Letter to the editor

The mutational landscape of atypical chronic myeloid leukemia

Stephen E. Langabeer¹[*]

EXCLI J 2019;18:Doc256



Dear Editor,

Atypical chronic myeloid leukemia (aCML) is a rare haematological malignancy classified as a myelodysplastic/myeloproliferative neoplasm (MDS/MPN). Diagnostic criteria include leucocytosis with left shift, dysgranulopoiesis, minimal basophila and monocytosis, a hypercellular bone marrow, less than 20 % myeloblasts in the blood or bone marrow, and absence of the distinct molecular abnormalities of classical MPN (Arber et al., 2016[1]). Until recently, treatment for aCML has been largely based on those agents used for either MDS or MPN type with varying degrees of success (Gotlib, 2017[5]). While haematopoietic allogeneic stem cell transplantation remains the only curative therapy, it is limited to those aCML patients eligible for such a procedure (Onida et al., 2017[11]). In other myeloid malignancies, targeted sequencing has identified recurrently mutated genes providing both insight into disease pathogenesis and helped to unmask therapeutically actionable molecular abnormalities.

Several studies have investigated the mutation profile of sizeable cohorts of aCML patients in chronic and blast crisis phases by targeted sequencing of recurrently mutated genes of myeloid malignancies. However, in order to comprehensively survey the current mutational landscape of aCML, these studies together with smaller series and case reports adopting such targeted sequencing approaches in the literature, are summarised in Figure 1(Fig. 1) (References in Figure 1: Piazza et al., 2013[13]; Meggendorfer et al., 2013[9]; Meggendorfer et al., 2014[10]; Gambacorti-Passerini et al., 2015[3]; Khanna et al., 2015[7]; Patnaik et al., 2017[12]; Langabeer et al., 2017[8]; Gilioli et al., 2018[4]; Gurnari et al., 2018[6]; Faisal et al., 2019[2]). Caveats include the use of evolving classification criteria for aCML, possible duplication of patients in two or more studies, and differences in the genes covered by independent targeted sequencing approaches.

From this summary, the most frequently mutated genes in aCML patients appear to be ASXL1, NRAS, SETBP1, SRSF2 and TET2. In addition to broad cytoreductive and supportive measures (Schwartz and Mascarenhas, 2019[14]), clinical responses with inhibitors of mutated NRAS and FLT3 have been observed in single cases validating this individualized approach (Khanna et al., 2015[7]; Langabeer et al., 2017[8]).

Due to the lack of a standard of care combined with the clinical and genetic heterogeneity of this malignancy, a personalized prognostic and therapeutic direction to aCML management is anticipated, facilitated by the progressively fundamental role of targeted mutation profiling.

Conflict of interest

The author declares no conflict of interest.

References

1. 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;127:2391-405.

2. Faisal M, Stark H, Büsche G, Schlue J, Teiken K, Kreipe HH, et al. Comprehensive mutation profiling and mRNA expression analysis in atypical chronic myeloid leukemia in comparison with chronic myelomonocytic leukemia. Cancer Med. 2019;8:742-50.

3. Gambacorti-Passerini CB, Donadoni C, Parmiani A, Pirola A, Redaelli S, Signore G, et al. Recurrent ETNK1 mutations in atypical chronic myeloid leukemia. Blood. 2015;125:499-503.

4. Gilioli A, Paolini A, Bonacorsi G, Luppi M. A typical atypical chronic myeloid leukemia. Clin Case Rep. 2018;6:915-6.

5. Gotlib J. How I treat atypical chronic myeloid leukemia. Blood. 2017;129:838-45.

6. Gurnari C, Panetta P, Fabiani E, Nardone AM, Postorivo D, Falconi G, et al. Identification of i(X)(p10) as the sole molecular abnormality in atypical chronic myeloid leukemia evolved into acute myeloid leukemia. Mol Clin Oncol. 2018;8:463-5.

7. Khanna V, Pierce ST, Dao KHT, Tognon CE, Hunt DE, Junio B, et al. Durable disease control with MEK inhibition in a patient with NRAS-mutated atypical chronic myeloid leukemia. Cureus. 2015;7:e414.

8. Langabeer SE, Comerford CM, Quinn J, Murphy PT. Molecular profiling and targeted inhibitor therapy in atypical chronic myeloid leukaemia in blast crisis. J Clin Pathol. 2017;70:1089.

9. Meggendorfer M, Bacher U, Alpermann T, Haferlach C, Kern W, Gambacorti-Passerini C, et al. SETBP1 mutations occur in 9% of MDS/MPN and in 4% of MPN cases and are strongly associated with atypical CML, monosomy 7, isochromosome i(17)(q10), ASXL1 and CBL mutations. Leukemia. 2013;27:1852-60.

10. Meggendorfer M, Haferlach T, Alpermann T, Jeromin S, Haferlach C, Kern W, et al. Specific molecular mutation patterns delineate chronic neutrophilic leukemia, atypical chronic myeloid leukemia, and chronic myelomonocytic leukemia. Haematologica. 2014;99:e246.

11. Onida F, de Wreede LC, van Biezen A, Eikema DJ, Byrne JL, Iori AP, et al. Allogeneic stem cell transplantation in patients with atypical chronic myeloid leukaemia: a retrospective study from the Chronic Malignancies Working party of the European Society for Blood and Bone Marrow Transplantation. Br J Haematol. 2017;177:759-65.

12. Patnaik MM, Barraco D, Lasho TL, Finke CM, Reichard K, Hoversten KP, et al. Targeted next generation sequencing and identification of risk factors in World Health Organization defined atypical chronic myeloid leukemia. Am J Hematol. 2017;92:542-8.

13. 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.

14. Schwartz LC, Mascarenhas J. Current and evolving understanding of atypical chronic myeloid leukemia. Blood Rev. 2019;33:74-81.

 

 

Figure 1: Mutated myeloid malignancy-associated genes (red shading) by targeted sequencing in aCML patients

 

[*] Corresponding Author:

Stephen E. Langabeer, Cancer Molecular Diagnostics, St. James's Hospital, Dublin, Ireland; Phone: +353-1-4103576, Fax: +353-1-4103513, eMail: slangabeer@stjames.ie