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Chronic Myelomonocytic Leukemia: Insights into Biology, Prognostic Factors, and Treatment

  • Leukemia (A Aguayo, Section Editor)
  • Published:
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Abstract

Purpose of Review

Chronic myelomonocytic leukemia (CMML) is a clonal hematological malignancy characterized by both dysplastic and proliferative features, with an inherent risk for leukemic transformation. With the help of this review, we aim to summarize key concepts with regards to CMML biology, diagnosis, risk stratification, and therapeutics.

Recent Findings

Based on recent studies, CMML is hallmarked by a relatively low genetic complexity, which contrasts with a compelling phenotypical heterogeneity, largely driven by epigenetic mechanisms. Recent advances in the characterization of CMML biology has led to an improvement in risk-stratification, by means of incorporating prognostically relevant gene mutations. This, however, has not significantly impacted available therapies and outcomes continue to remain poor.

Summary

Advances in CMML biology have better explained the phenotypic heterogeneity, while continuing to define the genetic and epigenetic landscape. In spite of recent advances, limited effective therapies exist and developing rationally derived therapeutic approaches is much needed.

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Abbreviations

ASXL1:

Additional sex combs like 1

BAP1:

BRCA1-associated protein 1

BCOR:

BCL6 corepressor

CBL:

Cbl proto-oncogene

CSF3R:

Colony-stimulating factor 3 receptor

DNMT3A:

DNA methyltransferase 3 alpha

EZH2:

Enhancer of zeste 2 polycomb repressive complex 2 subunit

FLT3:

Fms-related tyrosine kinase 3

IDH1/IDH2:

Isocitrate dehydrogenase 1/2

JAK2:

Janus kinase 2

NPM1:

Nucleophosmin 1

NRAS:

Neuroblastoma RAS viral oncogene homolog

PHF6:

Plant homeodomain finger protein 6

PRC1/2:

Polycomb repressive complex 1/2

PTPN11:

Protein tyrosine phosphatase non-receptor type 11

RUNX1:

Runt-related transcription factor 1

SETBP1:

SET binding protein 1

SF3B1:

Splicing factor 3b subunit 1

SRSF2:

Serine and arginine rich splicing factor 2

TET2:

Tet methylcytosine dioxygenase 2

TP53:

Tumor protein P53

U2AF1:

U2 small nuclear RNA auxiliary factor 1

SPRY2:

Sprouty RTK signaling antagonist 2

US FDA:

United States Food and Drug Administration

ZRSR2:

Zinc finger CCCH-type RNA binding motif and serine/arginine rich 2

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et al. Proposed revised criteria for the classification of acute myeloid leukemia: a report of the French-American-British cooperative group. Ann Intern Med. 1985;103(4):620–5.

    CAS  PubMed  Google Scholar 

  2. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405.

    CAS  PubMed  Google Scholar 

  3. Rollison DE, Howlader N, Smith MT, Strom SS, Merritt WD, Ries LA, et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood. 2008;112(1):45–52.

    CAS  PubMed  Google Scholar 

  4. Benzarti S, Daskalakis M, Feller A, Bacher VU, Schnegg-Kaufmann A, Rüfer A, et al. Trends of incidence and survival of patients with chronic myelomonocytic leukemia between 1999 and 2014: a comparison between Swiss and American population-based cancer registries. Cancer Epidemiol. 2019;59:51–7.

    PubMed  Google Scholar 

  5. Such E, Germing U, Malcovati L, Hrodek O. Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia. Transfuze a Hematologie Dnes. 2013;19(3):191.

    Google Scholar 

  6. Patnaik MM, Lasho TL, Finke CM, Hanson CA, Hodnefield JM, Knudson RA, et al. Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: prevalence, clinical correlates, and prognostic relevance. Am J Hematol. 2013;88(3):201–6.

    CAS  PubMed  Google Scholar 

  7. Patnaik MM, Itzykson R, Lasho T, Kosmider O, Finke C, Hanson C, et al. ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients. Leukemia. 2014;28(11):2206.

