All-trans Retinoic Acid in Refractory Mecom-rearranged Acute Myeloid Leukemia With T(3;3)(q21;q26.2): a Molecularly Guided Therapeutic Approach
Year: 2026
Type: article
Study design: Case Report
Abstract: Background Acute myeloid leukemia (AML) with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2) is a rare, adverse-risk subtype characterized by enhancer hijacking involving the GATA2 regulatory region, resulting in aberrant MECOM/EVI1 activation and reduced GATA2 expression. This molecular configuration is associated with marked resistance to conventional chemotherapy and poor clinical outcomes. Preclinical evidence and limited clinical data have suggested that all-trans retinoic acid (ATRA) may partially overcome EVI1-associated differentiation blockade. We report a patient with refractory MECOM-rearranged AML in whom ATRA was incorporated into salvage therapy on a molecularly guided basis. Case report A 58-year-old man was admitted with leukocytosis and thrombocytopenia. Molecular testing was negative for KMT2A::AFF1, BCR::ABL1, RUNX1::RUNX1T1, and CBFB::MYH11 rearrangements and for FLT3 and NPM1 mutations. Next-generation sequencing identified mutations in ASXL1, NRAS, GATA2 (variant allele frequency, 42%), and U2AF1. Conventional cytogenetics demonstrated 46,XY,t(3;3)(q21;q26.2)[20/20], establishing the diagnosis of AML with MECOM rearrangement and adverse-risk disease. The GATA2 variant was identified in the leukemic sample; its somatic versus germline origin was not established. Magnetic resonance imaging revealed a paravertebral T1–T2 soft-tissue mass and multiple vertebral lesions radiologically suspicious for extramedullary leukemic involvement. The patient did not respond to standard 7+3 induction chemotherapy. Salvage treatment with azacitidine plus venetoclax was subsequently initiated. Bone marrow assessment on day 21 demonstrated persistent disease with 11% blasts. During the second treatment cycle, ATRA was added after informed consent based on the biological rationale of targeting EVI1-associated transcriptional dysregulation. Venetoclax dosing was adjusted because of concomitant isavuconazole therapy for invasive fungal sinusitis. The patient remained clinically stable and was discharged with a plan to proceed to haploidentical allogeneic hematopoietic cell transplantation. Discussion and conclusion AML with t(3;3)(q21;q26.2) is driven by repositioning of a GATA2 enhancer toward MECOM, leading to EVI1 overexpression and disruption of normal hematopoietic differentiation. This biology is associated with resistance to conventional chemotherapy and poor outcomes. The additional GATA2 variant identified at a variant allele frequency of 42% cannot be classified as somatic solely based on the absence of clinical manifestations associated with germline GATA2 deficiency and would require dedicated germline assessment for definitive characterization. Preclinical studies and a small clinical pilot study in EVI1-overexpressing AML provide preliminary support for investigating ATRA as a differentiation-based therapeutic strategy in this molecular context. In the present case, ATRA was incorporated into salvage therapy as a hypothesis-driven intervention rather than an established standard of care. This report highlights the potential value of comprehensive molecular characterization in guiding individualized therapeutic strategies for highly refractory MECOM-rearranged AML and supports further prospective evaluation of retinoid-based approaches in EVI1-driven disease.
Institutions: Universidade de São Paulo, Hospital Felício Rocho
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7223142584