title: Hematologic toxicities associated with mTOR inhibitors temsirolimus and everolimus in cancer patients: a systematic review and meta-analysis.
abstract: BACKGROUND
  Mammalian target of rapamycin (mTOR) inhibitors, temsirolimus and everolimus, are currently approved for the treatment of several malignancies. Hematological toxicities have been reported with these drugs, but overall incidence and relative risk remains undefined. We perform an up-to-date meta-analysis to determine the incidence and risk of hematologic toxicities associated with mTOR inhibitors.
  
  
  METHODS
  Several databases were searched, including PubMed, Embase and Cochrane databases. Eligible studies included prospective phase II and III trials of temsirolimus and everolimus with adequate safety data profile reporting anemia, leucopenia, neutropenia or thrombocytopenia. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated by using either random effects or fixed effects models according to the heterogeneity of included studies.
  
  
  RESULTS
  A total of 5436 patients with a variety of solid tumors from 26 clinical trials were included for the meta-analysis. The overall incidences of mTOR inhibitor associated all-grade and high-grade hematologic toxicities were, respectively: anemia--38.8% and 7.5%; leucopenia--19.6% and 1.8%; neutropenia--14.9% and 5.6%; thrombocytopenia--33.1% and 3.6%. Compared to placebo/control arms, mTOR inhibitors were associated with a significantly increased risk of all-grade (RR 2.05, 95% CI: 1.52-2.77; p < 0.001) and high-grade anemia (RR 1.57, 95% CI: 1.20-2.05; p = 0.001), all-grade (RR 6.03, 95% CI: 2.76-13.14; p < 0.001) and high-grade thrombocytopenia (RR 2.73, 95% CI: 1.87-3.99; p < 0.001). Additionally, a non-significantly increased risk of all-grade leucopenia (RR 1.46, 95% CI: 0.66-3.23; p = 0.34) and neutropenia (RR 1.77, 95% CI: 0.80-3.93; p = 0.16) was observed in the mTOR inhibitor group, while the risk of high-grade leucopenia (RR 0.53, 95% CI: 0.31-0.90, p = 0.019) and neutropenia (RR 0.96, 95% CI: 0.62-1.51; p = 0.87) did not increase. Similar results were also observed in sub-group analysis according to mTOR inhibitor based regimens.
  
  
  CONCLUSIONS
  The use of mTOR inhibitors is associated with a significant increase in the risk of developing all-grade and high-grade anemia and thrombocytopenia compared with placebo/control arms.
authors.affiliation: Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.forename: Deying
authors.initials: D
authors.lastname: Tian
mesh_terms: D000740:Anemia / Q000139:chemically induced / Q000453:epidemiology; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D000068338:Everolimus; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use; D015994:Incidence; D009369:Neoplasms / Q000188:drug therapy; D009503:Neutropenia / Q000139:chemically induced / Q000453:epidemiology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D012306:Risk; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013921:Thrombocytopenia / Q000139:chemically induced / Q000453:epidemiology
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; C401859:temsirolimus; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus