{"entity":{"id":"rejuv-second-platinum-and-parp-inhibitors","kind":"term","name":"Platinum drugs and PARP inhibitors: the newer leukaemia risk","aka":["PARP inhibitor MDS risk","Platinum-related myeloid neoplasm","Lenalidomide second primary malignancy"],"tldr":"The leukaemia risk after chemotherapy was described in the era of mustards and etoposide, and it did not stay there. Platinum drugs carry it, PARP inhibitors raise it about two and a half times against placebo, and lenalidomide with oral melphalan raises it nearly fivefold against melphalan alone. The absolute numbers are small, but the choice of partner drug is sometimes a real decision.","summary":"What is done about it. For PARP inhibitors, a blood count before and during treatment and investigation of a cytopenia that does not resolve. For myeloma, the finding below changed practice: an alkylator-free partner, or cyclophosphamide instead of oral melphalan, alongside lenalidomide. These are decisions made with the treating team, and the record on choices made at treatment sets out the rest.\n\nPlatinum drugs. The SEER analysis of 700,612 adults treated for a first solid cancer between 2000 and 2013 found that use of known leukaemogenic agents in initial chemotherapy \"increased substantially since 2000, most notably for gastrointestinal tract cancers (esophagus, stomach, colon, and rectum; 10% in 2000-2001 to 81% during 2012-2013)\", driven by platinum compounds. The same analysis found newly emerging raised risks of therapy-related myeloid neoplasm in people treated since 2000 for oesophageal, cervical, prostate and possibly anal cancer, and since the 1990s for bone and joint and endometrial cancer. The second cancer risk of a chemotherapy era is measured a decade after that era begins, which is why the modern figures keep moving.\n\nPARP inhibitors. A meta-analysis pooled 18 placebo-controlled randomised trials covering 7,307 patients. PARP inhibitors raised the risk of myelodysplastic syndrome or acute myeloid leukaemia against placebo, with a Peto odds ratio of 2.63 (95% CI 1.13 to 6.14, p = 0.026) and no heterogeneity between studies. The absolute incidence was 0.73 per cent (0.50 to 1.07; 21 events in 4,533 patients) in the PARP inhibitor groups and 0.47 per cent (0.26 to 0.85; three events in 2,774 patients) in the placebo groups. In the WHO pharmacovigilance database, 178 reported cases were found, 99 of myelodysplastic syndrome and 79 of acute myeloid leukaemia; median treatment duration was 9.8 months (IQR 3.6 to 17.4) and median latency from first exposure 17.8 months (8.4 to 29.2). Of 104 cases reporting an outcome, 47 (45 per cent) ended in death. Most of those patients had already had platinum chemotherapy, so the meta-analysis measures the risk of adding a PARP inhibitor on top of it rather than the risk of the drug alone.\n\nLenalidomide, and the partner drug. An individual-patient meta-analysis of seven randomised trials in newly diagnosed myeloma covered 3,218 treated patients, 2,620 who received lenalidomide and 598 who did not. The cumulative incidence of any second primary malignancy at five years was 6.9 per cent (5.3 to 8.5) with lenalidomide and 4.8 per cent (2.0 to 7.6) without (hazard ratio 1.55, 1.03 to 2.34, p = 0.037). Split by type, the solid second cancers were not different (3.8 against 3.4 per cent, HR 1.1, 0.62 to 2.00, p = 0.72); the haematological ones were (3.1 per cent, 1.9 to 4.3, against 1.4 per cent, 0.0 to 3.6; HR 3.8, 1.15 to 12.62, p = 0.029). The finding that mattered was which combination carried it: lenalidomide with oral melphalan raised haematological second cancer risk against melphalan alone with a hazard ratio of 4.86 (2.79 to 8.46, p < 0.0001), while lenalidomide with cyclophosphamide (HR 1.26, 0.30 to 5.38) and lenalidomide with dexamethasone (HR 0.86, 0.33 to 2.24) did not. The authors' conclusion was that alternatives such as cyclophosphamide, or alkylator-free combinations, should be considered instead of oral melphalan alongside lenalidomide.