    CAS  PubMed  Google Scholar 

  8. •• Patnaik MM, Lasho TL, Vijayvargiya P, Finke CM, Hanson CA, Ketterling RP, et al. Prognostic interaction between ASXL1 and TET2 mutations in chronic myelomonocytic leukemia. Blood Cancer Journal. 2016;6:e385 This study investigated the prevalence and prognostic significance of genetic mutations in CMML. Authors confirmed the negative prognostic impact of ASXL1 mutations, and suggested a favorable prognostic impact of TET2 mutations, only in the absence of ASXL1 mutations.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. •• Merlevede J, Droin N, Qin T, Meldi K, Yoshida K, Morabito M, et al. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents. Nat Commun. 2016;7:10767 In this study, Merlevede et. al conducted a comprehensive analysis of genetic mutations in 49 CMML patients, combining whole-exome and whole-genome sequencing. They identified an average of 14±5 somatic mutations per coding sequence and thorough serial sequencing, showed that responses to HMA were associated with significant changes in DNA methylation and gene expression, without any decrease in mutational allele burdens, nor the prevention of acquiring additional genetic events and consequent clonal evolution. This suggests that HMA most likely act by epigenetically restoring balanced hematopoesis, with limited potential for modifying disease biology and natural history.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. • Ball M, List AF, Padron E. When clinical heterogeneity exceeds genetic heterogeneity: thinking outside the genomic box in chronic myelomonocytic leukemia. Blood. 2016;128(20):2381–7 In this review, the authors discuss the stark contrast between the clinical complexity and the molecular homogeneity of CMML, and offer an insight into novel genomic and non-genomic approaches that may help better understand CMML disease biology.

    CAS  PubMed  Google Scholar 

  11. Itzykson R, Kosmider O, Renneville A, Morabito M, Preudhomme C, Berthon C, et al. Clonal architecture of chronic myelomonocytic leukemias. Blood. 2013;121(12):2186–98.

    CAS  PubMed  Google Scholar 

  12. Orazi A, Chiu R, O'Malley DP, Czader M, Allen SL, An C, et al. Chronic myelomonocytic leukemia: the role of bone marrow biopsy immunohistology. Mod Pathol. 2006;19(12):1536–45.

    CAS  PubMed  Google Scholar 

  13. Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart DN, et al. Nomenclature of monocytes and dendritic cells in blood. Blood. 2010;116(16):e74–80.

    CAS  PubMed  Google Scholar 

  14. Wong KL, Tai JJ-Y, Wong W-C, Han H, Sem X, Yeap W-H, et al. Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets. Blood. 2011;118(5):e16–31.

    CAS  PubMed  Google Scholar 

  15. Selimoglu-Buet D, Wagner-Ballon O, Saada V, Bardet V, Itzykson R, Bencheikh L, et al. Characteristic repartition of monocyte subsets as a diagnostic signature of chronic myelomonocytic leukemia. Blood. 2015;125(23):3618–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Patnaik MM, Timm MM, Vallapureddy R, Lasho TL, Ketterling RP, Gangat N, et al. Flow cytometry based monocyte subset analysis accurately distinguishes chronic myelomonocytic leukemia from myeloproliferative neoplasms with associated monocytosis. Blood Cancer J. 2017;7(7):e584.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Talati C, Zhang L, Shaheen G, Kuykendall A, Ball M, Zhang Q, et al. Monocyte subset analysis accurately distinguishes CMML from MDS and is associated with a favorable MDS prognosis. Blood. 2017;129(13):1881–3.

    CAS  PubMed  Google Scholar 

  18. Onida F, Kantarjian HM, Smith TL, Ball G, Keating MJ, Estey EH, et al. Prognostic factors and scoring systems in chronic myelomonocytic leukemia: a retrospective analysis of 213 patients. Blood. 2002;99(3):840–9.

    CAS  PubMed  Google Scholar 

  19. Such E, Cervera J, Costa D, Sole F, Vallespi T, Luno E, et al. Cytogenetic risk stratification in chronic myelomonocytic leukemia. Haematologica. 2011;96(3):375–83.

    PubMed  Google Scholar 

  20. Tang G, Zhang L, Fu B, Hu J, Lu X, Hu S, et al. Cytogenetic risk stratification of 417 patients with chronic myelomonocytic leukemia from a single institution. Am J Hematol. 2014;89(8):813–8.

    PubMed  PubMed Central  Google Scholar 

  21. Patnaik MM, Lasho T, Finke C, Gangat N, Caramazza D, Holtan S, et al. WHO-defined ‘myelodysplastic syndrome with isolated del (5q)‘in 88 consecutive patients: survival data, leukemic transformation rates and prevalence of JAK2. MPL and IDH mutations Leukemia. 2010;24(7):1283.

