Recurrence after long-term use of poly ADP‐ribose polymerase inhibitors triggered by therapy-related myeloid neoplasms: a case report

Recurrence after long-term use of poly ADP‐ribose polymerase inhibitors triggered by therapy-related myeloid neoplasms: a case report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Recurrence after long-term use of poly ADP‐ribose polymerase inhibitors triggered by therapy-related myeloid neoplasms: a case report Yurika Yamada, Akira Yokoi, Hiroaki Kajiyama This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7221785/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Poly ADP-ribose polymerase inhibitors are used as maintenance therapy for recurrent ovarian cancer. Long-term use for relapsed patients who respond to treatment is acceptable; however, risks other than relapse have not been thoroughly examined. There has been growing concern that the use of poly ADP-ribose polymerase inhibitors in ovarian cancer patients, particularly those with recurrent disease, may be associated with an increased risk of therapy-related myeloid neoplasms. Here, we evaluated a case of disease recurrence and myeloid neoplasms following long-term treatment with poly ADP-ribose polymerase inhibitors. Case presentation: A 49-year-old woman presented with stage ⅢC (FIGO2014), high-grade serous ovarian carcinoma. In 2008, she underwent surgery and chemotherapy as initial treatment and achieved a complete response. Subsequently, she relapsed six times between 2010 to 2017 and underwent chemotherapy each time, which included paclitaxel, carboplatin, irinotecan, cisplatin, liposomal doxorubicin, docetaxel, and nedaplatin. At the time of her sixth relapse, her platinum-free interval was nine months, which is consistent with platinum-sensitive disease. She received five cycles of nedaplatin and was subsequently administered olaparib. No notable adverse events occurred during olaparib treatment. Five years after starting olaparib treatment, she developed myelodysplastic syndrome, which progressed to acute myeloid leukemia after two months. Olaparib treatment was stopped following the diagnosis of myelodysplastic syndrome. She underwent chemotherapy (eight cycles of venetoclax and azacitidine) for approximately one year following her diagnosis of acute myeloid leukemia, but showed no improvement. Furthermore, she developed abnormal genital bleeding and recurrent ovarian cancer manifested as a rectovaginal fistula. Although her ovarian cancer stopped progressing with olaparib treatment, she developed therapy-related myeloid neoplasms. Considering the seriousness of her condition, she was placed on best supportive care. She was eventually transferred to a hospice program, where she died from ovarian cancer and acute myeloid leukemia. Conclusions: Although poly ADP-ribose polymerase inhibitor treatment may promote long-term ovarian cancer survival, it may also increase the risk of fatal side effects, such as therapy-related myeloid neoplasms. For cases in which poly ADP-ribose polymerase inhibitors show sustained efficacy over a long period, it is important to consider the possibility that tumor cells have not been completely eradicated. Ovarian cancer poly ADP-ribose polymerase inhibitors therapy-related myeloid neoplasms Figures Figure 1 Figure 2 Background Ovarian cancer remains one of the most lethal gynecologic malignancies, primarily because of its high rate of recurrence and limited efficacy in the recurrent setting. Although the initial response to platinum-based chemotherapy is often favorable, the majority of patients experience relapse, and the prognosis for recurrent ovarian cancer is particularly poor [1]. Treatment of ovarian cancer with surgery and platinum-based chemotherapy has changed dramatically with the advent of poly ADP-ribose polymerase (PARP) inhibitors, particularly in patients with BRCA mutations or homologous recombination deficiency. In the SOLO2 trial, olaparib exhibited a significant improvement in progression-free survival (PFS) among patients with BRCA-mutated recurrent ovarian cancer, with long-term follow-up indicating durable responses that exceed five years in some cases [2]. Similarly, niraparib showed a PFS benefit in the NOVA trial, regardless of BRCA mutation status, thereby broadening the eligible patient population for PARP inhibitor therapy [3]. These studies support the long-term, and in some cases, indefinite use of PARP inhibitors until disease progression or unacceptable toxicity occurs. However, concerns have emerged regarding the long-term safety of this approach. Patients