Non-Myeloablative Allogeneic Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Hematologic Malignancies in High Risk Patients and in Patients With Debilitating Hematologic Diseases
Patients with malignant and non-malignant hematologic diseases including severe aplastic
anemia (SAA), paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS),
acute and chronic leukemias, Hodgkin's and non-Hodgkin's lymphoma and multiple myeloma can
now be cured by allogeneic bone marrow transplantation (BMT). This curative effect has been
ascribed to the use of high dose chemo-radiotherapy and the anti-tumor or anti-bone marrow
effect of the allograft. Dose intensification of conditioning regimens in attempts to
reduce disease recurrence has been largely unsuccessful because of increased toxicity and
mortality. Indeed, most evidence now points to donor-derived T-cells as being the principal
modality leading to the complete eradication of both malignant and non-malignant host
The assumption that successful allogeneic BMT relies on the myeloablative effect of
intensive but hazardous chemo-radiotherapy has largely restricted this therapeutic modality
to patients with malignant or life-threatening hematologic disorders under the age of 55
years. Treatment-related mortality increases substantially with age, prior intensive
treatment with chemo-radiotherapy, worsening performance status, and co-morbid medical
conditions. An unacceptable risk of death from conventional BMT renders many patients
ineligible for what may otherwise be curative therapy.
Several in vitro studies have demonstrated the existence of donor-derived CD4 and CD8
positive lymphocytes with specific reactivity for the patient's leukemia. These cells
provide a potent graft-versus-leukemia (GVL) effect. This GVL effect is best seen in
patients with CML relapsing after bone marrow transplantation, where a single infusion of
donor lymphocytes has been shown to induce complete remission. In addition to the potent
anti-leukemia effect of these cells, there is now strong evidence that donor T-cells are
capable of completely eradicating residual host hematopoietic cells in a non-myeloablative
transplant setting (graft-versus-marrow) leading to successful and complete donor
Non-myeloablative allogenic peripheral blood stem cell transplants are currently being
investigated in phase I/II trials assessing engraftment efficacy and toxicity at a number of
transplant centers. Preliminary data, including our own experience with greater than 150
patients undergoing this type of procedure, have shown a high rate of complete donor
engraftment with a low toxicity profile. Two recent studies investigating non-myeloablative
allo-transplantation in standard risk patients revealed an extremely low rate of
transplant-related complications and mortality.
The decreased risk of transplant-related complications associated with non-myeloablative
transplants expands the eligibility of transplant candidates as well as opens the
possibility to evaluate non-myeloablative regimens in patients at high risk for
complications with standard transplantation. Besides hematologic malignancies, allogeneic
BMT has been shown to be curative in a number of debilitating hematologic diseases which may
behave in a relatively indolent fashion, such as PNH and refractory anemia (RA) or
refractory anemia with ringed sideroblasts (RARS). However, the 30% risk of
treatment-related mortality with standard myeloablative allotransplantation usually
precludes these patients from potentially curative therapy, because of concerns about
shortening life in patients with these disorders. In this protocol we investigate
non-myeloablative allogeneic PBSC transplantation in two groups of subjects where standard
allogeneic transplantation is considered to have unacceptable toxicity.
Group A: Subjects with hematologic malignancies with factors putting them at high risk for
transplant related complications and mortality, including prior intensive chemo-radiotherapy
and co-morbid diseases.
Group B: Subjects with hematologic diseases (both clonal and non-clonal) associated with
reasonable longevity not currently considered for allogeneic BMT because of prohibitive
procedural mortality with conventional BMT (Enrollment closed October 2010).
In this protocol, eligible subjects are treated with an allogeneic peripheral blood stem
cell transplant from an HLA identical or single HLA antigen-mismatched family donor, using
an intensive immunosuppressive regimen without myeloablation in an attempt to decrease the
transplant related toxicities while preserving the anti-malignancy and/or anti-host marrow
effect of the graft. The low intensity non-myeloablative conditioning regimen should
provide adequate immunosuppression to allow stem cell and lymphocyte engraftment. T-cell
replete, donor-derived, granulocyte colony stimulating factor (G-CSF)-mobilized peripheral
blood stem cells (PBSC) will be used to establish hematopoietic and lymphoid reconstitution.
We will add back lymphocytes in recipients with less than 100% donor T-cell chimerism in an
attempt to prevent graft rejection and enhance a graft-versus-malignancy effect.
The primary endpoint of this study is transplant related mortality (200 day survival).
Other end points include engraftment, degree of donor-host chimerism, incidence of acute and
chronic graft versus host disease (GVHD), transplant related morbidity as well as
disease-free and overall survival.
Allocation: Non-Randomized, Masking: Open Label, Primary Purpose: Treatment
To evaluate engraftment by bone marrow chimerism analysis.
Richard W Childs, M.D.
National Heart, Lung, and Blood Institute (NHLBI)
United States: Federal Government
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