Chronic Myelomonocytic Leukemia: 2018 Update to Prognosis and Treatment
- 32 Downloads
Purpose of Review
Chronic myelomonocytic leukemia (CMML) is a rare and often aggressive myeloid malignancy. Historically, prognostic markers and therapeutic paradigms have been applied from myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPNs). Interest has increased recently in developing tailored approaches for the MDS/MPN overlap syndrome of CMML.
Multiple prognostic scores have been validated specifically for CMML in the past 5 years. These incorporate somatic mutations, with ASXL1 mutations repeatedly correlating with poor prognosis. Accurate prognostication can guide treatment. Hypomethylating agents (HMAs) and curative allogeneic blood or marrow transplantation (BMT) remain the most available standard treatments. Recently, a number of novel approaches using unapproved therapies (i.e., lenalidomide, ruxolitinib, sotatercept, and tipifarnib) have demonstrated some efficacy in CMML.
Increased recognition and interest in CMML have led to the development of a number of new prognostic models and potential treatment options. Standard treatment options remain limited and clinical trials should be strongly considered whenever available.
KeywordsChronic myelomonocytic leukemia (CMML) Mayo prognostic model CPSS ASXL1 Hypomethylating agents Allogeneic BMT
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 6.• Kunimoto H, Meydan C, Nazir A, Whitfield J, Shank K, Rapaport F, et al. Cooperative epigenetic remodeling by TET2 loss and NRAS mutation drives myeloid transformation and MEK inhibitor sensitivity. Cancer Cell. 2018;33(1):44–59 Important study that demonstrates the mechanism of TET2 and NRAS mutations as drivers of myeloid malignancies through activation of mitogen-activating protein kinase (MAPK) by epigenetic silencing. The study also highlights the potential for MAPK inhabitation as a therapeutic strategy. CrossRefGoogle Scholar
- 13.Mughal T, Cross N, Padron E, Tiu R, Savona M, Malcovati L, et al. An International MDS/MPN Working Group’s perspective and recommendations on molecular pathogenesis, diagnosis and clinical characterization of myelodysplastic/myeloproliferative neoplasms. Haematologica. 2015;100(9):1117–30.CrossRefGoogle Scholar
- 20.Patnaik M, Wassie E, Lasho T, Hanson C, Ketterling R, Tefferi A. Blast transformation in chronic myelomonocytic leukemia: risk factors, genetic features, survival, and treatment outcome. AJH. 2015;90(5):411–6.Google Scholar
- 22.Greenberg P, Cox C, LeBeau M, Fenaux P, Morel P, Sanz G, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89(6):2079–88.Google Scholar
- 27.• Nazha A, Patnaik M, Komrokji R, Al-Issa K, Daver N, Garcia-Manero G, et al. Model heterogeneity in predicting outcomes in patients with chronic myelomonocytic leukemia (CMML): an overestimation of survival in lower-risk group. Blood. 2017;130:4255 As multiple prognostic models have been validated for CMML, this study sought to compare the utility of each model. The predicted prognosis did often vary across models, all models were subject to errors in prediction especially for low risk patients, and no specific model was significantly superior. Google Scholar
- 31.• Elena C, Gallì A, Such E, Meggendorfer M, Germing U, Rizzo E, et al. Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia. Blood. 2016;128:1408–17 As the prognostic importance of somatic mutations in CMML has been increasingly recognized, this critical study introduced a prognostic model called the CPSS-mol that incorporates somatic mutations as predictors of decreased overall survival. CrossRefGoogle Scholar
- 32.Kantarjian H, O'brien S, Cortes J, Giles F, Faderl S, Jabbour E, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer. 2006;106(5):1090–8.CrossRefGoogle Scholar
- 35.• Kröger N, Eikema D-J, De Wreede L, van Biezen A, Beelen D, Finke J, et al. Comparison of allogeneic stem cell transplantation for transformed acute myeloid leukemia derived from MDS, CMML or MPN. A report of the Chronic Malignancies Working Party of EBMT. Blood. 2016;128:3499 Though allogeneic BMT is widely used in the treatment of CMML, data regarding outcomes is limited to small retrospective series. While also retrospective, this analysis from the EBMT, with a large sample size and long median follow-up of almost 4 years, is one of the most robust studies demonstrating outcomes after transplant. Google Scholar
- 36.Kröger N, Zabelina T, Guardiola P, Runde V, Sierra J, VanBiezen A, et al. Allogeneic stem cell transplantation of adult chronic myelomonocytic leukaemia. A report on behalf of the Chronic Leukaemia Working Party of the European Group for blood and marrow transplantation (EBMT). Br J Haematol. 2002;118(1):67–73.CrossRefGoogle Scholar
- 39.Padron E, Komrokji R, List A. The clinical management of chronic myelomonocytic leukemia. Clin Adv Hematol Oncol. 2014;12(3):172–8.Google Scholar
- 40.• Savona M, Malcovati L, Komrokji R, Tiu R, Mughal T, Orazi A, et al. An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood. 2015;125:1857–65 As an overlap syndrome with characteristics of both MDS and MPNs, CMML responses are not accurately assessed with existing response criteria for MDS and MPNs. Thus, an international consortium established response criteria for MDS/MPN overlap syndromes that are more reliable for CMML. CrossRefGoogle Scholar