with recurrent ovarian cancer are frequently exposed to multiple lines of cytotoxic chemotherapy, which is a risk factor for therapy-related myeloid neoplasms (t-MN), including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) [4]. Recent studies suggest a link between prolonged PARP inhibitor exposure and the development of t-MN, possibly because of cumulative genotoxic stress and clonal hematopoietic evolution [4, 5]. The cumulative effect of DNA-damaging therapies, including chemotherapy and PARP inhibitors, may contribute to clonal hematopoiesis and leukemogenesis. Here, we report a case of a patient who developed t-MN after long-term administration of olaparib, then experienced recurrent ovarian cancer after discontinuing olaparib treatment, and subsequently died. Case Presentation A 49-year-old woman (gravida 2, para2) presented with stage ⅢC (FIGO2014), high-grade serous ovarian carcinoma. A detailed timeline is shown in Figure 1. Her father had liver cancer. Neither her genetic nor tumor BRCA status was evaluated as she declined an evaluation. She underwent primary debulking surgery (PDS), not achieving complete surgery, but only bilateral salpingo-oophorectomy and omentectomy in June 2008. Pathological images of the surgical specimens are shown in Figure 2. Following surgery, she received six cycles of paclitaxel plus carboplatin (TC). Subsequently, she underwent hysterectomy and a secondary tumor debulking surgery. Because the tumor remained, she received three cycles of irinotecan and cisplatin therapy, after which she achieved a complete response (CR) based on a computed tomography (CT) scan. Two years after PDS (October 2010, 51 years old), she relapsed with a pelvic metastasis. She received three cycles of TC; however, a subsequent CT scan revealed a new small nodule several millimeters in size in her right lung. She was administered four cycles of liposomal doxorubicin. Following treatment, the pelvic metastasis disappeared in the CT scan, which was considered a CR. In August 2012 (53 years old), she experienced a second relapse with a 3-cm pelvic metastasis on the left side of her rectum. She received three cycles of TC; however, when she received the third cycle of TC, she had an allergic reaction to carboplatin. She received five cycles of nedaplatin instead and achieved a CR. In May 2014 (55 years old), she experienced a third relapse with a pelvic metastasis on the right side of her rectum. She received three cycles of docetaxel, but subsequently developed recurrent tumor progression. She was administered chemotherapy, which included seven cycles of nogitecan, and achieved a CR. In May 2015 (56 years old), she experienced a fourth relapse in the right side of her rectum. She received four cycles of irinotecan, but the recurrent tumor remained based on a CT scan. Subsequently, she underwent low anterior rectal resection, colostomy, and vaginal wall resection (R0 resection). In February 2016, she underwent a colostomy closure. In September 2016 (57 years old), she experienced a fifth relapse with left side pelvic metastasis based on a CT scan. She received six cycles of nedaplatin and achieved a CR. In December 2017 (58 years old), she experienced a sixth relapse with left side pelvic metastasis based on a CT scan. She received five cycles of nedaplatin and achieved a CR. Subsequently, she was administered olaparib in June 2018 (59 years old). In September 2023 (64 years old), her blood test revealed pancytopenia. She received bone marrow aspiration, and an examination showed a blast ratio of 18.5%, and dysplasia, including neutrophil degranulation, Pelger nucleus anomaly, and micromegakaryocytes. Her karyotype was complex at -7. She was diagnosed with MDS. Olaparib treatment was stopped as a result of the diagnosis. In November 2023, she developed AML. She received venetoclax and azacitidine. She received eight cycles of chemotherapy from November 2023 to August 2024, but showed no improvement. The results of bone marrow aspiration after her eighth cycle of chemotherapy showed that 57% of the bone marrow was myeloblastic. In addition, in October 2024, she presented with a rectovaginal fistula based on a CT scan, and was diagnosed with recurrent ovarian cancer. Considering the seriousness of her condition, she was placed on best supportive care. She was eventually transferred to hospice treatment, where she died from ovarian cancer and t-MN. Discussion and Conclusions PARP inhibitors bind and trap PARP1 and PARP2 on DNA at the site of single-strand breaks, which results in the production of