athanasios Galanopoulos16, Marisa Calabuig Muñoz18, Nicolas Bonadies19, Antonio Medina de Almeida20, Jaroslav Cermak21, Andrés Jerez22, Maria Julia Montoro23, Albert Cortés24, Alejandro Avendaño Pita25, Bernardo Lopez Andrade26, Eva Hellstroem-Lindberg8, Ulrich Germing7, Mikkael Aaron Sekeres5, Alan Francis List4, Argiris Symeonidis3, Guillermo Francisco Sanz27, Julian Larcher-Senn28, Richard Greil2. 1. Third 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. Electronic address: dr.lisa.pleyer@gmail.com. 2. Third 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. 3. Hematology Division, Department of Internal Medicine, University of Patras Medical School, Patras, Greece. 4. Malignant Hematology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. 5. Leukemia Program, Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA. 6. Institut Català d'Oncologia, Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain. 7. Department of Hematology, Oncology, and Clinical Immunology, Heinrich-Heine-University, Düsseldorf, Germany. 8. Center for Hematology and Regenerative Medicine, Department of Medicine, Huddinge, Karolinska Institute, and Department of Hematology, Karolinska University Hospital, Stockholm, Sweden. 9. Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Wels, Austria. 10. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. 11. Department of Hematology, Hospital Universitario y Politécnico La Fe, Valencia, Spain. 12. Fifth Medical Department, Hospital Hietzing, Vienna, Austria. 13. 141st Department of Internal Medicine, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece. 14. Institut Català d'Oncologia-Hospital Duran y Reynals, Hospitalet de Llobregat, Barcelona, Spain. 15. 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. 16. Department of Hematology, G GENNIMATAS General Hospital, Athens, Greece. 17. Hospital Universitario Central Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, University Institute of Oncology of Asturias-Cajastur Social Programme, Oviedo, Spain. 18. Hospital Clinico Universitario de Valencia, Valencia, Spain. 19. Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Switzerland. 20. Hospital da Luz, Lisbon, Portugal; Centro de Investigação Interdisciplinar em Saúde, Universidade Católica Portuguesa de Lisboa, Lisbon, Portugal. 21. Institute of Hematology and Blood Transfusion, Prague, Czech Republic. 22. Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB, Murcia, Spain. 23. Hematology Department, Vall d'Hebron Hospital Universitari, Experimental Hematology, Vall d'Hebron Institute of Oncology, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. 24. Hematology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 25. Hematology Department, Hospital Universitario de Salamanca, Salamanca, Spain. 26. Hematology Department Hospital Universitario Son Espases, Palma Mallorca, Spain. 27. Department of Hematology, Hospital Universitario y Politécnico La Fe, Valencia, Spain; Centro de Investigacion Biomedica en Red Cance, Instituto Carlos III, Madrid, Spain. 28. Assign Data Management and Biostatistics, Innsbruck, Austria.
Abstract
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.
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.
Authors: Monique F Smeets; Carl R Walkley; Jane Jialu Xu; Alistair M Chalk; Meaghan Wall; Wallace Y Langdon Journal: Leukemia Date: 2022-10-21 Impact factor: 12.883
Authors: Michael Leisch; Michael Pfeilstöcker; Reinhard Stauder; Sonja Heibl; Heinz Sill; Michael Girschikofsky; Margarete Stampfl-Mattersberger; Christoph Tinchon; Bernd Hartmann; Andreas Petzer; Martin Schreder; David Kiesl; Sonia Vallet; Alexander Egle; Thomas Melchardt; Gudrun Piringer; Armin Zebisch; Sigrid Machherndl-Spandl; Dominik Wolf; Felix Keil; Manuel Drost; Richard Greil; Lisa Pleyer Journal: Cancers (Basel) Date: 2022-05-17 Impact factor: 6.575
Authors: Heide-Marie Binder; Nicole Maeding; Martin Wolf; André Cronemberger Andrade; Balazs Vari; Linda Krisch; Fausto Gueths Gomes; Constantin Blöchl; Katharina Muigg; Rodolphe Poupardin; Anna M Raninger; Thomas Heuser; Astrid Obermayer; Patricia Ebner-Peking; Lisa Pleyer; Richard Greil; Christian G Huber; Katharina Schallmoser; Dirk Strunk Journal: Cells Date: 2021-11-26 Impact factor: 6.600
Authors: Sigrid Machherndl-Spandl; Eva Jäger; Agnes Barna; Michael Gurbisz; Renate Marschon; Temeida Graf; Elmir Graf; Christoph Geissler; Gregor Hoermann; Thomas Nösslinger; Michael Pfeilstöcker; Peter Bettelheim; Otto Zach; Ansgar Weltermann; Sonja Heibl; Josef Thaler; Armin Zebisch; Heinz Sill; Reinhard Stauder; Gerald Webersinke; Rajko Kusec; Ernst Ulsperger; Bruno Schneeweiss; Leopold Öhler; Ulrich Germing; Peter Valent; Heinz Tüchler; Klaus Geissler Journal: Eur J Haematol Date: 2021-06-01 Impact factor: 2.997