Patients with BRCA1/2-mutated ovarian, breast, prostate, or pancreatic tumors can be treated with poly ADP-ribose polymerase (PARP) inhibitors. PARP inhibitors, however, are known to cause therapy-related myeloid neoplasms (t-MN) in a subset of patients. Predisposing factors to t-MN development in the context of PARP inhibitor exposure are not well described.

To determine the frequency of t-MN in these patients, an institutional cohort of 265 patients with exposure to PARP inhibitors was identified. A subset of these patients with PARP inhibitor-related cytopenias underwent bone marrow biopsies. Among 265 patients, 17 (6.4%) underwent a bone marrow biopsy, which yielded a therapy-related hematologic diagnosis in 47% (8/17). Breast cancer metastasis to the marrow was found in one patient, and hemophagocytic lymphohistiocytosis was found in another.

We analyzed the molecular characteristics of t-MNs in 13 PARP inhibitor-exposed patients, including five additional PARP inhibitor-exposed patients diagnosed with t-MNs in community practices. Among patients with t-MNs, five had acute therapy-related myeloid leukemia (t-AML), six were diagnosed with therapy-related myelodysplastic syndrome (t-MDS), and two had therapy-related clonal cytopenias of uncertain significance (t-CCUS). Complex karyotypes were found in four of seven patients who underwent karyotyping (57%). Next-generation sequencing identified TP53 mutations in 7 of 9 patients analyzed (78%). Among patients with germline testing, four (40%) did not have a germline mutation identified, four (40%) had a BRCA1 pathogenic/likely pathogenic (P/LP) variant, and two (20%) had a BRCA2 P/LP variant. Four patients received supportive care and/or observation after blood cancer diagnosis, and six received t-MN-directed therapy. The median survival for patients who received t-MN-directed treatment was 148 days.

While cytopenias, particularly anemia, are known to occur with PARP inhibitor therapy, a subset of patients develop chronic cytopenias requiring bone marrow biopsy to evaluate for t-MN. Our study informs the expected findings of such biopsies.

GWR: advisory roles (Autolus, Kite) WS: advisory roles (Kura, Servier, Newave, Asofarma) AAP: advisory roles (AbbVie, Celgene/BMS, Sobi); institutional research funding (Pfizer, Kronos Bio, Sumitomo) OO: advisory roles (AbbVie, Celgene/BMS, Novartis, Incyte, Kymera therapeutics, Servier, Rigel); data safety board (Treadwell Therapeutics); institutional research funding (AbbVie, AstraZeneca, Celgene, Curis, Incyte, Shattuck Labs, K-group alpha). MJT: consulting (AbbVie, AstraZeneca, Celgene, Jannsen, Pharmacyclics, Roche/Genentech); research funding (Gilead, Jannsen, Merck, Nurix, Pharmacyclics, Syndax, TG therapeutics); institutional research funding (AbbVie). RAL: consulting (AbbVie, Amgen, Ariad/Takeda, Astellas, Celgene/BMS, Curis, CVS/Caremark, Epizyme, Immunogen, Jazz Pharmaceuticals, Kling Biotherapeutics, MedPace, MorphoSys, Novartis, Servier); institutional clinical research support (Astellas, Celgene, Cellectis, Daiichi Sankyo, Forty Seven/Gilead, Novartis, Rafael Pharmaceuticals); royalties from UpToDate. ASD: speaker (CE Concepts). MWD: consulting or advisory roles (Argenx); honoraria for educational writing (American Society of Hematology Self-Assessment Program); honoraria (Novartis)

This work was supported by the National Institutes of Health Clinical Therapeutics award (JMC) and the National Institutes of Health Loan Repayment Program.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

University of Chicago IRB Retrospective examination of blood cancers and cytopenias in patients treated with PARP inhibitors IRB23-0633 Approved: 5/19/2023 irbchairbsd.uchicago.edu

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Sharing Statement: Genomic data are available on request

Conflicts of Interest

GWR: advisory roles (Autolus, Kite)

WS: advisory roles (Kura, Servier, Newave, Asofarma)

AAP: advisory roles (AbbVie, Celgene/BMS, Sobi); institutional research funding (Pfizer, Kronos Bio, Sumitomo)

OO: advisory roles (AbbVie, Celgene/BMS, Novartis, Incyte, Kymera therapeutics, Servier, Rigel); data safety board (Treadwell Therapeutics); institutional research funding (AbbVie, AstraZeneca, Celgene, Curis, Incyte, Shattuck Labs, K-group alpha).

MJT: consulting (AbbVie, AstraZeneca, Celgene, Jannsen, Pharmacyclics, Roche/Genentech); research funding (Gilead, Jannsen, Merck, Nurix, Pharmacyclics, Syndax, TG therapeutics); institutional research funding (AbbVie).

RAL: consulting (AbbVie, Amgen, Ariad/Takeda, Astellas, Celgene/BMS, Curis, CVS/Caremark, Epizyme, Immunogen, Jazz Pharmaceuticals, Kling Biotherapeutics, MedPace, MorphoSys, Novartis, Servier); institutional clinical research support (Astellas, Celgene, Cellectis, Daiichi Sankyo, Forty Seven/Gilead, Novartis, Rafael Pharmaceuticals); royalties from UpToDate.

ASD: speaker (CE Concepts).

MWD: consulting or advisory roles (Argenx); honoraria for educational writing (American Society of Hematology Self-Assessment Program); honoraria (Novartis)

Genomic data are available on request