Blast Transformation in Chronic Myelomonocytic Leukemia: Risk Factors and Outcome

Background: Prognosis in chronic myelomonocytic leukemia (CMML) is dire and blast transformation (BT) is a main cause of death. Current risk factors and prognostic models are mostly designed to predict overall (OS) and not leukemia-free (LFS) survival. Established risk factors for OS in CMML include anemia, thrombocytopenia, leukocytosis, monocytosis, presence of circulating immature myeloid cells (IMC), peripheral blood (PB) and bone marrow (BM) blasts, lymphocytosis, ASXL1 mutations, high risk abnormal karyotype and advanced age. In the current study, we examined risk factors for BT in CMML and survival outcome after BT.

Methods: All CMML patients seen at our institution and with complete presentation data were considered. Clinical and laboratory variables, including cytogenetic information, at time of CMML diagnosis and also at time of BT were collected. DNA analysis for SRSF2, SF3B1, U2AF1, ASXL1 and SETBP1 mutations was carried out on specimens obtained at time of CMML diagnosis. We used both conventional and revised (see accompanying ASH 2014 abstract) cytogenetic risk models to query their influence in the current study population.

Results:

Clinical and laboratory features at time of CMML diagnosis:277 consecutive patients (median age 71 years, range 18-91; 67% males) with WHO-defined CMML were considered. 236 (85%) patients had CMML-1 and the remainder CMML-2. According to the molecular Mayo risk model, 86 (33%) were high, 77 (29%) were intermediate-2, 77 (29%) were intermediate-1 and 24 (9%) were low risk. Mutational frequencies were 40% for ASXL1 (n evaluable =264), 44% for SRSF2 (n evaluable =263), 5% for SETBP1 (n evaluable =263). According to the revised Mayo-French consortium cytogenetic risk model, karyotype was high risk in 5%, intermediate in 21% and low risk in 74%.

Risk factors for blast transformation (BT): At a median follow-up of 16.2 months for all 277 patients from time of CMML diagnosis, 204 (74%) deaths and 38 (14%) BTs were documented. Median time from CMML diagnosis to BT was 13.3 months. In univariate analysis, female sex, younger age, lower hemoglobin, higher leukocyte count, higher absolute monocyte count, higher lymphocyte count, presence of circulating immature myeloid cells (IMC), increased peripheral blood (PB) blast %, increased bone marrow (BM) blast %, BM blasts ≥10%, CMML-2, abnormal karyotype, high risk karyotype per the Spanish or Mayo-French consortium, and higher risk disease per Mayo, MDACC or Dusseldorf models were all associated with higher risk of BT. In contrast, ASXL1 (p=0.84), SRSF2 (p=0.28) or SETBP1 (p=0.97) mutations were not found to be significant. In multivariable analysis, only PB blast % (p<0.0001), presence of PB IMC (p=0.004) and younger age (p=0.03) remained significant.

Outcome of blast transformation: At time of BT, karyotype was abnormal in 58% and clonal evolution from time of CMML diagnosis was documented in 13 (36%) of 36 evaluable patients. Among the 38 patients with BT, induction chemotherapy was documented in 12 patients and allogeneic stem cell transplant (ASCT) in 6. At a median follow-up of 4.2 months from time of BT, 34 (89%) of the 38 patients with BT had died. Among the four patients who were alive at the time of this writing, 3 had received induction chemotherapy and two ASCT. Median survival of patients with BT, from time of disease transformation, was 4.5 months with 1, 2 and 3 year survival rates of approximately 30%, 16% and 3%, respectively. In univariate analysis, higher leukocyte count (p=0.01) and not receiving induction chemotherapy (p=0.03) were associated with shortened survival. Neither ASXL1 nor SRSF2 mutations affected survival after BT.

Conclusions: Blast transformation in CMML occurs in approximately 14% of patients followed for a median of less than 1.5 years. Presence of circulating immature cells and percentage of peripheral blood blasts are the major determinants of BT in CMML. Genetic risk factors for overall survival did not appear to influence leukemia-free survival. Prognosis of post-CMML BT is dismal with median survival of less than 6 months and a 3-year survival of less than 5%. Outcome was better in patients receiving induction chemotherapy followed by ASCT.