Atypical Chronic Myeloid Leukemia: Case Report and Review of Literature
Atypical chronic myeloid leukemia (aCML) is a BCR-ABL1 negative myelodysplastic/myeloproliferative (MDS/MPN) neoplasm. Patients typically present with elevated neutrophil counts and hypercellular bone marrow, but there are no specific genetic or molecular markers available to diagnose aCML and it is therefore a diagnosis of exclusion. Atypical CML is rare and carries a poor prognosis, and there is currently no standard of care for treatment. In the absence of an available clinical trial, current consensus is for patients with a suitable donor to undergo allogeneic stem cell transplantation, and a comprehensive evaluation for driver mutations should be performed to screen for the potential use of targeted agents. Without an actionable driver mutation, hypomethylating agents are an emerging treatment option based on four reports showing complete hematologic remission in 7 of 8 patients treated with decitabine.
1.Vardiman JBR, Arber DA. Introduction and overview of the classification of myeloid neoplasms. In: Swerdlow SCE, Harris NL, editors. International Agency for Research on Cancer, WHO classification of tumours of haematopoietic and lymphoid tissue. 4th ed. Geneva: WHO; 2008. p. 18–30.
2. Zoi K, Cross NCP. Molecular pathogenesis of atypical CML, CMML and MDS/MPN-unclassifiable. Int J Hematol 2015;101:229–42.
3. Tiu RV, Sekeres MA. Making sense of the myelodysplastic/ myeloproliferative neoplasms overlap syndromes. Curr Opin Hematol 2014;21:131–40.
4. Saqlain N, Ahmed N. Atypical chronic myeloid leukemia, BCRABL1 negative, in a 5-month baby – a rare presentation. J Coll Physicians Surg Pak 2016;26:103–5.
5. Schwartz LC, Mascarenhas J. Current and evolving understanding of atypical chronic myeloid leukemia. Blood Rev 2019;33:74–81.
6. Wang SA, Hasserjian RP, Fox PS, Rogers HJ, Geyer JT, Chabot-Richards D, et al. Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms. Blood 2014;123:2645–51.
7. 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;112:45–52.
8. Elliott MA, Hanson CA, Dewald GW, Smoley SA, Lasho TL, Tefferi A. WHO-defined chronic neutrophilic leukemia: a longterm analysis of 12 cases and a critical review of the literature. Leukemia 2005;19:313–7.
9. Costa R, Abdulhaq H, Haq B, Shadduck RK, Latsko J, Zenati M, et al. Activity of azacitidine in chronic myelomonocytic leuke-mia. Cancer 2011;117:2690–6.
10. Kong JH, Nam H, Go T-H, Hyun SY, Shim KY. Characteristics and survival of patients with atypical chronic myeloid leukemia. Blood Res 2019;54:233–6.
11. Itonaga H, Ota S, Ikeda T, Taji H, Amano I, Hasegawa Y, et al. Allogeneic hematopoietic stem cell transplantation for the treatment of BCR-ABL1-negative atypical chronic myeloid leukemia and chronic neutrophil leukemia: A retrospective nationwide study in Japan. Leuk Res 2018;75:50–7.
12. Sabnis AJ, Cheung LS, Dail M, Kang HC, Santaguida M, Hermiston ML, et al. Oncogenic Kras initiates leukemia in hematopoietic stem cells. PLoS Biol 2009;7:e59.
13. Braun BS, Tuveson DA, Kong N, Le DT, Kogan SC, Rozmus J, et al. Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. Proc Natl Acad Sci U S A 2004;101:597–602.
14. Van Meter ME, Díaz-Flores E, Archard JA, Passegué E, Irish JM, Kotecha N, et al. K-RasG12D expression induces hyperproliferation and aberrant signaling in primary hematopoietic stem/ progenitor cells. Blood 2007;109:3945–52.
15. 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;31:2428–36.
16. Fend F, Horn T, Koch I, Vela T, Orazi A. Atypical chronic myeloid leukemia as defined in the WHO classification is a JAK2 V617F negative neoplasm. Leuk Res 2008;32:1931–5.
