Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: An update

Haploidentical hematopoietic cell transplantation (HHCT) after high dose conditioning with CD34-selected stem cells has been complicated by high regimen related toxicities, slow engraftment and delayed immune reconstitution leading to increased treatment related mortality (TRM). A new regimen using reduced intensity conditioning (RIC) and graft CD3/CD19 depletion with anti-CD3 and anti-CD19 coated microbeads on a CliniMACS device may allow HHCT with lower toxicity and faster engraftment. CD3/CD19 depleted grafts not only contain CD34+ stem cells but also CD34 negative progenitors, natural killer, graft facilitating and dendritic cells. RIC was performed with fludarabine (150–200 mg/m2), thiotepa (10 mg/kg), melphalan (120 mg/m2) and OKT-3 (5 mg/day, day − 5 to + 14) and no posttransplant immunosuppression. Twenty nine patients (median age = 42 (range, 21–59) years) have been transplanted with this regimen. Diagnosis were AML (n = 16), ALL (n = 7), NHL (n = 3), MM (n = 2) and CML (n = 1). Patients were “high risk” with refractory disease or relapse after preceding HCT. The CD3/CD19 depleted haploidentical grafts contained a median of 7.6 × 106 (range, 3.4–17 × 106) CD34+ cells/kg, 4.4 × 104 (range, 0.006–44 × 104) CD3+ T cells/kg and 7.2 × 107 (range, 0.02–37.3 × 107) CD56+ cells/kg. Donor–recipient KIR-ligand-mismatch was found in 19 of 29 patients. The regimen was well tolerated with maximum acute toxicity being grade 2–3 mucositis. Because of severe neurotoxicity in 4 patients treated with 200 mg/m2 fludarabine, the dose was reduced to 150 mg/m2. Engraftment was rapid with a median time to > 500 granulocytes/μL of 12 (range, 10–21) days, > 20,000 platelets/μL of 11 (range, 7–38) days and full donor chimerism after 2–4 weeks in all patients. Incidence of grade II–IV° GVHD was 48% with grade II° = 10, III° = 2 and IV° = 2. One patient, who received the highest T-cell dose, developed lethal grade IV GVHD. TRM in the first 100 days was 6/29 (20%) with deaths due to idiopathic pneumonia syndrome (n = 1), mucormycosis (n = 1), pneumonia (n = 3) or GVHD (n = 1). Overall survival is 9/29 patients (31%) with deaths due to infections (n = 7), GVHD (n = 1) and relapse (n = 12) with a median follow-up of 241 days (range, 112–1271). In conclusion, this regimen is promising in high risk patients lacking a suitable donor, and a prospective phase I/II study is ongoing.