Specialized Blood Cell Transplants for Cancers of the Blood and Bone Marrow

Phase 2

Completed

Conditions: Myelodysplastic Syndrome
Myeloproliferative Disorders
Acute Lymphoblastic Leukemia
Acute Myelogenous Leukemia
Chronic Myelogenous Leukemia

Interventions: Procedure: T-cell replete PBPC allograft
Drug: G-CSF
Drug: Methotrexate
Drug: Cyclosporine

Registration Number: NCT00003838

Lead Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Brief Summary: The are a variety of cancerous diseases of the blood and bone marrow that can be potentially cured by bone marrow transplantation (BMT). Diseases like leukemia, lymphoma, and multiple myeloma are among the conditions that can be treated with BMT.

Some patients with these diseases can be treated with medical chemotherapy alone. However, patients who relapse following chemotherapy are usually not curable with additional chemotherapy treatments. The only option known to provide a potential cure if this occurs is BMT.

Allogenic transplants are cells collected from relatives of the patient. The transplant requires additional high intensity chemotherapy and radiation in order to destroy cancerous cells. In the process, many normal bone marrow cells are also destroyed. This is the reason for transplanting stem cells. The stem cells help to build new functioning bone marrow, red cells, white cells, and platelets. In addition, the immune cells from the donor are implanted into the recipient s body and help to fight off infection and kill remaining cancerous cells.

Unfortunately, the powerful doses of chemotherapy and radiation therapy associated with allogenic BMT have toxic side effects and often make BMTs too dangerous to attempt in many patients.

In order to reduce the complications of BMT, and make it a safer available option for patients with cancers of the blood and bone marrow, researchers have developed a new approach to the BMT.

In this study researchers plan to use stem cells collected from the blood stream of patient s relatives rather than from the bone marrow (blood progenitor/stem cell transplant). In addition, researchers plan to use low doses of chemotherapy and no radiation therapy to reduce side effects. The majority of the cancer killing effect will be the responsibility of the stem cell transplant rather than the chemotherapy.

Detailed Description: 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 (MM) 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 hematopoietic cells.

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 BMT, 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 hematopoietic engraftment.

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 paroxysmal nocturnal hemoglobinuria (PNH) and refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS). However, the 30% risk of treatment-related mortality (TRM) 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 peripheral blood stem cell (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 PBSC 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 PBSCs 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 202

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group A: Stem Cell Transplant in High Risk for Transplant Related Complications and Mortality	T-cell replete PBPC allograft	Participants at high risk for transplant related complications and mortality will receive a non-myeloablative preparative regimen of cyclophosphamide 60mg/kg/d x 2 days, and fludarabine 25mg/m\^2 intravenously daily x 5 days followed by a peripheral blood hematopoietic progenitor cell graft targeted to deliver \>5x10\^6 CD34+ cells/kg.
Group B: Stem Cell Transplant in Debilitating Hematologic Diseases	T-cell replete PBPC allograft	Participants with hematologic diseases associated with reasonable longevity, shown to be curable by allogeneic Bone Marrow Transplant (BMT) but where concern for a high procedural mortality with conventional BMT will receive a non-myeloablative preparative regimen of cyclophosphamide 60mg/kg/d x 2 days, and fludarabine 25mg/m\^2 intravenously daily x 5 days followed by a peripheral blood hematopoietic progenitor cell graft targeted to deliver \>5x10\^6 CD34+ cells/kg.
Donor	G-CSF	The HLA matched donor will receive granulocyte colony-stimulating factor (G-CSF) with apheresis collections of PBPC on day 5 and day 6 if required. G-CSF will be administered based on body weight for at least 5, and up to 7 days, subcutaneously.
Group A: Stem Cell Transplant in High Risk for Transplant Related Complications and Mortality	Methotrexate	Participants at high risk for transplant related complications and mortality will receive a non-myeloablative preparative regimen of cyclophosphamide 60mg/kg/d x 2 days, and fludarabine 25mg/m\^2 intravenously daily x 5 days followed by a peripheral blood hematopoietic progenitor cell graft targeted to deliver \>5x10\^6 CD34+ cells/kg.
Group A: Stem Cell Transplant in High Risk for Transplant Related Complications and Mortality	Cyclosporine	Participants at high risk for transplant related complications and mortality will receive a non-myeloablative preparative regimen of cyclophosphamide 60mg/kg/d x 2 days, and fludarabine 25mg/m\^2 intravenously daily x 5 days followed by a peripheral blood hematopoietic progenitor cell graft targeted to deliver \>5x10\^6 CD34+ cells/kg.
Group B: Stem Cell Transplant in Debilitating Hematologic Diseases	Methotrexate	Participants with hematologic diseases associated with reasonable longevity, shown to be curable by allogeneic Bone Marrow Transplant (BMT) but where concern for a high procedural mortality with conventional BMT will receive a non-myeloablative preparative regimen of cyclophosphamide 60mg/kg/d x 2 days, and fludarabine 25mg/m\^2 intravenously daily x 5 days followed by a peripheral blood hematopoietic progenitor cell graft targeted to deliver \>5x10\^6 CD34+ cells/kg.
Group B: Stem Cell Transplant in Debilitating Hematologic Diseases	Cyclosporine	Participants with hematologic diseases associated with reasonable longevity, shown to be curable by allogeneic Bone Marrow Transplant (BMT) but where concern for a high procedural mortality with conventional BMT will receive a non-myeloablative preparative regimen of cyclophosphamide 60mg/kg/d x 2 days, and fludarabine 25mg/m\^2 intravenously daily x 5 days followed by a peripheral blood hematopoietic progenitor cell graft targeted to deliver \>5x10\^6 CD34+ cells/kg.

