TAC/MTX vs. TAC/MMF/PTCY for Prevention of Graft-versus-Host Disease and Microbiome and Immune Reconstitution Study (BMT CTN 1703/1801) (1703/1801)

• ClinicalTrials.gov Identifier: NCT03959241
• Recruitment Status: Completed
• First Posted: May 22, 2019
• Results First Posted: January 12, 2024
• Last Update Posted: April 4, 2024
• Sponsor: Medical College of Wisconsin
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Blood and Marrow Transplant Clinical Trials Network; National Cancer Institute (NCI); National Marrow Donor Program
• Information provided by (Responsible Party): Medical College of Wisconsin

Study Description

Brief Summary:

1703: The study is designed as a randomized, phase III, multicenter trial comparing two acute graft-versus-host disease (aGVHD) prophylaxis regimens: tacrolimus/methotrexate (Tac/MTX) versus post-transplant cyclophosphamide/tacrolimus/mycophenolate mofetil (PTCy/Tac/MMF) in the setting of reduced intensity conditioning (RIC) allogeneic peripheral blood stem cell (PBSC) transplantation.

1801: The goal of this protocol is to test the primary hypothesis that the engraftment stool microbiome diversity predicts one-year non-relapse mortality in patients undergoing reduced intensity allogeneic HCT.

Condition or disease	Intervention/treatment	Phase
Acute Leukemia; Chronic Myelogenous Leukemia (CML); Myelodysplasia; Lymphoma	Procedure: Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Methotrexate; Drug: Tacrolimus; Drug: Methotrexate; Procedure: Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Mycophenolate Mofetil/Post-Transplant Cyclophosphamide; Drug: Mycophenolate Mofetil; Drug: Cyclophosphamide	Phase 3

Detailed Description:

1703: Graft-versus-Host Disease (GVHD) is a complication that affects many hematopoietic stem cell transplant (HSCT) patients; it occurs when the new cells from a transplant attack the recipient's body. The current standard GVHD prophylaxis regimen for patients with hematologic malignancies undergoing HSCT involves a combination of immunosuppressive agents given for the first 6 months after transplant.

The standard strategy of Tacrolimus/Methotrexate will be used as a control arm in comparison to one other treatment plan utilizing Tacrolimus/Mycophenolate Mofetil/Post-Transplant Cyclophosphamide. Study participants will receive an infusion of mobilized peripheral blood stem cell grafts on both arms. Study participants will be randomized to one of these two treatment arms.

1801: A relationship between the intestinal microbiota and graft-versus-host disease (GVHD) has long been appreciated but is still not well understood. Mice transplanted in germ-free conditions or treated with gut-decontaminating antibiotics developed less severe GVHD. Clinical studies initially suggested a benefit from near-total bacterial decontamination, but later showed no clear benefit and this approach was discontinued in the early 1990s. Partial gut decontamination continues to be practiced at many centers. More recently, the advent of next-generation sequencing (NGS) has resulted in cheaper and easier characterization of complex microbial mixtures. This has led to a renewed interest in evaluating the relationship between the microbiota and human health and disease, including recipients of hematopoietic cell transplantation (HCT). Similarly, NGS has also contributed to significant advancements in the investigator's understanding of immune reconstitution in HCT patients and how this may impact clinica outcomes.

The goal of this protocol is to test the primary hypothesis that the engraftment stool microbiome diversity predicts one-year non-relapse mortality in patients undergoing reduced intensity allogeneic HCT.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 431 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Patients will be randomized at a ratio of 1:1 between the treatment arms using permuted blocks of random sizes.
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: A Randomized, Multicenter, Phase III Trial of Tacrolimus/Methotrexate Versus Post-Transplant Cyclophosphamide/Tacrolimus/Mycophenolate Mofetil in Non-Myeloablative/Reduced Intensity Conditioning Allogeneic Peripheral Blood Stem Cell Transplantation (BMT CTN 1703; Progress III); Companion Study: Microbiome and Immune Reconstitution in Cellular Therapies and Hematopoietic Stem Cell Transplantation (BMT CTN 1801; Mi-Immune)
• Actual Study Start Date: June 25, 2019
• Actual Primary Completion Date: September 19, 2022
• Actual Study Completion Date: September 19, 2022

