Leukemia cutis with IDH1, DNMT3A and NRAS mutations conferring resistance to venetoclax plus 5-azacytidine in refractory AML

Recently, novel drugs like venetoclax plus 5-azacytidine (VA) were reported to have promising efficacy in refractory acute myeloid leukemia (AML). However, there are still some cases presented with novel drugs resistance, and its genetics composition and clinical phenotype are urging to study. We described a 58-year-old patient who was resistant to intensive chemotherapy. This refractory AML was presented with the persistence of RUNX1, IDH1 and DNMT3A mutations. RUNX1 mutations disappeared and leukemia cutis ensued after multiple chemotherapies. Leukemia cutis exhibited NRAS mutations in addition to IDH1 and DNMT3A mutations. With the VA salvage treatment, platelets were recovered to the normal level and blasts in bone marrow and peripheral blood were moderately controlled. However, leukemia cutis did not resolve. Unexpectedly, BM blasts obtained the new NRAS mutations after VA treatment, and consequently experienced leukostasis with two distinct leukemia clones. After survival of 230 days, this patient died because of spontaneous cerebral hemorrhage. This case highlights presentation of leukemia cutis with simultaneous mutations of IDH1, DNMT3A and NRAS in AML patients might act as a resistant niche to avoid the toxicity of multiple drugs including VA. There is unmet need to validate this result in the clinical trials or a large cohort of patients in the future.