Abstract

e19000 Background: Treatment with Poly(ADP-ribose) Polymerase proteins (PARP) has improved the survival of patients (pts) with solid malignancies harboring a homologous recombination deficiency (HRD). The association between PARP inhibitors (PARPi) and the development of myeloid neoplasms post cytotoxic therapy (MN-pCT) has been reported. We aim to describe the characteristics and outcomes of pts who develop MN-pCT after treatment with PARPi. Methods: Pts treated with PARPi at a single institution from July 2014 to August 2022, who developed MN-pCT (AML, MDS or CMML), were retrospectively evaluated. Diagnosis of MN-pCT was defined according to the 5th edition of the WHO criteria. Clinical and demographic characteristics along with cytogenetics and molecular features were analyzed. HRD was assessed by NGS on peripheral blood with a 13-gene panel. Results: 1462 pts were treated with PARPi at MDACC. Of these, 15 (1%) developed MN-pCT. These include 9 (60%) with MDS, 5 (34%) with AML, and 1 (7%) with B/Myeloid Mixed-Phenotype Acute Leukemia (MPAL). The median age was 62 (46-74) years and 14 (93%) were female. The most frequently used PARPi was olaparib in 9 (60%) pts. All pts had also previously received platinum-based agents and taxanes. Pts with 19 different solid tumors were included; 11 (85%) had active concomitant solid tumors at the time of MN-pCT. The median time from PARPi treatment to myeloid neoplasm (TTM) was 20.7 months (9.3-39.9). Cytogenetics and molecular features were available in 14 pts (93%). Eight (57%) had complex karyotype. The median number of mutations were 2 (0-4). TP53mut was present in 9 (64%) pts with a median VAF 47.3% (11.9-76.6%) of whom 6 (67%) were biallelic. The ORR to antileukemic therapy was 66% (n = 8): 3 (38%) had CR, 2 (25%) had PR, 2 (25%) had mCR with HI and 1 (13%) had isolated HI. The patient with B/myeloid MPAL was not evaluable for response. Of the responders, 7 (88%) pts relapsed at a median of 2.8 months (1.5-4.2). The median OS and EFS on the whole cohort were 7.8 (3.2-12.4) and 5.3 (3.8-6.7) months respectively. Conclusions: Development of MN-pCT in pts treated with PARPi is rare but most outcomes are very poor. Prospective analysis to evaluate pts at higher risk of developing MN-pCT is warranted in order to select pts who might benefit from novel therapies without increasing the risk of secondary myeloid malignancies. [Table: see text]

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