    CAS  PubMed  Google Scholar 

  22. Patnaik MM, Hanson C, Hodnefield J, Knudson R, Van Dyke D, Tefferi A. Monosomal karyotype in myelodysplastic syndromes, with or without monosomy 7 or 5, is prognostically worse than an otherwise complex karyotype. Leukemia. 2011;25(2):266.

    CAS  PubMed  Google Scholar 

  23. Wassie EA, Itzykson R, Lasho TL, Kosmider O, Finke CM, Hanson CA, et al. Molecular and prognostic correlates of cytogenetic abnormalities in chronic myelomonocytic leukemia: a M ayo C linic-F rench C onsortium S tudy. Am J Hematol. 2014;89(12):1111–5.

    CAS  PubMed  Google Scholar 

  24. Itzykson R, Kosmider O, Renneville A, Gelsi-Boyer V, Meggendorfer M, Morabito M, et al. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol. 2013;31(19):2428–36.

    CAS  PubMed  Google Scholar 

  25. Yamazaki J, Taby R, Vasanthakumar A, Macrae T, Ostler KR, Shen L, et al. Effects of TET2 mutations on DNA methylation in chronic myelomonocytic leukemia. Epigenetics. 2012;7(2):201–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell. 2011;20(1):11–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Itzykson R, Solary E. An evolutionary perspective on chronic myelomonocytic leukemia. Leukemia. 2013;27(7):1441–50.

    CAS  PubMed  Google Scholar 

  28. Kohlmann A, Grossmann V, Klein H-U, Schindela S, Weiss T, Kazak B, et al. Next-generation sequencing technology reveals a characteristic pattern of molecular mutations in 72.8% of chronic myelomonocytic leukemia by detecting frequent alterations in TET2, CBL, RAS, and RUNX1. J Clin Oncol. 2010;28(24):3858–65.

    CAS  PubMed  Google Scholar 

  29. Grossmann V, Kohlmann A, Eder C, Haferlach C, Kern W, Cross N, et al. Molecular profiling of chronic myelomonocytic leukemia reveals diverse mutations in> 80% of patients with TET2 and EZH2 being of high prognostic relevance. Leukemia. 2011;25(5):877.

    CAS  PubMed  Google Scholar 

  30. Kosmider O, Gelsi-Boyer V, Racoeur C, Jooste V, Vey N, Quesnel B, et al. TET2 gene mutation is a frequent and adverse event in chronic myelomonocytic leukemia. Haematologica. 2009;94(12):1676–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Smith AE, Mohamedali AM, Kulasekararaj A, Lim Z, Gäken J, Lea NC, et al. Next-generation sequencing of the TET2 gene in 355 MDS and CMML patients reveals low-abundance mutant clones with early origins, but indicates no definite prognostic value. Blood. 2010;116(19):3923–32.

    CAS  PubMed  Google Scholar 

  32. • Duchmann M, Yalniz FF, Sanna A, Sallman D, Coombs CC, Renneville A, et al. Prognostic role of gene mutations in chronic myelomonocytic leukemia patients treated with hypomethylating agents. EBioMedicine. 2018;31:174–81 This is a retrospective multi-center study that investigated the response rates among 174 CMML patients treated with HMA. The authors showed that ASXL1 mutations predicted a lower overall response rate, whereas the TET2 MT/ASXL1 WT genotype predicted a higher complete response rate; mutations in RUNX1 and CBL and higher WBC independently predicted worse OS, while the TET2 MUT/ASXL1 WT predicted better OS. Finally, current CMML-specific prognostic scores played a limited role in predicting HMA response.

    PubMed  PubMed Central  Google Scholar 

  33. Makishima H, Yoshida K, Nguyen N, Przychodzen B, Sanada M, Okuno Y, et al. Somatic SETBP1 mutations in myeloid malignancies. Nat Genet. 2013;45(8):942–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Patnaik MM, Barraco D, Lasho TL, Finke CM, Hanson CA, Ketterling RP, et al. DNMT3A mutations are associated with inferior overall and leukemia-free survival in chronic myelomonocytic leukemia. Am J Hematol. 2017;92(1):56–61.

    CAS  PubMed  Google Scholar 

  35. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17(3):225–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim S-H, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19(1):17–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Patnaik MM, Hanson C, Hodnefield J, Lasho T, Finke C, Knudson R, et al. Differential prognostic effect of IDH1 versus IDH2 mutations in myelodysplastic syndromes: a Mayo Clinic study of 277 patients. Leukemia. 2012;26(1):101.

