USE OF GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR (GM-CSF) IN COMBINATION WITH HYDROXYUREA AS POSTTRANSPLANT THERAPY IN CHRONIC MYELOGENOUS LEUKEMIA PATIENTS AUTOGRAFTED WITH UNMANIPULATED HEMATOPOIETIC-CELLS

Background and Objective. Allogeneic bone marrow transplantation remai ns the only potentially curative treatment for CML, but more than 70% of patients will be ineligible for allogeneic marrow transplant either because they do not have a suitable HLA-matched related or unrelated donor or because they are more than 50 years old. Several experimental and clinical findings support a role for autologous stem cell transpl antation (ASCT) in CML. It has been suggested that in the early phase following autografting the Ph-negative clone has a proliferative advan tage over the Ph-positive clone. We hypothesized that post-transplant GM-CSF administration could reactivate the functional activity of quie scent normal progenitors and prolong the duration of the post-transpla nt proliferative advantage of Ph-negative over Ph-positive progenitors . In order to evaluate the effect of post-transplant GM-CSF administra tion, a pilot clinical study was performed in which CML patients resis tant to IFN-alpha therapy were autografted with unmanipulated marrow o r blood cells and given prolonged GM-CSF therapy post-transplant. Meth ods. Five adult CML patients conditioned with the BAVC regimen were re infused with either marrow (n=2) or blood (n=3) cells and given granul ocyte-macrophage colony-stimulating factor (GM-CSF). Recombinant GM-CS F was initially administered at standard dosage (5 mu g/kg/day) until a white blood cell count greater than or equal to 2x10(9)/L was achiev ed on two consecutive examinations, and thereafter at a low dose (1 mu g/kg/day) for 5 to 9 months. On a weekly basis, GM-CSF was discontinu ed and hydroxyurea (1,000 mg/d) was given for two days. Results. Evide nce of trilineage engraftment was observed in all cases. At autografti ng, 3 out of the 5 patients revealed 8-9% Ph-negative metaphases. Duri ng the initial phase of hematopoietic regeneration,direct cytogenetic analysis revealed 81% and 100% Ph-negative metaphases in two cases; no nleukemic hematopoiesis progressively decreased and was no longer dete ctable at +9 months. One patient showed cyclic Ph-negative hematopoies is that appeared 3 months following autografting and peaked at +4 and +8 months. The fourth patient showed a low percentage (20%) of Ph-nega tive metaphases 1 month after ASCT, followed by a significant expansio n of nonleukemic hematopoiesis, which could be detected up to month +1 3. No evidence of Ph-negative hematopoiesis could be detected in one p atient. Three patients are in chronic phase 28, 30 and 31 months after autografting, respectively, and two patients evolved into blast crisi s. Interpretation and Conclusions. This pilot study demonstrates that combined GM-CSF and hydroxyurea therapy seems to be effective in induc ing and/or prolonging a transient period of Ph-negative hematopoiesis. The late appearance of Ph-negative hematopoiesis detected in two pati ents suggests an antileukemic activity of the combined GM-CSF/hydroxyu rea therapy rather than an antileukemic effect of the conditioning reg imen. (C) 1997, Ferrata Storti Foundation.