Abstracts Clinical Lymphoma, Myeloma & Leukemia September 2023 S284 AML-274 TAGALONG Trial: Phase II Study of Tagraxofusp and Azacitidine With or Without Venetoclax in Newly Diagnosed Secondary AML after Previous Exposure to Hypomethylating Agents Steven Green MD1, Brian Parkin MD2, Catherine Lai MD, MPH3, Ivana Gojo MD4, Joshua Zeidner MD5 1Roswell Park Comprehensive Cancer Center, Buffalo, USA. 2AdventHealth Medical Group Blood and Marrow Transplant at Orlando, Orlando, USA. 3Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA. 4Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, USA. 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, USA Context: Secondary AML (s-AML) patients with prior exposure to hypomethylating agents (p-HMAs) have dismal clinical outcomes and are excluded from many clinical trials. Tagraxofusp (TAG) is a CD123-directed targeted therapy that carries a truncated diphtheria toxin. Down-regulation of DPH1 is associated with TAG resistance and treatment with azacitidine (AZA) hypomethylated CpG motifs in the promoter region of DPH1, restoring sensitivity to TAG. Objective: To estimate the rate of complete remission (CR) in patients with newly diagnosed s-AML after p-HMAs receiving TAG + AZA with or without venetoclax. Design: Subjects must be ≥18 years old with newly diagnosed, untreated AML or MDS/AML (1019% blasts) per WHO 2022 or ICC 2022 criteria. All subjects must have CD123 expression by flow cytometry, a documented diagnosis of prior MDS, CMML, MPN, or MDS/MPN overlap syndrome, and have received at least 2 cycles of an HMA for their antecedent hematologic disease if progressed to AML or 4 cycles of HMA if MDS/AML. Excluded are subjects who are suitable for and are willing to receive intensive chemotherapy. Cycle 1 will consist of TAG administered at 12 mcg/kg IV daily for 3 consecutive days, followed by AZA administered at 75 mg/m2 SQ or IV daily on Day 4 through Day 10 of a 28-day cycle. For Cycle 2, TAG will be administered at 12 mcg/kg on D1-3 WITH AZA on D1-7. Subjects with a marrow CR after Cycle 2 will continue TAG+AZA on the same schedule (Arm A). Subjects that subsequently relapse after achieving a marrow CR, or who do not obtain a marrow CR after 2 cycles of treatment, will receive Arm B study treatment which involves the addition of venetoclax on Days 1 through 21 for up to 3 cycles until remission is achieved. Main Outcome Measure: Simon’s two-stage design will be utilized. The null hypothesis that the true CR rate is 15% will be tested against a one-sided alternative hypothesis of 30%. The null hypothesis will be rejected if 12 or more CRs are observed in 48 subjects. Continuous monitoring for toxicity will be performed. Keywords: AML, tagraxofusp, prior HMA, trial in progress AML-280 A Prospective Study to Evaluate the Prognostic Implications of Methylation and Expression of Wilms Tumor‑1 (WT‑1) Gene in Acute Myeloid Leukemia Harsh Goel PHD1, Anita Chopra MD1, Amar Ranjan MD1, Jagdish Prasad Meena MD2, Aditya Kumar Gupta MD2, Ganesh Kumar Viswanathan MD3, Sameer Bakhshi MD4, Maroof Ahmad Khan PHD5, Pranay Tanwar MD1 1Laboratory Oncology Unit, Dr. B.R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India. 2Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India. 3Department of Hematology, All India Institute of Medical Sciences, New Delhi, India. 4Department of Medical Oncology, Dr.B.R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India. 5Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India Context: Acute myeloid leukemia (AML) is a genetically heterogeneous hematological disorder distinguished by abnormal differentiation and clonal proliferation of myeloid progenitor cells in the bone marrow. The Wilms tumor-1 (WT-1) gene is a critical regulator of malignant hematopoiesis, which can either activate or repress genes to regulate cellular growth, differentiation, and proliferation of AML. However, its genetic and epigenetic roles remain unknown. Objective: This study aimed to investigate the expression levels and methylation status of the WT-1 gene in 143 newly diagnosed cases of AML. Design and Setting: This prospective clinical research was performed in our institution from 2020-2023. Patients or Other Participants: Bone marrow (BM) and peripheral blood (PB) samples were collected at the time of diagnosis (day-0) and after completion of induction chemotherapy (day-28). Fifteen non-malignant cases were recruited as controls. Methods: WT-1 gene expression and methylation status were assessed during both intervals (day-0 and day-28) by performing real-time polymerase chain reaction (RT-PCR) and methylation-specific polymerase chain reaction (MS-PCR). A flow cytometric immune-phenotyping study was also performed using a panel of monoclonal antibodies specific to AML. Results: Of the 143 subjects studied, 123 (83.67%) patients showed overexpression of the WT-1 gene at the time of diagnosis as compared with patients in complete remission (CR) remission or control samples (P=<0.001). Moreover, robust hypermethylation of the WT1 promoter was observed in 103 (70.06%) AML patients at the time of diagnosis as compared with patients in complete remission (CR) remission or control samples (P=<0.001). The flow cytometric immune-phenotyping study demonstrated that CD34, CD45, CD117, CD38, CD13, CD33, and CD56 were expressed as positive in most cases, while cCD79a CD19 CD7, cCD3, CD16, CD123, CD11b were negatively observed. In addition, significant positive correlations between WT-1 expression and methylation levels on day-0 and day-28 were observed (P<0.001). Conclusions: Overexpression and hypermethylation of the WT-1 gene correlate with the leukemic burden in most cases of AML. Thus, this gene can be considered a promising molecular marker for early diagnosis
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