    CAS  PubMed  Google Scholar 

  38. Fisher CL, Randazzo F, Humphries RK, Brock HW. Characterization of Asxl1, a murine homolog of additional sex combs, and analysis of the Asx-like gene family. Gene. 2006;369:109–18.

    CAS  PubMed  Google Scholar 

  39. Abdel-Wahab O, Pardanani A, Patel J, Wadleigh M, Lasho T, Heguy A, et al. Concomitant analysis of EZH2 and ASXL1 mutations in myelofibrosis, chronic myelomonocytic leukemia and blast-phase myeloproliferative neoplasms. Leukemia. 2011;25(7):1200.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Abdel-Wahab O, Adli M, LaFave LM, Gao J, Hricik T, Shih AH, et al. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell. 2012;22(2):180–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Scheuermann JC, de Ayala Alonso AG, Oktaba K, Ly-Hartig N, McGinty RK, Fraterman S, et al. Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature. 2010;465(7295):243.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Balasubramani A, Larjo A, Bassein JA, Chang X, Hastie RB, Togher SM, et al. Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1-BAP1 complex. Nat Commun. 2015;6:7307.

    CAS  PubMed  Google Scholar 

  43. Gelsi-Boyer V, Brecqueville M, Devillier R, Murati A, Mozziconacci M-J, Birnbaum D. Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases. J Hematol Oncol. 2012;5:12.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Sallman D, Padron E, Vaupel C, Cluzeau T, Al Ali NH, Lancet JE, et al. Prognostic impact of ASXL1 mutations in MDS and CMML. Blood. 2015;126(23):1673.

    Google Scholar 

  45. Lin Y, Zheng Y, Wang Z-C, Wang S-Y. Prognostic significance of ASXL1 mutations in myelodysplastic syndromes and chronic myelomonocytic leukemia: a meta-analysis. Hematology (Amsterdam, Netherlands). 2016;21(8):454–61.

    CAS  Google Scholar 

  46. 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(10):1408–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Patnaik MM, Vallapureddy R, Lasho TL, Hoversten KP, Finke CM, Ketterling R, et al. EZH2 mutations in chronic myelomonocytic leukemia cluster with ASXL1 mutations and their co-occurrence is prognostically detrimental. Blood cancer journal. 2018;8(1):12.

    PubMed  PubMed Central  Google Scholar 

  48. Meggendorfer M, Roller A, Haferlach T, Eder C, Dicker F, Grossmann V, et al. SRSF2 mutations in 275 cases with chronic myelomonocytic leukemia (CMML). Blood. 2012;120(15):3080–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Geissler K, Hinterberger W, Bettelheim P, Haas O, Lechner K. Colony growth characteristics in chronic myelomonocytic leukemia. Leuk Res. 1988;12(5):373–7.

    CAS  PubMed  Google Scholar 

  50. Padron E, Painter JS, Kunigal S, Mailloux AW, McGraw K, McDaniel JM, et al. GM-CSF-dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia. Blood. 2013;121(25):5068–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Ricci C, Fermo E, Corti S, Molteni M, Faricciotti A, Cortelezzi A, et al. RAS mutations contribute to evolution of chronic myelomonocytic leukemia to the proliferative variant. Clinical cancer research : an official journal of the American Association for Cancer Research. 2010;16(8):2246–56.

    CAS  Google Scholar 

  52. Patnaik MM, Pophali PA, Lasho TL, Finke CM, Horna P, Ketterling RP, et al. Clinical correlates, prognostic impact and survival outcomes in chronic myelomonocytic leukemia patients with the JAK2V617F mutation. Haematologica. 2019.

  53. Kuo M, Liang D, Huang C, Shih Y, Wu J, Lin T, et al. RUNX1 mutations are frequent in chronic myelomonocytic leukemia and mutations at the C-terminal region might predict acute myeloid leukemia transformation. Leukemia. 2009;23(8):1426.

    CAS  PubMed  Google Scholar 

  54. Damm F, Itzykson R, Kosmider O, Droin N, Renneville A, Chesnais V, et al. SETBP1 mutations in 658 patients with myelodysplastic syndromes, chronic myelomonocytic leukemia and secondary acute myeloid leukemias. Leukemia. 2013;27(6):1401.