double-strand breaks (DSBs). These DSBs are efficiently repaired in normal cells with functional homologous recombination repair systems; however, cancer cells with homologous recombination repair deficiency, such as BRCA loss-of-function mutations, must rely on low-fidelity repair pathways, which may increase genomic instability and ultimately lead to tumor cell death [6] [7]. Murai et al. showed that trapping PARP on DNA results in greater cytotoxicity in vivo [8]. In both cases, PARP inhibitors may act as cytocidal agents; however, in this case, the disease recurred when the PARP inhibitor was discontinued after long-term use (five years), suggesting that the PARP inhibitor may not only act as a cytocidal agent, but may simply cause the tumor to become dormant. PARP inhibitors can be used for long periods as maintenance therapy for recurrent ovarian cancer; however, there is no established period for their use, raising the question of how long they should be administered. PARP inhibitor treatment may increase the incidence of t-MN. The phase III SOLO2/ENGOT-Ov21 study revealed that the incidence of MDS and AML was 16/195 (8.2%) patients in the olaparib group and 4/99 (4%) patients in the placebo group [9]. A 2021 meta-analysis showed that maintenance treatment with PARP inhibitors following chemotherapy for recurrent ovarian carcinoma significantly increased the risk of MDS and AML compared with the placebo (relative risk: 2.17, 95% confidence interval: 1.50–3.15) [10]. The development of t-MN in ovarian cancer patients is not only related to PARP inhibitor treatment, but also to the number of chemotherapy treatments. A study in the US revealed that increased duration of exposure to DNA-damaging therapy (alkylating agents, antimetabolites, platinum-based antineoplastic agents, and topoisomerase inhibitors) was significantly associated with an increased risk of developing secondary MDS/AML during follow-up in ovarian cancer patients [4]. In the present case, the patient had received multiple chemotherapy treatments, and olaparib plus the other chemotherapy treatments likely contributed to the development of t-MN. In conclusion, PARP inhibitor treatment may offer the potential for long-term survival, but it must be administered with caution because of the potential for fatal side effects. However, this case suggests that PARP inhibitors cause only the tumor to become dormant, and it is difficult to decide whether to stop PARP inhibitor treatment. Therefore, further studies are needed to determine the optimal duration of PARP inhibitor treatment. Abbreviations PARP poly ADP-ribose polymerase PFS progression-free survival t-MN therapy-related myeloid neoplasms MDS myelodysplastic syndromes AML acute myeloid leukemia PDS primary debulking surgery TC paclitaxel plus carboplatin CR complete response CT computed tomography DSBs double-strand breaks Declarations Ethics approval and consent to participate Not required for case reports at our hospital. Single case reports are exempt from ethical approval in our institution. Clinical trial number: not applicable. Consent for publication Written informed consent was obtained from the patient’s next of kin for publication of this study. A copy of the written consent is available for review by the Editor-in-Chief of the journal on request. Availability of data and materials No datasets were generated or analyzed during the current study. Competing interests The authors declare that they have no competing interests. Funding This study was not supported by any sponsor or funder. Authors' contributions YY and AY were major contributors in article writing and editing various drafts of the manuscript. HK was the supervisor. All authors reviewed and approved the final manuscript. AY is the corresponding author. Acknowledgements We thank all stuff at Nagoya University hospital who cared this patient. References Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, Gaudet MM, Jemal A, Siegel RL: Ovarian cancer statistics, 2018 . CA Cancer J Clin 2018, 68 (4):284-296. Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM, Korach J, Huzarski T, Poveda A, Pignata S et al : Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial . Lancet Oncol 2017, 18 (9):1274-1284. Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, Fabbro M, Ledermann JA, Lorusso D, Vergote I et al : Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer . N Engl J Med 2016, 375 (22):2154-2164. Shenolikar R, Durden E, Meyer N, Lenhart G, Moore K: Incidence of secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with ovarian or breast cancer in a real-world setting in the United States . Gynecol Oncol 2018, 151 (2):190-195. Morice PM, Leary A, Dolladille C, Chrétien B, Poulain L, González-Martín A, Moore K, O'Reilly EM, Ray-Coquard I, Alexandre J: Myelodysplastic syndrome and acute myeloid leukaemia in patients treated with PARP inhibitors: a safety meta-analysis of randomised controlled trials and a retrospective study of the WHO pharmacovigilance database . Lancet Haematol 2021, 8 (2):e122-e134. Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D'Andrea AD: Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer . Cancer Discov 2015, 5 (11):1137-1154. Evans T, Matulonis U: PARP inhibitors in ovarian cancer: evidence, experience and clinical potential . Ther Adv Med Oncol 2017, 9 (4):253-267. Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, Ji J, Takeda S, Pommier Y: Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors . Cancer Res 2012, 72 (21):5588-5599. Trillsch F, Mahner S, Ataseven B, Asher R, Aryal N, Dubot C, Clamp A, Penson RT, Oza A, Amit A et al : Efficacy and safety of olaparib according to age in BRCA1/2-mutated patients with recurrent platinum-sensitive ovarian cancer: Analysis of the phase III SOLO2/ENGOT-Ov21 study . Gynecol Oncol 2022, 165 (1):40-48. Baradács I, Teutsch B, Váradi A, Bilá A, Vincze Á, Hegyi P, Fazekas T, Komoróczy B, Nyirády P, Ács N et al : PARP inhibitor era in ovarian cancer treatment: a systematic review and meta-analysis of randomized controlled trials . J Ovarian Res 2024, 17 (1):53. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7221785","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":508109638,"identity":"6b0958f0-cae8-4864-bf35-823ef187e694","order_by":0,"name":"Yurika Yamada","email":"","orcid":"","institution":"Nagoya University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yurika","middleName":"","lastName":"Yamada","suffix":""},{"id":508109639,"identity":"647561c0-5c07-4b27-9834-81cdbac88bad","order_by":1,"name":"Akira Yokoi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFElEQVRIiWNgGAWjYHACZgYGAxsgnYAhjFdLGslaGA5jasEJ+GckHzb4UHA+mp89ge3Bj182if0NPAYMP2oY2M1xaJG4kZacOMPgdu7Mngfshr19aYkzDvAYMPYcY2C2bMCh50aO8WEeoJYNNxLYJHh7Dic23H9jwMDbwMBscAC7DnmIlnO5+4FaJP8CtcwH2fIXjxYDoJZkHoMDuRskEtikeX4cTtwA1MKMzxbDM8+SDWcYJOfOOPOwTVq2Ic144wG2gsMyxyRw+kXuePJhiQ9/7HL725OPSb75YyM77wDzxodvamyScYUYg0ACjMXYwMDYxuAIMhvoJIlkA1xa+FFc/IfBHsa0w6llFIyCUTAKRhoAAMvlXakBUa+ZAAAAAElFTkSuQmCC","orcid":"","institution":"Nagoya University Graduate School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Akira","middleName":"","lastName":"Yokoi","suffix":""},{"id":508109640,"identity":"29a341c8-4645-4ffc-b75b-844549f4cca6","order_by":2,"name":"Hiroaki Kajiyama","email":"","orcid":"","institution":"Nagoya University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hiroaki","middleName":"","lastName":"Kajiyama","suffix":""}],"badges":[],"createdAt":"2025-07-26 14:23:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7221785/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7221785/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90363775,"identity":"7876aa85-5595-4ad9-b391-a09032d0f7f0","added_by":"auto","created_at":"2025-09-02 02:11:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":43702,"visible":true,"origin":"","legend":"\u003cp\u003eTimeline of patient medical history\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7221785/v1/5a224f8003a2ae233a96dff9.png"},{"id":90363777,"identity":"b2a1c44e-e561-4330-bfad-b555559eeff9","added_by":"auto","created_at":"2025-09-02 02:11:40","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":217190,"visible":true,"origin":"","legend":"\u003cp\u003ePathological images in primary debulking surgery display high grade serous carcinoma.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7221785/v1/e638663d9c17b096d1d00468.png"},{"id":95720587,"identity":"791e79a9-561c-4bf8-8bd8-3d09a5cf50bd","added_by":"auto","created_at":"2025-11-12 09:25:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1124284,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7221785/v1/c0ea56ce-abb0-4b1f-a1e9-8b4c9aca6914.