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Tacrolimus/Methotrexate; Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Methotrexate	Procedure: Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Methotrexate; Mobilized PBSC grafts will be administered on Day 0 to all patients according to individual institutional guidelines after appropriate processing and quantification has been performed by the local laboratory. Stem cells are administered through an indwelling central venous catheter. If infusion occurs over two days, Day 0 is the first day the infusion is initiated.; Other Name: HSCT; Drug: Tacrolimus; Tacrolimus will be given per institutional practices, orally at a dose of 0.05-0.06 mg/kg/day or intravenously at a dose of 0.02-0.03 mg/kg/day starting on Day -3. The dose of tacrolimus may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels per institutional guidelines with a suggested range of 5-15. If patients are on medications which alter the metabolism of tacrolimus (e.g.concurrent CYP3A4 inhibitors), the initial starting dose and subsequent doses should be altered as per institutional practices. Tacrolimus taper can be initiated at a minimum of 90 days post HCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices and patients should be off tacrolimus by Day 180 post HCT if there is no evidence of active GVHD.; Other Names: Prograf®; FK506; Drug: Methotrexate; Methotrexate will be administered at the doses of 15 mg/m2 IV bolus on Day +1, and 10 mg/m2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. Methotrexate should be dose reduced, given with leucovorin rescue, or held for complications such as severe mucositis per institutional guidelines.; Other Name: MTX
Experimental: Tacrolimus/MMF/PTCY; Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Mycophenolate Mofetil/Post-Transplant Cyclophosphamide	Procedure: Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Mycophenolate Mofetil/Post-Transplant Cyclophosphamide; Mobilized PBSC grafts will be administered on Day 0 to all patients according to individual institutional guidelines after appropriate processing and quantification has been performed by the local laboratory. Stem cells are administered through an indwelling central venous catheter. If infusion occurs over two days, Day 0 is the first day the infusion is initiated.; Other Name: HSCT; Drug: Tacrolimus; Tacrolimus will be given per institutional practices, orally at a dose of 0.05-0.06 mg/kg/day or intravenously at a dose of 0.02-0.03 mg/kg/day starting Day +5. Starting tacrolimus dose can be modified to account for possible drug interactions (e.g. concurrent CYP3A4 inhibitor use) according to institutional guides. Serum levels of tacrolimus will be measured at Day +7 and then should be checked weekly thereafter, and the dose adjusted accordingly to maintain a suggested level of 5-15 ng/mL. Tacrolimus taper can be initiated at a minimum of 90 days post HCT if there is no evidence of active GVHD. The rate of tapering will be done according to institutional practices but patients should be off tacrolimus by Day 180 post HCT if there is no evidence of active GVHD; Other Names: Prograf®; FK506; Drug: Mycophenolate Mofetil; MMF will be given at a dose of 15 mg/kg/dose ter in die (TID) (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1g TID, IV or PO). MMF prophylaxis will start Day +5 and discontinue after the last dose on Day +35, or may be continued if active GVHD is present.; Other Names: CellCept®; MMF; Drug: Cyclophosphamide; Cyclophosphamide [50 mg/kg ideal body weight (IBW); if actual body weight (ABW) < IBW, use ABW] will be given on Day +3 (between 60 and 72 hours after the start of the PBSC infusion) and on Day +4 post-transplant (approximately 24 hours after Day +3 cyclophosphamide). Cyclophosphamide will be given as an IV infusion over 1-2 hours (depending on volume).; Other Name: Cytoxan®

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With GVHD/Relapse or Progression-free Survival (GRFS) at One Year [ Time Frame: 1 year post randomization ]
   The primary endpoint is GRFS as a time to event endpoint from randomization. All randomized patients will be followed for one year; however, the primary endpoint will be analyzed as a time to event endpoint. The primary analysis will be done using the randomized population. An event for this time to event outcome is defined as grade III-IV acute GVHD, chronic GVHD requiring systemic immune suppression, disease relapse or progression, or death by any cause, whichever comes first. Time to event analyses were conducted. An unadjusted Kaplan-Meier analysis was done. Additionally, a multivariate Cox regression model adjusting for the following pre-specified covariates: age group (< 65 vs. 65+), disease risk index (low, intermediate, high/very high), planned RIC conditioning regimen (Fludarabine/Busulfan, Fludarabine/Melphalan, Other), donor type/HLA matching score (related 6/6, unrelated 7/8, unrelated 8/8), and planned use of post-transplant maintenance therapy (Yes vs. no).

