The new report suggests that patients treated with prolonged poly-ADP-ribose polymerase inhibitors after chemotherapy may need close hematological monitoring.
Patients with epithelial ovarian cancer (EOC) who are treated with chemotherapy followed by prolonged poly-ADP-ribose polymerase inhibitors (PARP) may face a the possibility of a heightened risk of severe hematological toxicity, according to a new report.
The report, based on the experience of a single European cancer center, suggests a higher risk than was found in other, larger studies. The new data were published in the International Journal of Cancer, and the authors noted that the cohort size is too small from which to draw any inferences
Most patients diagnosed with EOC will undergo debulking surgery followed by platinum-based chemotherapy, explained corresponding author Elisabetta Todisco, MD, PhD, of the European Institute of Oncology, in Milan. Though such treatment is considered the “gold standard” treatment, Todisco and colleagues noted that most patients will experience a relapse. One of the most promising treatments in such cases are PARP inhibitors, which are targeted therapies that kill cancer cells by blocking enzymes that let the cells repair DNA.
The therapy works because some cancer cells have a defect limiting their ability to repair DNA double-strand breaks via the homologous recombination repair pathway, the investigators wrote.
“These cancer cells have increased dependence on PARP to repair their DNA and to divide,” they said. “For these defective cells PARPi may be lethal by triggering ‘synthetic lethality.’”
The disruption of defective cells’ repair processes might also impact non-defective cells, they added.
While most side effects of the therapy can be easily managed, Todisco and colleagues said hematologic toxicities are less well-understood. In hopes of changing that, the team conducted a retrospective analysis of 130 patients who sought care for EOC and received PARPi after chemotherapy at the European Institute of Oncology.
Among the patients, overall survival at 5.5 years was 37%.
Nine patients suffered therapy-related hematological disorders (tr-HDs), a median of nearly 2 years (22.8 months) following PARPi exposure. Of those, 2 died before they could be treated; 2 were not indicated for treatment and continued to be monitored closely; and the remaining 5 underwent chemotherapy. In 3 of those 5 cases, chemotherapy was followed by allogeneic hematopoietic transplantation. Three of the 5 patients who were treated were in complete remission of their hematological and gynecological malignancies at 13, 19, and 25 months. The other two patients died as a result of the progression of their hematological disease.
At 6.9%, the rate of tr-HDs was higher in this study than in earlier, larger studies, where the incidence ranged from 1.1% to 1.5%, depending on which PARP was used: olaparib (Lynparza), rucaparib (Rubraca), or niraparib (Zejula). In the new study, 7% of patients treated with olaparib and 20% of patients treated with rucaparib developed tr-HDs.
“Intriguingly, despite equally heavy pretreatment, no tr-HDs were observed after niraparib, although all three PARP inhibitors exhibit highly similar hematological toxicity,” Todisco and colleagues said. However, they said their sample size was too small to infer broad conclusions.
All but one of the patients who experienced tr-HDs carried BRCA1/2 mutations, a population in which the PARPi therapy has been seen as particularly effective. The authors hypothesized that PARPi “may be harmful by triggering, through ‘synthetic lethality’ mechanisms, leukemic transformations.”
In addition, the researchers pointed out that it is unknown to what extent platinum‐based chemotherapy, other chemotherapies, or their combination with PARP inhibitors contributed to the hematologic issues, or if there were certain cytogenetic alterations or genetic variants already present before starting on a PARP.
In their conclusion, the investigators said that, though their study was small and based on a single center, it suggests that patients treated with chemotherapy followed by prolonged PARPi exposure need to be monitored closely.
“However, prompt and adequate treatment can lead to disease remission of both hematological and gynecological malignancies,” they said.
Todisco E, Gigli F, Mantiero M, et al. Clinical presentation, diagnosis and management of therapy-related hematological disorders in women with epithelial ovarian cancer treated with chemotherapy and poly-ADP-ribose polymerase inhibitors: A single-center experience [published online ahead of print, 2020 Aug 28]. Int J Cancer. 2020;10.1002/ijc.33269. doi:10.1002/ijc.33269