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Definition of therapy-related myeloid neoplasms (TRMN) is only based on clinical history of exposure to leukemogenic therapy. No specific molecular classification combining therapy-related acute myeloid leukemia and therapy-related myelodysplastic syndromes has been proposed. We aimed to describe the molecular landscape of TRMN at diagnosis, among 77 patients with previous gynecologic and breast cancer with a dedicated next-generation sequencing panel covering 74 genes. We investigated the impact of clonal hematopoiesis of indeterminate potential-associated mutations (CHIP-AMs defined as presence at TRMN stage of mutations described in CHIP with a frequency >1%) on overall survival (OS) and the clinical relevance of a modified genetic ontogeny-based classifier that categorized patients in 3 subgroups. The most frequently mutated genes were TP53 (31%), DNMT3A (19%), IDH1/2 (13%), NRAS (13%), TET2 (12%), NPM1 (10%), PPM1D (9%), and PTPN11 (9%). CHIP-AMs were detected in 66% of TRMN patients, with no impact on OS. Yet, patients with CHIP-AM were older and had a longer time interval between solid tumor diagnosis and TRMN. According to our modified ontogeny-based classifier, we observed that the patients with TP53 or PPM1D mutations had more treatment lines and complex karyotypes, the “MDS-like” patients were older with more gene mutations, while patients with “De novo/pan-AML” mutations were younger with more balanced chromosomal translocations. Median OS within each subgroup was 7.5, 14.5, and 25.2 months, respectively, with statistically significant difference in multivariate analysis. These results support the integration of cytogenetic and molecular markers into the future TRMN classification to reflect the biological diversity of TRMN and its impact on outcomes.

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Introduction: Therapy-related Myeloid Neoplasms (TRMN) arise after cytotoxic chemotherapy and/or radiotherapy administered for a prior neoplasm and have dismal outcome. Inherited predisposition or direct induction of fusion transcripts can be responsible of TRMN. Recent evidence suggests that patient with Clonal Hematopoiesis of Indeterminate Potential (CHIP) may have an increased risk of TRMN. In gynecological and breast cancers, CHIP mutations have been described in around 25 % of patients (Coombs et al., Cell Stem Cell 2017). In this setting, we aimed to identify the impact of CHIP-associated mutations in overall survival of TRMN. Methods: In this retrospective study, we included patients with TRMN diagnosed and/or treated at Gustave Roussy Cancer Center between January 2004 and December 2018 if they had a previous breast or gynecological cancer, DNA samples available at TRMN diagnosis and a signed informed consent. We performed a targeted 77 genes mutational analysis using Next Generation Sequencing (NGS), using Haloplex technique (Agilent), sequencing on MiSeq (Illumina). If any somatic mutation associated with hematological malignancies could define CHIP, the most frequent genes mutated in original CHIP papers are: ASXL1, ASXL2, ATM, BCOR, CBL, CHEK2, DNMT3A, IDH1, IDH2, JAK2, PPM1D, SF3B1, SRSF2, TET2 and TP53. These will define "CHIP-associated mutations" at TRMN diagnosis. According to results, patients were classified into "CHIP-associated mutations" or "no-CHIP" categories (no mutations detected or all the other mutations detected at TRMN diagnosis). Moreover, patients were also classified into 3 subgroups according to a modified genetic ontogeny-based classifier (Lindsley et al., Blood 2015): "P53/PPM1D" subgroup, "MDS and AML with MDS mutations" subgroup, and "de novo/pan-AML" subgroup. Survival analyses were performed using GraphPad software. Results: 77 patients were identified: 49 therapy-related AML (t-AML) (64%) and 28 therapy-related MDS (t-MDS) (36%). Median age at TRMN diagnosis was 62 years [36-86] and median time interval between primary cancer and TRMN was 5.1 years. Primary cancers were breast (70%), ovarian (23%), endometrial (4%) and cervical (3%) cancers. Patients were treated with radiotherapy alone (13%), cytotoxic agent alone (19%), or chemotherapy/radiotherapy (68%). The most frequently mutated genes at TRMN diagnosis were: TP53 (31%), DNMT3A (19%), NRAS (13%), TET2 (12%), NPM1 (10%), PPM1D (9%), PTPN11 (9%) (Fig1A). 10% of patients had no gene mutation detected. According to 2017 ELN risk stratification, genetic risk for t-AML was favorable, intermediate and adverse in 19 (39%), 14 (28%) and 16 patients (33%), respectively. According to IPSS score, 86% of the t-MDS patients were classified as High risk/Intermediate 2 and 14% as Intermediate 1/Low risk. Treatment options included best supportive care for 16 patients (21%), low dose chemotherapy for 26 patients (34%), or intensive chemotherapy/allogenic transplant for 34 patients (45%). Based on Lindsley's modified classifier median overall survival for "P53/PPM1D", "MDS" and "de novo/pan-AML" subgroups were 12, 17 and 25 months, respectively (p=0.009) (Fig1B). "CHIP-associated mutations" were detected in 53 patients (69%) with no significant impact on overall survival (Fig1C). Interestingly, age at TRMN diagnosis in patients with "CHIP-associated mutations" vs patients with "no-CHIP" was higher (65 vs 56 years old, p=0.002) and the time interval between cancer diagnosis and TRMN was longer (6.6 [0.9-38.1] vs 2.9 [1.2-8.5] years, p< 0.001) (Fig1D). CHIP emergence was not correlated with type of cancer's treatment or with number of treatment lines. "P53/PPM1D" subgroup was more frequent in patients treated with 2 lines or more for their primary cancer than in patients who received only 1 line of treatment (50% and 25% respectively, p=0.03). Conclusion: TRMN occurring after gynecological or breast cancers are of bad prognosis, especially for P53 and PPM1D mutated patients. Our results show that CHIP related mutations are found in a large percentage of patients and could be responsible for emergence of TRMN, especially in older patients. Figure 1 Disclosures de Botton: Forma: Consultancy, Research Funding; Bayer: Consultancy; Daiichi: Consultancy; Novartis: Consultancy; Astellas: Consultancy; Abbvie: Consultancy; Pierre Fabre: Consultancy; Syros: Consultancy; Agios: Consultancy, Research Funding; Janssen: Consultancy; Pfizer: Consultancy; Servier: Consultancy; Celgene: Consultancy, Speakers Bureau. Micol:AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy.

