Cori Abikoff, MD
,
Pediatrics, New York Medical College, Valhalla, NY
Qiuhu Shi, PhD
,
Biostatistics, New York Medical College, Valhalla, NY
Roger Giller, MD
,
Pediatrics, The Children's Hospital, Denver, University of Colorado School of Medicine, Aurora, CO
Michael A. Pulsipher, MD
,
Primary Children's Medical Center, University of Utah School of Medicine, Salt Lake City, UT
Paul Szabolcs, MD
,
Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA
Shalini Shenoy, MD
,
Pediatrics, Washington University, St. Louis Children's Hospital, St. Louis, MO
Theodore B Moore, MD
,
Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA
Lauren Harrison, RN
,
Pediatrics, New York Medical College, Valhalla, NY
Erin Morris, RN, BSN
,
Pediatrics, New York Medical College, Valhalla, NY
Olga Militano, PharmD
,
Pediatrics, New York Medical College, Valhalla, NY
Janet Ayello, MS, MT(ASCP)
,
Pediatrics, New York Medical College, Valhalla, NY
Mildred Semidei-Pomales, MS
,
Pediatrics, New York Medical College, Valhalla, NY
Sandra Foley, RN, MSN, CPNP
,
Pediatrics, New York Medical College, Valhalla, NY
Xiaokui Zhang, PhD
,
Celgene Cellular Therapeutics, Warren, NJ
Jodi Gurney
,
Celgene Cellular Therapeutics, Warren, NJ
Jessica Hochberg, MD
,
Pediatric Hematology/Oncology, New York Medical College, New Rochelle, NY
Lee-Ann Baxter Lowe, PhD
,
Surgery, University of California San Francisco, San Francisco, CA
Mitchell S. Cairo, MD
,
Pediatrics, New York Medical College, Valhalla, NY
Background: The safety and efficacy of UCB as a donor source for hematopoietic stem cell (HSC) transplantation is well established (Wagner/Cairo et al, Blood, 1996; Kurtzberg et al, NEJM,1996). Further, the naiveté of these cells allows for greater HLA mismatch and leads to decreased rates of chronic GVHD (Liao/Cairo et al, Exp Hem,2011). However, the number of HSC’s in each UCB unit is significantly less than that obtained from peripheral blood and bone marrow (Cairo/Kurtzberg et al, Transfusion, 2005), prolonging time to engraftment (Cairo et al, Blood,1997). With longer periods of neutropenia increasing the risk of infectious complications in UCB transplantation, much effort has been made to improve time to engraftment in UCB transplants. One strategy developed by Cellgene Cellular Therapeutics (CCT) is co-infusion of UCB with HPDSC’s. HPDSC’s, derived from CCT’s proprietary process, represent a more immature HSC source, containing a higher concentration of CD34+ cells as well as CD34+/CD45- cells than UCB. Augmenting the graft with early progenitors may increase the engraftment potential of UCB. Studies using a NOD/SCID mouse model demonstrate earlier engraftment when HPDSC’s are combined with UCB transplant and increased engraftment compared to UCB or HPDSC's alone.
Objective: To determine the feasibility and safety of combined UCB transplantation with HPDSC’s using myeloablative or reduced intensity conditioning for malignant and non-malignant diseases.
Methods: We have developed a multicenter consortium (CCT-HPDSC-UCBT-PI-001) to investigate this approach (Figure1A). Patients with eligible malignant and non-malignant diseases who have a single or double UCB donor (4/6-6/6 HLA matched) with a total nucleated cell (TNC) dose >5.0 x 107 /kg either alone or combined are eligible. The experimental design is depicted in Figure 1B.
Results: To date 3 patients have been transplanted on this protocol. 1 received a single UCB unit for adrenoleukodystrophy (ALD) and 2 received double UCB transplants for acute lymphoblastic leukemia (ALL). Pre-thaw TNC/kg of HPDSC were 5.6 x106, 3.9 x106, and 3.1 x106 for patients 1-3 respectively. The characteristics of the pre-thaw UCB are summarized in Table 1. All 3 patients are alive at 52-170 days post-transplant with no acute GVHD observed to date and time to neutrophil engraftment ranging from 14-53 days. In each case, host and HPDSC chimerisms diminished to low or undetectable levels over time, but mixed chimerism has persisted in the double cord blood transplants as far out as day +100. These results are further summarized in Table 1.
Summary: These data suggest that UCB transplantation in conjunction with HPDSC infusion is safe and well tolerated for children with malignant and nonmalignant diseases. A larger cohort and longer follow-up will be required to determine the safety and clinical significance of these early findings. (NCT01586455).