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Recurrence after long-term use of poly ADP‐ribose polymerase inhibitors triggered by therapy-related myeloid neoplasms: a case report","fulltext":[{"header":"Background","content":"\u003cp\u003eOvarian cancer remains one of the most lethal gynecologic malignancies, primarily because of its high rate of recurrence and limited efficacy in the recurrent setting. Although the initial response to platinum-based chemotherapy is often favorable, the majority of patients experience relapse, and the prognosis for recurrent ovarian cancer is particularly poor [1]. Treatment of ovarian cancer with surgery and platinum-based chemotherapy has changed dramatically with the advent of poly ADP-ribose polymerase (PARP) inhibitors, particularly in patients with BRCA mutations or homologous recombination deficiency. In the SOLO2 trial, olaparib exhibited a significant improvement in progression-free survival (PFS) among patients with BRCA-mutated recurrent ovarian cancer, with long-term follow-up indicating durable responses that exceed five years in some cases [2]. Similarly, niraparib showed a PFS benefit in the NOVA trial, regardless of BRCA mutation status, thereby broadening the eligible patient population for PARP inhibitor therapy [3]. These studies support the long-term, and in some cases, indefinite use of PARP inhibitors until disease progression or unacceptable toxicity occurs.\u003c/p\u003e\n\u003cp\u003eHowever, concerns have emerged regarding the long-term safety of this approach. Patients with recurrent ovarian cancer are frequently exposed to multiple lines of cytotoxic chemotherapy, which is a risk factor for therapy-related myeloid neoplasms (t-MN), including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) [4]. Recent studies suggest a link between prolonged PARP inhibitor exposure and the development of t-MN, possibly because of cumulative genotoxic stress and clonal hematopoietic evolution [4, 5]. The cumulative effect of DNA-damaging therapies, including chemotherapy and PARP inhibitors, may contribute to clonal hematopoiesis and leukemogenesis. Here, we report a case of a patient who developed t-MN after long-term administration of olaparib, then experienced recurrent ovarian cancer after discontinuing olaparib treatment, and subsequently died.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 49-year-old woman (gravida 2, para2) presented with stage ⅢC (FIGO2014), high-grade serous ovarian carcinoma. A detailed timeline is shown in Figure 1. Her father had liver cancer. Neither her genetic nor tumor BRCA status was evaluated as she declined an evaluation.\u003c/p\u003e\n\u003cp\u003eShe underwent primary debulking surgery (PDS), not achieving complete surgery, but only bilateral salpingo-oophorectomy and omentectomy in June 2008. Pathological images of the surgical specimens are shown in Figure 2. Following surgery, she received six cycles of paclitaxel plus carboplatin (TC). Subsequently, she underwent hysterectomy and a secondary tumor debulking surgery. Because the tumor remained, she received three cycles of irinotecan and cisplatin therapy, after which she achieved a complete response (CR) based on a computed tomography (CT) scan.\u003c/p\u003e\n\u003cp\u003eTwo years after PDS (October 2010, 51 years old), she relapsed with a pelvic metastasis. She received three cycles of TC; however, a subsequent CT scan revealed a new small nodule several millimeters in size in her right lung. She was administered four cycles of liposomal doxorubicin. Following treatment, the pelvic metastasis disappeared in the CT scan, which was considered a CR.\u003c/p\u003e\n\u003cp\u003eIn August 2012 (53 years old), she experienced a second relapse with a 3-cm pelvic metastasis on the left side of her rectum. She received three cycles of TC; however, when she received the third cycle of TC, she had an allergic reaction to carboplatin. She received five cycles of nedaplatin instead and achieved a CR.\u003c/p\u003e\n\u003cp\u003eIn May 2014 (55 years old), she experienced a third relapse with a pelvic metastasis on the right side of her rectum. She received three cycles of docetaxel, but subsequently developed recurrent tumor progression. She was administered chemotherapy, which included seven cycles of nogitecan, and achieved a CR.\u003c/p\u003e\n\u003cp\u003eIn May 2015 (56 years old), she experienced a fourth relapse in the right side of her rectum. She received four cycles of irinotecan, but the recurrent tumor remained based on a CT scan. Subsequently, she underwent low anterior rectal resection, colostomy, and vaginal wall resection (R0 resection). In February 2016, she underwent a colostomy closure.\u003c/p\u003e\n\u003cp\u003eIn September 2016 (57 years old), she experienced a fifth relapse with left side pelvic metastasis based on a CT scan. She received six cycles of nedaplatin and achieved a CR.