Myeloid neoplasms post PARP inhibitors for ovarian cancer

Abstract

The incidence of myeloid neoplasms following treatment with poly (ADP-ribose) polymerase inhibitors (PARPi) in patients with ovarian cancer has been gradually increasing over the last few years. The cumulative exposure to PARPi and the improved overall survival of patients with ovarian cancer may represent key underlying explanations behind such trend. Fortunately, the earlier introduction of PARPi in the frontline setting reduces the risk of developing secondary myeloid neoplasms. The etiopathogenesis is still unclear but is likely to be multifactorial. The first 2 years of PARPi exposure seem to be the critical window for the onset of myeloid neoplasms post PARPi, with persistent cytopenia recognized as an early warning sign. Despite intensive treatment strategies, the outcome remains poor. There is an unmet clinical need to learn how to minimize risk, make an early diagnosis, and manage myeloid neoplasms post PARPi. First, decision making regarding the optimal maintenance treatment should avoid a ‘PARPi-for-all’ strategy. PARPi should be used cautiously in cases of high baseline risk for myeloid neoplasms and/or patients who are less likely to have a benefit. Active surveillance, accurate differential diagnosis, and prompt hematological referral are key management pillars. This review discusses what is known on this emerging issue as well as unresolved questions.

Poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer: lessons learned and future directions

“…The paradigm shift of PARPi in the upfront setting reduces the risk of developing secondary myeloid neoplasms. 21 Indeed, patients receiving PARPi after only one line of chemotherapy have been less exposed to prior cytotoxic treatments and thus are at lower risk of accumulating DNA damage and leukemogenic progression. Moreover, the duration of PARPi treatment in the first-line setting is limited, from 2 to 3 years, compared with until progression or unacceptable toxicity in the recurrent disease, thus further reducing the risk of developing secondary neoplasms.…”

“…PARPi rechallenge appeared to be also safe; however, more longterm data are required to properly assess the safety of re-treating patients with PARPi, especially when considering the risk of myeloid neoplasms. 21 The 6th OCCC suggests that PARPi rechallenge may be considered in cases of prior PARPi exposure of 18 months in the first line and 12 months (or, in more detail, 12 months in BRCAm and 6 months in BRCAwt patients) in further lines. 38 Larger-scale prospective research is warranted to shed more light on the role of PARPi rechallenge, which might change the treatment algorithm of ovarian cancer in the future.…”

“…The paradigm shift of PARPi in the upfront setting reduces the risk of developing secondary myeloid neoplasms 21. Indeed, patients receiving PARPi after only one line of chemotherapy have been less exposed to prior cytotoxic treatments and thus are at lower risk of accumulating DNA damage and leukemogenic progression.…”

“…If confirmed, these findings will allow prolongation of the therapeutic effect of PARPi beyond oligoprogression and also extend the platinum-free interval. PARPi rechallenge appeared to be also safe; however, more long-term data are required to properly assess the safety of re-treating patients with PARPi, especially when considering the risk of myeloid neoplasms 21. The 6th OCCC suggests that PARPi rechallenge may be considered in cases of prior PARPi exposure of 18 months in the first line and 12 months (or, in more detail, 12 months in BRCAm and 6 months in BRCAwt patients) in further lines 38…”

Chasing Immune Checkpoint Inhibitors in Ovarian Cancer: Novel Combinations and Biomarker Discovery

“…Despite the fact that these promising results provide a biological rationale for combining ICIs and PARPis, confirmatory large trials with a control arm are warranted to define if such a chemotherapy-free regimen can be considered as an option for patients with platinum-sensitive recurrent EOC. Moreover, a careful evaluation of the safety profile of these combinations and the possible long-term toxicities should be considered [ 85 ].…”