Introduction Clonal selection is one of the mechanisms leading to therapy-related myeloid neoplasms (TRMN). A preexisting somatic mutation in hematopoietic stem cell (defined as clonal hematopoiesis [CH]) emerges under pressure of chemotherapy or radiotherapy, leading to TRMN development. Most of these mutations belong to the DNA damage response (DDR) pathway as TP53 or PPM1D mutations and are known to confer a dismal prognosis. Recently authorized for the treatment of ovarian cancers (OC), the poly (ADP-ribose) polymerase inhibitors (PARPi) represent a promising targeted therapy. However, by inducing DNA damage and altering DNA repair process, PARP inhibition could represent a challenge for the genetic stability of the healthy tissues. Thus, we assessed the effect of PARP inhibition on the development of CH and TRMN after PARPi treatment for OC (TRMN-PARPi) in combination with chemotherapies. Methods Firstly, we performed a targeted 77 genes mutational analysis using Next Generation Sequencing (NGS) in 13 patients exposed to PARPi without TRMN. Secondly, we retrospectively identified, with the help of the UNIHEM group of Unicancer, 17 patients who experienced TRMN-PARPi. Clinical, biological and survival data were collected and compared to 23 OC patients with TRMN not treated with PARPi (Gustave Roussy institutional database). Lastly, NGS was performed for 3 patients with TRMN-PARPi with sequential sampling. Patient's samples were obtained with informed consent. Results Thirteen OC patients during maintenance treatment with PARPi without TRMN were explored by NGS. Median age at NGS was 64.5 years old (yo) (40.5-75.3). 4/13 (31%) patients harbored BRCA1/2 germline mutation. Time between OC diagnosis and NGS was 4.3 y (1-11.6). The median number of chemotherapy line at PARPi initiation was 2 (1-3). 7 received Olaparib, 5 Niraparib and 1 Rucaparib. The median duration of PARPi treatment before NGS was 4.7 months (1.1-25.1). 12/13 patients experienced hematological toxicities during the PARPi treatment. CH was found in 10/13 (77%) patients (Figure 1a), including mutations of DDR genes in 8/10 (80%). 6/8 (75%) patients had 2 or more gene mutations. Next we identified 17 cases of TRMN occurring during or after PARPi administration for OC (6/17 [35%] t-AML and 11/17 [65%] t-MDS). 12/17 (71%) patients had BRCA germline mutations (7 BRCA1 and 5 BRCA2). All received Olaparib with a median dose of 600mg/d (400-1200). Median duration of Olaparib treatment was 1.7 years (0.2-4.6). TRMN-PARPi were described 1.4 months (0-10.9) after the end of PARPi administration. We compared these patients to a cohort of TRMN post OC not treated by PARPi. Number of therapy lines for OC, time between TRMN and OC diagnosis, median age at TRMN, were, for TRMN-PARPi, 2 (1-8), 5.9 y (0.9-20.8), 64.4 yo (46-74); respectively, compared to 3 (1-8), 4.9 y (1.7-36.9), 59.3 yo (35.7-85.7); (p=ns). TRMN-PARPi cytogenetic was unfavorable for 16/17 (94%) (including 11/17 [65%] complex karyotype) compared to 16/23 (70%) (11/23 [48%] complex karyotype). C Median survival was significantly lower in the TRMN-PARPi group 3.9 months 95%CI [2.0-9.7] and 6.1 months 95%CI [4.1-15.8] respectively, p=0.046, Fig 1b). However, median survival from OC diagnosis was not different between the two groups 6.2 y 95%CI [5.6-NA] for TRMN-PARPi vs 5.6 y 95%CI [5.0-11.6]. NGS was available for 8/17 TRMN-PARPi and revealed mutations in DDR genes in 7/8 patients (6 patients with TP53 mutation, 2 with PPM1D mutation). For 3 patients, we had samples from OC stage, before PARPi administration. We found that mutations from TRMN stage were present at lower frequency, confirming clonal selection by PARPi treatment (Figure 1c). Conclusions Here we described, for the first time, a cohort of TRMN patients previously treated with PARPi for an OC. Intriguingly, most of these TRMN occurred with a short latency at the end of PARPi treatment, with unfavorable cytogenetic and very short OS. Moreover, we found a very high percentage of CH involved in the DDR pathway (62%) in patients under PARPi treatment without TRMN suggesting a potential clonal selection which could lead ultimately to TRMN. PARPi are now indicated in 1rst line high grade OC regardless of BRCA status, which should expand indications. Benefit for OC patients is not questionable; however, caution will be warranted for patients with CH before PARPi treatment, especially implicating DDR mutations. Disclosures Etienne: Incyte: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau.

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