TY - JOUR
T1 - Use of granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with hydroxyurea as post-transplant therapy in chronic myelogenous leukemia patients autografted with unmanipulated hematopoietic cells
AU - Carlo-Stella, Carmelo
AU - Regazzi, Ester
AU - Andrizzi, Cristina
AU - Savoldo, Barbara
AU - Garau, Daniela
AU - Montefusco, Enrico
AU - Vignetti, Marco
AU - Mandelli, Franco
AU - Rizzoli, Vittorio
AU - Meloni, Giovanna
PY - 1997/5
Y1 - 1997/5
N2 - Background and Objective. Allogeneic bone marrow transplantation remains 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 transplantation (ASCT) in CML. It has been suggested that in the early phase following autografting the Ph-negative clone has a proliferative advantage over the Ph-positive clone. We hypothesized that post-transplant GM-CSF administration could reactivate the functional activity of quiescent normal progenitors and prolong the duration of the post-transplant proliferative advantage of Ph-negative over Ph- positive progenitors. In order to evaluate the effect of post-transplant GM- CSF administration, a pilot clinical study was performed in which CML patients resistant to IFN-α therapy were autografted with unmanipulated marrow or blood cells and given prolonged GM-CSF therapy post-transplant. Methods. Five adult CML patients conditioned with the BAVC regimen were reinfused with either marrow (n=2) or blood (n=3) cells and given granulocyte-macrophage colony-stimulating factor (GM-CSF). Recombinant GM- CSF was initially administered at standard dosage (5 pg/kg/day) until a white blood cell count ≤2x109/L was achieved on two consecutive examinations, and thereafter at a low dose (1 μg/kg/day) for 5 to 9 months. On a weekly basis, GM-CSF was discontinued and hydroxyurea (1,000 mg/d) was given for two days. Results. Evidence of trilineage engraftment was observed in all cases. At autografting, 3 out of the 5 patients revealed 8-9% Ph-negative metaphases. During the initial phase of hematopoietic regeneration, direct cytogenetic analysis revealed 81% and 100% Ph-negative metaphases in two cases; nonleukemic hematopoiesis progressively decreased and was no longer detectable at +9 months. One patient showed cyclic Ph-negative hematopoiesis that appeared 3 months following autografting and peaked at +4 and +8 months. The fourth patient showed a low percentage (20%) of Ph-negative metaphases 1 month after ASCT, followed by a significant expansion of nonleukemic hematopoiesis, which could be detected up to month +13. No evidence of Ph- negative hematopoiesis could be detected in one patient. Three patients are in chronic phase 28, 30 and 31 months after autografting, respectively, and two patients evolved into blast crisis. Interpretation and Conclusions. This pilot study demonstrates that combined GM-CSF and hydroxyurea therapy seems to be effective in inducing and/or prolonging a transient period of Ph- negative hematopoiesis. The late appearance of Ph-negative hematopoiesis detected in two patients suggests an antileukemic activity of the combined GM-CSF/hydroxyurea therapy rather than an antileukemic effect of the conditioning regimen.
AB - Background and Objective. Allogeneic bone marrow transplantation remains 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 transplantation (ASCT) in CML. It has been suggested that in the early phase following autografting the Ph-negative clone has a proliferative advantage over the Ph-positive clone. We hypothesized that post-transplant GM-CSF administration could reactivate the functional activity of quiescent normal progenitors and prolong the duration of the post-transplant proliferative advantage of Ph-negative over Ph- positive progenitors. In order to evaluate the effect of post-transplant GM- CSF administration, a pilot clinical study was performed in which CML patients resistant to IFN-α therapy were autografted with unmanipulated marrow or blood cells and given prolonged GM-CSF therapy post-transplant. Methods. Five adult CML patients conditioned with the BAVC regimen were reinfused with either marrow (n=2) or blood (n=3) cells and given granulocyte-macrophage colony-stimulating factor (GM-CSF). Recombinant GM- CSF was initially administered at standard dosage (5 pg/kg/day) until a white blood cell count ≤2x109/L was achieved on two consecutive examinations, and thereafter at a low dose (1 μg/kg/day) for 5 to 9 months. On a weekly basis, GM-CSF was discontinued and hydroxyurea (1,000 mg/d) was given for two days. Results. Evidence of trilineage engraftment was observed in all cases. At autografting, 3 out of the 5 patients revealed 8-9% Ph-negative metaphases. During the initial phase of hematopoietic regeneration, direct cytogenetic analysis revealed 81% and 100% Ph-negative metaphases in two cases; nonleukemic hematopoiesis progressively decreased and was no longer detectable at +9 months. One patient showed cyclic Ph-negative hematopoiesis that appeared 3 months following autografting and peaked at +4 and +8 months. The fourth patient showed a low percentage (20%) of Ph-negative metaphases 1 month after ASCT, followed by a significant expansion of nonleukemic hematopoiesis, which could be detected up to month +13. No evidence of Ph- negative hematopoiesis could be detected in one patient. Three patients are in chronic phase 28, 30 and 31 months after autografting, respectively, and two patients evolved into blast crisis. Interpretation and Conclusions. This pilot study demonstrates that combined GM-CSF and hydroxyurea therapy seems to be effective in inducing and/or prolonging a transient period of Ph- negative hematopoiesis. The late appearance of Ph-negative hematopoiesis detected in two patients suggests an antileukemic activity of the combined GM-CSF/hydroxyurea therapy rather than an antileukemic effect of the conditioning regimen.
KW - Autologous stem cell transplantation
KW - Chronic myelogenous leukemia
KW - Granulocyte-macrophage colony-stimulating factor
KW - Hydroxyurea
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M3 - Article
C2 - 9234574
AN - SCOPUS:18844464721
VL - 82
SP - 291
EP - 296
JO - Haematologica
JF - Haematologica
SN - 0390-6078
IS - 3
ER -