\u003c/p\u003e\n\u003cp\u003eIn December 2017 (58 years old), she experienced a sixth relapse with left side pelvic metastasis based on a CT scan. She received five cycles of nedaplatin and achieved a CR. Subsequently, she was administered olaparib in June 2018 (59 years old).\u003c/p\u003e\n\u003cp\u003eIn September 2023 (64 years old), her blood test revealed pancytopenia. She received bone marrow aspiration, and an examination showed a blast ratio of 18.5%, and dysplasia, including neutrophil degranulation, Pelger nucleus anomaly, and micromegakaryocytes. Her karyotype was complex at -7. She was diagnosed with MDS. Olaparib treatment was stopped as a result of the diagnosis.\u003c/p\u003e\n\u003cp\u003eIn November 2023, she developed AML. She received venetoclax and azacitidine. She received eight cycles of chemotherapy from November 2023 to August 2024, but showed no improvement. The results of bone marrow aspiration after her eighth cycle of chemotherapy showed that 57% of the bone marrow was myeloblastic. In addition, in October 2024, she presented with a rectovaginal fistula based on a CT scan, and was diagnosed with recurrent ovarian cancer. Considering the seriousness of her condition, she was placed on best supportive care. She was eventually transferred to hospice treatment, where she died from ovarian cancer and t-MN.\u003c/p\u003e"},{"header":"Discussion and Conclusions","content":"\u003cp\u003ePARP inhibitors bind and trap PARP1 and PARP2 on DNA at the site of single-strand breaks, which results in the production of double-strand breaks (DSBs). These DSBs are efficiently repaired in normal cells with functional homologous recombination repair systems; however, cancer cells with homologous recombination repair deficiency, such as BRCA loss-of-function mutations, must rely on low-fidelity repair pathways, which may increase genomic instability and ultimately lead to tumor cell death [6] [7]. Murai et al. showed that trapping PARP on DNA results in greater cytotoxicity in vivo [8]. In both cases, PARP inhibitors may act as cytocidal agents; however, in this case, the disease recurred when the PARP inhibitor was discontinued after long-term use (five years), suggesting that the PARP inhibitor may not only act as a cytocidal agent, but may simply cause the tumor to become dormant.\u003c/p\u003e\n\u003cp\u003ePARP inhibitors can be used for long periods as maintenance therapy for recurrent ovarian cancer; however, there is no established period for their use, raising the question of how long they should be administered. PARP inhibitor treatment may increase the incidence of t-MN. The phase III SOLO2/ENGOT-Ov21 study revealed that the incidence of MDS and AML was 16/195 (8.2%) patients in the olaparib group and 4/99 (4%) patients in the placebo group [9]. A 2021 meta-analysis showed that maintenance treatment with PARP inhibitors following chemotherapy for recurrent ovarian carcinoma significantly increased the risk of MDS and AML compared with the placebo (relative risk: 2.17, 95% confidence interval: 1.50–3.15) [10].\u003c/p\u003e\n\u003cp\u003eThe development of t-MN in ovarian cancer patients is not only related to PARP inhibitor treatment, but also to the number of chemotherapy treatments. A study in the US revealed that increased duration of exposure to DNA-damaging therapy (alkylating agents, antimetabolites, platinum-based antineoplastic agents, and topoisomerase inhibitors) was significantly associated with an increased risk of developing secondary MDS/AML during follow-up in ovarian cancer patients [4]. In the present case, the patient had received multiple chemotherapy treatments, and olaparib plus the other chemotherapy treatments likely contributed to the development of t-MN.\u003c/p\u003e\n\u003cp\u003eIn conclusion, PARP inhibitor treatment may offer the potential for long-term survival, but it must be administered with caution because of the potential for fatal side effects. However, this case suggests that PARP inhibitors cause only the tumor to become dormant, and it is difficult to decide whether to stop PARP inhibitor treatment. Therefore, further studies are needed to determine the optimal duration of PARP inhibitor treatment.