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Experienced Transplant Related Mortality	200 days	Number of Participants who experienced transplant related mortality by Day 200

Secondary Outcome Measures

Name	Time	Method
Number of Participants Overall Survival	enrollment to date of death, up to 5 years	Number of participants overall survival. Overall survival is defined as number participants alive following stem cell transplant
Number of Participants With Complete Donor Myeloid (CD34+) and T-cell (CD3+) Chimerism	Up to Day 100	Number of participants with complete donor myeloid chimerism. Myeloid (CD34+) and T-cell (CD3+) chimerisms were determined by PCR analysis of short tandem repeats (STR). Complete donor chimerism is defined as \>95% donor-derived cells in the peripheral blood in a specific lineage.
Median Days to Neutrophil Engraftment	Day 30	Median days to neutrophil recovery. Neutrophil recovery is defined as the first day of two consecutive days in which the ANC was 500 K/ml or greater unsupported by growth factors or granulocyte transfusion.
Number of Participants Who Experienced Acute GVHD Grades II-IV	Up to Day 100	Number of participants who experienced acute GVHD grades II-IV Acute-GVHD was graded and staged prospectively using criteria from the 1994 Consensus Conference on Acute-GVHD Grading. Grades are defined as: Grade II: Skin = rash on 25-50 percent body surface area; Liver = Total Bilirubin 3.1-6.0 mg/dL; Lower GI = Diarrhea 1001-1500 mL/day. Grade III: Skin = Rash on \>50% of body surface; Liver = Total Bilirubin 6.1 - 15.0 mg/dL; Lower GI = Diarrhea \> 1500 mL/day. Grade IV: Skin = Generalized erythroderma plus bullous formation; Liver = Total Bilirubin \>15 mg/dL; Lower GI = Severe abdominal pain with or without ileus. Grade II GVHD as moderate, grade III as severe, and grade IV life-threatening.
Number of Participant Who Experienced Chronic Graft Versus Host Disease Following Stem Cell Transplant	Day 100 up to 3 years	Number of participant who experienced chronic graft versus host disease (GVHD) following stem cell transplant The diagnosis of clinical features of chronic-GVHD was determined prospectively and classified retrospectively into limited or extensive based on the Revised Seattle Classification. Chronic GvHD severity categorized as "limited" is defined as: localized skin lesions with or without limited hepatic involvement and "extensive" is defined as: generalized skin involvement, major hepatic complications, or involvement of any other organ.
Number of Participants That Remained Disease-free Survival	Up to 5 years	Number of participants that remained Disease-free survival following stem cell transplant. Disease-free survival is defined as survival free of disease relapse or disease progression following stem cell transplant.