Predictors of outcomes in adults with acute myeloid leukemia and KMT2A rearrangements

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.

Advancing the standard: venetoclax combined with intensive induction and consolidation therapy for acute myeloid leukemia

“…Conversely, patients with KMT2A -rearranged AML (traditionally considered an adverse cytogenetic feature) 51 also appear to respond favorably to VEN in combination with intensive chemotherapy. In patients treated with FLAG-IDA + VEN, 100% ( N = 7; R/R-AML: 4, ND-AML:3) of patients with KMT2A -rearranged AML attained a CRc, with 80% attaining a MRD-negative CRc based on reverse transcriptase-polymerase chain reaction; 38 12-month OS in this molecular subgroup was an impressive 80%.…”

t(4;11) translocation in hyperdiploid de novo adult acute myeloid leukemia: A case report

“…Among the multiple MLL -r AML subtypes distinguished by TPGs, MLL – AF4 , also known as t(4;11)(q21;q23), is rare, especially in adult patients. According to previous reports, t(4;11) only accounts for 0.8%–1.2% of MLL -r AML[ 9 , 13 , 14 , 17 ] and 0.05% of all AML[ 10 ]. Existing reports on t(4;11) AML differ in age and pathological pattern, covering pediatric, secondary AML and acute megakaryoblastic leukemia[ 18 - 20 ], yet there are no reports of adult de novo AML with t(4;11).…”

“…The most common MLL -r subgroup is MLL – AF4 [also known as KMT2A – AFF1 , or t(4;11)(q21;q23)], which is formed by translocation between MLL and AF4 genes (located on chromosome 4q21), and occurs almost entirely in acute lymphoblastic leukemia (ALL)[ 16 ]. By contrast, t(4;11) AML only accounts for 0.8%–1.2% of MLL -r+ AML[ 9 , 13 , 14 , 16 , 17 ]. Limited by the sample size, t(4;11) AML has not been analyzed as a single subgroup, and its characteristics, pathogenesis and therapeutic options have not been established.…”

Menin Inhibitors in Acute Myeloid Leukemia—What Does the Future Hold?

“…17 Although up to 80 different fusion partners for KMT2A have been reported in the literature, 4 fusion partners (AF4, AF9, AF10, and ENL) constitute more than 70% of all rearrangements in leukemia. 18,19 The biological sequelae of these rearrangements occurring at the stem cell level result in clinically diverse disease presentations. Overall KMT2A rearrangements have been identified in approximately 5% to 10% of acute leukemias including AML, acute lymphoblastic leukemia (ALL), and mixed phenotype acute leukemia (MPAL) and presenting in all age ranges from infants to older adults.…”