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Clinical Advisory: Randomized, Multi-Center, Phase III Study of Allogeneic Stem Cell Transplantation Comparing Regimen Intensity in Patients with Myelodysplastic Syndrome or Acute Myeloid Leukemia (BMT CTN 0901)

The National Institutes of Health's (NIH) National Heart, Lung, and Blood Institute (NHLBI) has suspended enrollment for the clinical study BMT CTN 0901 conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) after preliminary data appeared to show benefit for one approach to the intensity of conditioning for allogeneic stem cell transplantations in patients eligible for the study.

This trial, sponsored by the NHLBI and the NIH's National Cancer Institute (NCI), compares outcomes following myeloablative (high-intensity) conditioning versus reduced-intensity conditioning in preparation for allogeneic hematopoietic stem cell transplantation in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML); participants enrolled in this study must have been able to tolerate a high-intensity conditioning regimen. The specific patient inclusion and exclusion requirements are listed on the following page.

In this study, patients were randomized to either a myeloablative or a reduced-intensity conditioning regimen, with the choice of regimen, from the options below, left to the transplant center.

The 3 myeloablative (high-intensity) regimens allowed in this study were:

  1. Busulfan at high doses (16 mg/kg PO or 12.8 mg/kg IV) and Fludarabine (120-180 mg/m2)
  2. Busulfan at high doses (16 mg/kg PO or 12.8 mg/kg IV) and Cyclophosphamide (120 mg/kg)
  3. Cyclophosphamide (120 mg/kg) and Total Body Irradiation (1200-1420 cGy)

The 2 reduced-intensity conditioning regimens allowed in this study were:

  1. Fludarabine (120-180 mg/m2) and Busulfan at low doses (≤ 8 mg/kg PO or 6.4 mg/kg IV)
  2. Fludarabine (120-180 mg/m2) and Melphalan (≤ 150 mg/m2)

Graft sources included bone marrow or mobilized peripheral blood progenitor cells, but umbilical cord blood was not permitted. The use of anti-thymocyte globulin (ATG) was permitted, though not required, at the dose and schedule of ATG administration per institutional standards.

A preliminary data review by the NHLBI Data and Safety Monitoring Board (DSMB) appears to show that a sufficient number of patients have been enrolled to potentially answer the study objectives. Preliminary review of study data appears to suggest a benefit of the myeloablative conditioning regimens used in this study over the reduced-intensity conditioning regimens used in this study for patients who met the study's eligibility criteria.

The NHLBI accepted the recommendation of the DSMB, which is an independent advisory group of experts in stem cells therapy, biostatistics, medical ethics, and clinical trial design. The DSMB has been monitoring the study since it began in May 2011. The study enrolled 272 of an originally planned 356 participants at 32 transplant centers before enrollment of new study participants was permanently closed on April 18, 2014. The DSMB recommended that all patients currently enrolled in the study continue to receive their protocol-directed therapy and evaluations.

This medical advisory applies only to patients with myelodysplastic syndrome or acute myeloid leukemia who meet the same criteria used in the study. Inclusion criteria for study participants were:

  • Age 18 to 65 years old.
  • Diagnosis of MDS or AML with fewer than 5 percent myeloblasts in the bone marrow and no leukemic myeloblasts in the peripheral blood on morphologic analysis performed within 30 days of the conditioning regimen.
  • For those receiving treatment of their MDS or AML prior to transplantation: a) Interval between the start of the most recent cycle of conventional cytotoxic chemotherapy and enrollment must be at least 30 days; b) Interval between completing treatment with a hypomethylating agent or other non-cytotoxic chemotherapy and enrollment must be at least 10 days.
  • Must have a related donor who is a 7/8 or 8/8 match at HLA-A, -B, -C (serologic typing or higher resolution) and -DRB1 (at high resolution using DNA-based typing), or an unrelated donor who is a 7/8 or 8/8 match at HLA-A, -B, -C, and -DRB1 at high resolution using DNA-based typing.
  • Hematopoietic Stem Cell Transplant-Specific Comorbidity Index Score (HCT-CI) less than or equal to 4.
  • Organ function: a) Cardiac function: Ejection fraction greater than or equal to 40 percent, b) Hepatic function: total bilirubin less than or equal to 2 times the upper limit of normal and ALT and AST less than or equal to 3 times the upper limit of normal, c) Pulmonary function: DLCO percent (corrected for hemoglobin) greater than or equal to 40 percent and FEV1 greater than or equal to 50.
  • Creatinine clearance greater than or equal to 50mL/min based on the Cockcroft-Gault formula.

Exclusion criteria for study participants were:

  • Prior allograft or prior autograft.
  • Symptomatic coronary artery disease.
  • Leukemia involvement in the central nervous system (CNS) within 4 weeks of enrollment for patients with a history of prior CNS leukemia involvement (i.e., leukemic blasts previously detected in the cerebral spinal fluid).
  • Karnofsky Performance Score less than 70.
  • Patients receiving supplemental oxygen.
  • Planned use of donor lymphocyte infusion therapy.
  • Patients with uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms).
  • Patients seropositive for the human immunodeficiency virus (HIV).
  • Patients with prior malignancies, except resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent greater than 5 years previously allowed. Cancer treated with curative intent less than 5 years previously will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs.
  • Females who are pregnant or breastfeeding.
  • Fertile men and women unwilling to use contraceptive techniques during and for 12 months following treatment.

The trial's main objective was to compare survival rates between the two intensities of conditioning 18 months after the transplant procedure. Full results from the study will be available at a later date. While the study is no longer enrolling, participants who already have undergone a conditioning procedure will continue to be followed for the full 18 months, as specified in the study. There are about 13,000 new cases of MDS and 18,860 new cases of AML each year in the United States, according to the American Cancer Society, although not all persons with these diseases would be eligible for the treatments in this study.

Find more information about this clinical trial at http://clinicaltrials.gov/show/NCT01339910 or https://web.emmes.com/study/bmt2/protocol/0901_protocol/0901_protocol.html