A Multicenter Pilot Study of Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation With In-vivo T-cell Depletion to Evaluate the Role of NK Cells and KIR Mis-matches in Relapsed or Refractory High-risk Neuroblastoma.
- To determine the feasibility of allogeneic hematopoietic stem cell transplantation
after a reduced-intensity conditioning regimen comprising fludarabine phosphate,
busulfan, and anti-thymocyte globulin, in terms of donor engraftment,
transplant-related mortality, and development of acute and chronic graft-vs-host
disease, in pediatric patients with high-risk relapsed or refractory neuroblastoma.
- To elucidate the role of natural killer (NK) cells as effectors of graft-vs-tumor
effect in these patients.
- To evaluate the role of killer immunoglobulin-like receptor (KIR) mismatches in the
donor-recipient pairs on the outcomes of these patients.
- To determine the incidence of progression-free survival at 1 year post-transplantation
in these patients.
OUTLINE: This is a multicenter study.
- Reduced-intensity conditioning regimen: Patients receive fludarabine phosphate IV over
1 hour on days -10 to -6, busulfan IV over 2 hours once on day -10 (test dose) and then
every 6 hours on days -5 and -4, and anti-thymocyte globulin IV over 6-8 hours on days
-3 to -1 and on day 2.
- Transplantation: Patients undergo allogeneic bone marrow or G-CSF-mobilized peripheral
blood stem cell transplantation on day 0.
- Graft-vs-host disease (GVHD) prophylaxis: Patients receive cyclosporine or tacrolimus
IV or orally beginning on day -2 and continuing until day 60 or day 100, followed by a
taper until day 100 or day 180 in the absence of GVHD. Patients also receive
mycophenolate mofetil IV or orally on days 1-30, followed by a taper until day 60 in
the absence of GVHD.
Blood samples are collected at baseline and on days 30, 60, and 100 for correlative
laboratory studies. Samples are analyzed for killer immunoglobulin-like receptor (KIR)
mismatches by genotyping and immunophenotyping methods (PCR and flow cytometry); natural
killer (NK) cell reconstitution by flow cytometry; and NK cell function, NK cell
allo-reactivity by ELISPOT and ELISA.
After completion of study treatment, patients are followed periodically for 1 year.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Feasibility as measured by the incidence of donor engraftment, transplant-related mortality, and grade III-IV acute graft-vs-host disease (GVHD) at day 100 and the incidence of extensive chronic GVHD within the first year post-transplantation
The safety and feasibility of reduced intensity allogeneic HSCT will be established in this population by monitoring the incidence of adverse events- 100 day mortality,incidence of severe acute GVHD and non-engraftment of donor cells.
100 days post-HSCT
Sandeep Soni, MD
Nationwide Children's Hospital
United States: Institutional Review Board
|Nationwide Children's Hospital||Columbus, Ohio 43205-2696|
|Children's Memorial Hospital||Chicago, Illinois 60614|
|Morgan Stanley Children's Hospital of NY||New York, New York|
|Children's Hopsital of Wisconsin||Milwaukee, Wisconsin|