Pentostatin based non-myeloablative conditioning regimen in patients with high-risk hematologic malignancy
Genetic Association Studies
Translational Medical Research
Pentostatin is one of several purine analogs with significant immunosuppressive activity in addition to efficacy in hématologie malignancies. In a phase 1/11 evaluation escalating doses of Pentostatin (2mg/m2 x 3-5 days), ARA-C (2gm/m2 x 4 days) and Mitoxantrone ( 12mg/m2 x 3days) were administered as a conditioning regimen prior to allô BMT. Peripheral blood stem cells from matched sibling donors were mobilized with GCSF 5mcg/kg and GMCSF 250mcg/m2 and infused on Day 0. GVHD prophylaxis included CSA 1.5mg/kg BID and short course MTX. Donor cell engraftment was assessed by microsatellite assays on peripheral blood T-lymphocytes and by cytogenetic evaluation in sex mismatched cases. T-cell and B-cell subsets were done at baseline and at regular intervals post transplant. To date 5 patients at high risk for standard allo BMT are évaluable for toxicity, recovery and engraftment. Diagnosis include CML(l), Aplastic Anemia(l), Myelofibrosis(l), AML(l) and Hodgkin's disease( 1 ). Patients were all females; median age 49; range 34-61. The reasons for non-myeloablative regimen included: age> 55(2), PS < ECOG(2) and EF < 40( 1 ). Nonhematalogic toxicity was generally mild and included nausea, vomiting, diarrhea, hepatic dysfunction and mucositis. Reversible grade III toxicity was seen in 2 patients; isolated hyperbilirubiema( 1 ) and mucositis( 1 ). AH patients experienced grade IV myelosuppression. One patient expired on Day 15 due to progression of disease and septicemia. Hématologie recovery was documented in the other four patients. No patients have developed acute GVHD. Preliminary results of T-cell subsets demonstrate low CDS counts out of proportion to CD4. T-cell subsets upon initial recovery revealed CDS % between 9 and 23, and absolute CDS numbers between 37 and 457. CD4 % ranged between 51 and 85 percent. CD4/CD8 ratios ranged from 2.2 to 9.4. Day 30 engraftment data of donor cells is so far available for two patients and demonstrated 10% donor cells in the patient with CML and 80% in the patient with myelofibrosis. These preliminary results demonstrate that a Pentostatin based nonmyeloablative conditioning regimen results in allogeneic stem cell engraftment in patients with high-risk hématologie disease including patients with severe myelofibrosis and heavily transfused aplastic anemia. T-cell subsets in patients post transplant demonstrated CD4 suppression as well as significant CDS depression suggesting a pattern of immunosuppression associated with pentostatin that may be different than that seen with other purine analogs and TBI non-myeloablative conditioning regimens. This provides rationale for the use of this regimen in conjunction with partially matched related donor or MUD transplants.