A Prospective Study of an HLA-Haploidentical Peripheral Blood Stem Cell Transplantation Regimen Based on Modification of the Dose of Posttransplant Cyclophosphamide for Poor Prognosis or Refractory Hematological Malignancies

Abstract

The optimal dose of posttransplant cyclophosphamide (PTCy) for use in patients undergoing HLA-haploidentical hematopoietic cell transplantation with posttransplant cyclophosphamide (PTCy-haplo) has not been sufficiently examined. This study evaluates the safety and efficacy of HLA-haploidentical hematopoietic cell transplantation with a reduced dose of PTCy for patients with a poor prognosis or those with refractory hematological malignancies. We conducted a prospective clinical study of PTCy-haplo with peripheral blood stem cells (PBSCs) using a modified PTCy dosage regimen consisting of 50 mg/kg on day 3 posttransplantation and a reduced dose of 25 mg/kg on day 4. The cumulative incidences of grades II to III and IV acute graft-versus-host disease (GVHD) at day 100 posttransplantation were 30% and 0%, respectively. The cumulative incidence of moderate-to-severe chronic GVHD after transplantation was 7.0%. The cumulative incidence of nonrelapse mortality at 1 year posttransplantation was 6.1%. Overall survival (OS) at 1 year was 66%. In addition, the restricted cubic-spline Cox regression analysis showed nonlinear relationship between the number of infused CD34+ cells and CD3+ cells, and OS. A graft composition of >4.54 × 106/kg CD34+ cells and >1.85 × 108/kg but ≤3.70 × 108/kg CD3+ cells was significantly associated with better survival, irrespective of the disease status (hazard ratio, 0.13; 95% confidence interval, 0.04–0.41; P < 0.001). These results suggest that PTCy-haplo with PBSCs using a de-escalated dose of 50 mg/kg on day 3 and 25 mg/kg on day 4 posttransplantation is a feasible option.

Graft-versus-tumor effect of post-transplant cyclophosphamide-based allogeneic hematopoietic cell transplantation

“…In a prospective study of HLA-haploidentical PBSCT with modified doses of PTCy, we recently reported that the number of infused CD34 + and CD3 + cells affected the incidence of relapse in a nonlinear fashion, and that there might be optimal numbers of infused CD34 + and CD3 + cells ( 85 ). Importantly, that study involved a non-linear restricted cubic spline Cox regression analysis, and showed that a graft composition of > 4.54 × 10 6 /kg CD34 + cells and > 1.85 × 10 8 /kg but ≤ 3.70 × 10 8 /kg CD3 + cells was significantly associated with a lower incidence of relapse/progression (HR, 0.31, P=.038).…”

“…We have long suspected that PTCy may attenuate the GVT effect, and have used a reduced dose of PTCy in prospective trials ( 85 , 97 ). Our institution was the first in Japan to introduce PTCy-haplo, and we have used a reduced dose of PTCy since 2009 with the aim of enhancing the GVT effect and reducing PTCy toxicity.…”

“…Our institution was the first in Japan to introduce PTCy-haplo, and we have used a reduced dose of PTCy since 2009 with the aim of enhancing the GVT effect and reducing PTCy toxicity. Based on our study results, we assume that a dose reduction to 75 mg/kg (50 mg/kg on day 3 and 25 mg/kg on day 4) is possible even when PB is used as a stem cell source ( 85 ). However, there is no clear evidence that reducing PTCy dose enhances the GVT effect.…”