Haploidentical Allogeneic Hematopoietic Cell Transplantation in Adults Using Reduced Intensity Conditioning and CD3/CD19-Depleted Grafts: Interim Analysis of a Phase I/II Study.

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 high treatment related mortality (TRM). A new regimen using reduced intensity conditioning (RIC) and immunomagnetic CD3/CD19 graft depletion may allow HHCT with lower toxicity and faster engraftment. CD3/CD19 depleted grafts not only contain CD34+ stem cells but also graft-facilitating cells, CD34- progenitors, dendritic and natural killer cells which may allow stable engraftment even without a megadose of CD34+ cells.

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 CD3/CD19 graft depletion has been initiated. No post grafting immunosuppression was applied if the graft contained <5x10⁴ CD3+ cells/kg.

To date, 51 patients with a median age of 45 years (range, 19–65) have been enrolled in this study. Diagnosis were AML (n=34), ALL (n=7), NHL (n=6), MM (n=2), and CML (n=2). Patients were “high risk” because of relapsed or refractory disease (n=30), or relapse after preceding HCT (auto=7, allo=14). Stage at HCT was complete remission (n=25) and partial remission (n=26). The CD3/CD19 depleted haploidentical grafts contained a median of 7.1 x 10⁶ (range, 3.4–18x10⁶) CD34+cells/kg, 3.9 x10⁴ (range, 0.6–44x10⁴) CD3+T cells/kg and 2.8x10⁷ (range, 0.02–37.3x10⁷) CD56+cells/kg. The regimen was well tolerated with maximum acute toxicity being CTC-grade 1–2 mucositis. Five cases of reversible peripheral neuropathy and three cases of progressive multifocal leukencephalopathy (PML) occurred posttransplant in heavily pretreated patients. Engraftment was rapid with median time to >500 granulocytes/μL of 12 days (range, 9–50) and to >20000 platelets/μL of 11 days (range, 7–38). Full donor chimerism was reached after 2–4 weeks in all but four patients (median of 14 days (range, 7–215)). Four patients experienced rejection/non-engraftment, two were rescued by a second CD3/CD19 depleted graft from another haploidentical donor. Incidence of grade II-IV acute GVHD was 51% with grade II=16, III=6 and IV=4. So far there are six cases of limited chronic GVHD and one case of extensive chronic GVHD. TRM in the first 100 days was 11/51 (22%) and overall 20/51 (39%). Overall survival is 17/51 patients (33%) with deaths due to relapse (n=14), infection (n=15), PML (n=2), GVHD (n=2) and cardiac failure (n=1), with a median follow-up of alive patients of 397 days (range, 62–1180). This results in a Kaplan-Meier estimate 1-year survival of 37%. So far, we did not observe a statistical significant survival advantage for patient transplanted from a KIR-mismatched donor (28/51 patients).

This regimen with low toxicity as well as fast and sustained engraftment is promising in high risk patients lacking a suitable donor. To investigate the treatment protocol earlier in course of disease a new study for high-risk patients with acute leukemia in first complete remission is in preparation.