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).

Figures

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.