    CAS  PubMed  Google Scholar 

  55. Laborde R, Patnaik MM, Lasho T, Finke C, Hanson C, Knudson R, et al. SETBP1 mutations in 415 patients with primary myelofibrosis or chronic myelomonocytic leukemia: independent prognostic impact in CMML. Leukemia. 2013;27(10):2100.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Patnaik MM, Vallapureddy R, Yalniz FF, Hanson CA, Ketterling RP, Lasho TL, et al. Therapy related-chronic myelomonocytic leukemia (CMML): molecular, cytogenetic, and clinical distinctions from de novo CMML. Am J Hematol. 2018;93(1):65–73.

    CAS  PubMed  Google Scholar 

  57. Przychodzen B, Gu X, You D, Hirsch CM, Clemente MJ, Viny AD, et al. PHF6-somatic mutations and their role in pathophysiology of MDS and AML. Am Soc Hematology; 2015.

  58. Patnaik MM, Wassie EA, Lasho TL, Hanson CA, Ketterling R, Tefferi A. Blast transformation in chronic myelomonocytic leukemia: risk factors, genetic features, survival, and treatment outcome. Am J Hematol. 2015;90(5):411–6.

    PubMed  Google Scholar 

  59. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89(6):2079–88.

    CAS  PubMed  Google Scholar 

  60. Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Kantarjian H, O'brien S, Ravandi F, Cortes J, Shan J, Bennett JM, et al. Proposal for a new risk model in myelodysplastic syndrome that accounts for events not considered in the original international prognostic scoring system. Cancer: Interdisciplinary International Journal of the American Cancer Society. 2008;113(6):1351–61.

    CAS  Google Scholar 

  62. Patnaik MM, Padron E, LaBorde R, Lasho T, Finke C, Hanson C, et al. Mayo prognostic model for WHO-defined chronic myelomonocytic leukemia: ASXL1 and spliceosome component mutations and outcomes. Leukemia. 2013;27(7):1504.

    CAS  PubMed  Google Scholar 

  63. Savona MR, Malcovati L, Komrokji R, Tiu RV, Mughal TI, Orazi A, et al. An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood. 2015;125(12):1857–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Duchmann M, Braun T, Micol J, Platzbecker U, Park S, Pilorge S, et al. Validation of response assessment according to international consortium for MDS/MPN criteria in chronic myelomonocytic leukemia treated with hypomethylating agents. EBioMedicine. 2018 May;31:174-181

  65. Xicoy B, Germing U, Jimenez MJ, Garcia O, Garcia R, Schemenau J, et al. Response to erythropoietic-stimulating agents in patients with chronic myelomonocytic leukemia. Eur J Haematol. 2016;97(1):33–8.

    CAS  PubMed  Google Scholar 

  66. Patnaik MM, Tefferi A, editors. Chronic myelomonocytic leukemia: focus on clinical practice. Mayo Clin Proc; 2016: Elsevier.

  67. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20(10):2429–40.

    CAS  PubMed  Google Scholar 

  68. 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. The Lancet Oncology. 2009;10(3):223–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Sekeres MA, Othus M, List AF, Odenike O, Stone RM, Gore SD, 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;35(24):2745.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Kantarjian H, Issa JPJ, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer: Interdisciplinary International Journal of the American Cancer Society. 2006;106(8):1794–803.

    CAS  Google Scholar 

  71. Padron E, DeZern AE, Niyongere S, Ball MC, Balasis M, Ramadan H, et al. Promising results of a phase 1/2 clinical trial of ruxolitinib in patients with chronic myelomonocytic leukemia. Am Soc Hematology; 2017.

  72. Assi R, Kantarjian HM, Garcia-Manero G, Cortes JE, Pemmaraju N, Wang X, et al. A phase II trial of ruxolitinib in combination with azacytidine in myelodysplastic syndrome/myeloproliferative neoplasms. Am J Hematol. 2018;93(2):277–85.

    CAS  PubMed  Google Scholar 

  73. • Patnaik MM, Ali H, Gupta V, Schiller GJ, Lee S, Yacoub A, et al. Results from ongoing phase 1/2 clinical trial of tagraxofusp (SL-401) in patients with relapsed/refractory chronic myelomonocytic leukemia (CMML). Am Soc Hematology; 2018. This abstract reported the interim results from the ongoing phase 1/2 clinical trial of tagraxofusp (SL-401) in patients with relapsed/refractory CMML (NCT02268253). The investigators showed that tagraxofusp monotherapy resulted in significant reductions in spleen sizes along with BM morphological responses, with a manageable safety profile.