Secondary Outcome Measures :

1. Percentage of Participants With Grades II-IV and III-IV Acute GVHD at Day 100 Post-transplant [ Time Frame: Days 100 post-transplant ]
   Acute GVHD was graded according to Mount Sinai aGVHD International Consortium (MAGIC) Criteria (Harris et al. 2016) with higher grade indicating worse outcomes. Grade I aGVHD is defined as Skin stage 1-2 and stage 0 for both GI and liver. Grade II is stage 3 skin, stage 1 GI, or stage 1 liver. Grade III is stage 2-3 GI or stage 2-3 liver. Grade IV is stage 4 skin or stage 4 liver. The cumulative incidence of acute GVHD grade II-IV and III-IV at Day 100 was estimated using the Aalen-Johansen estimator with 95% confidence intervals, treating death prior to aGVHD as a competing event. The cumulative incidences of Minnesota standard and high risk aGVHD at Day 100 were determined with 95% confidence intervals. Time to aGVHD is defined as time from transplant until onset of grades II-IV and III-IV aGVHD, respectively. A multivariate Cox regression model was used to compare the treatment groups, with adjustment for same baseline characteristics as for the primary endpoint.
2. Participants With Maximum Acute GVHD at One Year Post-transplant [ Time Frame: One year post-transplant ]
   Acute GVHD were graded according to Mount Sinai Acute GVHD International Consortium (MAGIC) Criteria (Harris et al. Biology of Blood and Marrow Transplantation 2016; 22:4-10). The higher acute GVHD grade indicates worse outcomes. Grade 0 is no acute GVHD of any organ. Grade I acute GVHD is defined as Skin stage of 1-2 and stage 0 for both GI and liver organs. Grade II is stage 3 of skin, or stage 1 of GI, or stage 1 of liver. Grade III is stage 2-3 for GI, or stage 2-3 of liver. Grade IV is stage 4 of skin, or stage 4 of liver. Max acute GVHD by one-year post-transplant was computed.
3. Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant [ Time Frame: Day 100 post-transplant ]
   Organ stages were graded according to Mount Sinai Acute GVHD International Consortium (MAGIC) Criteria (Harris et al. 2016). Higher stage in any organ indicates worse outcomes. For skin, stage 0-no GVHD rash; 1-Maculopapular Rash <25% BSA; 2-Maculopapular Rash 25-50% BSA; 3-Maculopapular Rash >50% BSA; 4-Generalized Erythroderma Plus Bullous Formation and Desquamation >5% BSA. For Lower GI, 0-No Diarrhea or Diarrhea-Adult: <500 mL/day, <3 Episodes/day; Child: <10 mL/kg/day, <4 Episodes/day; 1-Diarrhea-Adult: 500-999 mL/day, 3-4 Episodes/day; Child: 10-19.9 mL/kg/day, 4-6 Episodes/day; 2-Diarrhea-Adult: 1000-1500 mL/day, 5-7 Episodes/day; Child: 20-30 mL/kg/day, 7-10 Episodes/day; 3-Diarrhea-Adult: >1500 mL/day, >7 Episodes/day; Child: >30 mL/kg/day, >10 Episodes/day; 4-Severe Abdominal Pain With or Without Ileus or Grossly Bloody Stool. For liver, 0-Bilirubin <2.0 mg/dL; 1-Bilirubin 2.0-3.0 mg/dL; 2-Bilirubin 3.1-6.0 mg/dL; 3-Bilirubin 6.1-15.0 mg/dL; 4-Bilirubin >15.0 mg/dL
4. Participants With Maximum Stage of Upper GI at Day 100 Post-transplant [ Time Frame: Day 100 post-transplant ]
   Organ stages were graded according to Mount Sinai Acute GVHD International Consortium (MAGIC) Criteria (Harris et al. 2016). Higher stage in any organ indicates worse outcomes. For upper GI, stage 0 is no or intermittent nausea, vomiting, or anorexia; stage 1 is persistent nausea, vomiting, or anorexia. The maximum stages of Upper GI at patient level were summarized at Day 100.
5. Percentage of Participants With Chronic GVHD Post-transplant [ Time Frame: 6, 12 months post-transplant ]
   Percentage of participants with chronic GVHD (cGVHD) at one-year will be estimated with 95% confidence intervals for each treatment group using the cumulative incidence estimate with the complementary log-log transformation, treating death prior to cGVHD as a competing event. Chronic GVHD is based on NIH Consensus Criteria (2014 NIH Consensus Criteria) and includes mild, moderate and severe chronic GVHD. Eight organs were scored on a 0-3 scale to reflect degree of cGVHD involvement. Liver and pulmonary function test results and use of systemic therapy for treatment of cGVHD were also recorded. Assessment of cGVHD occurred up to one-year post-transplant. This endpoint considers any cGVHD onset. A multivariate Cox regression model for the cause-specific hazard of cGVHD was used to compare the treatment groups, after adjustment for baseline characteristics as described for the primary endpoint.
