Table 1.

Selected BMT CTN Studies with significant findings

EVALUATING CONDITIONING REGIMENS

0301 Phase I/II trial of fludarabine-based conditioning for allogeneic marrow transplantation from human leukocyte antigen (HLA)-compatible unrelated donors in severe aplastic anemia: Optimizing transplantation regimens for rare diseases is difficult and requires a multicenter effort. This study determined that fludarabine is not sufficiently immune suppressive to replace cyclophosphamide in conditioning regimens for unrelated donor transplantation for aplastic anemia. Additionally, it found excess toxicity with a commonly used dose of cyclophosphamide when combined with fludarabine. This unexpected finding is anticipated to change practice in many centers. (28,43)

0401 Phase III trial comparing Rituxan/BEAM versus Bexxar/BEAM prior to autologous HCT for persistent or relapsed chemotherapy-sensitive diffuse large B cell non-Hodgkin lymphoma (DLBCL): Determined that addition of radioimmunotherapy to the standard conditioning regimen of BEAM provides no clinical benefit for patients undergoing autologous HCT for DLBCL. Although several small Phase II studies suggested that dose-intensification might decrease relapse, the primary cause of treatment failure after autologous HCT for DLBCL, this study failed to show an impact on relapse but did show increased toxicity. Future trials will focus on maintenance strategies and/or immune therapies after HCT to improve disease control, marking a significant change in direction for the field. (24)

0601 Phase II trial of unrelated donor HCT for children with severe sickle cell disease using a reduced-intensity conditioning regimen: Determined that a reduced-intensity conditioning regimen of alemtuzumab, fludarabine, and melphalan, although effective for engraftment of bone marrow, was associated with unacceptably high levels of graft failure after cord blood transplantation in children with sickle cell anemia. This disappointing finding using cord blood indicates the need for novel strategies for the large number of sickle cell disease patients who cannot find an HLA-matched adult donor. (42)

GRAFT-VERSUS-HOST DISEASE (GVHD) PREVENTION AND TREATMENT

0303: A single-arm, multicenter Phase II trial of transplants of HLA-matched, CD34+ enriched, T cell depleted peripheral blood stem cells isolated by the CliniMACS system in the treatment of patients with acute myeloid leukemia (AML) in first or second complete remission: Confirmed, in a multicenter setting, the feasibility and consistency of T cell depletion by CD34 selection, with results in AML that warranted development of a Phase III trial versus non-T cell depleted transplantation. These data were used by the Food and Drug Administration in its determination to approve, for the first time, a CD-34 selection column for clinical use in the US. A Phase III trial comparing outcomes of CD34-selected transplants using this approach with standard bone marrow transplants followed by calcineurin-inhibitor based GVHD prophylaxis (BMT CTN 1301 PROGRESS II) has recently opened in the BMT CTN. (11)

0302: Initial systemic treatment of acute GVHD: a Phase II randomized trial evaluating etanercept, mycophenolate mofetil, denileukin diftitox, and pentostatin: Identified the most promising agent to move into a Phase III trial (see 0802 below). Data from this trial were also used to determine that GVHD biomarker panels can be used for early identification of patients at high or low risk for treatment non-responsiveness or death and that biomarker panels may provide opportunities for early intervention and improved survival following HCT. The wider use of biomarkers to identify patients at high risk of GVHD will allow us to tailor our therapies to better control this complication in these patients and to reduce toxicity in patients who are unlikely to benefit from intensive immune suppression. The BMT CTN is now incorporating biomarker-defined risk stratification into the design of its GVHD treatment trials. (14,18,21)

0802: A Phase III randomized, double blind trial evaluating corticosteroids with mycophenolate mofetil versus corticosteroids with placebo as initial systemic treatment of acute GVHD: Found no benefit in GVHD-free survival when mycophenolate mofetil was added to corticosteroids for initial therapy of acute GVHD requiring system treatment. Although these results were discouraging, the BMT CTN has used these data to focus on a newer therapeutic agent, sirolimus, in the upcoming BMT CTN 1501 study using a biomarker risk stratification developed in BMT CTN 0302 and 0802 to identify patients with standard risk who might be able to avoid corticosteroid therapy. Other agents are being considered for testing in patients with high risk acute GVHD. The Network’s ability to conduct GVHD trials in a timely manner allows for definitive Phase III results to be quickly disseminated and promising agents to be efficiently tested.

0402: A Phase III randomized, multicenter trial comparing sirolimus / tacrolimus with tacrolimus / methotrexate as GVHD prophylaxis after HLA-matched, related peripheral blood stem cell transplantation: Identified a high risk of toxicity when sirolimus is substituted for standard methotrexate for GVHD prophylaxis when the conditioning regimen includes busulfan, and no advantage in acute GVHD-free survival. Although this study showed a modest improvement in grade III–IV acute GVHD, the findings do not support substituting sirolimus for methotrexate since it may increase toxicity in patients who receive busulfan for conditioning, it was associated with higher risks of chronic GVHD, and it did not improve survival. Novel approaches to preventing GVHD are needed and are being explored in the accruing BMT CTN 1203 PROGRESS I and 1301 PROGRESS II studies. (25,35)

