Haploidentical Allogeneic Hematopoietic Cell Transplantation in Adults with CD3/CD19-Depleted Grafts after Reduced-Intensity Conditioning: A Phase I/II Study.

Introduction: Haploidentical hematopoietic cell transplantation (HHCT) after high dose conditioning with a megadose of CD34-selected stem cells has been complicated by regimen related toxicities, slow engraftment and delayed immune reconstitution leading to a high treatment related mortality (TRM). A new regimen using graft CD3/CD19 depletion and reduced intensity conditioning (RIC) may allow HHCT with lower toxicity and faster engraftment. CD3/CD19 depleted grafts not only contain CD34+ stem cells but also CD34 negative progenitors, dendritic-, natural killer- and other graft-facilitating cells which may allow stable engraftment even without the use of a megadose of CD34+ cells.

Methods: A multicenter phase I/II study of HHCT using RIC with fludarabine (150–200 mg/m²), thiotepa (10 mg/kg), melphalan (120 mg/m²), OKT-3 (5 mg/day, day −5 to +14) and graft CD3/CD19 depletion with anti-CD3 and anti-CD19 coated microbeads on a CliniMACS device has been initiated. No post grafting immunosuppression was applied if the graft contained <5×10⁴ CD3+ cells/kg.

Results: To date, 36 patients (median age=46 [range, 21–65] years) have been enrolled in this study. Diagnosis were AML (n=20), ALL (n=7), NHL (n=3), MM (n=2), CML (n=2) and MCL (n=2). Patients were high risk with refractory disease or relapse after preceding HCT (auto=6, allo=12). The CD3/CD19 depleted haploidentical grafts contained a median of 7.5 × 10⁶ (range, 3.4–17×10⁶) CD34+cells/kg, 2.8×10⁴(range, 0.4–44×10⁴) CD3+T-cells/kg and 3.8×10⁷ (range, 0.02–37.3 x10⁷) CD56+cells/kg. Donor-recipient KIR-ligand-mismatch was found in 20 of 36 patients. The regimen was well tolerated with maximum acute toxicity being grade 2–3 mucositis. Five cases of reversible peripheral neuropathy and 3 cases of progressive multifocal leukencephalopathy (PML) occurred posttransplant in heavily pretreated patients. Engraftment was rapid with median time to >500 granulocytes/μL of 12 (range, 9–21) days, >20000 platelets/μL of 11 (range, 7–30) days and full donor chimerism after 2–4 weeks in all but one patient. Incidence of grade II-IV GVHD was 36% with grade II=9, III=2 and IV=2. TRM in the first 100 days was 10/36 (27%). Overall survival is 16/36 patients (44%) with deaths due to relapse (n=9), infection (n=9), GVHD (n=1) and PML (n=1) with a median follow-up of 194 days (range, 14–1271), resulting in a Kaplan-Meier 1 year survival estimate of 41%. We did not observe a statistical significant survival advantage for patient transplanted from a KIR-mismatched donor.

Conclusion: This regimen is promising in high risk patients lacking a suitable donor, and a prospective phase I/II study is ongoing.