6. Number of Participants Experiencing Chronic GVHD With Maximum Severity at 12 Months Post-transplant [ Time Frame: 12 months post-transplant ]
   Chronic GVHD data were collected directly from providers and chart review as defined by the NIH Consensus Conference Criteria. Eight organs were scored on a 0-3 scale to reflect degree of chronic GVHD involvement per the NIH global severity scores of mild, moderate and severe chronic GVHD. The maximum severity of chronic GVHD through 12 months post-transplant will be tabulated by treatment arm.
7. Number of Participants With Immunosuppression-Free Survival (ISFS) at 1 Year Post-transplant [ Time Frame: 1 year post-transplant ]
   Participants who are alive, relapse-free, and do not need ongoing immune suppression (IS) to control GVHD at one year post-transplant are considered successes for the endpoint immunosuppression-free survival (ISFS). Immune suppression is defined as any systemic agents used to control or suppress GVHD. Corticosteroid doses greater than 10 mg were considered active systemic immune suppression treatment. Participants who discontinued immune suppression within 15 days or less prior to the 1-year time point was considered to be on immune suppression for this endpoint.
8. Percentage of Participants With Immunosuppression-Free Survival (ISFS) at 1 Year Post-transplant [ Time Frame: 1 year post-transplant ]
   Participants who are alive, relapse-free, and do not need ongoing immune suppression to control GVHD at one year post-transplant are considered successes for the endpoint immunosuppression-free survival (ISFS). Percentage of participants alive, relapse free, and off immune suppression at 1 year post-transplant were described for each treatment group, along with 95% Clopper-Pearson confidence intervals.
9. Percentage of Participants With Neutrophil Recovery Post-transplant [ Time Frame: Days 28 and day 100 post-transplant ]
   Neutrophil recovery is defined as achieving an absolute neutrophil count (ANC) greater than or equal to 500/mm^3 for three consecutive measurements on three different days. The first of the three days will be designated the day of neutrophil recovery. The competing event is death without neutrophil recovery. For participants who never drop ANC below 500/mm^3, the date of neutrophil recovery will be Day +1 post-transplant. The cumulative incidence of neutrophil recovery by Day 28 and Day 100 was described for each treatment group with point estimates and 95% confidence intervals using the complementary log-log transformation and treating death as a competing event.
10. Percentage of Participants With Platelet Recovery Post-transplant [ Time Frame: Day 60 and Day 100 post-transplant ]
    Platelet recovery is defined by two different metrics: the first day of a sustained platelet count greater than or equal to 20,000/mm^3 or greater than or equal to 50,000/mm^3 with no platelet transfusions in the preceding seven days. The first day of sustained platelet count above these thresholds will be designated the day of platelet engraftment. For participants who never drop their platelet count below 20,000/mm^3 or 50,000/mm^3, the date of platelet recovery will be Day +1 post HCT. The competing event is death without platelet recovery. The cumulative incidence estimate of platelet recovery by Day 60 and Day 100 were described by treatment group with 95% confidence intervals (complementary log-log transformation), treating death as a competing event.
11. Percentage of Participants With Lymphocyte Recovery Post-transplant [ Time Frame: Day 60, Day 100, 6 Months, and 1 year post-transplant ]
