Highlights
- •The overall risk of MDS/AML was similar in patients who were randomly assigned to receive PARPi compared to controls.
- •PARPi use was associated with an increase in risk of MDS/AML in the front-line setting, but not in the recurrent setting.
- •PARPi use was associated with an increase in risk of MDS/AML in studies with a low proportion of heavily pretreated patients.
- •Among studies that included a high proportion of heavily pretreated patients, PARPi use was not associated with MDS/AML.
Abstract
Background
Clinical trials demonstrated that PARPi (poly [adenosine diphosphate–ribose]-ADP polymerase
inhibitor) therapy is effective in solid tumors. However, long term effects such as
therapy-related myelodysplastic syndrome or acute myeloid leukemia (MDS/AML) are poorly
described. We sought to quantify whether PARPi therapy is associated with the development
of MDS/AML.
Methods
Medline, Embase, and Cochrane databases were searched (inception to January 6, 2020)
and phase 2 and 3 clinical trials that randomized patients with solid tumors to a
PARPi or control therapy were included. The PRISMA guidelines were used to extract
data independently by multiple authors. We extracted person-time and number of cases
of MDS/AML in the PARPi and control arms of each study and pooled results with a random-effects
Poisson regression model. The pooled incidence rate ratio (IRR) for MDS/AML among
patients randomized to PARPi therapy was compared to those randomized to a control.
Results
We identified 14 studies that included 5739 patients. Accounting for intra-study clustering,
the risk of MDS/AML was similar in patients who were randomly assigned to receive
PARPi compared to controls (IRR 1.32, 95% confidence interval [CI] 0.78–2.26). In
the front-line setting, PARPi therapy was associated with developing MDS/AML (IRR
5.43, 95% CI 1.51–19.60). Among patients treated for recurrence, however, the risk
of MDS/AML appeared to be similar among patients randomized to PARPi or control treatment.
Among studies that included only patients with a BRCA mutation, the risk of MDS/AML was similar in both treatment groups (IRR 0.83, 95%
CI 0.45–1.53), but PARPi therapy was associated with MDS/AML in studies with an unrestricted
population (IRR 2.43, 95% CI 1.17–5.06).
Conclusion
The pooled overall effect was not statistically significant. However, treatment with
PARPi was associated with a statistically significant increase in the incidence of
MDS/AML among patients receiving front-line cancer therapy and those with limited
prior exposure to chemotherapy.
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Gynecologic OncologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-Ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer.J. Clin. Oncol. 2012; 30: 372-379https://doi.org/10.1200/JCO.2011.36.9215
- Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial.Lancet. Oncol. 2015; 16: 87-97https://doi.org/10.1016/S1470-2045(14)71135-0
- Olaparib versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA1/2 mutation (SOLO3): a randomized phase III trial.J. Clin. Oncol. 2020; 38: 1164-1174https://doi.org/10.1200/JCO.19.02745
- Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial.Lancet. Oncol. 2016; 17: 1579-1589https://doi.org/10.1016/S1470-2045(16)30376-X
- Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer.N. Engl. J. Med. 2016; 375: 2154-2164https://doi.org/10.1056/NEJMoa1611310
- Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet. 2017; 390: 1949-1961https://doi.org/10.1016/S0140-6736(17)32440-6
- 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: 1274-1284https://doi.org/10.1016/S1470-2045(17)30469-2
- Maintenance Olaparib in patients with newly diagnosed advanced ovarian Cancer.N. Engl. J. Med. 2018; 379: 2495-2505https://doi.org/10.1097/01.ogx.0000552695.03241.d6
- Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer.N. Engl. J. Med. 2019; 381: 2403-2415https://doi.org/10.1056/NEJMoa1909707
- Niraparib in patients with newly diagnosed advanced ovarian cancer.N. Engl. J. Med. 2019; 381: 2391-2402https://doi.org/10.1056/NEJMoa1910962
- Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.N. Engl. J. Med. 2019; 381: 2416-2428https://doi.org/10.1056/NEJMoa1911361
- Olaparib for metastatic breast Cancer in patients with a Germline BRCA mutation.N. Engl. J. Med. 2017; 377: 523-533https://doi.org/10.1056/NEJMoa1706450
- Talazoparib in patients with advanced breast cancer and a germline BRCA mutation.N. Engl. J. Med. 2018; 379: 753-763https://doi.org/10.1056/NEJMoa1802905
- Maintenance olaparib for germline BRCA -mutated metastatic pancreatic cancer.N. Engl. J. Med. 2019; 381: 317-327https://doi.org/10.1056/NEJMoa1903387
- 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: 190-195https://doi.org/10.1016/j.ygyno.2018.09.003
- FDA Approves Niraparib for First-Line Maintenance of Advanced Ovarian Cancer.(accessed July 9, 2020)
- FDA approval summary: olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy.Clin. Cancer Res. 2015; 21: 4257-4261https://doi.org/10.1158/1078-0432.CCR-15-0887
- Therapy-related myeloid neoplasms: when genetics and environment collide.Nat. Rev. Cancer. 2017; 17: 513-527https://doi.org/10.1038/nrc.2017.60
- Association of chemotherapy for solid tumors with development of therapy-related Myelodysplastic syndrome or acute myeloid leukemia in the modern era.JAMA Oncol. 2019; 5: 318-325https://doi.org/10.1001/jamaoncol.2018.5625
- Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group.JAMA. 2000; 283: 2008-2012https://doi.org/10.1001/jama.283.15.2008
- RoB 2: a revised tool for assessing risk of bias in randomised trials.BMJ. 2019; : l4898https://doi.org/10.1136/bmj.l4898
- Meta-analysis of incidence rate data in the presence of zero events.BMC Med. Res. Methodol. 2015; 15: 42https://doi.org/10.1186/s12874-015-0031-0
- Comparison of random-effects meta-analysis models for the relative risk in the case of rare events: a simulation study.Biom. J. 2020; 62: 1597-1630https://doi.org/10.1002/bimj.201900379
- Long-term safety in patients with recurrent ovarian cancer treated with niraparib versus placebo: results from the phase III ENGOT-OV16/NOVA trial.Gynecol. Oncol. 2020; 159: 442-448https://doi.org/10.1016/j.ygyno.2020.09.006
- Final overall survival (OS) results from SOLO2/ENGOT-ov21: A phase III trial assessing maintenance olaparib in patients (pts) with platinum-sensitive, relapsed ovarian cancer and a BRCA mutation.J. Clin. Oncol. 2020; 38: 6002https://doi.org/10.1200/JCO.2020.38.15_suppl.6002
- Iniparib plus chemotherapy in metastatic triple-negative breast Cancer.N. Engl. J. Med. 2011; 364: 205-214https://doi.org/10.1056/NEJMoa1011418
- A phase II randomized study evaluating the addition of iniparib to gemcitabine plus cisplatin as first-line therapy for metastatic non-small-cell lung cancer.Ann. Oncol. 2014; 25: 2156-2162https://doi.org/10.1093/annonc/mdu384
- Phase III study of Iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast Cancer.J. Clin. Oncol. 2014; 32: 3840-3847https://doi.org/10.1200/JCO.2014.55.2984
- SOLTI NeoPARP: a phase II randomized study of two schedules of iniparib plus paclitaxel versus paclitaxel alone as neoadjuvant therapy in patients with triple-negative breast cancer.Breast Cancer Res. Treat. 2015; 154: 351-357https://doi.org/10.1007/s10549-015-3616-8
- Veliparib in combination with whole-brain radiation therapy for patients with brain metastases from non-small cell lung cancer: results of a randomized, global, placebo-controlled study.J. Neuro-Oncol. 2017; 131: 105-115https://doi.org/10.1007/s11060-016-2275-x
- Niraparib maintenance therapy in patients with recurrent ovarian cancer after a partial response to the last platinum-based chemotherapy in the ENGOT-OV16/NOVA trial.J. Clin. Oncol. 2019; 37: 2968-2973https://doi.org/10.1200/JCO.18.02238
- Long-term ef fi cacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy.Br. J. Cancer. 2018; https://doi.org/10.1038/s41416-018-0271-y
- Olaparib maintenance therapy in platinum-sensitive relapsed ovarian Cancer.N. Engl. J. Med. 2012; 366: 1382-1392https://doi.org/10.1056/NEJMoa1105535
- Randomized, placebo-controlled, phase II study of Veliparib in combination with carboplatin and paclitaxel for advanced/metastatic non–small cell lung Cancer.Clin. Cancer Res. 2017; 23: 1937-1944https://doi.org/10.1158/1078-0432.CCR-15-3069
- Randomized, double-blind, phase II study of temozolomide in combination with either veliparib or placebo in patients with relapsed-sensitive or refractory small-cell lung cancer.J. Clin. Oncol. 2018; 36: 2386-2394https://doi.org/10.1200/JCO.2018.77.7672
- Adaptive randomization of veliparib–carboplatin treatment in breast cancer.N. Engl. J. Med. 2016; 375: 23-34https://doi.org/10.1056/NEJMoa1513749
- Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial.Lancet Oncol. 2018; 19: 497-509https://doi.org/10.1016/S1470-2045(18)30111-6
- Veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in patients with BRCA1/2 locally recurrent/metastatic breast cancer: randomized phase II study.Ann. Oncol. 2018; 29: 154-161https://doi.org/10.1093/annonc/mdx505
- Preferred reporting items for systematic reviews andMeta-analyses: the PRISMA statement.PLoS Med. 2009; 6e1000097https://doi.org/10.1371/journal.pmed.1000097
- OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer.Ann. Oncol. 2019; 30: 558-566https://doi.org/10.1093/annonc/mdz012
- 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: e122-e134https://doi.org/10.1016/S2352-3026(20)30360-4
- Statistical methods for meta-analyses including information from studies without any events-add nothing to nothing and succeed nevertheless.Stat. Med. 2015; 34: 1097-1116https://doi.org/10.1002/sim.6383
- The Yusuf-Peto method was not a robust method for meta-analyses of rare events data from antidepressant trials.J. Clin. Epidemiol. 2017; 91: 129-136https://doi.org/10.1016/j.jclinepi.2017.07.006
- Performance of the Peto odds ratio compared to the usual odds ratio estimator in the case of rare events.Biom. J. 2016; 58: 1428-1444https://doi.org/10.1002/bimj.201600034
- PARP inhibitors in the Management of Ovarian Cancer: ASCO guideline.J. Clin. Oncol. 2020; 38: 3468-3493https://doi.org/10.1200/JCO.20.01924
- Evolving risk of therapy-related acute myeloid leukemia following cancer chemotherapy among adults in the United States, 1975-2008.Blood. 2013; 121: 2996-3004https://doi.org/10.1182/blood-2012-08-448068
- Association of Therapy for autoimmune disease with Myelodysplastic syndromes and acute myeloid leukemia.JAMA Oncol. 2017; 3: 936https://doi.org/10.1001/jamaoncol.2016.6435
- Brca1 deficiency causes bone marrow failure and spontaneous hematologic malignancies in mice.Blood. 2016; 127: 310-313https://doi.org/10.1182/blood-2015-03-635599
- Inherited mutations in cancer susceptibility genes are common among survivors of breast cancer who develop therapy-related leukemia.Cancer. 2016; 122: 304-311https://doi.org/10.1002/cncr.29615
- Germline mutations in the DNA damage response genes BRCA1, BRCA2, BARD1 and TP53 in patients with therapy related myeloid neoplasms.J. Med. Genet. 2012; 49: 422-428https://doi.org/10.1136/jmedgenet-2011-100674
Article info
Publication history
Published online: March 15, 2021
Accepted:
March 5,
2021
Received:
January 22,
2021
Identification
Copyright
© 2021 Elsevier Inc. All rights reserved.
