Abstracts Clinical Lymphoma, Myeloma & Leukemia September 2023 S308 AML-503 An Unusual Presentation of Acute Promyelocytic Leukemia (APML): Complex Cytogenetic Isochromosome 17 and WT1 Gene Mutation in the Absence of PML‑RARA Fusion Protein Priya Tanwar MBBS, MD, Vagisha Sharma MBBS, Amitabh Singh MBBS, MD, Kushal Kriplani MBBS Department of Pediatrics, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi, India Context: APML is a distinct subtype of acute myeloid leukemia (AML) characterized by a fusion gene resulting from the t(15:17) translocation in 90% of cases. Early diagnosis and treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) can lead to a remission rate of 90%. APML can also present with complex chromosomal translocations, impacting prognosis. Objective: To present a patient with APML, without the promyelocytic leukemiaretinoic acid receptor alpha (PML-RARA) fusion protein, involving isochromosome 17 and a WT1 gene mutation. Patient: A 3-yearold boy presented with fever and loss of appetite for 10 days, along with abdominal distension present for 4 days. Initially, bone marrow aspiration revealed the presence of 22% blasts; subsequently, the patient was referred to our hospital. Additional diagnostic procedures included bone marrow aspiration, flow cytometry, and a comprehensive panel of molecular and cytogenetic tests. Results: The child was admitted for urgent evaluation with a complete blood count revealing abnormal values (white blood cell count, 1.09x105/ mm3; platelets, 0.27x105/mm3; hemoglobin, 9.2 g/dL). Bone marrow aspiration showed myeloperoxidase (MPO)-positive blasts expressing cluster of differentiation (CD)-13, CD33, CD117, and MPO but lacking the human leukocyte antigen (HLA)-DR isotype and CD34 typical of APML. Further molecular and cytogenetic investigations were conducted. The child received APML chemotherapy (cytarabine, daunorubicin, ATRA) and was closely monitored for bleeding or disseminated intravascular coagulation. The first cycle was well tolerated without bleeding episodes. The molecular panel did not detect the common PML-RARA fusion protein found in most APML patients. Cytogenetic analysis revealed isochromosome 17(q10) and trisomy 8 and 21, indicating a diagnosis of cryptic APML. Genetic testing identified a WT1 gene mutation, a known poor prognostic factor in pediatric AML (6%–15% of cases). The child completed consolidation chemotherapy cycles and is currently in maintenance, with undetectable bone marrow transcripts. Conclusion: The occurrence of isochromosome 17q in APML is rare (estimated 0.6%–4.9%), and its prognostic significance is debated due to its low prevalence. Identifying such patients is crucial. This case highlights the importance of using multiple testing methods to detect cryptic and variant translocations. Overlooking these variants could cause treatment delays, particularly when suspicion is high. Keywords: AML, pediatric cancer, acute promyelocytic leukemia, genetic markers, prognosis, cytogenetics, isochromosome 17, WT1 mutation, case AML-516 KOMET‑007 Trial in Progress: A Phase I Study of Ziftomenib in Combination With Venetoclax or Venetoclax/ Azacitidine, or Standard Induction Cytarabine/Daunorubicin (7+3) Chemotherapy in Combination With Ziftomenib, for the Treatment of Patients With Acute Myeloid Leukemia Amer Zeidan MBBS1, Amir Fathi MD2, Ghayas Issa MD3, Harry Erba MD, PhD4, Julie Mackey Ahsan MS5, Daniel Corum PhD5, Blake Tomkinson PhD5, Tom Kozlek MD5, Mollie Leoni MD5, Eunice Wang MD6 1Yale University, New Haven, CT, USA. 2Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. 3The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 4Duke Cancer Institute, Durham, NC, USA. 5Kura Oncology, Boston, MA, USA. 6Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA Context: Relapsed or refractory (R/R) acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutations (NPM1m) or lysine (K)-specific methyltransferase 2A (KMT2A) rearrangement (KMT2Ar) represents a high unmet need. Ziftomenib is a potent and selective inhibitor that targets the menin–mixed-lineage leukemia– KMT2A interaction driving leukemogenesis in these subtypes. An ongoing phase I/II study (KO-MEN 001) has demonstrated meaningful clinical activity and tolerability with ziftomenib monotherapy in R/R AML. In preclinical testing, ziftomenib combined with venetoclax induced synergistic lethality in NPM1m and KMT2Ar human AML cell lines and patient-derived cells. Moreover, treatment with ziftomenib plus venetoclax/azacitidine has induced prolonged durable remissions in mice with KMT2Ar AML xenografts. Therefore, administration of ziftomenib in combination with standard of care therapies may provide additional clinical benefit for patients with newly diagnosed or R/R NPM1m and KMT2Ar menin-dependent AML. Objectives: Primary: To establish the minimum biologically effective dose-limiting toxicities and recommended phase II dose of ziftomenib, combined with nonintensive chemotherapy (NIC) and intensive chemotherapy (IC) backbones, in each genetically defined cohort. Secondary: To establish preliminary antileukemic efficacy (including measurable residual disease–negative responses and number of patients able to transition to subsequent allogeneic stem cell transplantation) and pharmacokinetic and pharmacodynamic data. Exploratory endpoints: include biomarkers for efficacy and resistance, pharmacodynamic biomarkers, and activity in isolated myeloid sarcoma. Design: KOMET-007 (NCT05735184) is a 2-part dose escalation (phase Ia) and expansion (phase Ib) study to evaluate the safety, tolerability, and preliminary antileukemic activity of ziftomenib in combination with NIC and IC in patients with NPM1m and KMT2Ar AML. During phase Ia, the ziftomenib dose will be escalated with standard doses of either venetoclax and azacitidine (zifto/ven/aza) or cytarabine and daunorubicin (zifto/7+3) in defined genetic cohorts (NPM1m and KMT2Ar) using a rule-based approach (n=6 per cohort/dose level) to select ziftomenib doses for expansion and validation in phase Ib. The phase Ib portion will also evaluate zifto/ven/aza in newly diagnosed
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