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Editorials
Are next-generation sequencing results knocking on Heaven’s door for transplantation planning in chronic myelomonocytic leukemia?
Guillermo F. Sanz,1,2,3,4 Mariam Ibañez1,2,4,5 and Elvira Mora1,2
1Department of Hematology, Hospital Universitario y Politécnico La Fe, Valencia; 2Instituto de Investigación Sanitaria La Fe, Valencia 3Department of Medicine, University of Valencia, Valencia; 4Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Instituto de Salud Carlos III, Madrid and 5Departamento de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad CEU Cardenal Herrera, Valencia, Spain
E-mail: GUILLERMO SANZ - sanz_gui@gva.es doi:10.3324/haematol.2019.240853
Chronic myelomonocytic leukemia (CMML) is a heterogeneous malignant myeloid disorder included in the 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia in the category of myelodysplastic syndromes/myeloproliferative neoplasms. CMML patients show a diverse biological, clinical picture and heterogeneous prognosis, with short overall survival (OS) and increased risk of progression to acute myeloid leukemia. The diagnosis of CMML requires a monocyto- sis, defined as an absolute monocyte count above 1x109/L that should represent >10% of the white blood count (WBC) differential, which persists for more than 3 months and for which other causes of reactive monocy- tosis have been excluded. The current World Health Organization classification includes three CMML groups, divided on the basis of blast counts, for better prognosti- cation: CMML-0 [<2% peripheral blood (PB) and <5% bone marrow (BM) blasts]; CMML-1 (2-4% PB and/or 5- 9% BM blasts); and CMML-2 (5-19% PB and/or 10-19% BM blasts). The classical French-American-British classifi- cation, still widely used, divides CMML into so-called “dysplastic” CMML (WBC ≤13x109/L) and ”myeloprolif- erative” CMML (WBC >13 x109/L).
Cytogenetic abnormalities and somatic mutations are found in, respectively, 25-30% and up to 95% of CMML patients and both have a strong influence on OS. The val- idated CMML-specific cytogenetic risk classification rec- ognizes three risk categories: low-risk (normal karyotype or loss of the Y chromosome as a single anomaly; ~78%), high-risk (trisomy 8 or abnormalities of chromosome 7, or complex karyotype; ~12%), and intermediate-risk (all other abnormalities; ~9%).1 The most frequently mutated genes in CMML affect epigenetic regulation and DNA methylation (ASXL1 and TET2), RNA splicing (SRSF2), and transcription (RUNX1) and signaling pathways (RAS).2-4 Frameshift and nonsense ASXL1 mutations con- fer an adverse prognosis,2-4 aggravated when EZH2 and ASXL1 mutations co-occur.5 DNMT3A and TP53 muta- tions, although less common in CMML, have also been associated with poorer OS.6,7 It is noteworthy that the number of mutations also influences patients’ outcomes, as recently demonstrated in a study in which a shorter OS was observed in CMML patients with three or more con- comitant mutations.7
Specific prognostic scoring systems for individual risk assessment are essential in order to provide risk-adapted treatment. The most commonly used are the CMML-spe- cific prognostic scoring system (CPSS),8 the MD Anderson Cancer Center prognostic score (MDAPS)9 and
the revised International Prognostic Scoring System (IPSS- R)10 (the last only being applicable to “dysplastic” CMML). More recent scoring systems that also include somatic mutations are those by the Groupe Français des Myélodysplasies (GFM),2 the Mayo Clinic3, and the molec- ular CPSS.4 All these molecular prognostic scoring sys- tems consider ASXL1 mutations; the molecular CPSS also takes into account mutations in NRAS, SETBP1, and RUNX1.
Allogeneic hematopoietic cell transplant (HCT) is the only potentially curative therapy for patients with CMML but the number of transplant-eligible patients is low because of these individuals’ advanced age, comor- bidities, and frailty. A recent multicenter retrospective study with 1,656 CMML patients of whom 89 received an allogeneic HCT demonstrated the benefit of HCT for patients with higher-risk disease as determined by the CPSS11 and multiple retrospective studies have document- ed a 3-year OS rate of 30-40%.12-15 For high-risk trans- plant-ineligible and/or lower-risk patients the most wide- ly used therapies are hydroxyurea, hypomethylating agents, and best supportive care. Recent evidence sug- gests that hypomethylating agents might be superior to hydroxyurea.11
Many studies have evaluated the prognostic factors for transplantation outcomes in CMML patients, with con- tradictory results.16 As would be expected, patients trans- planted in complete remission13 as well as those with <5% blasts at transplantation14 had better outcomes in comparison to those with more advance disease at trans- plantation. The favorable effect of using hypomethylat- ing agents before transplantation over intensive chemotherapy is debatable.14-16 In a large study by the Center for International Blood and Marrow Transplantation Research (CIBMTR), the CPSS score at the time of HCT strongly influenced OS after transplan- tation.15 Table 1 shows the predictive factors for increased relapse or reduced OS evidenced in major studies on allo- genic HCT for CMML.
In this issue of Haematologica, Woo and colleagues, ana- lyze long-term outcomes after allogeneic HCT in 129 patients with CMML from a single institution and evalu- ate clinical and molecular risk factors associated with out- comes.17 Of note, this study is the first to evaluate the impact of somatic mutations determined by next-genera- tion sequencing (NGS) on allogeneic HCT outcomes in a large and homogeneous series of patients from a single institution. In a subcohort of 52 patients in whom a NGS panel of 75 genes was used, 85% of patients had at least one mutation, congruent with previous reports on
haematologica | 2020; 105(3)