    Lymphocyte recovery is defined as the first day of sustained absolute lymphocyte count greater than or equal to 1000/mm^3. The competing event is death without lymphocyte recovery. The cumulative incidence estimate of Lymphocyte recovery were described by treatment group with 95% confidence intervals (complementary log-log transformation), treating death as a competing event.
12. Number of Participants With Each Level of Donor Cell Engraftment Post-transplant [ Time Frame: Day 28 and Day 100 post-transplant ]
    Donor cell engraftment were assessed with donor/recipient chimerism studies. Mixed chimerism is defined as the presence of donor cells, as a proportion of total cells to be less than 95% but at least 5% in the bone marrow or peripheral blood. Full donor chimerism is defined as greater than or equal to 95% of donor cells. Mixed and full chimerism will be evidence of donor cell engraftment. Donor cells of less than 5% will be considered as graft rejection. The number of participants with each level of chimerism described above is described as part of this outcome.
13. Summary Statistics for Donor Chimerism [ Time Frame: Day 28 and Day 100 post-transplant ]
    Donor cell engraftment were assessed with donor/recipient chimerism studies. Mixed chimerism is defined as the presence of donor cells, as a percentage of total cells to be less than 95% but at least 5% in the bone marrow or peripheral blood. Full donor chimerism is defined as greater than or equal to 95% of donor cells. Mixed and full chimerism will be evidence of donor cell engraftment. Donor cells of less than 5% will be considered as graft rejection. Donor chimerism at Day 28 and Day 100 after transplant in each of the randomized treatment arms will be described numerically as median and range for those evaluable.
14. Percentage of Participants With Disease Relapse at 1 Year Post-transplant [ Time Frame: 1 year post-transplant ]
    Disease relapse/progression is defined as being alive and free of relapse/progression of the primary disease. The time from transplant until relapse/progression of the primary disease, or cumulative incidence, was estimated at one-year post-transplant along with 95% CIs computed using the complementary log-log transformation, treating death prior to disease relapse as a competing event. A multivariate Cox regression model for the cause-specific hazard of relapse or progression will be used to compare the treatment groups, after adjustment for baseline characteristics as described for the primary endpoint.
15. Percentage of Participants With Treatment-related Mortality (TRM) Post-transplant [ Time Frame: Days 100, 180 and 1 year post-transplant ]
    An event for this endpoint TRM is death without evidence of disease progression or recurrence. Disease progression or recurrence will be considered a competing event. The time from transplant until TRM, or cumulative incidence, estimated at specific time points along with 95% CIs computed using the complementary log-log transformation, treating relapse/progression of the primary disease as a competing risk. A multivariate Cox regression model for the cause-specific hazard of TRM was used to compare the treatment groups, after adjustment for baseline characteristics as described for the primary endpoint.
16. Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant [ Time Frame: 1 year post-transplant ]
    All Grade 3-5 toxicities will be tabulated by grade for each randomized treatment arm, by type of toxicity as well as the peak grade overall. Toxicities were evaluated using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
17. Frequencies of Infections Categorized by Infection Type [ Time Frame: 1 year post-transplant ]
    All Grade 2 and 3 infections were reported according to the BMT CTN Technical Manual of Procedures (MOP) up to 1 year post-transplant. The frequency of Grade 2-3 infections and the number of participants experiencing infections occurring within 1 year post-transplant, are tabulated by treatment arm, organism, time period of infection onset, and severity, with Grade defined per the BMT CTN Technical MOP.
