Cotransplantation of Mesenchymal Stem Cells Prompted Platelets Recovery in HLA-Haploidentical/Mismatched Blood and Marrow Transplantation: A Randomized Phase II Study.

Up to now, HSCT has remained the standard and effective therapy for many hematopoietic malignant diseases and some non-malignant hematopoietic diseases. The HLA-matched sibling is the best source of donors; however, such donors are available for only approximately 30% of patients, especially in P.R.China. Virtually almost everyone possesses at least one HLA-haploidentical family donor. However, the use of such donors has presented a major challenge due to graft-versus-host disease (GVHD) and graft rejection. Peking University established a new approach for HLA-mismatched/hapoidentical HSCT using G-CSF primed bone marrow plus G-CSF-mobilized peripheral blood stem cells without ex vivo T cell depletion after the patients were treated with a modified BU/CY2+ATG regimen. Although the result was comparable to that in HLA matched sibling donor transplantation, there are still have room to improve the hemapoeitic/immune reconstitution, reduce the incidence and grade of GVHD further. Mesenchymal stem cell (MSC) is a pluripotent stem cell, supports hematopoeitc progenitors in vitro and posses potent immunosuppressive properties. We hypothesized that cotransplantation of culture-expanded MSCs and hematopoietic stem cells (HSCs) could facilitate engraftment and lessen graft-versus-host disease (GVHD). A phase I study has assessed the safety of contransplantation of MSC, and then a randomized, open-label phase II trial had been conducted in our institution during 2007.6–2008.6. Total twenty-nine patients with leukemia in CR were enrolled in this trial and randomized into study (n=14) or control group (n=15). Three patients in the study group had been found ineligible after randomized: one had relapsed leukemia just before conditioning, another had HLA identical donor and the third one is too overweighed to be infused of enough MSC. The remaining received the G-CSF-mobilized BM and PB from the HLA-mismatched/hapoidentical donor as have been published. Patients in the study group were given culture-expanded MSCs intravenously (3.0–5.0 × 105/kg) from the same donor or health volunteer within 24 hours before infusion of G-BM and PB. Baseline demographic and disease characteristics were balanced between the two groups. MSC infusions were well tolerated, without any infusion-related adverse events. All patients but one in the control group had achieved sustained neutrophil recovery. The median times to neutrophil (absolute neutrophil count ≥0.5 × 10⁹/L) engraftment were 11 days (range, 11–19 days) and 11.5 days (range, 10–23 days) in the study and control groups respectively (p=1.0). There were 2 patients in the control group dead before the platelets engraftment, the median times to platelet recovery (platelet count ≥20 × 10⁹/L ) were 13 days(range 9–52 days) and 19 days (range 10–36 days) (P=0.18). The platelet engraftment was prompted in the study group as for the time to count ≥50 ×10⁹/L (21 days vs 26.5 days, P=0.047). Acute GVHD was observed in 7/11 of patients in study group, 2 had grade I, 5 had grade II. The cumulative incidence of grade II to IV acute GVHD was 48.9%. One patient in the control group had engraftment failure and another was dead of infection on +22 days. Of the thirteen remaining patients, nine patients experienced acute GVHD, 2 had grade I, 6 had grade II and 1 had grade IV. The cumulative incidence of grade II to IV acute GVHD was 61.1%. Our study demonstrated that cotransplantation of culture-expanded MSCs from donor or health volunteer in HLA-haploidentical/mismatched HSCT is feasible and safe. It is seems that MSCs are capable of accelerating hematopoietic cell engraftment, especially for platelet. Further study should be done to reveal whether MSC could reduce the incidence of acute GVHD.