  74. Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, Buckstein R, Santini V, et al. The medalist trial: results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept to treat anemia in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts (RS) who require red blood cell (RBC) transfusions. Am Soc Hematology; 2018.

  75. Hadjadj J, Michel M, Chauveheid MP, Godeau B, Papo T, Sacre K. Immune thrombocytopenia in chronic myelomonocytic leukemia. Eur J Haematol. 2014;93(6):521–6.

    PubMed  Google Scholar 

  76. Prica A, Sholzberg M, Buckstein R. Safety and efficacy of thrombopoietin-receptor agonists in myelodysplastic syndromes: a systematic review and meta-analysis of randomized controlled trials. Br J Haematol. 2014;167(5):626–38.

    CAS  PubMed  Google Scholar 

  77. Gao Y, Gong M, Zhang C, Kong X, Ma Y. Successful eltrombopag treatment of severe refractory thrombocytopenia in chronic myelomonocytic leukemia: two cases reports: a CARE-compliant article. Medicine. 2017;96(43).

    PubMed  PubMed Central  Google Scholar 

  78. Ramadan H, Duong VH, Al Ali N, Padron E, Zhang L, Lancet JE, et al. Eltrombopag use in patients with chronic myelomonocytic leukemia (CMML): a cautionary tale. Clinical Lymphoma Myeloma and Leukemia. 2016;16:S64–S6.

    Google Scholar 

  79. Pophali P, Horna P, Lasho TL, Finke CM, Ketterling RP, Gangat N, et al. Splenectomy in patients with chronic myelomonocytic leukemia: indications, histopathological findings and clinical outcomes in a single institutional series of thirty-nine patients. Am J Hematol. 2018;93(11):1347–57.

    PubMed  PubMed Central  Google Scholar 

  80. Patnaik MM, Tefferi A. Chronic myelomonocytic leukemia: 2018 update on diagnosis, risk stratification and management. Am J Hematol. 2018;93(6):824–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. •• Coston T, Pophali P, Vallapureddy R, Lasho TL, Finke CM, Ketterling RP, et al. Suboptimal response rates to hypomethylating agent therapy in chronic myelomonocytic leukemia; a single institutional study of 121 patients. Am J Hematol. 2019. This study assessed HMA response rate in 121 CMML patients according to both IWG-MDS and MDS/MPN overlap syndrome response criteria. The authors showed that, although HMA-treated patients had an overall survival advantage compared to HMA-untreated patients, the response rates were low with very low rates of true CR.

  82. Zang DY, Deeg HJ, Gooley T, Anderson JE, Anasetti C, Sanders J, et al. Treatment of chronic myelomonocytic leukaemia by allogeneic marrow transplantation. Br J Haematol. 2000;110(1):217–22.

    CAS  PubMed  Google Scholar 

  83. Kröger N, Zabelina T, Guardiola P, Runde V, Sierra J, Van Biezen 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.

    PubMed  Google Scholar 

  84. Kerbauy DM, Chyou F, Gooley T, Sorror ML, Scott B, Pagel JM, et al. Allogeneic hematopoietic cell transplantation for chronic myelomonocytic leukemia. Biology of Blood and Marrow Transplantation. 2005;11(9):713–20.

    PubMed  Google Scholar 

  85. Elliott MA, Tefferi A, Hogan W, Letendre L, Gastineau D, Ansell SM, et al. Allogeneic stem cell transplantation and donor lymphocyte infusions for chronic myelomonocytic leukemia. Bone Marrow Transplant. 2006;37(11):1003.

    CAS  PubMed  Google Scholar 

  86. Ocheni S, Kröger N, Zabelina T, Zander A, Bacher U. Outcome of Allo-SCT for chronic myelomonocytic leukemia. Bone Marrow Transplant. 2009;43(8):659.

    CAS  PubMed  Google Scholar 

  87. Krishnamurthy P, Lim Z, Nagi W, Kenyon M, Mijovic A, Ireland R, et al. Allogeneic haematopoietic SCT for chronic myelomonocytic leukaemia: a single-Centre experience. Bone Marrow Transplant. 2010;45(10):1502.

    CAS  PubMed  Google Scholar 

  88. Eissa H, Gooley TA, Sorror ML, Nguyen F, Scott BL, Doney K, et al. Allogeneic hematopoietic cell transplantation for chronic myelomonocytic leukemia: relapse-free survival is determined by karyotype and comorbidities. Biology of Blood and Marrow Transplantation. 2011;17(6):908–15.

