A Pilot Trial of Unrelated Cord Blood Transplantation (UCBT) and Unmatched Human Placental Derived Stem Cells (HPDSC) in Children and Young Adults with Malignant and Non-Malignant Disease

Background

Initial studies by our group and others demonstrated that myeloablative conditioning (MAC) followed by UCBT (matched at 4-6/6 HLA loci) in children with malignant and non-malignant diseases was safe and well tolerated (Wagner/Cairo et al, Blood, 1996; Kurtzberg et al, NEJM,1996). However, there is a low concentration of CD34+ hematopoietic progenitor cells (HPC) in banked CB (Cairo/Kurtzberg et al, Transfusion, 2005), resulting in delayed hematopoietic reconstitution and  10-20% incidence of graft failure resulting in increased  transplant-related mortality (TRM) (Cairo et al, Blood,1997; Satwani/Cairo et al, BBMT,2013). More recently, Robin et al have demonstrated human stem and progenitor cells were detected in placental tissue (Robin et al, Cell Stem Cell, 2009). Celgene Cellular Therapeutics (CCT) has developed a proprietary, sterile closed perfusion process for the collection of Human Placental Derived Stem Cells (HPDSC) from full term placentas. HPDSC are rich in HPCs, HPC CFU forming capabilities, low in HLA Class I and II expression and enhance in-vivo engraftment when combined with UCBT in NOD-SCID animals (Mendez-Ferrer et al, Nature,2010).

Objective

To determine the safety and feasibility of administering unmatched HPDSC in conjunction with single and double UCBTs following MAC or reduced-intensity conditioning (RIC) in children and adults with malignant and non-malignant diseases.

Methods

We developed a multicenter consortium (CCT-HPDSC-UCBT-PI-001) to investigate this approach (Fig. 1A).  Patients with eligible malignant and non-malignant diseases with a single CB donor product (4/6–6/6 HLA match) and total nucleated cell dose (TNC) ≥5.0 x 10⁷/kg or double UCBT (4/6–6/6 HLA match) and combined TNC ≥5.0 x 10⁷/kg are eligible. The experimental design is depicted in Fig. 1B.

Results

Nine patients enrolled to date: six with high-risk malignant conditions (relapsed or hypodiploid Precursor B ALL, FLT3+ AML, T-cell ALL induction failure) and three with non-malignant disorders (X-linked adrenoleukodystrophy, chronic granulomatous disease, congenital amegakaryocytic thrombocytopenia). Mean ± SD CB CD34 (3.9 ± 1.8x10⁵/kg) and HPDSC CD34 doses (0.3 ± 0.15 x10⁵/kg) (p=0.00005) were used. All recipients engrafted fully. Full (96-100%) UCBT donor chimerism and 0% HPDSC was observed. Median time to neutrophil engraftment was 22 days post UCBT (range 13-53 days). Only one of 9 patients developed ≥ grade II AGVHD. Seven of 9 patients are alive at 80- 460 days post UCBT. One patient died from PTLD and one from GVHD and fungal infection.

Summary

These preliminary results suggest that single or double UCBT combined with unrelated HPDSC infusion in children with malignant and non-malignant diseases is safe and well tolerated.  A larger cohort and longer follow-up will be required to determine the safety and clinical significance of these early findings. (NCT01586455)