Successful Haploidentical Hematopoietic Stem Cell Transplantation with Azacitidine and Venetoclax Maintenance Therapy for Acute Myeloid Leukemia with NUP98-RARG Gene Fusion

To the Editor,

NUP98-RARG-positive acute myeloid leukemia (AML) has morphological, immunophenotypic, and clinical manifestations of acute promyelocytic leukemia but lacks t(15;17)(q24;q21)/PML-RARA fusion [1]. Almost all of these subtypes of AML exhibit resistance to all-trans retinoic acid [2,3] and have poor prognosis [4]. Alkaloid-based chemotherapy regimens may be beneficial for AML with NUP98/RARG fusion [5,6]. However, the value of haploidentical hematopoietic stem cell transplantation (HID-HSCT) in AML patients with NUP98-RARG rearrangement is unknown due to the limited number of reported cases.

A 39-year-old female was admitted due to skin ecchymosis. Her D-dimer level was 16020 ng/mL (reference range: 0-256 ng/mL). Morphological examination of bone marrow (BM) smears revealed hypercellularity, with 87% abnormal promyelocytic granulocytes (Figure 1A). A peroxidase-stained BM smear showed strong positivity (Figure 1B). Immunophenotypic analysis revealed that the leukemic cells were positive for myeloperoxidase, CD13, CD33, CD117, CD71, and HLA-DR and negative for CD34, CD11b, and CD38 (Figure 1C). However, detection results for the PML-RARA fusion transcript and karyotype analysis of typical t(15;17) were negative. RNA sequencing identified the NUP98-RARG fusion transcript. The karyotype of G-banding showed 46,XX,t(11;12)(p15;q13),t(15;21)(q11.1;q21) in 20/20 analyzed metaphases (Figure 1D). Reverse transcriptase polymerase chain reaction (PCR) was then performed on the BM sample with primers 5’-CTGTTGGTTCGACCCTG-3’ and 5’-GGACATGCCCACTTCG-3’, which further suggested the presence of NUP98-RARG fusion. To identify the breaking point of NUP98-RARG, the PCR product was subjected to Sanger sequencing. Sequence analysis of the NUP98-RARG fusion transcript revealed that NUP98 exon 12 was fused in-frame to RARG exon 4 (Figure 1E). Finally, the patient was diagnosed with AML with NUP98-RARG gene fusion.

Figure 1.

The morphological (A, B: bone marrow smear stained with Wright-Giemsa, 400^x), immunophenotypic (C), and cytogenetic (D) analysis results of bone marrow cells at diagnosis. (E) Sanger sequencing for NUP98-RARG PCR products; (F) bone marrow morphology upon complete remission (bone marrow smear stained with Wright-Giemsa, 400^x).

The patient was treated with venetoclax in combination with homoharringtonine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor (HCAG) chemotherapy. Complete remission (CR) was achieved on the 14^th day of treatment according to the evaluation of BM morphology (Figure 1F), and minimal residual disease as assessed by flow cytometry was negative. NUP98-RARG gene fusion was negative according to next-generation sequencing after one course of consolidation chemotherapy identical to the induction regimen. The patient proceeded with myeloablative HID-HSCT from a half-matched related donor using conditioning therapy based on the Beijing Protocol [7,8]. The quantities of infused mononuclear cells and CD34+ cells of the grafts were 7.8x10⁸/kg and 3.1x10⁶/kg, respectively. The durations of neutrophil and platelet engraftment were 12 days and 15 days, respectively. She received post-transplant maintenance with azacitidine (75 mg/m²/day on days 1-5) and venetoclax (400 mg/day on days 1-14) for two cycles. The patient refused to undergo any further treatment for personal reasons. She remained in CR and negative for NUP98-RARG gene fusion, and overall survival had surpassed 20 months at the last follow-up.

Our case suggests that HID-HSCT with azacitidine and venetoclax maintenance therapy could be a highly efficient treatment option for AML with NUP98-RARG gene fusion.