18. Number of Participants With Grade 2 and 3 Infections [ Time Frame: 1 year post-transplant ]
    All Grade 2 and 3 infections were reported according to the BMT CTN Technical Manual of Procedures (MOP) up to 1 year post-transplant. The frequency of Grade 2-3 infections and the number of participants experiencing infections occurring within 1 year post-transplant, are tabulated by treatment arm, organism, time period of infection onset, and severity, with Grade defined per the BMT CTN Technical MOP.
19. Percentage of Participants With Grade 2 and 3 Infections [ Time Frame: 6 months and 1 year post-transplant ]
    Grade 2 and 3 infections, as defined by the BMT CTN Technical Manual of Procedures (MOP), are reported on the study. The cumulative incidence of infections post transplantation, treating death as a competing risk, were compared between the treatment groups using the Gray's test.
20. Percentage of Participants With CMV at Day 100 Post-transplant [ Time Frame: Day 100 post-transplant ]
    The cumulative incidence of initiation of systemic treatment for CMV was compared between the treatment groups using the Gray's test, with death treated as a competing risk. Estimates of the cumulative incidence of CMV reactivation are provided at Day 100 post-transplant.
21. Percentage of Participants With Disease-Free Survival (DFS) at 1 Year Post-transplant [ Time Frame: 1 year post-transplant ]
    DFS is defined as being alive and free of relapse/progression of the primary disease. The time from transplant until death or relapse/progression (DFS failure) was described for each treatment arm using the Kaplan-Meier estimator, with numbers of subjects at risk at specific time points presented for each treatment group. A multivariate Cox regression model for the hazard of death will be used to compare the treatment groups, after adjustment for baseline characteristics as described for the primary endpoint.
22. Percentage of Participants With Overall Survival (OS) at 1 Year Post-transplant [ Time Frame: 1 year post-transplant ]
    The event for this endpoint OS is death from any cause post-transplant. Time to overall survival is defined as the time interval between date of transplant and date of death from any cause. Surviving participants will be censored at last follow-up or 1 year post-transplant, whichever comes first. The time from transplant until death from any cause was described graphically for each treatment arm using the Kaplan-Meier estimator, with numbers of subjects at risk at specific time points presented for each treatment group. A multivariate Cox regression model for the hazard of death will be used to compare the treatment groups, after adjustment for baseline characteristics as described for the primary endpoint.
23. Percentage of Participants With Lymphoproliferative Disease (PTLD) at 1 Year Post-Transplant [ Time Frame: 1 year Post-Transplant ]
    The cumulative incidence of lymphoproliferative disease at 1-year post-transplant is described with 95% confidence intervals for each treatment group using the Aalen-Johansen estimator, treating death as a competing event.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age 18.0 years or older at the time of enrollment on Segment A
2. Patients with acute leukemia or chronic myelogenous leukemia with no circulating blasts and with less than 5% blasts in the bone marrow
3. Patients with myelodysplasia/chronic myelomonocytic leukemia with no circulating blasts and with less than 10% blasts in the bone marrow (higher blast percentage allowed in MDS due to lack of differences in outcomes with <5% vs. 5-10% blasts in this disease)
4. Patients with relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma with chemosensitive disease at time of transplantation
5. Patients with lymphoma [follicular lymphoma, Hodgkin lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma and anaplastic large cell lymphoma] with chemosensitive disease at the time of transplantation
6. Planned reduced intensity conditioning regimen (see eligible regimens in Table 2.4a)