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePARP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003epoly ADP-ribose polymerase\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePFS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eprogression-free survival\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003et-MN\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003etherapy-related myeloid neoplasms\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMDS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003emyelodysplastic syndromes\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAML\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eacute myeloid leukemia\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePDS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eprimary debulking surgery\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003epaclitaxel plus carboplatin\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecomplete response\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecomputed tomography\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDSBs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003edouble-strand breaks\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot required for case reports at our hospital. Single case reports are exempt from ethical approval in our institution. Clinical trial number: not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient’s next of kin for publication of this study. A copy of the written consent is available for review by the Editor-in-Chief of the journal on request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo datasets were generated or analyzed during the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was not supported by any sponsor or funder.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYY and AY were major contributors in article writing and editing various drafts of the manuscript. HK was the supervisor. All authors reviewed and approved the final manuscript. AY is the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all stuff at Nagoya University hospital who cared this patient.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTorre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, Gaudet MM, Jemal A, Siegel RL: \u003cstrong\u003eOvarian cancer statistics, 2018\u003c/strong\u003e. \u003cem\u003eCA Cancer J Clin \u003c/em\u003e2018, \u003cstrong\u003e68\u003c/strong\u003e(4):284-296.\u003c/li\u003e\n\u003cli\u003ePujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM, Korach J, Huzarski T, Poveda A, Pignata S\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eOlaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial\u003c/strong\u003e. \u003cem\u003eLancet Oncol \u003c/em\u003e2017, \u003cstrong\u003e18\u003c/strong\u003e(9):1274-1284.\u003c/li\u003e\n\u003cli\u003eMirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, Fabbro M, Ledermann JA, Lorusso D, Vergote I\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eNiraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer\u003c/strong\u003e. \u003cem\u003eN Engl J Med \u003c/em\u003e2016, \u003cstrong\u003e375\u003c/strong\u003e(22):2154-2164.\u003c/li\u003e\n\u003cli\u003eShenolikar R, Durden E, Meyer N, Lenhart G, Moore K: \u003cstrong\u003eIncidence of secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with ovarian or breast cancer in a real-world setting in the United States\u003c/strong\u003e. \u003cem\u003eGynecol Oncol \u003c/em\u003e2018, \u003cstrong\u003e151\u003c/strong\u003e(2):190-195.\u003c/li\u003e\n\u003cli\u003eMorice PM, Leary A, Dolladille C, Chr\u0026eacute;tien B, Poulain L, Gonz\u0026aacute;lez-Mart\u0026iacute;n A, Moore K, O\u0026apos;Reilly EM, Ray-Coquard I, Alexandre J: \u003cstrong\u003eMyelodysplastic syndrome and acute myeloid leukaemia in patients treated with PARP inhibitors: a safety meta-analysis of randomised controlled trials and a retrospective study of the WHO pharmacovigilance database\u003c/strong\u003e. \u003cem\u003eLancet Haematol \u003c/em\u003e2021, \u003cstrong\u003e8\u003c/strong\u003e(2):e122-e134.\u003c/li\u003e\n\u003cli\u003eKonstantinopoulos PA, Ceccaldi R, Shapiro GI, D\u0026apos;Andrea AD: \u003cstrong\u003eHomologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer\u003c/strong\u003e. \u003cem\u003eCancer Discov \u003c/em\u003e2015, \u003cstrong\u003e5\u003c/strong\u003e(11):1137-1154.\u003c/li\u003e\n\u003cli\u003eEvans T, Matulonis U: \u003cstrong\u003ePARP inhibitors in ovarian cancer: evidence, experience and clinical potential\u003c/strong\u003e. \u003cem\u003eTher Adv Med Oncol \u003c/em\u003e2017, \u003cstrong\u003e9\u003c/strong\u003e(4):253-267.\u003c/li\u003e\n\u003cli\u003eMurai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, Ji J, Takeda S, Pommier Y: \u003cstrong\u003eTrapping of PARP1 and PARP2 by Clinical PARP Inhibitors\u003c/strong\u003e. \u003cem\u003eCancer Res \u003c/em\u003e2012, \u003cstrong\u003e72\u003c/strong\u003e(21):5588-5599.