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

Morice, Pierre‐Marie; Léary, Alexandra; Dolladille, Charles; Chrétien, Basile; Poulain, Laurent; González-Martín, Antonio; Moore, Kathleen; O'Reilly, Eileen Mary; Ray‐Coquard, Isabelle; Alexandre, Jonas

doi:10.1016/s2352-3026(20)30360-4

Cited by 169 publications

(159 citation statements)

References 46 publications

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“…Limitation for data from trials: First, adverse events generally reportable only up to 30 days following the last treatment date according to CTCAEs. Therefore, events occurring after 30 days following last treatment would not have been captured, which create a bias in the analysis [28] . Second, We collected events of SJS and TEN from both published data (from published literature) and unpublished data (from ClinicalTrials.gov), we chose to include events from the ClinicalTrials.gov, as it comprehensively reports all serious adverse events and updates events reporting even after publication [29] .There might be bias surrounding the inclusion of unpublished data, as this data was not peer-reviewed.…”

Section: Discussionmentioning

confidence: 99%

Stevens-Johnson syndrome/toxic epidermal necrolysis in patients treated with immune checkpoint inhibitors: A safety analysis of clinical trials and FDA pharmacovigilance database

Zhu

Chen

et al. 2021

eClinicalMedicine

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Background: The association between immune checkpoint inhibitors (ICIs) and Stevens-Johnsons syndrome (SJS) /toxic epidermal necrolysis (TEN) is unclear. We assessed the risk of SJS and TEN related to ICIs, via a systematic analysis of SJS/TEN cases reported in clinical trials and the FDA Adverse Event Reporting System (FAERS). Methods: We explored ICIs related SJS/TEN events in randomized control trials available in Clinical-Trials.gov and electronic databases (Pubmed, Embase, the Cochrane Central Register of Controlled Trials) up to 12 January 2021. Meta-analysis was performed by using Peto odds ratios (ORs) with 95% CIs. In a separate retrospective pharmacovigilance study of FAERs, cases of ICIs related SJS/TEN were extracted between the first quarter (Q1) of 2004 and Q4 of 2020. Disproportionality was analyzed using the proportional reports reporting odds ratio (ROR) and information components (IC). PROSPERO registration number: CRD42021232399. Findings: A total of 20 RCTs (11597 patients) were included. ICIs were associated with an increased risk of SJS/ TEN (OR= 4.33, 95%CI:1.90À9.87). FAERS pharmacovigilance data identified 411 cases of SJS (n = 253) or TEN (n = 184) related to ICIs therapy. ICIs were significantly associated with SJS/TEN (n = 411; ROR=2.88, 95%CI:2.61À3.17; IC=1.49, 95%CI:1.35À1.65). The median onset time of SJS/TEN was 25.5 days (SJS:21.5 days; TEN:32 days) (n = 190), 97.5% of patients discontinued use of ICIs when suffering from SJS/TEN (n = 201). Of 305 cases that reported outcomes, 113 (37%) resulted in death (SJS:19.9%, TEN:61.6%). Interpretation: These data suggest that ICIs were significantly associated with increased risk of SJS/TEN.

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Section: Discussionmentioning

confidence: 99%

Stevens-Johnson syndrome/toxic epidermal necrolysis in patients treated with immune checkpoint inhibitors: A safety analysis of clinical trials and FDA pharmacovigilance database

Zhu

Chen

et al. 2021

eClinicalMedicine

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“…In addition, newer cancer therapies such as poly (ADP-ribose) polymerase inhibitors, peptide receptor radionucleotide therapy, and hematopoietic growth factors have been associated with the development of t-MN. [54][55][56] Analysis of the cytogenetic profile, molecular features, and germline predisposition syndromes associated with these t-MNs will be necessary to understand and hopefully minimize the risk conferred by treatment with these DNA-damaging agents.…”