17. Jones AV, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 2005;106:2162–8.
18. Levine RL, Loriaux M, Huntly BJ, Loh ML, Beran M, Stoffregen E, et al. The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. Blood 2005;106:3377–9.
19. Grand FH, Hidalgo-Curtis CE, Ernst T, Zoi K, Zoi C, McGuire C, et al. Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. Blood 2009;113:6182–92.
20. Sanada M, Suzuki T, Shih LY, Otsu M, Kato M, Yamazaki S, et al. Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature 2009;460:904–8.
21. Itzykson R, Kosmider O, Renneville A, Morabito M, Preudhomme C, Berthon C, et al. Clonal architecture of chronic myelomonocytic leukemias. Blood 2013;121:2186–98.
22. Lin P, Jones D, Medeiros LJ, Chen W, Vega-Vazquez F, Luthra R. Activating FLT3 mutations are detectable in chronic and blast phase of chronic myeloproliferative disorders other than chronic myeloid leukemia. Am J Clin Pathol 2006;126:530–3.
23. Grand FH, Iqbal S, Zhang L, Russell NH, Chase A, Cross NCP. A constitutively active SPTBN1-FLT3 fusion in atypical chronic myeloid leukemia is sensitive to tyrosine kinase inhibitors and immunotherapy. Exp Hematol 2007;35:1723–7.
24. Walz C, Erben P, Ritter M, Bloor A, Metzgeroth G, Telford N, et al. Response of ETV6-FLT3-positive myeloid/lymphoid neoplasm with eosinophilia to inhibitors of FMS-like tyrosine kinase 3. Blood 2011;118:2239–42.
25. Maxson JE, Gotlib J, Pollyea DA, Fleischman AG, Agarwal A, Eide CA, et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med 2013;368:1781–90.
26. Tefferi A, Lim KH, Levine R. Mutation in TET2 in myeloid cancers. N Engl J Med 2009;361:1117; author reply 1117–8.
27. Piazza R, Valletta S, Winkelmann N, Redaelli S, Spinelli R, Pirola A, et al. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet 2013;45:18–24.
28. Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 2009;114:144–7.
29. Saqlain N, Ahmed N. Atypical chronic myeloid leukemia, BCRABL1 negative, in a 5-month baby – a rare presentation. J Coll Physicians Surg Pak 2016;26:103–5.
30. Jankowska AM, Szpurka H, Tiu RV, Makishima H, Afable M, Huh J, et al. Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood 2009;113:6403–10.
31. Kosmider O, Gelsi-Boyer V, Cheok M, Grabar S, Della-Valle V, Picard F, et al; Groupe Francophone des Myélodysplasies. TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs). Blood 2009;114:3285–91.
32. Szuber N, Tefferi A. Chronic neutrophilic leukemia: new science and new diagnostic criteria. Blood Cancer J 2018;8.19.
33. Elliott MA, Tefferi A. Chronic neutrophilic leukemia: 2018 update on diagnosis, molecular genetics and management. Am J Hepatol 2018;93:578–87.
34. Gotlib J. How I treat atypical chronic myeloid leukemia. Blood 2017;129:838–45.
35. Liangshu You LM. The first case of decitabine successfully in treatment of atypical chronic myeloid leukemia with CEBPA double mutation. Chemotherapy 2013;2:1–3.
36. Tong X, Li J, Zhou Z, Zheng D, Liu J, Su C. Efficacy and side-effects of decitabine in treatment of atypical chronic myeloid leukemia. Leuk Lymphoma 2015;56:1911–3.
37. Hausmann H, Bhatt VR, Yuan J, Maness LJ, Ganti AK. Activity of single-agent decitabine in atypical chronic myeloid leukemia. J Oncol Pharm Pract 2016;22:790–4.
38. Jiang H, Wu Z, Ren LI, Tao D, Tong H. Decitabine for the treatment of atypical chronic myeloid leukemia: A report of two cases. Oncol Lett 2016;11:689–92.