\n\nWhat is not known. Whether the immunotherapies and antibody-drug conjugates now in first-line use carry any such risk is not yet measurable, because the latency is longer than their time in practice. A reader who is told that a new drug has no second cancer risk should know that the usual reason is that nobody has been followed long enough to see one.","asOf":"2026-10-02","wikipedia":"https://en.wikipedia.org/wiki/PARP_inhibitor","links":[{"label":"Morice et al., 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)","url":"https://doi.org/10.1016/S2352-3026(20)30360-4"},{"label":"Palumbo et al., Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: a meta-analysis of individual patient data (Lancet Oncol 2014)","url":"https://doi.org/10.1016/S1470-2045(13)70609-0"},{"label":"Morton et al., Association of chemotherapy for solid tumors with development of therapy-related myelodysplastic syndrome or acute myeloid leukemia in the modern era (JAMA Oncol 2019)","url":"https://doi.org/10.1001/jamaoncol.2018.5625"},{"label":"Morton et al., Evolving risk of therapy-related acute myeloid leukemia following cancer chemotherapy among adults in the United States, 1975 to 2008 (Blood 2013)","url":"https://doi.org/10.1182/blood-2012-08-448068"}],"tags":["rejuvenation","survivorship","second-cancers","blood","targeted-therapy"],"related":["rejuv-second-cancers-overview","rejuv-second-alkylating-agents-and-myeloid-neoplasms","rejuv-second-choices-made-at-treatment"],"cancers":["ovarian","multiple-myeloma","aml","mds","colorectal","esophageal"],"sections":["rejuvenation","supportive-care"],"technologies":["survivorship-care-plan"],"targets":[],"drugs":["cisplatin","carboplatin","olaparib","niraparib","lenalidomide","melphalan","cyclophosphamide"],"companies":[],"institutions":[],"pathways":[],"terms":["secondary-malignancy","late-effects"],"trials":[],"people":[],"bottlenecks":["b-toxicity-qol","b-survivorship"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"category":"Side effects"},"route":"/terms/rejuv-second-platinum-and-parp-inhibitors/","neighbours":{"term":[{"id":"rejuv-second-alkylating-agents-and-myeloid-neoplasms","kind":"term","name":"Alkylating agents and therapy-related myeloid neoplasms","route":"/terms/rejuv-second-alkylating-agents-and-myeloid-neoplasms/"},{"id":"rejuv-second-choices-made-at-treatment","kind":"term","name":"Choices made at the time of treatment that change the second cancer risk","route":"/terms/rejuv-second-choices-made-at-treatment/"},{"id":"late-effects","kind":"term","name":"Late effects and survivorship toxicity","route":"/terms/late-effects/"},{"id":"rejuv-second-cancers-overview","kind":"term","name":"Second cancers after treatment: what the risk is, and what is done about it","route":"/terms/rejuv-second-cancers-overview/"},{"id":"secondary-malignancy","kind":"term","name":"Secondary malignancy (therapy-related cancer)","route":"/terms/secondary-malignancy/"}],"cancer":[{"id":"aml","kind":"cancer","name":"Acute myeloid leukaemia","route":"/cancers/aml/"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"multiple-myeloma","kind":"cancer","name":"Multiple myeloma","route":"/cancers/multiple-myeloma/"},{"id":"mds","kind":"cancer","name":"Myelodysplastic syndromes / neoplasms (MDS)","route":"/cancers/mds/"},{"id":"esophageal","kind":"cancer","name":"Oesophageal cancer","route":"/cancers/esophageal/"},{"id":"ovarian","kind":"cancer","name":"Ovarian cancer","route":"/cancers/ovarian/"}],"section":[{"id":"rejuvenation","kind":"section","name":"Recovery & Rejuvenation","route":"/fronts/rejuvenation/"},{"id":"supportive-care","kind":"section","name":"Supportive Care & Survivorship","route":"/fronts/supportive-care/"}],"technology":[{"id":"survivorship-care-plan","kind":"technology","name":"Survivorship care and late-effects surveillance","route":"/technologies/survivorship-care-plan/"}],"drug":[{"id":"carboplatin","kind":"drug","name":"Carboplatin","route":"/drugs/carboplatin/"},{"id":"cisplatin","kind":"drug","name":"Cisplatin","route":"/drugs/cisplatin/"},{"id":"cyclophosphamide","kind":"drug","name":"Cyclophosphamide","route":"/drugs/cyclophosphamide/"},{"id":"lenalidomide","kind":"drug","name":"Lenalidomide","route":"/drugs/lenalidomide/"},{"id":"melphalan","kind":"drug","name":"Melphalan (including hepatic delivery system)","route":"/drugs/melphalan/"},{"id":"niraparib","kind":"drug","name":"Niraparib","route":"/drugs/niraparib/"},{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"}],"bottleneck":[{"id":"b-survivorship","kind":"bottleneck","name":"Survivorship and late effects are neglected","route":"/bottlenecks/b-survivorship/"},{"id":"rejuv-agenda-latency-outruns-the-evidence","kind":"bottleneck","name":"The newest treatments have not existed long enough for their late effects to appear","route":"/bottlenecks/rejuv-agenda-latency-outruns-the-evidence/"},{"id":"b-toxicity-qol","kind":"bottleneck","name":"Toxicity and quality of life are undervalued","route":"/bottlenecks/b-toxicity-qol/"}],"idea":[{"id":"idea-rejuv-second-cancer-latency-cohort-for-new-drugs","kind":"idea","name":"Enrol every new systemic therapy into a registry linkage that will still report in thirty years","route":"/ideas/idea-rejuv-second-cancer-latency-cohort-for-new-drugs/"}]}}