Co-Transplantation of Haploidentical Bone Marrow Derived Mesenchymal Stem Cells Overcomes Graft Dysfunction and Improves Hematological and Lymphocyte Recovery in Haploidentical Stem Cell Transplantation.
Authors: van Velzen-Ball Lynne Margaret , Bernado Marie Ester , Locatelli Franco , Roelofs Helene , Lankester Arjan , Egeler R. Maarten , Fibbe Willem E. 
Published: October 2019

Abstract
Haploidentical peripheral blood stem cell transplantation from a parent is an accepted form of therapy in children lacking a suitable donor who require stem cell transplantation. The risk of graft failure/rejection increases with the intense T cell depletion resulting from positive CD34 selection. Mesenchymal stem cells (MSCs) isolated from bone marrow can be expanded to sufficient numbers for clinical use. MSCs can improve hematological recovery but their role in overcoming graft dysfunction post transplant is unknown.
We present results of co-transplantation of MSCs in children undergoing haplo-identical PBSCT compared to 48 historical controls.
MSCs were isolated from donor marrow and expanded under GMP conditions approximately 4–5 weeks before transplantation. MSCs (fresh or cryopreserved) were administered i.v. 4 hours before donor G-CSF mobilized PBSCs. To date, 8 children have been treated in two centers.Conditioning depended on underlying disease. No additional GvHD prophylaxis was given. Engraftment and immune recovery was compared to the control group. The local ethical committees approved the study. Characteristics and results are summarized in Table 1. There was no difference for age, gender, transplant indication, donor type or CD34+ or CD3+ cells infused. In comparison to historical controls (23% graft dysfunction) all patients had 100% documented and sustained engraftment. Hematological recovery of leucocytes was faster (p=0,008) with lymphocyte rather than neutrophil recovery accounting for this. Near significance in reticulocyte and platelet recovery (p=0.09; 0.08 resp) was evident. Viral reactivations were common in both patients and controls. Acute GvHD was 12.5% in the patient group compared to 39.5% of eligible controls. Two patients died, one relapse and one infection compared to 17 controls (9 relapse, 5 infection, 3 GvHD). Longer follow-up and immune recovery data are continuing.
Our results suggest MSC co-transplantation overcomes graft dysfunction and stabilizes engraftment. MSC use is feasible and safe without infusional toxicities. Based on our findings, where graft dysfunction, delayed hematological and immune recovery compromise the success of stem cell transplant outcome, clinical randomized studies of MSCs are warranted.
Table 1. PATIENT/CONTROL CHARACTERISTICS PATIENT CONTROL All patients received MSC between 1–2 x 106/kg MALE 4 (50%) 29 (60%) FEMALE 4 (50%) 19 (40%) AGE (range) 8y 2mo (2–15y 6m) 8y (6mo-17y 7mo) MALIGNANT DISEASES 5 (62%) 34 (70%) IMMUNE DEFICENCIES 2 (25%) 6 (13%) BENIGN CONDITIONS 1 (13%) 8 917%) DONOR MALE 5 24 DONOR FEMALE 3 24 CD34 INFUSED 31.8 (SD 3.1) 20 (SD 6.8) NS CD3 INFUSED 0.3 (SD 0.30) 0.68 (SD 0.7) NS aGvHD 1 13 OVERALL SURVIVAL 6 (75%: FU 3–48mo) 31(64%: FU 2–6Y) Table 2. HEMATOLOGICAL RECOVERY PATIENTS CONTROLS Average (days) SD (days) Average (days) SD (days) P value (T-test) SD: Standard deviation : NS: not significant LEUCOCYTES >1.0 X 109/L 12 1.9 16 4.15 0.008 NEUTROPHILS >0.5 X 109/L 13 1.5 15 3.6 0.14 (NS) PLATELETS >20 X 109/L 13 2.7 21 14.7 0.08 (near significance) RETICULOCYTES >20 16 4.9 27 13.7 0.09