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Autologous Stem Cell Transplantation: Sequential Production of Hematopoietic Cytokines Underlying Granulocyte Recovery¹

Departments of Gynecology and Obstetrics [G. B., G. S., P. B., S. M.], and Semeiotic Medicine [G. M., L. P., M. L. F., B. B.], Catholic University, 00168 Rome, Italy; Department of Hematology-Oncology, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy [U. T., R. M., C. P.]; and Thomas Jefferson University, Philadelphia, Pennsylvania 19107 [C. P.]

We investigated the serum concentrations of a variety of cytokines [granulocyte-macrophage-colony-stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), interleukin (IL) 1, IL-3, IL-6, IL-8, erythropoietin, tumor necrosis factor , -interferon in 10 patients with advanced ovarian cancer undergoing autologous peripheral blood stem cell (PBSC) harvesting followed by treatment with high-dose cisplatin, etoposide, and carboplatin and PBSC transplantation (chemotherapy was administered on days 1 through 3, PBSCT on day 6). Preliminary observations on cytokine serum levels were performed for 4 patients; on this basis, the kinetics of cytokines was then investigated in greater detail at closely sequential times in 6 further patients.

We observed a consistent pattern of sequential GM-CSF, G-CSF, and IL-8 release after chemotherapy/PBSCT in all 10 cases, including the 6 patients monitored in detail: (a) at days 5–10 a GM-CSF peak; (b) at days 12–14 a pronounced release of both G-CSF and IL-8, which always preceded granulocyte recovery by 7 days. At days 17–23, a second GM-CSF peak was monitored in 5 of the 6 patients analyzed in detail, as well as in the other 4 cases. Particularly relevant are the observations that: (a) the peak of G-CSF serum concentration and neutrophil number in the recovery phase are strikingly and directly correlated, thus indicating a key role for G-CSF in granulocyte rescue; (b) the time courses of G-CSF and IL-8 levels are strictly parallel, thereby suggesting a coordinate stimulus for production of granulocytes, mediated by G-CSF, and their activation/migration capacity, mediated by IL-8.

Results were essentially negative for IL-3, tumor necrosis factor , and -interferon concentrations (except in one case for each cytokine). An early peak of IL-1 was observed in all 3 analyzed patients, while an IL-6 peak was monitored at days 13–15 in all 4 patients analyzed in detail.

The present results indicate a sequential coordinate pattern of cytokine release after ablative therapy and PBSCT and shed light on the mechanisms mediating the recovery of granulocytes, and more generally of hematopoiesis, after stem cell transplantation. Furthermore, these studies may contribute to the design of improved protocols for cytokine administration following myelosuppressive anticancer therapy, as well as to the prediction of granulocytic response.

¹ This work was supported by the "Terepia dei Tumori" Program, Intituto Superiore di Sauità, Rouse and "Pzogetto Finalizzato Applicazioni Cliniche della Ricerca Oncologica" (Grants g2. 02344.PF 3g and g2. 02363. PF3g to C. P. and U. T., respectively).

² To whom requests for reprints should be addressed.

Received 9/ 3/92. Accepted 1/11/93.

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