Objectives

To examine the safety and effectiveness of a non-myeloablative stem cell transplant using umbilical cord blood as a treatment option for patients with leukemia or lymphoma and no suitable related donor.

Background

Chemotherapy is a common treatment option for patients with aggressive forms of the blood cancers leukemia and lymphoma, but other treatment methods may need to be considered if the cancer does not respond well to chemotherapy, or if the cancer returns. In such cases, it may be recommended that the patient receive a stem cell transplant, commonly using donated bone marrow. A first degree relative is likely to be the best candidate for donation if the human leukocyte antigen (HLA) markers are a sufficient match. For patients lacking a HLA-matched related donor, it is routine to initiate an unrelated donor search. However some patients, particularly ethnic minorities, experience disease progression while awaiting identification of a suitably HLA-matched donor. Recently, stem cell transplants using umbilical cord blood have become a viable alternative option to treat these types of cancers.

Typically patients undergoing a stem cell transplant receive high doses of chemotherapy before the transplant to prepare their bodies to accept the donor stem cells. In this study, participants received a type of stem cell transplant called a non-myeloablative transplant, which is a reduced intensity conditioning (RIC) method of transplantation that does not require high doses of chemotherapy. RIC can be preferable in patients that are older and less clinically fit, and therefore less able to withstand the chemotherapeutic agents’ toxicity levels.

The BMT CTN 0604 study was one of two parallel multicenter phase 2 studies; the other of which was BMT CTN 0603, which used partially HLA-mismatched related bone marrow (Haplo-marrow) transplantation. The goal of these studies was to generate pilot multicenter data to support a future phase 3 randomized clinical trial.

Participants

Patients less than 71 years of age with acute leukemia or lymphoma and lacking a suitable HLA-matched related donor were eligible to participate. Patients less than 22 years of age were eligible if they were ineligible for the BMT CTN 0501 trial. Acute leukemia was required to be in morphologic complete remission. Large-cell, mantle-cell, and Hodgkin lymphomas were required to have achieved at least a partial remission with treatment before allogeneic hematopoietic cell transplantation. Low-grade lymphoma patients were required to have failed two prior chemotherapy regimens. Patients who had undergone prior autologous transplantation were not excluded as long as three months had elapsed since the procedure. Participants were also required to have adequate organ function, including a left ventricular ejection fraction of at least 35% and specific liver, kidney, pulmonary, and physical functioning scores within acceptable ranges. A total of 54 individuals were enrolled in the study and 50 were included in the analysis.

Design

Participants underwent a reduced intensity conditioning regimen prior to receiving the double umbilical cord blood (dUCB) transplant, which included two chemotherapeutic agents, cyclophosphamide and fludarabine, and a small dose of radiation. Cyclophosphamide was administered intravenously at 50 mg/kg six days before the transplant. Fludarabine was administered intravenously at 40 mg/m2 (adjusted for creatinine clearance) each day for five days before the transplant. A single dose of 200 cGy total body irradiation was performed one day prior to transplantation. Participants also received cyclosporine and mycophenolate mofetil (MMF) beginning three days before the transplant as prophylaxis for graft-versus-host-disease (GVHD). Participants could receive tacrolimus instead of cyclosporine.

At transplantation, patients received two partially HLA-matched umbilical cord blood units from unrelated donors. The maximum allowable mismatch between the UCB unit and the recipient, or between the UCB units, was 2 of 6 HLA loci. Each unit contained a minimum of 1.5 × 107 nucleated cells, or 2.0 × 107 for units that were not red cell depleted, per kilogram of recipient weight. Units were thawed and infused per institutional practice after validation using methods approved by the study. After transplantation, filgrastim, a granulocyte-colony stimulating factor, was initiated at 5 μg/kg a day and continued until the absolute neutrophil count was at least 2000/μL for three consecutive days. Participants continued to receive MMF for 30 days after the transplant or 7 days after engraftment, whichever was later, and cyclosporine or tacrolimus until 180 to 200 days after the transplant. Supportive care, including blood product administration, prophylaxis, therapy for infection, and treatment of GVHD, was at the discretion of treating physicians and transplantation center practices.

The primary outcome was participant survival from the time of transplant to 180 days. Secondary end points included progression-free survival and cumulative incidences of hematopoietic recovery, acute or chronic GVHD, relapse, and non-relapse mortality.

Conclusions

Survival at 180 days after double umbilical cord blood transplant was 74%. Collectively, the results of BMT CTN 0603 and 0604 confirm the utility of dUCB and Haplo-marrow as alternative donor sources for reduced intensity conditioning hematopoietic cell transplantation, providing a rationale for an additional clinical trial to assess the relative efficacy of these two strategies.

Brunstein CG, Fuchs EJ, Carter SL, et al. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood. 2011;118(2):282-288. doi:10.1182/blood-2011-03-344853.

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