7. Patients must have a related or unrelated peripheral blood stem cell donor as follows:

   1. Sibling donor must be a 6/6 match for Human Leukocyte Antigen-A (HLA)-A and -B at intermediate (or higher) resolution, and -DRB1 at high resolution using DNA-based typing, and must be willing to donate peripheral blood stem cells and meet institutional criteria for donation.
   2. Unrelated donor must be a 7/8 or 8/8 match at HLA-A, -B, -C and -DRB1 at high resolution using DNA-based typing. Unrelated donor must be willing to donate peripheral blood stem cells and meet National Marrow Donor Program (NMDP) criteria for donation.
8. Cardiac function: Left ventricular ejection fraction at least 45%
9. Estimated creatinine clearance acceptable per institutional guidelines
10. Pulmonary function: Diffusing capacity of lung for carbon monoxide (DLCO) corrected for hemoglobin at least 40% and forced expiratory volume at one second (FEV1) predicted at least 50%
11. Liver function acceptable per institutional guidelines
12. Karnofsky Performance Score at least 60%
13. Female patients (unless postmenopausal for at least 1 year before the screening visit, or surgically sterilized), agree to practice two (2) effective methods of contraception at the same time, or agree to completely abstain from heterosexual intercourse, from the time of signing the informed consent through 12 months post-transplant (see Section 2.6.4 for definition of postmenopausal)
14. Male patients (even if surgically sterilized), of partners of women of childbearing potential must agree to one of the following: practice effective barrier contraception (see Section 2.6.4 for list of barrier methods), or abstain from heterosexual intercourse from the time of signing the informed consent through 12 months post-transplant
15. Plans for the use of post-transplant maintenance therapy must be disclosed upon enrollment and must be used irrespective of the outcome of the randomization. Please note that THIS DOES NOT INCLUDE INVESTIGATIONAL AGENTS and maintenance therapy with investigational treatment requires approval by the study chairs.
16. Voluntary written consent obtained prior to the performance of any study-related procedure that is not a part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

Exclusion Criteria:

1. Prior allogeneic transplant
2. Active central nervous system (CNS) involvement by malignant cells
3. Patients with secondary acute myeloid leukemia arising from myeloproliferative disease, including chronic myelomonocytic leukemia (CMML)
4. Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment.
5. Presence of clinically significant fluid collection (ascites, pleural or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated
6. Patients seropositive for human immunodeficiency virus (HIV) with detectable viral load. HIV+ patients with an undetectable viral load on antiviral therapy are eligible.
7. Myocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia.
8. Female patients who are pregnant (as per institutional practice) or lactating
9. Patients with a serious medical or psychiatric illness likely to interfere with participation in this clinical study
10. Patients with prior malignancies except resected non-melanoma skin cancer or treated cervical carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent < 5 years previously must be reviewed and approved by the Protocol Officer or Chairs.
11. Planned use of antithymocyte globulin (ATG) or alemtuzumab in conditioning regimen

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham

Birmingham, Alabama, United States, 35294

United States, California

City of Hope National Medical Center

Duarte, California, United States, 91010

University of California, San Francisco

San Francisco, California, United States, 94143

Stanford Hospital and Clinics

Stanford, California, United States, 94305

United States, Florida

University of Florida College of Medicine (Shands)