- 41.Wattel E, Guerci A, Hecquet B, Economopoulos T, Copplestone A, Mahé B, et al. A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia. Groupe Français des Myélodysplasies and European CMML Group. Blood. 1996;88(7):2480–7.Google Scholar
- 42.• Santini V, Allione B, Zini G, Gioia D, Lunghi M, Poloni A, et al. A phase II, multicentre trial of decitabine in higher-risk chronic myelomonocytic leukemia. Leukemia. 2018;32(2):413–8 Hypomethylating agent therapy has become a standard treatment for CMML based largely on clinical trials in MDS that included a small subset of CMML patients. In contrast, this multicenter prospective study was designed specifically to evaluate the treatment of CMML patients with the hypomethylating agent decitabine, and still demonstrated favorable responses that justified the use of this therapy. CrossRefGoogle Scholar
- 46.Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10(3):223–32.CrossRefGoogle Scholar
- 51.Montalban-Bravo G, Bose P, Alvarado Y, Daver N, Ravandi F, Borthakur G, et al. Initial results of a phase 2 study of guadecitabine (SGI-110), a novel subcutaneous (sc) hypomethylating agent, for patients with previously untreated intermediate-2 or high risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML). Blood. 2016;128(346).Google Scholar
- 52.Garcia-Manero G, Griffiths E, Roboz G, Busque L, Wells R, Odenike O, et al. A phase 2 dose-confirmation study of oral ASTX727, a combination of oral decitabine with a cytidine deaminase inhibitor (CDAi) cedazuridine (E7727), in subjects with myelodysplastic syndromes (MDS). Blood. 2017;130:4274.Google Scholar
- 53.Symeonidis A, vanBiezen A, deWreede L, Piciocchi A, Finke J, Beelen D, et al. Achievement of complete remission predicts outcome of allogeneic haematopoietic stem cell transplantation in patients with chronic myelomonocytic leukaemia. A study of the Chronic Malignancies Working Party of the European Group for blood and marrow transplantation. BJH. 2015;171(2):239–46.CrossRefGoogle Scholar
- 55.Eissa H, Gooley T, Sorror M, Nguyen F, Scott B, Doney K, et al. Allogeneic hematopoietic cell transplantation for chronic myelomonocytic leukemia: relapse-free survival is determined by karyotype and comorbidities. BBMT. 2011;17(6):908–15.Google Scholar
- 56.Liu H, Ahn K, Hu Z-H, MehdiHamadani NT, Wirk B, et al. Allogeneic hematopoietic cell transplantation for adult chronic myelomonocytic leukemia. BBMT. 2017;23(5):767–75.Google Scholar
- 57.Kongtim P, Popat U, Jimenez A, Gaballa S, ElFakih R, Rondon G, et al. Treatment with hypomethylating agents before allogeneic stem cell transplant improves progression-free survival for patients with chronic myelomonocytic leukemia. BBMT. 2016;22(1):47–53.Google Scholar
- 59.• Sekeres M, Othus M, List A, Odenike O, Stone R, Gore S, et al. Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia: North American Intergroup Study SWOG S1117. J Clin Oncol. 2017;20(35):2745–53 This phase II study suggests that the combination of azacitidine and lenalidomide may be superior to azacitidine alone in the treatment of MDS and CMML. Confirmation of this result in an ongoing phase III study would be expected to change the standard first-line therapy to the combination of hypomethylating agent and lenalidomide. CrossRefGoogle Scholar
- 64.Platzbecker U, Germing U, Götze K, Kiewe P, Wolff T, Mayer K, et al. Luspatercept increases hemoglobin and reduces transfusion burden in patients with low-intermediate risk myelodysplastic syndromes (MDS): long-term results from phase 2 PACE-MDS study. Blood. 2016;128:3168.Google Scholar
- 67.Patnaik MM, DAS MAS, Luger S, Bejar R, Hobbs GS, DeZern AE, et al. Preliminary results from an open-label, phase 2 study of tipifarnib in chronic myelomonocytic leukemia (CMML). Blood. 2017;130:2963.Google Scholar
- 70.Padron E, Painter J, Kunigal S, Mailloux A, McGraw K, McDaniel J, et al. GM-CSF-dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia. Blood. 2013.Google Scholar
- 72.Patnaik M, Gupta V, Gotlib J, Carraway H, Wadleigh M, Schiller G, et al. Results from ongoing phase 2 trial of SL-401 in patients with advanced, high-risk myeloproliferative neoplasms including chronic myelomonocytic leukemia. Blood. 2016;128:4245.Google Scholar
- 74.Damaj G, Duhamel A, Robin M, Beguin Y, Michallet M, Mohty M, et al. Impact of azacitidine before allogeneic stem-cell transplantation for myelodysplastic syndromes: a study by the Société Française de Greffe de Moelle et de Thérapie-Cellulaire and the Groupe-Francophone des Myélodysplasies. JCO. 2012;30(36):4533–440.CrossRefGoogle Scholar
- 76.Runde V, deWitte T, Arnold R, Gratwohl A, Hermans J, vanBiezen A, et al. Bone marrow transplantation from HLA-identical siblings as first-line treatment in patients with myelodysplastic syndromes: early transplantation is associated with improved outcome. Chronic Leukemia Working Party of the European Group for blood and marrow transplantation. Bone Marrow Transplant. 1998;21(3):255–61.CrossRefGoogle Scholar