Thrombocytopenia after high-dose chemotherapy and autologous stem cell transplantation: an unresolved problem and possible approaches to resolve it.

Abstract

Prolonged thrombocytopenia is a frequent clinical problem in cancer patients undergoing high-dose chemotherapy and autologous transplantation. The use of GM-CSF as an adjuvant to autologous bone marrow transplantation (ABMT) has significantly reduced the duration of neutropenia after high-dose chemotherapy but failed to accelerate platelet recovery in transplanted patients. The more rapid hematopoietic reconstitution obtained by autologous mobilized peripheral blood progenitor cell transplantation (PBPCT) after high-dose chemotherapy has resulted in its increasing use instead of ABMT. However, PBPCT does not always produce faster platelet engraftment after high-dose chemotherapy, and persistent thrombocytopenia remains a significant clinical problem in PBPC-transplanted patients. The duration of severe thrombocytopenia (requiring frequent platelet transfusions) until platelet recovery varies widely depending on the quality of the autograft and previous radiotherapy or chemotherapy. The median days to reach 20,000/microliters platelets ranged from 10 to 32 days. Pilot clinical studies in which cancer patients were transplanted with enriched CD34+ cell autografts, obtained from G-CSF-mobilized PB, showed a similar platelet recovery after high-dose chemotherapy but also wide variation among the patients. The median days to reach 20,000/microliters platelets ranged from 9 to 38 days. The dose of CFU-GM in the autograft has been identified as the best predictive factor for hematopoietic recovery (p < 0.0001) after high-dose chemotherapy and autologous PBPCT in 118 patients with hematologic malignancies. A similar assessment of the megakaryocyte progenitor cells (BFU-MK and CFU-MK) in the autograft not only could predict time to platelet recovery but also could help to optimize the number and method of mobilization of the PBPC required to shorten the problematic obligatory 2-week duration of thrombocytopenia after high-dose chemotherapy. A routine assessment of the number of BFU-MK and CFU-MK present in each autograft and correlation with platelet recovery after transplantation would enable us to define the clinical threshold cell dose required for rapid platelet recovery. Recently, several non-specific cytokines with thrombopoietic activity have been evaluated in phase I clinical trials, including interleukin-1, interleukin-3 followed by GM-CSF, interleukin-6, and interleukin-11 in cancer patients, showing an encouraging trend toward a decrease in thrombocytopenia after chemotherapy. The recently cloned specific platelet cytokine, thrombopoietin, is currently undergoing phase I clinical studies, and the results are awaited with interest.