Section: Discussionmentioning

confidence: 99%

Therapy-Related Myeloid Neoplasms in 109 Patients Following Radiation Monotherapy

et al. 2021

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Therapy-related myeloid neoplasms (t-MNs) are a late complication of cytotoxic therapy and are defined as a distinct entity by the World Health Organization. While the link between chemotherapy exposure and risk of subsequent t-MN is well-described, the association between radiation monotherapy (RT) and t-MN risk is less definitive. We analyzed 109 consecutive patients who developed t-MNs after RT and describe latencies, cytogenetic profile, mutation analyses, and clinical outcomes. The most common cytogenetic abnormality was a clonal abnormality in chromosome 5 and/or 7, which was present in 45% of patients. The median latency from RT to t-MN diagnosis was 6.5 years, with the shortest latency in patients with balanced translocations. 1-year overall survival (OS) was 52% and 5-year OS was 22% for the entire cohort. Patients with chromosome 5 and/or 7 abnormalities experienced worse 1-year OS (37%) and 5-year OS (2%) when compared to other cytogenetic groups (p<0.0001). 16 patients underwent NGS; ASXL1 and TET2 were the most commonly mutated genes (n=4). In addition, 17 patients underwent germline variant testing and 3 carried pathogenic or likely pathogenic germline variants. In conclusion, patients with t-MN after RT monotherapy have increased frequencies of chromosome 5 and/or 7 abnormalities, which are associated with poor overall survival. In addition, pathogenic germline variants may be common in patients with t-MN after RT monotherapy.

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“…In studies included in our meta-analysis, only one patient occurred PARPi-AML at 2 years after randomization (41 days after receiving the lase dose of talazoparib) and died 18 days after diagnosis. Although PARPi-MDS/AML had a high mortality rate (45%), the incidence of PARPi-MDS/AML was very low (0.73%, 95% CI [0.50–1.07]) based on a meta-analysis including 18 placebo-controlled RCTs [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of PARP inhibitors in patients with BRCA-mutated advanced breast cancer: A meta-analysis and systematic review

Sun¹,

Wang²,

Zhang³

et al. 2021

The Breast

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Objective This meta-analysis aimed to investigate the efficacy and safety of poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors in BRCA- mutated advanced breast cancer patients comprehensively. Methods We conducted a systematic literature research through PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, China National Knowledge Infrastructure (CNKI), wanfang, China Biology Medicine disc (CBMdisc), and ClinicalTrials.gov from inception to January 2021. Randomized controlled trials (RCTs) with available data comparing PARP inhibitors versus control therapy in BRCA -mutated advanced breast cancer were eligible for analysis. Statistical analyses were performed with Review Manager (RevMan) version 5.4 and R version 4.0.3. Results 1706 studies were retrieved in total, and 4 RCTs with 1540 patients were eligible for meta-analysis finally. The results showed that progression-free survival (PFS) and overall survival (OS) were significantly improved in germline BRCA -mutated breast cancer patients with PARP inhibitors (HR 0.64, 95% CI [0.56–0.74]; HR 0.86, 95% CI [0.74–0.99], respectively) with no significant heterogeneity across studies (I 2 = 22%, χ 2 p = 0.28; I 2 = 0%, χ 2 p = 0.70, respectively). There was no significant difference in the overall adverse events (AEs), grade≥3 AEs and AEs leading to treatment discontinuation between PARP inhibitor arms and control arms (RR 1.01, 95% CI [0.99–1.02]; RR 0.95, 95% CI [0.83–1.09]; RR 1.17, 95% CI [0.87–1.57], respectively). Based on the available data, PARP inhibitors provided comparable or better results than control arms in improving the quality of life in BRCA -mutated advanced breast cancer patients. Conclusions PARP inhibitors prolonged PFS and OS among patients with BRCA -mutated advanced breast cancer with tolerable safety and improved quality of life.

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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

Cited by 169 publications

References 46 publications

Stevens-Johnson syndrome/toxic epidermal necrolysis in patients treated with immune checkpoint inhibitors: A safety analysis of clinical trials and FDA pharmacovigilance database

Stevens-Johnson syndrome/toxic epidermal necrolysis in patients treated with immune checkpoint inhibitors: A safety analysis of clinical trials and FDA pharmacovigilance database

Therapy-Related Myeloid Neoplasms in 109 Patients Following Radiation Monotherapy

Efficacy and safety of PARP inhibitors in patients with BRCA-mutated advanced breast cancer: A meta-analysis and systematic review

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