Leukemia cutis with IDH1 , DNMT3A and NRAS mutations conferring resistance to venetoclax plus 5-azacytidine in refractor
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LETTER TO THE EDITOR
Open Access
Leukemia cutis with IDH1, DNMT3A and NRAS mutations conferring resistance to venetoclax plus 5-azacytidine in refractory AML JingHan Wang1,2†, Xingnong Ye1,2,3†, Cuihua Fan4†, Jie Zhou3, Shuna Luo3, Jingxia Jin3, Dan Chen3, Yan Zheng3, Cai Wu3, Xiaoqiong Zhu3, Jie Jin1,2,3* and Jian Huang1,2,3*
Abstractr 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. Keywords: Acute myeloid leukemia, BCL-2 inhibitors, Leukemia cutis To the Editor: Approximately 30% of newly diagnosed patients with acute myeloid leukemia (AML) do not achieve complete remission with intensive induction therapy, and therefore are classified as refractory or resistant disease (RRD) [1]. RRD is among the most challenging scenarios in AML management. With the * Correspondence: [email protected]; [email protected] † Jing Han Wang, Xingnong Ye and Cuihua Fan contributed equally to this work. 1 Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, P.R. China Full list of author information is available at the end of the article
growing clinical translation of genomics into daily routine [2–5], RRD has been becoming an important field for novel drug investigation. Recently, the welltolerated regimens venetoclax plus 5-azacytidine (VA) were proved to be highly effective in these patients [6]. However, the features related to VA resistance are still under investigation. Here, we present with a RRD patient with a clinical and molecular picture of VA resistance. The patient is a 58-year-old man with a morphological and immunological diagnosis of AML-M2 (Fig. 1a-b) and a past history of myocardial infarction (MI). His physical examination was
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