RISK FACTORS FOR RAPAMYCIN-INDUCED THROMBOCYTOPENIA AND LEUKOPENIA IN RENAL TRANSPLANT RECIPIENTS

Abstract

233 Purpose: This study sought to assess the risk factors that predispose patients treated with rapamycin (RAPA) to drug-induced thrombocytopenia and leukopenia. Methods: The present data set of 184 renal transplant recipients followed for at least 1 year includes 119 patients treated with RAPA and 65 demographically similar recipients without RAPA. All patients were treated with a consistent concentration-controlled regimen of cyclosporine (CsA) and tapering doses of prednisone. Thrombocytopenia was defined as platelet count <150 × 103 cell/mm3; leukopenia, as white blood cell count <5,000/mm3. An analysis of variance compared serial trough concentrations of RAPA (C0) with the incidence, persistence, and severity of drug-induced adverse effects, expressed as the percentage change from baseline values. Results: The mean pretransplant platelet count was 280 × 103 cell/mm3 (SD ± 79.6); the white blood cell count, 12,000/mm3 (SD ± 560). Neither the ethnic background (Caucasian vs. African-American) nor the pretransplant CMV serologic status correlated with either the incidence or the severity of post-transplant thrombocytopenia or leukopenia. However, the McNemar test indicated a significant correlation between the occurrences of the two adverse effects (p=0.001). Despite continuous RAPA treatment, the overall incidence of thrombocytopenia decreased from 63% at week 1 to 23% at week 7, remaining constant at this level over 12 months. The incidence but not the degree of thrombocytopenia was highest during the first 5 weeks (p=0.004) of treatment, and correlated with RAPA concentrations ≥16 ng/ml (p=0.0001). The Relative Risk of occurrence increased by 1.59 as C0 values increased from <5 ng/ml to 5-10 ng/ml, an additional 1.59 to 11-15 ng/ml from 5-10 ng/ml, an additional 1.59 to 16-20 ng/ml, and an additional 1.59 to ≥21 ng/ml. The incidence of leukopenia showed a similar association with RAPA C0 (p=0.0001) particularly at levels ≥16 ng/ml. There was a 1.72 relative risk over each step in the range of drug concentrations described above. However, no association was shown between drug concentrations and either the duration or the severity of leukopenia. Although the rates of thrombocytopenia or leukopenia are concentration-dependent, these adverse effects resolved spontaneously in about 65% of cases. Among the other 35%, 22% of patients required dose reduction, only 12% required temporary suspension, and none required permanent cessation of RAPA therapy. The CsA average concentration, namely, the quotient of area under the concentration curve and the time interval (in hours), showed no relation to the occurrence or degree of thrombocytopenia and/or leukopenia. Conclusion: Thrombocytopenia and leukopenia, not-infrequent adverse reactions to RAPA therapy, generally resolve spontaneously, without modification of the drug dose.