Abstract

Haploidentical CD34+ purified peripheral blood stem cell transplantation (PBSCT) is associated with an increased risk of graft failure/rejection. Animal models suggest that MSCs may promote engraftment after hematopoietic stem cell transplanation (HSCT) but there role in overcoming graft failure in human HSCT is still unclear. We recently reported our initial findings in 13 children receiving MSCs in conjunction with haplo-PBSCT. Here we report our extended series of 20 patients, now including those with MDS known to have an increased risk of rejection. MSCs were isolated from marrow of PBSCT donors and expanded under GMP conditions using same batch FCS containing medium and a standardized protocol, approximately 4–5 weeks before transplantation. MSCs (fresh or cryopreserved) were administered i.v. 4 hours before the allograft. Conditioning depended on underlying disease. No pharmacological GvHD prophylaxis was given after PBSCT. Characteristics of the patients and results are summarized in table 1. In comparison to historical controls (20% graft failure), all patients given MSCs showed successful and stable engraftment (p=0.03). Hematological recovery was accelerated (see table 2). Viral reactivations did not differ between patients and controls. MSC use was feasible and safe without infusion toxicities. In contrast to our initial findings, our extended analysis shows a statistically significant reduction in graft failure rates for patients cotransplanted with MSCs. Moreover, MSC cotransplantation may also prevent graft rejection in patients with MDS. In view of these findings, cotransplantation of MSCs could become standard practice for optimizing the outcome of children given this type of allograft.

Table 1:

Patient characteristics and summary of results

PATIENT (n=20)CONTROL (n=52)P VALUE
Male/female 14/6 (70/30%) 31/21 (60/40%) 0.6 
Age (range) 8 years (2–16) 8 years (1–17) NS 
All hematological malignancies 16 (80%) 40 (70%) 1.0 
MDS 2 (10%) 5 (10%) 1.0 
Immune deficiencies 2 (10%) 2 (4%) NS 
Other 2 (10%) 10 (9%) NS 
Donor male/female 10/10 29/23 NS 
Conditioning    
TBI/Chemo based 12/8 30/22 1.0 
N of CD34+cells infused (median, range) 21.3 (11.2–38.6) 23 (12.1–47.5) NS 
N. of CD3+ cells infused (mean, SD) 0.3 (0.30) 0.5 (0.7) NS 
aGvHD   0.2 
I-II 12  
III-IV  
Relapse 4/16 (25%) 8/40 (20%) NS 
Infectious deaths 2 (10%) 7 (13%) NS 
GRAFT FAILURE 11 0.03 
PATIENT (n=20)CONTROL (n=52)P VALUE
Male/female 14/6 (70/30%) 31/21 (60/40%) 0.6 
Age (range) 8 years (2–16) 8 years (1–17) NS 
All hematological malignancies 16 (80%) 40 (70%) 1.0 
MDS 2 (10%) 5 (10%) 1.0 
Immune deficiencies 2 (10%) 2 (4%) NS 
Other 2 (10%) 10 (9%) NS 
Donor male/female 10/10 29/23 NS 
Conditioning    
TBI/Chemo based 12/8 30/22 1.0 
N of CD34+cells infused (median, range) 21.3 (11.2–38.6) 23 (12.1–47.5) NS 
N. of CD3+ cells infused (mean, SD) 0.3 (0.30) 0.5 (0.7) NS 
aGvHD   0.2 
I-II 12  
III-IV  
Relapse 4/16 (25%) 8/40 (20%) NS 
Infectious deaths 2 (10%) 7 (13%) NS 
GRAFT FAILURE 11 0.03 
Tabel 2.

Patient hematopoietic recovery compared to controls

PATIENTSCONTROLSP value (student t-test
Median (days, range)SD (days)Median (days, range)SD (days)
P value equal or less than 0.05 is considered significant 
Leucocyte 〉1.0 × 109/L 11.5 (9–16) 2.0 14 (9–26) 4.2 0.01 
Neutrophils 〉0.5 × 109/L 12 (10–17) 1.9 13 (9–27) 4.6 0.06 
Platelets 〉20 × 109/L 11 (9–24) 3.8 13 (7–100) 22.3 0.11 
Reticulocytes 〉20 × 109/L 12 (10–31) 5.0 23 (9–41) 10.2 0.01 
PATIENTSCONTROLSP value (student t-test
Median (days, range)SD (days)Median (days, range)SD (days)
P value equal or less than 0.05 is considered significant 
Leucocyte 〉1.0 × 109/L 11.5 (9–16) 2.0 14 (9–26) 4.2 0.01 
Neutrophils 〉0.5 × 109/L 12 (10–17) 1.9 13 (9–27) 4.6 0.06 
Platelets 〉20 × 109/L 11 (9–24) 3.8 13 (7–100) 22.3 0.11 
Reticulocytes 〉20 × 109/L 12 (10–31) 5.0 23 (9–41) 10.2 0.01 

Author notes

Disclosure:Research Funding: This work has been partly supported by grants from Istituto Superiore di Sanità (National Program on Stem Cells), European Union (FP6 program ALLOSTEM), Regione Lombardia (Research Project: ‘Trapianto di cellule staminali adulte per scopi di terapia cellulare sostitutiva, riparativa e rigenerativa’), Fondazione Cariplo to F.L. and the Dutch Program for Tissue Engineering.