\u003c/li\u003e\n\u003cli\u003eTrillsch F, Mahner S, Ataseven B, Asher R, Aryal N, Dubot C, Clamp A, Penson RT, Oza A, Amit A\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eEfficacy and safety of olaparib according to age in BRCA1/2-mutated patients with recurrent platinum-sensitive ovarian cancer: Analysis of the phase III SOLO2/ENGOT-Ov21 study\u003c/strong\u003e. \u003cem\u003eGynecol Oncol \u003c/em\u003e2022, \u003cstrong\u003e165\u003c/strong\u003e(1):40-48.\u003c/li\u003e\n\u003cli\u003eBarad\u0026aacute;cs I, Teutsch B, V\u0026aacute;radi A, Bil\u0026aacute; A, Vincze \u0026Aacute;, Hegyi P, Fazekas T, Komor\u0026oacute;czy B, Nyir\u0026aacute;dy P, \u0026Aacute;cs N\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003ePARP inhibitor era in ovarian cancer treatment: a systematic review and meta-analysis of randomized controlled trials\u003c/strong\u003e. \u003cem\u003eJ Ovarian Res \u003c/em\u003e2024, \u003cstrong\u003e17\u003c/strong\u003e(1):53.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Ovarian cancer, poly ADP-ribose polymerase inhibitors, therapy-related myeloid neoplasms","lastPublishedDoi":"10.21203/rs.3.rs-7221785/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7221785/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003ePoly ADP-ribose polymerase inhibitors are used as maintenance therapy for recurrent ovarian cancer. Long-term use for relapsed patients who respond to treatment is acceptable; however, risks other than relapse have not been thoroughly examined. There has been growing concern that the use of poly ADP-ribose polymerase inhibitors in ovarian cancer patients, particularly those with recurrent disease, may be associated with an increased risk of therapy-related myeloid neoplasms. Here, we evaluated a case of disease recurrence and myeloid neoplasms following long-term treatment with poly ADP-ribose polymerase inhibitors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation: \u003c/strong\u003eA 49-year-old woman presented with stage ⅢC (FIGO2014), high-grade serous ovarian carcinoma. In 2008, she underwent surgery and chemotherapy as initial treatment and achieved a complete response. Subsequently, she relapsed six times between 2010 to 2017 and underwent chemotherapy each time, which included paclitaxel, carboplatin, irinotecan, cisplatin, liposomal doxorubicin, docetaxel, and nedaplatin. At the time of her sixth relapse, her platinum-free interval was nine months, which is consistent with platinum-sensitive disease. She received five cycles of nedaplatin and was subsequently administered olaparib. No notable adverse events occurred during olaparib treatment. Five years after starting olaparib treatment, she developed myelodysplastic syndrome, which progressed to acute myeloid leukemia after two months. Olaparib treatment was stopped following the diagnosis of myelodysplastic syndrome. She underwent chemotherapy (eight cycles of venetoclax and azacitidine) for approximately one year following her diagnosis of acute myeloid leukemia, but showed no improvement. Furthermore, she developed abnormal genital bleeding and recurrent ovarian cancer manifested as a rectovaginal fistula. Although her ovarian cancer stopped progressing with olaparib treatment, she developed therapy-related myeloid neoplasms. Considering the seriousness of her condition, she was placed on best supportive care. She was eventually transferred to a hospice program, where she died from ovarian cancer and acute myeloid leukemia.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eAlthough poly ADP-ribose polymerase inhibitor treatment may promote long-term ovarian cancer survival, it may also increase the risk of fatal side effects, such as therapy-related myeloid neoplasms. For cases in which poly ADP-ribose polymerase inhibitors show sustained efficacy over a long period, it is important to consider the possibility that tumor cells have not been completely eradicated.\u003c/p\u003e","manuscriptTitle":"Recurrence after long-term use of poly ADP‐ribose polymerase inhibitors triggered by therapy-related myeloid neoplasms: a case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-02 02:11:36","doi":"10.21203/rs.3.rs-7221785/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"606db87d-bb18-4c29-9fa1-80a476136c82","owner":[],"postedDate":"September 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-12T09:24:57+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-02 02:11:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7221785","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7221785","identity":"rs-7221785","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}