Therapy related myeloid neoplasms (t-MNs) following PARP inhibitors (PARPi): Real-life experience.
Authors: Marmouset Vincent , Decroocq Justine , Garciaz Sylvain , Etienne Gabriel , Belhabri Amine , Gastaud Lauris , Bertoli Sarah , Simand Celestine , Uzunov Madalina , Chantepie Sylvain , Genthon Alexis , Berthon Celine , Chiche Edmond , Dumas Pierre-Yves , Blanc-Durand Felix , Pautier Patricia , Pages Arnaud , Marzac Christophe , Leary Alexandra , Micol Jean Baptiste ,   UNIHEM, ALFA, FILO & GFM GROUP
Published: June 2022

7057 Background: PARPi have shown promising results in several cancers, especially breast (BC) and ovarian cancer (OC), but may be associated with an increased risk of t-MNs. A careful monitoring of hematologic toxicity to exclude this risk is necessary. Here we described, in a real-life setting, the management of these adverse effect. Methods: First,we described, in a large cancer center, the profile of t-MN patients among OC patients treated with PARPi addressed in hematological consultation for cytopenias. Secondly, we compared t-MN post OC characteristics according to previous exposition to PARPi. Lastly, we described a large national observatory of 69 t-MNs post PARPi to decipher specific characteristics of these t-MNs. Results: From 2016 to 2021, among 373 PARPi treated patients for OC, 37 (10%) were explored for cytopenia’s leading to 13 (3,5%) t-MNs diagnosis. No differences were seen in terms of age, BRCA1/2 status, type of PARPi, hemoglobin level but patients with t-MNs developed delayed cytopenias post-PARPi initiation (11 months vs to 4 months, p = 0.01), had a longer PARPi exposition (9 months vs 3 months, p = 0.01), lower platelets level (74 G/L vs 173 G/L, p = 0.0005), more cytopenias (2 vs 1, p = 0.0005). 77% of t-MNs patients had a TP53 mutated t-MNs, 33% of patients w/o t-MNs had TP53 mutated clonal hematopoiesis. In the last 20 years, 37 patients were addressed for t-MN post OC at our institute, with an increased incidence of 50% during the last 6 years. Compared to t-MN not exposed to PARPi, t-MN-PARPi patients had more BRCA1/2 predisposition (61.5% vs 0% p = 0.03), their OC tended to be non-progressive (CR/PR/SD = 62.5% vs 38.5%, p = 0.3) and tend to have more TP53 mutated t-MNs (77% vs 47%, p = 0.1). Median OS for t-MNs post PARPi was poor at 8.2 months (CI95% [2.03-18.7]) but not significantly different form other t-MNs (p = 0.8). We then studied 69 t-MNs-PARPi including 28 AML and 41 MDS in patient with history of OC (75%), BC (9%) or both (16%). Median age was 64 years, 80% received Olaparib, 72.5% had a BRCA1/2 predisposition. Median time between cancer diagnosis and initiation of PARPi was 44 months and median duration of PARPi treatment was 14 months. History of haematological toxicity secondary to PARPi was reported in 51% of patients. Karyotype was often complex (61%) associated with a high rate of TP53 mutation (70.5%). Median OS was 9.7 months (CI95%, 5.3-13.9). In multivariate analysis, a longer delay between the end of PARPi treatment and t-NM diagnosis (HR 1.046, p = 0.02), as well Olaparib treatment compared to others PARPi (HR 5.82, p = 0.003 and AML diagnosis (HR 2.485, p = 0.01) were associated with shorter OS. Conclusions: We describe in a large series a higher incidence of t-MNs post PARPi than previously reported. Unfavorable cytogenetic and molecular abnormalities associated with these t-MNS explained the poor OS. Early detection is crucial particularly in case of delayed appearance of cytopenias.