Leukopenia following high-dose chemotherapy with autologous stem cell retransfusion in patients with testicular cell cancer
V. Nock (1, 2), A. Lindauer (3), U. Jaehde (3), C. Kloft (1)
(1) Martin-Luther-Universitaet Halle-Wittenberg, Dept. Clinical Pharmacy, Halle, Germany (2) Graduate Research Training program PharMetrX (3) University of Bonn, Dept. Clinical Pharmacy, Bonn, Germany
Objectives: Myelosuppression is one of the most important dose-limiting adverse events in many anticancer regimens. In a clinical study 19 patients received a combination therapy of carboplatin, etoposide and thiotepa/ifosfamid including stem cell reinfusion. The current data analysis describes the leukopenic effect in this regimen using PK/PD modelling.
Methods: Data from 17 patients receiving carboplatin, etoposid and thiotepa at doses up to 1500, 2400, 750 mg/m², respectively, and data from 2 patients receiving 10000 mg/m² ifosfamide instead of thiotepa were available for data analyses (drug and leukocyte concentrations) as well as additional data on stem cell reinfusion on day 7 for 18 IDs. Sampling resulted in a median of 25.9, 20.7, 18.5 and 4.4 data points for leukocytes, carboplatin, etoposide and thiotepa per patient, respectively. Leukocyte concentrations before therapy, at nadir as well as time to nadir and time until recovery to grade 1 leukopenia were investigated. Modelling and simulation activities were performed using NONMEMTM VI, statistical analyses using R 2.10.
Results: The median leukocyte count before therapy was 3.97x109 cells/L (range: 1.75-14.75x109 cells/L). Median nadir counts of 0.08 x109 cells/L (range 0.02-0.14x109 cells/L) were reached after 236 h (±39 h), reflecting a grade 4 leukopenia. Recovery to a leukocyte count above 3x109 cells/L was observed after a median time of 408 h (±75 h) for patients receiving stem cell retransfusion. In total a mean of 3.5x108 mononuclear cells (range 2.1x108- 3.2x1010), 2.9x106 CD34+ cells (range 0.10- 1.38x107) and 1.82x105 CFU-GM (range 31.0x-4.49x105) were retransfused. First modelling of the concentration-time profiles of the three drugs suggested disposition pharmacokinetic parameters in line with previous knowledge. The time course of leukocytes after nadir revealed a steep increase in concentration followed by a pronounced rebound after retransfusion of stem cells.
Conclusions: Due to the rich data situation and results from statistical analyses, individual drug concentration-time profiles will be generated. These results will be used in a sequential modelling approach to describe leukopenia with a semi-mechanistic model [1], including PK profiles and information about the stem cell retransfusions mentioned above.
References:
[1] LE Friberg et al. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol 20:4713-21 (2002).
[2] A Lindauer et al. Population pharmacokinetics of high-dose carboplatin in children and adults. Ther Drug Monit 2010 [Epub ahead of print].
