Allogeneic Hematopoietic Stem Cell Transplantation (Allo-HSCT) with Human Placenta-Derived Stem Cells (HPDSC) Combined with Unrelated Cord Blood (UCB) for Malignant and Non-Malignant Disorders (IND 14949)

Background Myeloablative (MAC) or reduced toxicity conditioning (RTC) followed by UCBT in children with malignant and non-malignant diseases is safe and effective (Geyer/Cairo, BJH 2011). However, concentration of CD34 + HPCs in UCB is low, leading to delayed hematopoietic reconstitution and high incidence of engraftment failure (Satwani/Cairo, BBMT 2013). HPDSCs are rich in HPCs, low in HLA Class I/II expression and T-cells, and have regenerative, anti-inflammatory, and immunosuppressive properties (Liao/Cairo, Stem Cells Translational Medicine 2018). Objective To determine the safety and efficacy of HPDSC with UCBT in children with malignant and non-malignant diseases. Design/Method 4-6/6 HLA matched UCB with TNC ≥ 5 × 10 7 /kg (4/6 HLA match) or ≥ 3.5 × 10 7 /kg (5-6/6 HLA match) were included. Patients received MAC or RTC followed by UCB plus HPDSC infusion. GVHD prophylaxis consisted of tacrolimus and mycophenolate mofetil as previously described  (Bhatia/Cairo, BBMT 2009). Results To date, 28 patients ≤18 years were enrolled, 15 males and 13 females. Mean age in years ± SD was 6.8±5.5. There were 12 patients with non-malignant disease including ALD (2), CAT (1), CGD (1), SCID (2), dyskeratosis congenita (1), congenital neutropenia (1), SAA (2), LCH (1), and SDS (1) and 16 patients with malignant disease including pre B-cell ALL- CR1 (4), pre B-cell ALL - CR2 (4), T-cell ALL – CR1 (1), AML-CR1 (4), JMML-CR1 (1), TLL - CR1 (1), and BL - CR2 (1). Mean UCB TNC±SD and CD34±SD infused were 7.7 × 10 7 ±5.0/kg and 0.48 × 10 6 ±0.59/kg, respectively. There were no SAEs associated with HPDSC infusions. Four patients were removed prior to day 180 due to progressive disease (1) and engraftment failure necessitating alternative treatment (3). Probability of neutrophil engraftment was 89.2%, median day 22 (13-53). Of neutrophil engrafted evaluable patients (n=22), the probability of platelet engraftment by day 100 was 90.9%, median day 42 (20-98). Of neutrophil engrafted, evaluable patients at day 30, 60, 100 and 180, mean whole blood UCB chimerism was 92, 99, 96 and 99%, respectively. Average whole blood HPDSC chimerism was 95 : 0.9-51.9). Of patients without grade 2-4 aGVHD, normalization of CD3+, CD19+, and CD56+ cells occurred by day 100, and CD8+ and CD4+ cells by day 270. The probability of OS at 1 year was 78.0% (CI 95 : 55.0-90.2). Deaths occurred due to systemic adenovirus (3), RSV (1) and relapse (1). Conclusions These results suggest that UCBT with HPDSC is safe and well tolerated, has a lower than expected probability of Grade 2-4 aGVHD, and results in robust immune reconstitution. A larger cohort and longer follow-up is required to determine the clinical significance of these findings.