A Pilot Study of EPOCH-F/R Induction Chemotherapy and Reduced-Intensity, HLA-Matched, Related Allogeneic Hematopoietic Stem Cell Transplantation, With Cyclosporine & Methotrexate GVHD Prophylaxis for Refractory or Relapsed Hematologic Malignancies
Allogeneic hematopoietic stem cell transplantation (HSCT) is potentially curative for
refractory hematologic malignancies, but its application has been limited historically by
morbidity and mortality from conventional transplant preparative regimens and
graft-versus-host disease (GVHD). Donor T cells mediate GVHD and also help to eradicate
malignancies through an immune-dependent graft-versus-tumor effect. Efforts to decrease
preparative regimen toxicity have led to reduced-intensity or 'nonmyeloablative' regimens,
facilitating the study of allogeneic HSCT in a broader population. As a promising strategy
for reducing GVHD, donor Th2 cells were shown to abrogate Th1-mediated GVHD without
impairing engraftment in murine models of allogeneic HSCT. These findings led to a phase
I/II clinical study of donor Th2 cells for the prevention of GVHD during reduced-intensity
allogeneic HSCT (CC 99-C-0143); preliminary results suggest that a randomized trial will be
necessary to evaluate donor Th2 cells further.
In CC 99-C-0143, a novel induction chemotherapy regimen, EPOCH-Fludarabine (EPOCH-F), was
well tolerated and effective for sequential host immune depletion. However, a significant
proportion of patients failed to achieve satisfactory disease control before transplant,
providing a basis for intensifying this induction regimen. Furthermore, the initial 20
patients treated on this study experienced relatively high rates of acute GVHD and
considerable morbidity associated with cyclosporine monotherapy for GVHD prevention,
indicating that future studies should use more aggressive prophylaxis. These observations
warrant modifying our approach to allogeneic HSCT before undertaking a randomized study of
donor Th2 cells.
We now propose a pilot study of HLA-matched, related, reduced-intensity allogeneic HSCT in
refractory hematologic malignancies, using an intensified EPOCH-F induction chemotherapy
regimen with rituximab added for patients with CD20+ malignancies (EPOCH-F/R). This regimen
will be evaluated for toxicity and disease control before transplantation. GVHD prophylaxis
will consist of a standard dual-agent regimen, cyclosporine/methotrexate; the impact of this
change on hematopoietic recovery, donor/recipient chimerism, and the incidence of acute GVHD
will be assessed.
Immune reconstitution following allogeneic HSCT is an important research interest among
Experimental Transplantation and Immunology Branch Investigators. Current evidence suggests
a critical role for interleukin-7 (IL-7) in CD4+ T cell homeostasis, and interleukin-15
(IL-15) appears crucial to CD8+ T cell and NK cell homeostasis. The relationships between
these cytokines and lymphocyte subpopulations have not been studied in the setting of
allogeneic HSCT; such analysis may enhance our understanding of engraftment kinetics,
graft-versus-host disease, and immune reconstitution. We will correlate serum IL-7 and
IL-15 levels with changes in circulating T-cell and NK-cell subpopulations during EPOCH-F/R
induction chemotherapy, after transplantation, and with the development of GVHD.
Interventional
Primary Purpose: Treatment
Daniel H Fowler, M.D.
Principal Investigator
National Cancer Institute (NCI)
United States: Federal Government
030077
NCT00051311
January 2003
Name | Location |
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National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda, Maryland 20892 |