Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: a phase II study

Abstract

Background: We report a prospective multicenter phase II study of haploidentical hematopoietic stem cell transplantation using CD3/CD19-depleted grafts after reduced intensity conditioning with fludarabine, thiotepa, melphalan and OKT-3.

Design and methods: Sixty-one adults with a median age of 46 years (range 19-65 years) have been enrolled. Diagnoses were acute myeloid leukemia (n=38), acute lymphoblastic leukemia (n=8), non-Hodgkin's lymphoma (n=6), myeloma (n=4), chronic myeloid leukemia (n=3), chronic lymphatic leukemia (n=1) and myelodysplastic syndrome (n=1). Patients were considered high risk because of refractory disease (n=18), cytogenetics (n=6), complete remission (≥ 2) (n=9), chemosensitive relapse in partial remission (n=4) or relapse after prior hematopoietic stem cell transplantation (n=15 allogeneic, n=8 autologous, n=1 both). At haploidentical hematopoietic stem cell transplantation, 30 patients were in complete remission and 31 in partial remission. Grafts contained a median of 7.0 × 10(6) (range 3.2-22) CD34(+) cells/kg, 4.2 × 10(4) (range 0.6-44) CD3(+) T cells/kg and 2.7 × 10(7) (range 0.00-37.3) CD56(+) cells/kg.

Results: Engraftment was rapid with a median of 12 days to granulocytes more than 0.5 × 10(9)/L (range 9-50 days) and 11 days to platelets more than 20 × 10(9) (range 7-38 days). Incidence of grade IIIV acute graft-versus-host-disease and chronic graft-versus-host-disease was 46% and 18%, respectively. Non-relapse mortality on Day 100 was 23% and 42% at two years. Cumulative incidence of relapse/progression at two years was 31%. Kaplan-Meier estimated 1-year and 2-year overall survival with median follow up of 869 days (range 181-1932) is 41% and 28%, respectively.

Conclusions: This regimen allows successful haploidentical hematopoietic stem cell transplantation with reduced intensity conditioning in high-risk patients lacking a suitable donor. (clinicaltrials.gov identifier:NCT00202917).

Figure 1.

(A) Cumulative incidence of NRM adjusted for relapse as competing risk. (B) Kaplan-Meier estimate of disease free and overall survival. Overall survival (OS): number of days from transplantation to death from any cause. Patients who were still alive at follow up were censored at the last follow-up date. Event free survival (EFS): number of days from haplo-HSCT until relapse/progression/death. Patients without evidence of relapse/progression were censored at last follow-up date or date of death.

Figure 2.

Kaplan-Meier estimate of overall survival in different subgroups. Log rank test was used to compare Kaplan-Meier estimates between different patient groups. (A) Main diagnosis groups. (B) Complete versus partial remission in patients with AML. (C) Influence of chronic GVHD on survival (landmark analysis). (D) CD³ content of the graft; cut off ⁷⁵,⁰⁰⁰ CD³+ cells/kg. (E) KIR mismatch.

Figure 3.

Donor chimerism after haplo-HSC. (A) Percentage of donor chimerism on different days after haplo-HSCT (n=⁵⁵). Seven patients died before reaching complete chimerism. (B) Percentage of T-cell chimerism (n=20) analyzed by flow cytometry.