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Gene mutations may improve prognosis models for certain patients with leukemia subtype

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ATLANTA — Contrary to previous research, treatment with hypomethylating agents seem to only partially negate the poor prognosis of certain mutations among patients with chronic myelomonocytic leukemia, according to findings presented at the ASH Annual Meeting and Exposition.

Matthieu Duchmann, of the Gustave Roussy Institute of Oncology in France, and colleagues conducted a multicenter retrospective analysis of 183 patients with chronic myelomonocytic leukemia (median age, 72 years) treated with either azacitidine or decitabine.

The researchers aimed to identify the specific prognostic value of recurrent gene mutations among patients treated with hypomethylating agents.

Seventy-six patients received azacitidine and 107 patients received decitabine for a median of seven cycles (interquartile range [IQR], 4-15). Median white blood cell count was 15.1 x 10⁹/L.

Patients had low (71%), intermediate (12%) and high (17%) cytogenetic risk, according to chronic myelomonocytic leukemia (CMML)-specific prognostic scoring system.

Overall response rate to the hypomethylating agents was 54%, including 17% complete responses. No significant difference appeared between the azacitidine and decitabine arms.

After a median follow-up of 36.7 months, median OS was 24.2 months and median acute myeloid leukemia-free survival was 19.2 months. Ten percent of patients received transplants after hypomethylating agents. Censoring at transplant did not affect study results.

Patients who received decitabine had higher white blood cell counts (P = .01), nonsignificant trends toward lower platelet count and worse cytogenetic risk, with a nonsignificant trend toward worse OS.

Propensity matching on previous treatment with chemotherapy, as well as white blood cell, platelets and peripheral blasts count, and cytogenetic risk and ASXL1 status at hypomethylating agent onset, confirmed the lack of OS benefit with azacitidine in the 144 patients that could be successfully matched (P = .4).

The researchers obtained molecular data from Sanger sequencing (n = 74) and next-generation sequencing (n = 109).

The analysis focused on genes analyzed in 90% or more of patients and found mutated in 10% or more of patients.

The molecular spectrum of the cohort appeared comparable to previous CMML reports, according to study data, and dominated by frequent mutations in SRSF2 (46%), ASXL1 (45%) and TET2 (39%). Mutation frequencies in these genes did not differ between patients on azacitidine or decitabine, as well as Sanger and NGS.

A lower ORR occurred among patients with ASXL1 mutations (ASXL1^mut 44% vs. ASXL1^wt 62%, P = .02), whereas only TET2 mutations predicted a higher complete response rate (TET2^mut 22% vs. TET^2wt 11%, P = .02), according to univariate analysis.

In another univariate analysis, mutations in RUNX1 (13% of patients, P = .006) and, to a lesser extent, ASXL1 (45% of patients, P = .07) and CBL (12% of patients, P = .08) appeared associated with shorter OS.

No significant interaction appeared between TET2 and ASXL1 or SRSF2 status in terms of ORR or OS.

Splenomegaly (P = .045), white blood cell counts > 13 x 10⁹/L (P = .003), platelets < 100 x 10⁹/L (P = .045), peripheral immature myeloid cells > 2% (P = .02), peripheral blasts > 1% (P = .02) and high-risk karyotype (P = .047) appeared associated with worse OS.

A multivariate Cox model showed independent predictors of OS included RUNX1 mutations (P = .007), splenomegaly (P = .049), white blood cell counts > 13 x 10⁹/L (P = .005), platelets < 100 x 10⁹/L (P = .046) and high-risk karyotype (P = .04).

“We could, therefore, build a CMML-hypomethylating agent model where patients with none, one, two, three or four of these five criteria were found to have distinct median OS ranging from 9.8 months to 54.8 months,” the researchers wrote. “Though [CMML-specific prognostic scoring system] (P = .001) and [Groupe Francophone des Myelodysplasies] risk scores both predicted survival of hypomethylating-treated CMML (P .001), our proposed CMML-hypomethylating index proved superior to both risk scores. RUNX1 mutations confer a poor prognosis in CMML treated with hypomethylating agents and can be integrated with clinical and hematological parameters to improve prognostication of CMML patients treated with hypomethylating agents, when compared with ‘classical’ CMML risk scores.” – by Ryan McDonald

Reference:

Duchmann M, et al. Abstract 159. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.

Disclosures: Duchmann reports no relevant financial disclosures. Please see the full study for a list of all other authors’ relevant disclosures.