Similar Molecular Pattern in Therapy Related Acute Myeloid Leukemia in Patients Treated with Purp Inhibitors for Metastatic Ovarian Cancer
Authors: Chiusolo Patrizia , Marchetti Claudia , Rossi Monica , Minnella Gessica , Di Stefano Mirella , Fagotti Anna , Leone Giuseppe , Scambia Giovanni , Sica Simona 
Published: February 2021

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors exploit defects in DNA repair to induce tumor-selective damage, in fact PARP inhibition can lead to the accumulation of DNA double strand breaks in neoplastic cells sparing normal ones. Olaparib (AZD2281; KU-0059436) is a novel, orally active PARP inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. It is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy. Overall in clinical trials, the incidence of Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) in patients treated with Olaparib monotherapy, including long-term follow up, was &lt;1.5% and the majority of events had a fatal outcome. The duration of therapy with Olaparib in patients who developed secondary MDS/cancer-therapy related AML varied from &lt; 6 months to &gt; 2 years. All of these patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy.
Here we describe 5 consecutive patients affected by metastatic ovarian cancer BRCA+ treated after chemotherapy with PURPi who developed therapy-related AML (sAML) in our center in a short period between June 2019 and July 2020.
Patients'characteristics: Median age at ovarian cancer diagnosis was 49y (range 45-53), the median number of chemotherapy lines before PURPi treatment was 4 (range 3-5), the median interval between PURPi treatment and the onset of sAML was 22 months (range 18-24). Four out of 5 patients were submitted to Olaparib administration and one to Niraparib.
At the onset of cytopenia all patients were submitted to bone marrow aspiration, molecular and cytogenetic tests; in all cases the diagnosis was of sAML according to WHO classification. Cytogenetic analysis was not evaluable in 1 out 5 patients, in the other cases we discovered: 1) a complex karyotype including chromosome 17 deletion, 2) -5q and -7q, 3) -5q and 4) normal karyotype. None of them had recurrent molecular alterations including NPM1 mutations or FLT3-ITD, but when we analysed subclonal mutations we found that in 4 of them TP53 mutations were recurrent (1 one patient'analysis is still ongoing). We found the following TP53 mutations: c.376-1G&gt;A (splice acceptor), c.78delT, c.524G&gt;A (in two patients). The median variant allelic frequency was 25%. In two of them we were able to study the ovarian tissue collected at cancer diagnosis and the TP53 mutations were not present.
This is the first report which describes subclonal mutations in sAML developing after PURP inhibitor therapy
In conclusion therapy-related AML is a well described complication of chemotherapy and our patients had exposure to chemotherapy and therefore had higher risk for developing leukemia from exposure to chemotherapy and PARP inhibitors. In the natural history of the ovarian cancer, patients might be exposed to leukemogenic therapies which may have an additive effect and increase the risk of developing AML during PURP inhibitors' therapy. Molecular mechanism undergoing this complications, including mutations of TP53, should be further investigated.

Disclosures
Sica: F. Hoffmann-La Roche Ltd:Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding.