Clinical Outcomes and Co-Occurring Mutations in Patients with RUNX1-Mutated Acute Myeloid Leukemia

Abstract

(1) Runt-related transcription factor 1 (RUNX1) mutations in acute myeloid leukemia (AML) are often associated with worse prognosis. We assessed co-occurring mutations, response to therapy, and clinical outcomes in patients with and without mutant RUNX1 (mRUNX1); (2) We analyzed 328 AML patients, including 177 patients younger than 65 years who received intensive chemotherapy and 151 patients >65 years who received hypomethylating agents. RUNX1 and co-existing mutations were identified using next-generation sequencing; (3) RUNX1 mutations were identified in 5.1% of younger patients and 15.9% of older patients, and were significantly associated with increasing age (p = 0.01) as well as intermediate-risk cytogenetics including normal karyotype (p = 0.02) in the elderly cohort, and with lower lactate dehydrogenase (LDH; p = 0.02) and higher platelet count (p = 0.012) overall. Identified co-occurring mutations were primarily ASXL1 mutations in older patients and RAS mutations in younger patients; FLT3-ITD and IDH1/2 co-mutations were also frequent. Younger mRUNX1 AML patients treated with intensive chemotherapy experienced inferior treatment outcomes. In older patients with AML treated with hypomethylating agent (HMA) therapy, response and survival was independent of RUNX1 status. Older mRUNX1 patients with prior myelodysplastic syndrome or myeloproliferative neoplasms (MDS/MPN) had particularly dismal outcome. Future studies should focus on the prognostic implications of RUNX1 mutations relative to other co-occurring mutations, and the potential role of hypomethylating agents for this molecularly-defined group.

New directions for emerging therapies in acute myeloid leukemia: the next chapter

“…In addition, unsatisfactory response rates and survival have been reported for conventional chemotherapy in patients with adverse cytogenetic risk or high-risk molecular mutations, such as TP53 (refs. 8 – 10 ). Elderly patients with high-risk features and poor performance status have induction-related mortality rates in the range of 15–30% (refs.…”

Comparison of mutational profiles and clinical outcomes in patients with acute myeloid leukemia with mutated RUNX1 versus acute myeloid leukemia with myelodysplasia-related changes with mutated RUNX1

“…However, we observed that AML-MRC with RUNX1 mut is associated with inferior OS compared to AML with RUNX1 mut . This observation is clinically important since poor treatment response and inferior survival outcome associated with RUNX1 mut could be further compromised in AML-MRC patients [21,22]. Although CPX-351 was recently approved as a front-line therapy in AML-MRC patients and hypomethylating agents are commonly used in AML patients who are not eligible for the intensive chemotherapy [23][24][25][26][27], there is still lack of data regarding the optimal treatment in this unique group of AML-MRC with RUNX1 mut patients.…”

Acute myeloid leukemia and prognosis in the era of molecular markers

“…AML with mutated RUNX1 is provisional entity in the new 2016 WHO classification. RUNX1 mutations are present in about 10% of AML, more frequent in older male patients and patients with wildtype NPM1 and CEBPA [29]. There is an association of RUNX1 mutation and immature morphology (minimally differentiated AML/M0 FAB).…”