GRAFT SOURCES

0501: Multicenter, open label, randomized trial comparing single versus double umbilical cord blood transplantation in pediatric patients with leukemia and myelodysplasia: Demonstrated no survival benefit and more acute GVHD for children receiving infusion of two umbilical cord blood units versus one umbilical cord blood unit after transplantation for hematologic malignancies. This collaborative study with the Children’s Oncology Group indicates, unexpectedly, that increasing cell dose beyond the accepted minimum by adding another cord blood unit does not improve survival after cord blood transplantation in children and increases the risk of acute GVHD. This has important implications for future strategies to improve hematopoietic recovery and decrease transplant-related mortality after cord blood HCT. (27)

0201: A Phase III randomized, multicenter trial comparing G-CSF mobilized peripheral blood stem cell with marrow transplantation from HLA compatible unrelated donors: Found no difference in survival for recipients of unrelated donor peripheral blood versus bone marrow grafts, but an increased risk of chronic GVHD requiring prolonged immune suppression with peripheral blood grafts. Although peripheral blood has largely replaced bone marrow as a graft source for unrelated donor transplantation, this study suggests that this may not be appropriate in the myeloablative conditioning setting, which has important implications for clinical practice. This is the largest prospective study of unrelated donor transplantation ever performed. It would not have been possible without the infrastructure provided by the BMT CTN. An ancillary study shows that patients in this trial were representative of the larger population of patients receiving HCT during the time period. (10,57)

0603/0604: Multicenter, Phase II trials of non-myeloablative conditioning and transplantation of partially HLA-mismatched bone marrow / umbilical cord blood from unrelated donors in patients with hematologic malignancies: Confirmed single-center results in a multicenter setting using reduced-intensity conditioning and haploidentical bone marrow transplantation or double cord blood transplantation in adults with hematologic malignancies, with data supporting a subsequent Phase III trial. Acceptable outcomes of double cord and haploidentical bone marrow transplantation suggest that many more adults should be offered HCT, even when an HLA-matched adult donor is not available. These approaches are now being compared in a randomized Phase III trial (BMT CTN 1101). (3,51)

DISEASE TREATMENT

0704 (CALGB 100104): A Phase III, randomized, double-blind study of maintenance therapy with CC-5013 or placebo following autologous stem cell transplantation for multiple myeloma: Determined lenalidomide maintenance therapy dramatically improves progression-free survival and overall survival after autologous HCT for multiple myeloma. The BMT CTN was an important contributor to this study, which was led by Cancer and Leukemia Group B and used its Network and the CIBMTR database to devise an accrual plan that allowed the trial to successfully meet its enrollment target after initial accrual difficulties. The data have led to a major change in clinical practice, with most myeloma patients now receiving lenalidomide maintenance after transplantation. (5)

0502 (CALGB 100103): Phase II study of allogeneic HCT for older patients with AML in first morphologic complete remission using a non-myeloablative preparative regimen: Demonstrated the feasibility and effectiveness of allogeneic HCT using reduced intensity conditioning in this first prospective US cooperative group trial conducted in a homogeneously treated group of older AML patients in first remission. The study demonstrates that, with reduced-intensity conditioning, patients older than 60 can benefit from the graft-versus-leukemia effects of allogeneic HCT with outcomes similar to younger patients. These data should increase the use of HCT in older AML patients and provides justification for extending the upper age range in allograft trials. (4)

0701: Phase II trial of non-myeloablative allogeneic HCT for patients with relapsed follicular non-Hodgkin lymphoma beyond first complete response: Demonstrated that allogeneic HCT using a rituximab-containing reduced-intensity conditioning regimen confers high complete response rates, a low incidence of relapse / progression, and prolonged survival with acceptable toxicity in heavily pretreated follicular lymphoma patients.(68) This study provides justification for future trials comparing nontransplant with transplant salvage strategies in this disease, which has the potential to change practice.

SUPPORTIVE CARE

0101: A randomized double-blind trial of fluconazole versus voriconazole for the prevention of invasive fungal infections in allogeneic blood and marrow transplant recipients: Demonstrated that fluconazole, a low-cost antifungal agent, has similar efficacy and is generally more cost-effective than the newer and more expensive drug, voriconazole, in preventing serious fungal infections in the first 6 months after HCT but that voriconazole may be cost-effective for those undergoing allogeneic HCT for AML. This Phase III comparison of fluconazole and voriconazole indicates that newer is not always better and that, for most patients, standard fluconazole is effective fungal prophylaxis. However, an ancillary study suggested there is a subset of patients for whom primary antifungal prophylaxis with voriconazole may be more appropriate, allowing more informed treatment planning by transplant centers. (22,47) Both of these findings inform general HCT practice.

QUALITY OF LIFE

0902: A Phase III randomized, multicenter trial testing whether exercise or stress management improves functional status and symptoms of autologous and allogeneic recipients: Demonstrated no improvement in physical or mental quality of life with exercise training, stress management training, or combined stress management and exercise training compared to usual care. This trial tested modest, easily applied interventions in the early transplant period. While lack of an effect was disappointing, the trial enrolled more than 700 patients enrolled in 19 months, demonstrating that the BMT CTN has an effective infrastructure to conduct studies addressing quality of life issues. (20)