Phase I Study of Cladribine, Cytarabine (Ara-C), Granulocyte Colony Stimulating Factor (G-CSF) (CLAG Regimen) and Simultaneous Escalating Doses of Imatinib Mesylate (Gleevec) in Relapsed/Refractory AML
Background: Receptor activated tyrosine kinases like c-kit, c-fms and PDGFR are known targets of inhibition by imatinib mesylate (Gleevec) and are expressed on AML blasts. Marrow stromal cells and monocytes express the ligands KIT ligand, M-CSF and PDGF capable of activating survival pathways in the...
Saved in:
| Published in: | Blood Vol. 108; no. 11; p. 1958 |
|---|---|
| Main Authors: | , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
Elsevier Inc
16-11-2006
|
| Online Access: | Get full text |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | Background: Receptor activated tyrosine kinases like c-kit, c-fms and PDGFR are known targets of inhibition by imatinib mesylate (Gleevec) and are expressed on AML blasts. Marrow stromal cells and monocytes express the ligands KIT ligand, M-CSF and PDGF capable of activating survival pathways in these leukemic cells. Imatinib mesylate is a substrate of the multidrug resistance and ABC - transporters expressed in AML cells and displays a modest activity alone in AML in vitro and in vivo. Given the synergy in vitro between Ara-C and Gleevec on AML cell growth inhibtion, we initiated a Phase I study combining CLAG + Gleevec in AML patients.
Method: Patients with relapsed, refractory AML or CML myeloid blast crisis were eligible to receive Cladribine 5 mg/m2 Days 3–7, Cytarabine 2 gm/m2 Days 3–7, G-CSF 300 mcg Days 2–7, and escalating doses of imatinib mesylate given on Days 1–15. The level 1 Gleevec dose was 400 mg, while level 2 was 600 mg and the level 3 dose 800 mg. Patients were allowed to receive a second course of treatment if a CR was not attained after the first course, and were eligible for allogeneic stem cell transplantation (ASCT) if a donor was available.
Results: A total of 15 patients have been enrolled 14 AML and 1 CML blast crisis, 6 patients with relapse within 6 months following initial induction/consolidation, 5 patients relapsed within 6–12 months of therapy, 3 patients had refractory disease and 3 patients relapse following myeloablative ASCT. No dose limiting toxicity was reached. The dose escalation occured as planned and there was no clear evidence of added toxicity due to Gleevec. One patient with an extensive cardiac history died of cardiac causes on day 1 of therapy, no other deaths occured within 30 days of starting therapy. One patient had a grade 3 skin rash at level 2 and did not receive imatinib on the second induction therapy. None of the 15 patients treated have had a drug- related cause of death: the most common toxicities encountered during induction therapy were nausea, vomiting, ALT and AST increase, rash and diarrhea and were transient and/or reversible. There were two drug-nonrelated deaths one CNS bleed in a persistently thrombocytopenic patient after ANC recovery and ovelwhelming sepsis in another patient. Out of 14 evaluable patients 12 achieved a hypocellular marrow after initial induction with one additional patient achieving a hypocellular marrow following a second course of the same regimen. One patient had persistence of disease and was switched to another treatment. Out of the 12 evaluable patients 5 acheived a complete response (42%) with 4 of these patients achieving a complete cytogenetic response as well (33%). The relapse free interval ranged from 35 to 206 + days in evaluable patients. Imatinib mesylate (up to 800 mg) plus CLAG is a safe and well tolerated non anthracycline based salvage regimen in patients with relapsed/refractory AML. |
|---|---|
| ISSN: | 0006-4971 1528-0020 |
| DOI: | 10.1182/blood.V108.11.1958.1958 |