Abstract
Acute myeloid leukemia (AML) with rearrangement of the lysine methyltransferase 2a gene (KMT2Ar) has adverse outcomes. However, reports on the prognostic impact of various translocations causing KMT2Ar are conflicting. Less is known about associated mutations and their prognostic impact. In a retrospective analysis, we identified 172 adult patients with KMT2Ar AML and compared them to 522 age-matched patients with diploid AML. KMT2Ar AML had fewer mutations, most commonly affecting RAS and FLT3 without significant impact on prognosis, except for patients with ≥2 mutations with lower overall survival (OS). KMT2Ar AML had worse outcomes compared with diploid AML when newly diagnosed and at relapse, especially following second salvage (median OS of 2.4 vs 4.8 months, P < 0.0001). Therapy-related KMT2Ar AML (t-AML) had worse outcomes compared with de novo KMT2Ar AML (median OS of 0.7 years vs 1.4 years, P < 0.0001). Allogeneic hematopoietic stem cell transplant (allo-HSCT) in first remission was associated with improved OS (5-year, 52 vs 14% for no allo-HSCT, P < 0.0001). In a multivariate analysis, translocation subtypes causing KMT2Ar did not predict survival, unlike age and allo-HSCT. In conclusion, KMT2Ar was associated with adverse outcomes regardless of translocation subtype. Therefore, AML risk stratification guidelines should include all KMT2Ar as adverse.
Highlights
Chromosomal translocations involving 11q23 where the lysine methyltransferase 2a gene (KMT2A) is located cause acute leukemias with high rates of resistance and relapse following standard treatments [1]
The most common translocations were t(9;11)(p21;q23)/ KMT2A-MLLT3 detected in 97 patients (57%), followed by t (6;11)(q27;q23)/KMT2A-MLLT4 detected in 19 patients (11%), t (11;19)(q23;p13.1)/KMT2A-ELL in 14 patients (8%), t(11;19)(q23; p13.3)/KMT2A-MLLT1 in 10 patients (6%), t(11;19)(p23;q13)/ KMT2A-EEN in 10 patients (6%), t(10;11)(q12;q23)/KMT2AMLLT10 in 3 patients (2%), and t(4;11)(q21;q23)/KMT2A-MLLT2 in 2 patients (1%) (Fig. 1A, B)
When compared to KMT2Ar Acute myeloid leukemia (AML) without central nervous system (CNS) involvement (CNS-), we found no difference in variables usually thought to confer an increased risk of CNS involvement such as elevated white blood cell count, a monocytic phenotype (72 vs 67% in CNS- disease, P = 0.8) or presence of extramedullary involvement (35 vs 36% in CNS- disease, P = 0.8) (Supplemental Table 10)
Summary
Chromosomal translocations involving 11q23 where the lysine methyltransferase 2a gene (KMT2A) is located cause acute leukemias with high rates of resistance and relapse following standard treatments [1]. KMT2Ar leukemias affect the myeloid lineage, lymphoid lineage, or both. They are associated with an adverse prognosis when occurring in infants, children, or adults with leukemia [2,3,4]. In other genotypes of AML, previous exposure to chemotherapy leads to worse clinical outcomes, there have been conflicting reports on the prognostic impact of this factor in KMT2Ar AML [7,8,9]. Results across studies on this difference in prognostic impact are not consistent, with some indicating similar adverse outcomes with all KMT2Ar AML [8, 9, 11, 12]. Much less is known about the clinical outcomes associated with KMT2Ar in the relapsed or refractory (R/R) setting
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