Blood and Marrow Clinical Trials Network (BMT CTN) A Phase III Randomized, Multicenter Trial Comparing Sirolimus/Tacrolimus With Tacrolimus/Methotrexate as Graft-versus-Host Disease Prophylaxis After HLA-Matched, Related Peripheral Blood Stem Cell Transplantation (0402) - Catalog


Blood and Marrow Clinical Trials Network (BMT CTN) A Phase III Randomized, Multicenter Trial Comparing Sirolimus/Tacrolimus With Tacrolimus/Methotrexate as Graft-versus-Host Disease Prophylaxis After HLA-Matched, Related Peripheral Blood Stem Cell Transplantation (0402)

Accession Number



BMT CTN-0402

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BSI Study IDs


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Specimen ID Type


Study Website

The Framingham Heart Study Group requires that the requestor must obtain full or expedited IRB/Ethics Committee review and approval to obtain these data. Waivers or a determination that the research is exempt from ethical regulations do not suffice.


Study type

Clinical Trial

Collection Type

Open BioLINCC Study

Cohort type



Drug: Tacrolimus

Drug: Methotrexate

Drug: Sirolimus

Study Open Date (Data)


Study Open Date (Specimens)


Date materials available


Last updated


Study period

November 2006 - October 2015

Study Contacts
NHLBI Division



Blood Disease

HIV study classification


COVID study classification


Pre-Website # of Specimens Shipped


# of Returned Specimens



Leukemia, Lymphocytic, Acute
Leukemia, Myelocytic, Acute
Leukemia, Myeloid, Chronic
Myelodysplastic Syndromes


The primary objective was to determine if the combination of tacrolimus and sirolimus (Tac/Sir) was more effective than tacrolimus and methotrexate (Tac/Mtx) in preventing acute graft-versus-host disease and early mortality after allogeneic related donor hematopoietic cell transplantation.


Stem cell transplantation is a standard therapy for leukemia and myelodysplastic disorders. Recipients of human leukocyte antigen (HLA)-matched, related donor (MRD) stem cell transplants are at risk for a number of infections and complications. One of these complications is a condition known as acute graft-versus-host disease (GVHD). Recipients of HLA-MRD stem cell transplants for the treatment of myelodysplastic disorders and leukemia experience a 35% incidence of GVHD. Furthermore, GVHD contributes significantly to 1-year early treatment-related mortality (TRM) estimates of approximately 20%.

The standard prophylaxis regimen for GVHD is a calcineurin inhibitor combined with methotrexate. Calcineurin inhibitors block calcineurin, a protein phosphatase that catalyzes some of the intracellular processes associated with T-lymphocyte activation. Inhibition is achieved by binding to immunophilins. The result is reduced production of interleukin-2 and reduced proliferation of T-cells. Methotrexate, an antineoplastic antimetabolite, has immunosuppressant properties that prevents the synthesis of tetrahydrofolate. Tetrahydrofolate is necessary for synthesis of thymidylate, an essential component of DNA. Of particular clinical concern is the theory that the injury caused by methotrexate to tissues could play a contributory role in initiation of the cytokine cascade associated with GVHD.

The standard prophylaxis regimen for GVHD was established in the mid-1980s. Minor alterations to the standard regimen have shown limited effect on TRM outcomes in spite of the improvements that have been made to allogeneic hematopoietic cell transplantation (HCT) outcomes. Sirolimus, a rapamycin inhibitor, has been suggested as an alternative for methotrexate. Previous studies have suggested that sirolimus use results in decreased incidence of acute GVHD and treatment-related toxicity after HLA-MRD and unrelated donor transplantation, at the expense of higher rates of endothelial injury syndromes. Sirolimus has additional immunomodulatory properties that include effects on antigen-presenting cells, the thymus, and preservation of regulatory T-cell subsets after transplantation. The purpose of this study was to determine if sirolimus, in place of methotrexate, would produce improved outcomes in GVHD and TRM.


