A new study confirmed an elevated risk for myelodysplastic syndrome or acute myeloid leukemia (MDS/AML) after poly(ADP-ribose) polymerase (PARP) inhibitor therapy in women with ovarian cancer and identified potential predictive factors that might help guide individual risk prediction. 

Results suggested that PARP inhibitor-related myeloid neoplasms “may have unique clinical or molecular associations” that could help delineate risk, Amma Asare, MD, PhD, with University of Texas MD Anderson Cancer Center, Houston, reported in a presentation at the Society of Gynecologic Oncology 2024 Annual Meeting on Women’s Cancer.

Understanding an individual patient’s risk is important as secondary hematologic malignancies associated with PARP inhibitor therapy have particularly poor patient outcomes, Asare explained. Currently, the ability to predict risk “remains limited.”

The study team identified 32,356 patients treated for any gynecological cancer at their institution from 2000 to 2022. 

The rate of secondary MDS/AML in the total population hovered around 1%, consistent with prior reports, said Asare. However, the rate was roughly 10-fold higher among ovarian cancer patients treated with a PARP inhibitor ( 32 cases among 355 patients, 9%).

In comparing those who did and did not develop secondary leukemia, the researchers found that time from diagnosis of ovarian cancer to start of treatment with a PARP inhibitor was longer in those who developed secondary leukemia. There was no association between total days of PARP inhibitor use or age at the start of treatment. 

When looking at chemotherapy-related factors, fewer patients who received PARP inhibitor therapy and developed secondary leukemia had previously received neoadjuvant chemotherapy. 

“We also noted a higher number of carboplatin cycles and total lines of chemotherapy in those with secondary leukemia,” Asare said. 

When looking at patient-specific factors, Asare and her colleagues noted enrichment in germline BRCA1 mutations in those who developed secondary leukemia compared to all other mutation types. 

There was also a lower minimum platelet value during PARP inhibitor therapy in those who developed secondary leukemia, but no association between type of PARP inhibitor or platelet minimum prior to treatment.

Multivariate analysis identified three significant factors: Administration of neoadjuvant chemotherapy was associated with a protective effect (OR, 0.24; P = .017), and low platelets during PARP inhibitor treatment (OR, 0.99; = .014) and higher total carboplatin cycles (OR, 1.15; P = .13) were associated with secondary leukemia. 

Molecular analysis showed that 68% of the secondary leukemias in PARP inhibitor-treated patients had missense mutations in the DNA binding domain of TP53.

“These data support important roles for both genetic and environmental factors in PARP [inhibitor]-associated hematologic malignancy,” the authors conclude in their conference abstract. 

Platelet declines during PARP inhibitor administration are a “potential predictor of future MDS/AML risk,” they add. “These changes may be used to inform individual risk prediction and guide evidence-based administration and surveillance of patients treated with PARP inhibitors.” 

Risk-Benefit Balance 

That there were no differences across PARP inhibitor type suggests a “class effect” in the risk for secondary leukemia, said Ying Liu, MD, MPH, with Memorial Sloan Kettering Cancer Center, New York, who was discussant for the study.

It is worth noting that there was no association with duration of PARP inhibitor use and increased risk for MDS/AML, which is different from some other trials, she added. 

Enrichment in TP53 in those who developed leukemia is also “very interesting,” said Liu. “It brings up the question of whether TP53 clonal hematopoiesis could potentially be a marker of increased MDS and AML risks with PARP inhibitor use.”

The totality of the data to date suggest that we really need to appreciate the risks and toxicities of PARP inhibitors, “and we really need to balance that risk with the benefits,” she said. “And to determine the benefits, we need better biomarkers.”

The study had no specific funding. Asare and Liu had no relevant disclosures.

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