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

• Published in: Haematologica (Roma) 1997-05, Vol.82 (3), p.291-296
• Main Authors: Carlo-Stella, C, Regazzi, E, Andrizzi, C, Savoldo, B, Garau, D, Montefusco, E, Vignetti, M, Mandelli, F, Rizzoli, V, Meloni, G
• Format: Article
• Language: English
• Subjects: Adult; Amsacrine - administration & dosage; Antineoplastic agents; Antineoplastic Agents, Alkylating - therapeutic use; Antineoplastic Combined Chemotherapy Protocols; Biological and medical sciences; Carmustine - administration & dosage; Cell Lineage; Combined Modality Therapy; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); Cytarabine - administration & dosage; Drug Resistance, Neoplasm; Etoposide - administration & dosage; Female; Graft Survival - drug effects; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Granulocyte-Macrophage Colony-Stimulating Factor - therapeutic use; Hematopoiesis - drug effects; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - drug effects; Humans; Hydroxyurea - therapeutic use; Interferon-alpha - therapeutic use; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - therapy; Male; Medical sciences; Neoplastic Stem Cells - drug effects; Pharmacology. Drug treatments; Pilot Projects; Recombinant Proteins - pharmacology; Recombinant Proteins - therapeutic use; Salvage Therapy; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome
• ISSN: 0390-6078; 1592-8721

Dipartimento di Ematologia, Universita di Parma, Italy. 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-alpha 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 micrograms/kg/day) until a white blood cell count > or = 2 x 10(9)/L was achieved on two consecutive examinations, and thereafter at a low dose (1 microgram/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