Gainesville, Florida, United States, 32610

University of Miami

Miami, Florida, United States, 33136

H. Lee Moffitt Cancer Center

Tampa, Florida, United States, 33624

United States, Georgia

Emory University

Atlanta, Georgia, United States, 30322

Blood & Marrow Transplant Program at Northside Hospital

Atlanta, Georgia, United States, 30342

United States, Illinois

University of Chicago

Chicago, Illinois, United States, 60637

Loyola University

Maywood, Illinois, United States, 60153

United States, Indiana

Indiana University Simon Cancer Center

Indianapolis, Indiana, United States, 46202

Indiana BMT - St. Francis Hospital

Indianapolis, Indiana, United States, 46327

United States, Iowa

University of Iowa Hospitals and Clinics

Iowa City, Iowa, United States, 52242-1009

United States, Kansas

University of Kansas Hospital

Kansas City, Kansas, United States, 66160

United States, Maryland

Johns Hopkins University

Baltimore, Maryland, United States, 21231

United States, Massachusetts

Dana Farber Cancer Institute/Brigham & Women's

Boston, Massachusetts, United States, 02115

Dana Farber Cancer Institute/Massachusetts General Hospital

Boston, Massachusetts, United States, 02115

United States, Michigan

University of Michigan

Ann Arbor, Michigan, United States, 48109

Karmanos Cancer Institute, Children's Hospital of Michigan

Detroit, Michigan, United States, 48201

United States, Minnesota

University of Minnesota

Minneapolis, Minnesota, United States, 55455

Mayo Clinic - Rochester

Rochester, Minnesota, United States, 55905

United States, Missouri

Washington University/Barnes Jewish Hospital

Saint Louis, Missouri, United States, 63110

United States, New York

Mount Sinai Medical Center

New York, New York, United States, 10029

Memorial Sloan-Kettering Cancer Center

New York, New York, United States, 10174

United States, North Carolina

University of North Carolina

Chapel Hill, North Carolina, United States, 27599

Duke University Medical Center

Durham, North Carolina, United States, 27705

United States, Ohio

University Hospitals of Cleveland/Case Western

Cleveland, Ohio, United States, 44106

Cleveland Clinic Foundation

Cleveland, Ohio, United States, 44195

Ohio State/Arthur G. James Cancer Hospital

Columbus, Ohio, United States, 43210

United States, Oregon

Oregon Health & Science University

Portland, Oregon, United States, 97239-3098

United States, Pennsylvania

University of Pennsylvania Cancer Center

Philadelphia, Pennsylvania, United States, 19104

United States, South Carolina

Medical University of South Carolina

Charleston, South Carolina, United States, 29425

United States, Texas

Baylor College of Medicine/The Methodist Hospital

Houston, Texas, United States, 77030

University of Texas, MD Anderson Cancer Research Center

Houston, Texas, United States, 77030

United States, Virginia

Virginia Commonwealth University, MCV Hospital

Richmond, Virginia, United States, 23298

United States, Washington

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States, 98109-1024

United States, Wisconsin

University of Wisconsin Hospital & Clinics

Madison, Wisconsin, United States, 53792-5156

Medical College of Wisconsin

Milwaukee, Wisconsin, United States, 53211

Sponsors and Collaborators

Medical College of Wisconsin

National Heart, Lung, and Blood Institute (NHLBI)

Blood and Marrow Transplant Clinical Trials Network

National Cancer Institute (NCI)

National Marrow Donor Program

Investigators

• Study Director: Mary Horowitz, MD, MS; Center for International Blood and Marrow Transplant Research

  Study Documents (Full-Text)

Documents provided by Medical College of Wisconsin:

Study Protocol  [PDF] November 16, 2020

Statistical Analysis Plan  [PDF] July 26, 2021

Informed Consent Form  [PDF] January 24, 2021

More Information

Additional Information:

Blood and Marrow Transplant Clinical Trials Network Website 

Publications:

Bolanos-Meade J, Hamadani M, Wu J, Al Malki MM, Martens MJ, Runaas L, Elmariah H, Rezvani AR, Gooptu M, Larkin KT, Shaffer BC, El Jurdi N, Loren AW, Solh M, Hall AC, Alousi AM, Jamy OH, Perales MA, Yao JM, Applegate K, Bhatt AS, Kean LS, Efebera YA, Reshef R, Clark W, DiFronzo NL, Leifer E, Horowitz MM, Jones RJ, Holtan SG; BMT CTN 1703 Investigators. Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis. N Engl J Med. 2023 Jun 22;388(25):2338-2348. doi: 10.1056/NEJMoa2215943.

• Responsible Party: Medical College of Wisconsin
• ClinicalTrials.gov Identifier: NCT03959241
• Other Study ID Numbers: BMT CTN 1703/1801; 2U10HL069294-11 ( U.S. NIH Grant/Contract )
• First Posted: May 22, 2019
• Results First Posted: January 12, 2024
• Last Update Posted: April 4, 2024
• Last Verified: April 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Results will be published in a manuscript and supporting information submitted to NIH BioLINCC (including data dictionaries, case report forms, data submission documentation, documentation for outcomes dataset, etc where indicated).
• Supporting Materials: Study Protocol; Informed Consent Form (ICF)
• Time Frame: Within 6 months of official study closure at participating sites.
• Access Criteria: Available to the public
• URL: https://biolincc.nhlbi.nih.gov/home/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Medical College of Wisconsin:

Acute Leukemia; Chronic Myelogenous Leukemia (CML); Myelodysplasia (MDS); Lymphoma; GVHD prophylaxis; Acute GVHD

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Preleukemia; Myelodysplastic Syndromes; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Myeloproliferative Disorders; Bone Marrow Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Precancerous Conditions; Mycophenolic Acid; Cyclophosphamide; Methotrexate; Tacrolimus; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents