135: A Two Step Approach to Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for High Risk Patients with Hematologic Disorders (2008)

Post transplant cyclophosphamide (CTX) has been utilized to induce donor host tolerance in allogeneic HSCT. While promising, the long term risk of MDS and AML from exposure of the graft to CTX is unknown, and the optimal T cell dose to deliver using this approach remains undefined. To address these issues, 12 high-risk patients underwent haploidentical HSCT from related donors for disorders of hematopoiesis using a two step approach. Nine of 12 (75%) patients had evidence of disease at the time of HSCT. In the GVH direction, 10 of 12 were 4/8 matches with their donors at HLA-A, B, C and DRB1; the other 2 patients were 5/8 and 6/8 matches. Nine of the 12 patients were given a myeloablative conditioning regimen of TBI (1.5 Gy) BID on days -9 through -6. Three received a nonmyeloablative conditioning regimen of fludarabine and ARA-C on days-11 through -8 and one 2 Gy fraction of TBI on day -6. The patients received 2 × 108/kg of their donor's CD3+ lymphocytes after completion of TBI on day -6, followed by rest days on day -5 and -4. On days -3 and -2, CTX was given at a dose of 60 mg/kg/day for the purpose of tolerization of the donor lymphocytes. On day 0, donor CD34+ cells were infused. When possible, the number of non-tolerized T-cells in the CD34+ product was limited to 5 × 104/kg. Tacrolimus and CellCept were used as GVHD prophylaxis. All of the patients developed fevers between DLI and CTX. Some patients also developed mild diarrhea and a rash, which in one case was biopsy-positive for GVHD. All patients engrafted. GVHD was generally mild, and easily controlled with corticosteroids which could be rapidly tapered in all but one patient. Five patients have died, three of relapsed disease and two of infections. An additional patient is alive, but with relapsed disease. Six patients are well and in CR at a range of 19–298 days post HSCT. CD4+ recovery appears to occur at a pace comparable to that of matched-sibling HSCT recipients. This 2 step procedure promotes the establishment of donor-recipient tolerance by in vivo CTX exposure, but avoids any effects of G-CSF on donor lymphocytes, allows delivery of a precise dose of T cells to all patients, and eliminates CTX exposure of the hematopoietic precursors. Patients who lack matched-sibling donors can be successfully transplanted on this protocol with little significant GVHD. Infection and relapse remain problems, but likely can be reduced through transplantation of patients earlier in their disease course.Tabled 1Patient DataAgeDiseaseHSCT TypeDLI Dose/kg ×108CD 34 Dose/kg ×106T Cells/kg in CD34 Product ×104GVHD GradeOutcome19AML - PIFMyeloablative2.01.410.260Died-Relapse @ d + 6755CML & AML - PIFMyeloablative2.03.625.0INED @ d + 29826ALL - CR2Myeloablative2.02.166.9IINED @ d + 22144AML - CR2Myeloablative1.83.834.4IINED @ d + 18632SAAMyeloablative2.01.720.13IIIDied-Infection @ d + 10159AML - Resist Relapse 1Myeloablative2.04.110.390Died-Relapse @ d + 9160Biph Leuk - Resist Relapse 1Myeloablative2.02.740.82IDied-Infection @ d + 4248AML-PIFMyeloablative2.04.570.29INED @ d + 5358AML-CR2Myeloablative2.03.040.270NED @ d + 4667AML-PIFNon-myeloablative2.04.334.5IIAlive @ d + 166-Relapse73AML-PIFNon-myeloablative2.04.380.0590Died-Relapse @ d + 5536AML-Relapse post Match Sib HSCTNon-myeloablative2.03.040.010NED @ d + 19 Open table in a new tab