Chemotherapy Followed by Allogeneic Stem Cell Transplantation for Hematologic Malignancies
|ClinicalTrials.gov Identifier: NCT00741455|
Recruitment Status : Active, not recruiting
First Posted : August 26, 2008
Last Update Posted : March 26, 2018
|Condition or disease||Intervention/treatment||Phase|
|Hematologic Malignancies||Procedure: Stem Cell Transplant Drug: G-CSF Drug: Fludarabine Drug: cyclophosphamide Drug: Cyclosporine Drug: Methotrexate||Not Applicable|
Allogeneic bone marrow transplantation (BMT) became feasible in the 1960s after elucidation of the Human Leukocyte Antigen (HLA) complex. Since then, the therapy has evolved into an effective treatment for many hematologic disorders. Otherwise incurable malignancies are frequently cured by this approach, with the likelihood of cure ranging from 10% to 85%, depending on the disease and the disease status. The treatment strategy incorporates very large doses of chemotherapy and often radiation to eliminate cancer cells and to immunosuppress the recipient to allow the engraftment of donor cells. Donor cells give rise to hematopoiesis within two to three weeks, rescuing the patient from the effects of high dose therapy. In the ideal situation, immune recovery and recipient-specific tolerance occurs over the following 6-18 months, and the patient is cured of their underlying malignancy, off immunosuppression, with a functionally intact donor-derived immune system. However, complications are common and include fatal organ damage from the effects of high dose chemotherapy, infection, hemorrhage, and, in particular, graft-versus-host disease (GvHD). A realistic estimate of transplant-related mortality in the standard HLA-matched sibling setting is approximately 25%. The risk of treatment-related mortality limits the success and certainly precludes its use in older patients. Thus, new strategies in transplantation are needed.
With the growing understanding that much of the curative potential of allogeneic bone marrow or stem cell transplant (SCT) is from an immune anti-tumor effect of donor cells, known as graft-versus-leukemia (GvL) or graft-versus-tumor (GvT), a new strategy is being employed that shifts the emphasis from high-dose chemo-radiotherapy to donor-derived, immune-mediated anti-tumor therapy. In this approach, patients receive preparative regimens that, while having some anti-tumor activity, are mainly designed to be immunosuppressive enough to allow engraftment of donor stem cells and lymphocytes. Engrafted lymphocytes then mediate a GvL effect; if the GvL effect of the initial transplant is not sufficient, then additional lymphocytes may be infused (achievement of engraftment allows additional lymphocytes to "take" in the recipient without requiring any additional conditioning of the recipient). The lower intensity of the preparative regimen lessens the overall toxicity by minimizing the doses of chemo-radiotherapy. In addition, less intensive preparative regimens may be associated with less GvHD, as much evidence suggests that high-dose therapy contributes to the syndrome of GvHD by causing tissue damage, leading to a cytokine milieu which enhances activation of graft-versus-host (GvH) effector cells. Thus, such an approach may allow the safer use of allogeneic transplants in standard populations and may allow extension of allogeneic transplantation to patients who could not receive standard (myeloablative) transplants because of age or co-morbidities. This protocol investigates a non-myeloablative transplant approach, using fludarabine and cyclophosphamide, to allow engraftment of allogeneic cells, which may then mediate anti-tumor effects.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||22 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Non-Myeloablative Chemotherapy Followed by HLA-Matched Related Allogeneic Stem Cell Transplantation for Hematologic Malignancies|
|Study Start Date :||June 2004|
|Estimated Primary Completion Date :||January 2023|
|Estimated Study Completion Date :||December 2023|
Experimental: Study Treatment
Chemotherapy, stem cell transplantation, HLA-Matched related allogeneic stem cell transplantation, leukapheresis, G-CSF, peripheral blood stem cell transplant, fludarabine, cyclophosphamide, donor lymphocyte infusion, cyclosporine, methotrexate
Procedure: Stem Cell Transplant
Donor: Prior to mobilization, leukapheresis to collect CD3+ cells. The donor will then receive G-CSF (10 mcg/kg/day) with leukapheresis collection of peripheral blood stem cells on days 5, 6 and 7 as needed. Goal of leukapheresis will be > 5 x 106 CD34+cells/kg of recipient.
Patient: Peripheral Blood Stem Cell (PBSC) Transplant. Fludarabine 25mg/m2/d IV over 30 minutes on days -6 to -2, followed by cyclophosphamide 1g/m2/d IV on days -3 and -2. This will be followed by allogeneic stem cell infusion 48 hours later.
Donor Lymphocyte Infusion (DLI) and Adjustment of Immunosuppression: Cyclosporine (CSA) and methotrexate (MTX) will be used for GvHD prophylaxis with target CSA levels of 200-400 ng/ml.
Other Name: HLA-Matched Related Allogeneic Stem Cell TransplantationDrug: G-CSF
10 mcg/kg/day on days 5, 6, and 7Drug: Fludarabine
25 mg/m2/d IV over 30 minutes on days -6 to -2Drug: cyclophosphamide
1 g/m2/d IV on days -3 and -2Drug: Cyclosporine
used for GvHD prophylaxis with target CSA levels of 200-400 ng/mlDrug: Methotrexate
used for GvHD prophylaxis with target CSA levels of 200-400 ng/ml
- Bone marrow engraftment [ Time Frame: Within 30 days of bone marrow transplant ]Rates of successful engraftment.
- Donor chimerism [ Time Frame: Post-transplant days +30, +60, +100, +180 and +365 ]Complete donor chimerism
- Graft-versus-host disease [ Time Frame: Post-transplant procedure through death ]Collect the number of incidents of acute and chronic graft-versus-host disease
- Overall survival [ Time Frame: Post-transplant procedure through death ]Mortality rates in subjects after successful completion of a bone marrow transplant
- Collection of adverse events [ Time Frame: Until the 6th Bone Marrow Transplant performed in subjects on study ]Determine the level of toxicity experienced by subjects who receive protocol treatment and bone marrow transplant
- Assess disease response [ Time Frame: Post-transplant procedure through death ]Review and assess the tumor response rate
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00741455
|United States, New Hampshire|
|Dartmouth-Hitchcock Medical Center|
|Lebanon, New Hampshire, United States, 03756|
|Principal Investigator:||John M Hill, MD||Dartmouth-Hitchcock Medical Center|
|Principal Investigator:||Kenneth R Meehan, MD||Dartmouth-Hitchcock Medical Center|