Multiple TET2 mutations confer additional survival benefit in both myelodysplastic and myeloproliferative chronic myelomonocytic leukemia subtypes

Abstract

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping myelodysplastic (MD) and myeloproliferative (MP) features [1, 2]. Somatic TET2 mutations (TET2^MT) are present in 40–60% of CMML patients and are associated with improved overall (OS) and acute leukemia free survival (LFS) [3, 4]. This is due, in part, to a protective effect of TET2^MT in the context of adverse ASXL1^MT and a higher response rate to hypomethylating agents (HMA) [4, 5]. Approximately 50% of TET2 mutated cases have multiple TET2^MT (range 47-52% [4,5,6]) which have been associated with better survival outcomes [4]. As TET2^MT are frequent early ancestral events, multi-hit TET2^MT are often subclonal and mostly occur in trans, contributing to biallelic TET2 inactivation [7, 8].

CMML is subclassified into MD and MP subtypes based on a white blood cell count of <13 × 10⁹/L for MD-CMML [1]. Although CMML is considered a single disease entity for risk stratification [9,10,11], these subtypes are distinct, with MP-CMML being enriched for RAS-pathway mutations and associated with inferior survival [12]. Whether the survival benefits associated with TET2^MT extend to both CMML subtypes is unknown.