Eligible participants were 2 to 60 years of age, of either gender, and were undergoing transplantation for one of the following conditions: acute leukemia in remission, myelodysplastic disorder, or chronic myeloid leukemia in chronic or accelerated phase. All participants were required to have a 6/6 Class I HLA-A and B and molecular Class II DRB1 matched sibling donor medically able and willing to donate peripheral blood stem cells that also met institutional criteria for stem cell donation.

Participants were excluded from participating in the trial for the following: prior allogenic or autologous transplant, HIV or another uncontrolled active infection, pregnant or breast-feeding, known allergy to sirolimus, requiring voriconazole at time of study entry, currently receiving another investigational drug (unless cleared by protocol officer or chair), or participants with a history of cancer.

Participants were excluded from continuation for the following laboratory criteria if measured within 4 weeks of study entry: measured creatinine clearance <50mL/min/1.72m2 ; direct bilirubin, ALT, or AST greater than two times the upper limit of normal; cholesterol or triglycerides level >500mg/dL; forced vital capacity (FVC) or forced expiratory volume (FEV1) <60% predicted value, corrected for Hemoglobin (adults only); overt hypoxemia in children measured by <92% SaO2; cardiac ejection fraction >45% in adults or <26% children.

A total of 304 participants were enrolled in the study. 151 participants were randomized to the tacrolimus/sirolimus (Tac/Sir) treatment, which 149 completed and 2 did not undergo transplantation. 153 participants were randomized to the tacrolimus/methotrexate (Tac/Mtx) treatment, which 152 completed and 1 did not undergo transplantation.


BMT 0402 was an interventional study with the purpose of determining the best combination of medications for the prevention of GVHD after HLA-MRD peripheral blood stem cell transplantation. Two GVHD prophylaxis conditioning regimens were tested: tacrolimus/sirolimus (Tac/Sir) and tacrolimus/methotrexate (Tac/Mtx). The study was Phase III, and designed to be multicenter, randomized, open label, and with parallel assignment treatment arms. Randomization occurred within 7 days of initiation of pretransplantation conditioning therapy, and was performed in a 1:1 ratio with the use of random block sites, stratified by transplantation center. The transplant physician selection of treatment occurred prior to participant’s assignment to the study. All parties involved in the trial knew the treatment arm assigned to each participant.

Participants received pretransplantation myeloablative conditioning with total body irradiation in combination with either cyclophosphamide or etoposide. Initially, a conditioning regimen comprised of myeloablative doses of busulfan with CY was permitted, however this was removed due to excess toxicity and veno-occulusive disease of the liver. The participants that received busulfan-based conditioning were not included in the primary outcome analyses. PBSC donors received filgrastim and underwent large volume apheresis with a goal of collecting 2 to 10 × 106/kg CD34+ stem cells. No graft manipulation was allowed prior to the infusion of the stem-cell product.

For GVHD prophylaxis, tacrolimus was begun on day −3 for all participants at a dose of 0.02 mg/kg/day by continuous IV infusion, adjusted to maintain a serum concentration of 5 to 10 ng/mL. For participants in the Tac/Sir group, sirolimus was started on day −3 with a 12 mg oral loading dose, followed by daily oral doses of 4 mg, adjusted to maintain a serum trough concentration of 3 to 12 ng/mL. For participants in the Tac/Mtx group, methotrexate was IV administered on day +1 (15 mg/m2), +3, +6, and +11 (10 mg/m2 each day).

The primary endpoint of grades II-IV acute GVHD-free survival was assessed 114 days from the time of randomization based on intention-to-treat. The study had 80% power to detect a 15% difference between the 2 prophylaxis strategies based on the standardized difference in Kaplan-Meier estimates with a 2-sided α of 5%. A committee of investigators blinded to GVHD prophylaxis assignment reviewed all case records, focusing on the incidence of acute and chronic GVHD, relapse, toxicity, and causes of death. Participants were followed for two years after transplantation for evaluation of secondary endpoints, which included cumulative incidence of acute GVHD, time to neutrophil and platelet engraftment, mucositis severity, rate of veno-occlusive disease, thrombotic microangiopathy infection, cytomegalovirus reactivation, treatment-related mortality, malignant disease relapse, all infections, overall survival, and time to discharge after transplant.


