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.
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 one patient. Three patients are in chronic phase 28, 30 and 31 months after autografting, respectively, and two patients evolved into blast crisis.


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.
Carlo-Stella
C
C
Dipartimento di Ematologia, Università di Parma, Italy.
Regazzi
E
E
Andrizzi
C
C
Savoldo
B
B
Garau
D
D
Montefusco
E
E
Vignetti
M
M
Mandelli
F
F
Rizzoli
V
V
Meloni
G
G
D000328:Adult; D000677:Amsacrine / Q000008:administration & dosage; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D002330:Carmustine / Q000008:administration & dosage; D019070:Cell Lineage; D003131:Combined Modality Therapy; D003561:Cytarabine / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006085:Graft Survival / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology / Q000627:therapeutic use*; D006410:Hematopoiesis / Q000187:drug effects; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use*; D016898:Interferon-alpha / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000628:therapy*; D008297:Male; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010865:Pilot Projects; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D016879:Salvage Therapy; D016019:Survival Analysis; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D016896:Treatment Outcome
D018906:Antineoplastic Agents, Alkylating; D016898:Interferon-alpha; D011994:Recombinant Proteins; D000677:Amsacrine; D003561:Cytarabine; D005047:Etoposide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002330:Carmustine; D006918:Hydroxyurea