ATRA and ATO can induce remission in NPM1-mutated AML: First clinical report of a chemo-free strategy

Abstract

Abstract Background:Acute myeloid leukemia (AML) with NPM1 mutation may present with an immunophenotype mimicking acute promyelocytic leukemia (APL), including CD34- and HLA-DR-negativity. There is emerging preclinical evidence that all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) may have activity against NPM1-mutated AML, but no clinical documentation has confirmed such efficacy to date.Case Presentation:A 52-year-old female Jehovah's Witness, with a history of tricuspid valve malformation and no transfusional support, presented with pancytopenia and leukocytosis due to circulating blasts with dysplastic hypergranular promyelocyte-like morphology. Bone marrow evaluation showed 81% blasts with APL-like features. Immunophenotyping revealed an APL-mimicking profile (CD34–, HLA-DR–, MPO+, CD33++, CD13+, CD64+). ATRA was started immediately, and ATO was added after immunophenotypic confirmation.Despite the striking morphologic and immunophenotypic similarity to APL, RT-PCR and FISH for PML::RARA were negative. Karyotyping showed a normal female karyotype. Next-generation sequencing revealed NPM1 (VAF 24.8%) and DNMT3A (VAF 25.1%) mutations without FLT3 and TP53 alterations, confirming the diagnosis of NPM1-mutated AML with APL-like phenotype.Due to the patient's religious beliefs and cardiac comorbidity, intensive chemotherapy and transplantation were contraindicated. Notably, after two weeks of ATRA/ATO, the patient achieved complete hematologic remission with negative measurable residual disease (MRD) and undetectable NPM1 by PCR. She was transitioned to azacitidine and venetoclax. At time of reporting, she remains clinically well, transfusion-independent, and in sustained remission, without any cytopenia.Discussion:This is, to our knowledge, the first description of a successful remission of NPM1-mutated AML using ATRA and ATO, consistent with emerging preclinical data. The case highlights the diagnostic challenges in APL-like AML and underscores the potential of ATRA/ATO as a chemo-free therapeutic bridge in patients with NPM1 mutations and contraindications to standard therapy.Conclusion:This case opens a potential therapeutic window for patients with NPM1-mutated AML, particularly those ineligible for intensive treatment. ATRA and ATO may induce remission even in the absence of PML::RARA, warranting further exploration in prospective studies.