Participants who received Tac/Sir engrafted significantly earlier and had significantly less severe oropharyngeal mucositis after transplantation; however, no difference was observed in the primary end point of GVHD-free survival at 114 days post randomization between participants treated with Tac/Sir and Tac/Mtx.

Blood. 2014 Aug 21; 124(8): 1372–1377.

Disease classification


Mat types

WBC Pellets

The study population available in BioLINCC study data may be lower than total study enrollment due to Informed Consent restrictions and other factors.

  • Subjects

    Total of 304 subjects:
    151 in the Sirolimus/Tacrolimus arm
    153 in the Tacrolimus/Methotrexate arm

    Last Modified: May 1, 2017, 11:50 a.m.
  • Age
      Sirolimus/Tacrolimus Tacrolimus/Methotrexate All
    N % N % N %
    10 - <15 0 0 1 0.65 1 0.33
    15 - <20 4 2.65 3 1.96 7 2.30
    20 - <25 4 2.65 6 3.92 10 3.29
    25 - <30 12 7.95 19 12.42 31 10.20
    30 - <35 13 8.61 12 7.84 25 8.22
    35 - <40 15 9.93 19 12.42 34 11.18
    40 - <45 28 18.54 25 16.34 53 17.43
    45 - <50 40 26.49 29 18.95 69 22.70
    50 - <55 25 16.56 24 15.69 49 16.12
    55 - <60 10 6.62 15 9.80 25 8.22


    Last Modified: May 1, 2017, 11:50 a.m.
  • Sex
      Sirolimus/Tacrolimus Tacrolimus/Methotrexate All
    N % N % N %
    Male 77 50.99 85 55.56 162 53.29
    Female 74 49.01 68 44.44 142 46.71


    Last Modified: May 1, 2017, 11:50 a.m.
  • Race
      Sirolimus/Tacrolimus Tacrolimus/Methotrexate All
    N % N % N %
    White 133 88.08 130 84.97 263 86.51
    Black 7 4.64 6 3.92 13 4.28
    Asian 5 3.31 5 3.27 10 3.29
    Other or Unknown 3 1.99 9 5.88 12 3.95
    Not Answered 3 1.99 3 1.96 6 1.97

    Last Modified: May 1, 2017, 11:50 a.m.

Please note that biospecimen availability is subject to review by the NHLBI, BioLINCC, and the NHLBI Biorepository. Certain biospecimens may not be made available for your request. Section 3 of the BioLINCC handbook describes the components of the review process

  • Material Types

    Plasma, Serum, White blood cells

    Last Modified: May 1, 2017, 11:50 a.m.
  • General Freeze/Thaw Status

    Last Modified: Oct. 26, 2018, 11:49 a.m.
  • Visits (Vials)


      Serum Plasma White Blood Cells Total
    Day 0 2,132 744 0 2,876
    Day 28 1,978 501 0 2,479
    Day 100 1,750 435 0 2,185
    Day 180 1,558 843 0 2,401
    Day 270 87 54 0 141
    Day 365 1,234 646 0 1,880
    Day 730 868 593 0 1,461
    Donor 282 938 919 2,139


    Last Modified: Oct. 26, 2018, 11:49 a.m.
  • Visits (Subjects)
    Total number of subjects Average volume (ml) per subject
    Day 0 243 4.63
    Day 28 233 4.77
    Day 100 213 4.78
    Day 180 184 4.77
    Day 270 9 4.71
    Day 365 151 4.49
    Day 730 99 4.66
    Donor 30 4.44
    Total number of subjects Average volume (ml) per subject
    Day 0 230 1.98
    Day 28 206 1.50
    Day 100 185 1.54
    Day 180 183 2.71
    Day 270 9 3.35
    Day 365 150 2.64
    Day 730 99 3.55
    Donor 175 2.76
      White Blood Cells
    Total number of subjects Average vials per subject
    Donor 145 6.34

    Last Modified: Oct. 26, 2018, 11:49 a.m.