    PubMed  Google Scholar 

  89. Kroger N, Zabelina T, De Wreede L, Berger J, Alchalby H, Van Biezen A, et al. Allogeneic stem cell transplantation for older advanced MDS patients: improved survival with young unrelated donor in comparison with HLA-identical siblings. Leukemia. 2013;27(3):604–9.

    CAS  PubMed  Google Scholar 

  90. Park S, Labopin M, Yakoub-Agha I, Delaunay J, Dhedin N, Deconinck E, et al. Allogeneic stem cell transplantation for chronic myelomonocytic leukemia: a report from the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. Eur J Haematol. 2013;90(5):355–64.

    PubMed  Google Scholar 

  91. Sanchez ME, Abbi KKS, Tamari R, Jakubowsky A, Papadopoulos EB, Devlin SM, et al. Allogeneic transplantation for chronic myelomonocytic leukemia (CMML) is associated with high disease-free survival even in the setting of high-risk disease. Am Soc Hematology; 2014.

  92. Bajel AR, Curley C, Lim ABM, Handunnetti S, Getta B, Thompson PA, et al. Allogeneic stem cell transplantation (Allo-SCT) for chronic myelomonocytic leukemia—a multicentre Australian experience: prognostic factors for survival and relapse. Am Soc Hematology; 2014.

  93. Symeonidis A, Van Biezen A, de Wreede 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. Br J Haematol. 2015;171(2):239–46.

    PubMed  Google Scholar 

  94. • Liu HD, Ahn KW, Hu Z-H, Hamadani M, Nishihori T, Wirk B, et al. Allogeneic hematopoietic cell transplantation for adult chronic myelomonocytic leukemia. biology of blood and marrow transplantation. Journal of the American Society for Blood and Marrow Transplantation. 2017;23(5):767–75 This study evaluated 209 adult patients who underwent alloHCT for CMML and identified higher CPSS scores at time of transplant, lower Karnofsky performance status, and BM graft source as independent predictors of inferior overall survival.

    Google Scholar 

  95. Kongtim P, Popat U, Jimenez A, Gaballa S, El Fakih R, Rondon G, et al. Treatment with hypomethylating agents before allogeneic stem cell transplant improves progression-free survival for patients with chronic myelomonocytic leukemia. Biology of Blood and Marrow Transplantation. 2016;22(1):47–53.

    CAS  PubMed  Google Scholar 

  96. Potter VT, Iacobelli S, van Biezen A, Maertens J, Bourhis J-H, Passweg JR, et al. Comparison of intensive chemotherapy and hypomethylating agents before allogeneic stem cell transplantation for advanced myelodysplastic syndromes: a study of the myelodysplastic syndrome subcommittee of the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplant Research. Biology of Blood and Marrow Transplantation. 2016;22(9):1615–20.

    CAS  PubMed  Google Scholar 

  97. de Witte T, Bowen D, Robin M, Malcovati L, Niederwieser D, Yakoub-Agha I, et al. Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel. Blood. 2017;129(13):1753–62.

    PubMed  PubMed Central  Google Scholar 

  98. Yoshimi A, Balasis ME, Vedder A, Feldman K, Ma Y, Zhang H, et al. Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML. Blood. 2017;130(4):397–407.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Ma Y, Rix LR, Zhang Q, Balasis ME, Komrokji RS, Rix U, et al. Pacritinib (PAC) synergistically potentiates azacitidine (5AZA) cytotoxicity in chronic myelomonocytic leukemia (CMML). Am Soc Hematology; 2015.

  100. Yang H, Bueso-Ramos C, DiNardo C, Estecio MR, Davanlou M, Geng QR, et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia. 2014;28(6):1280–8.

    CAS  PubMed  Google Scholar 

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  1. Department of Medicine, Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Giacomo Coltro & Mrinal M. Patnaik

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  1. Giacomo Coltro
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Giacomo Coltro declares that he has no conflict of interest.

Mrinal M. Patnaik served on an advisory board for Stem Line Pharmaceuticals. The honorarium was issued directly to Mayo Clinic.

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Coltro, G., Patnaik, M.M. Chronic Myelomonocytic Leukemia: Insights into Biology, Prognostic Factors, and Treatment. Curr Oncol Rep 21, 101 (2019). https://doi.org/10.1007/s11912-019-0855-6

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