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Calcineurin Inhibitor-Free Interventions BMT CTN 1301 for Prevention of Graft-versus-Host Disease (BMT CTN 1301)

Sponsor
National Heart, Lung, and Blood Institute (NHLBI) (NIH)
Overall Status
Completed
CT.gov ID
NCT02345850
Collaborator
Blood and Marrow Transplant Clinical Trials Network (Other), National Cancer Institute (NCI) (NIH)
346
Enrollment
28
Locations
3
Arms
62.2
Actual Duration (Months)
12.4
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The study is designed as a three arm randomized Phase III, multicenter trial comparing two calcineurin inhibitor (CNI)-free strategies for Graft-versus-Host Disease (GVHD) prophylaxis to standard tacrolimus and methotrexate (Tac/Mtx) in patients with hematologic malignancies undergoing myeloablative conditioning hematopoietic stem cell transplantation.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

Chronic Graft-versus-Host Disease (GVHD) is a complication that affects many hematopoietic stem cell transplant (HSCT) survivors; 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. Often, patients develop GVHD and continue on these agents for much longer periods. The combination of calcineurin inhibitors (tacrolimus and cyclosporine A) with methotrexate (MTX) is the most common GVHD prophylaxis used worldwide in the context of myeloablative conditioning transplants. This regimen demonstrates better control of acute GVHD, but is less effective against chronic GVHD. Management of chronic GVHD remains a challenge and it has become a significant health problem in transplant survivors with more frequent use of mobilized peripheral blood stem cells. Additionally, several issues arise with the standard approach including various toxicity symptoms and side effects, increased risk of thrombotic microangiopathy due to CNI, no prevention of other infectious diseases, and no prevention for disease relapse.

This standard strategy of Tac/MTX will be used as a control in comparison to two other treatment plans both utilizing CNI-free methods: CD34 selected T-cell depletion in peripheral blood stem cell (PBSC) grafts, and infusion of bone marrow (BM) grafts followed by post-transplant Cyclophosphamide (PTCy). Study participants will be randomized to one of these three treatment arms.

Study Design

Study Type:
Interventional
Actual Enrollment :
346 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Prevention
Official Title:
A Randomized, Multi-Center, Phase III Trial of Calcineurin Inhibitor-Free Interventions for Prevention of Graft-versus-Host Disease (BMT CTN 1301; Progress II)
Actual Study Start Date :
Aug 1, 2015
Actual Primary Completion Date :
Oct 5, 2020
Actual Study Completion Date :
Oct 5, 2020

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Tacrolimus/Methotrexate Control Arm

Unmanipulated bone marrow graft with Tacrolimus/Methotrexate GVHD prophylaxis. Tacrolimus will be maintained at therapeutic doses for a minimum of 90 days. Methotrexate will be dosed at 5-15mg/m^2 for a maximum of 4 doses post-transplant. Cyclosporine may be substituted for tacrolimus if the patient is intolerant of tacrolimus or per institutional practice.

Procedure: Unmanipulated Bone Marrow Graft with Tacrolimus/Methotrexate
Unmanipulated BM 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.

Drug: Tacrolimus
Tacrolimus will be given orally or intravenously per institutional standards starting 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, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of tacrolimus (e.g. azoles), 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 HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD.
Other Names:
  • Prograf®
  • FK506

    • Drug: Methotrexate
    Methotrexate will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of methotrexate should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices. Leucovorin rescue is allowed according to institutional practices.
    Other Names:
  • MTX

    		•
    Experimental: CD34 Selection Arm

    Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products.

    Procedure: Mobilized CD34-selected Peripheral Blood Stem Cell graft
    Mobilized CD34-selected 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.
    Experimental: Post Transplant Cyclophosphamide

    Unmanipulated Bone Marrow Graft with Cyclophosphamide

    Procedure: Unmanipulated Bone Marrow Graft with Cyclophosphamide
    Unmanipulated BM 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.

    Drug: Cyclophosphamide
    Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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 Names:
  • Cytoxan®

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Chronic GVHD-free, Relapse-free Survival (CRFS) Probability [2 years]

      The primary endpoint of the trial is Chronic GVHD/Relapse-Free Survival (CRFS), treated as a time to event variable. An event for this time to event outcome is defined as moderate to severe chronic GVHD, disease relapse, or death by any cause. Participant will be censored if lost to follow up prior to 2 years. Time is from randomization to the event of moderate to severe chronic GVHD, disease relapse, death, last follow up, or 2 years, whichever comes first. The primary analysis is performed using the intent-to-treat principle (ITT) so that all randomized patients are included in the analysis.

    Secondary Outcome Measures

    1. Percentage of Participants With Overall Survival (OS) [2 Years]

      OS is a key secondary endpoint, with explicit control of the type I error rate through a gatekeeper approach. Formal significance testing of OS between a CNI-free strategy and the control will be conducted if the corresponding CRFS comparison is significant. This OS comparison will be done using a Bonferroni adjusted significance level of 0.05/3 to account for three potential CNI-free comparisons to the control. Otherwise, survival analyses will be considered exploratory. Death from any cause is considered as event for this endpoint. Participant is censored if lost to follow up.

    2. Percentage of Participants With Relapse-free Survival [2 Years]

      The events for this endpoint RFS are death and relapse of the underlying malignancy. The analyses of this endpoint use the transplanted populations and time is from transplant to the event of disease relapse or death, or last follow up, whichever comes first.

    3. Percentage of Participants With Treatment-related Mortality [2 Years]

      The events for this endpoint TRM are deaths prior to relapse of the underlying malignancy. The analyses of this endpoint will use the transplanted populations, and time will be from transplant to the first of disease relapse, death, or last follow up. TRM are evaluated using the cumulative incidence function. Deaths without relapse are the events for this endpoint and relapse is a competing risk for this endpoint.

    4. Participants With Immunosuppression-free Survival [1 Year]

      Patients who are alive, relapse-free, and do not need ongoing immune suppression to control GVHD at one year post HSCT are considered successes for this endpoint. Immune suppression is defined as any systemic agents used to control or suppress GVHD.

    5. Percentage of Participants With Disease Relapse [2 Years]

      Relapse is defined by either morphological evidence of acute leukemia or MDS consistent with pre-transplant features, or radiologic evidence of lymphoma, documented or not by biopsy. The event is defined as increase in size of prior sites of disease or evidence of new sites of disease, documented or not by biopsy. Relapse is adjudicated by ERC. Disease relapse is analyzed using cumulative incidence function with death as a competing risk. The analyses of this endpoint use the transplanted populations, and the time will be measured from transplant to the earliest of death, relapse/progression, or last follow up.

    6. Percentage of Participants With Neutrophil Engraftment [Day 28]

      Neutrophil recovery is defined as achieving an absolute neutrophil count (ANC) ≥ 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.

    7. Percentage of Participants With Platelet Recovery [Day 60]

      Platelet recovery is defined as the first day of a sustained platelet count >20,000/mm^3 with no platelet transfusion in the preceding seven days. The first day of sustained platelet count above this threshold will be designated the day of platelet engraftment. The competing event is death without platelet recovery.

    8. Participants With Primary Graft Failure [Day 28]

      Primary graft failure is defined as no neutrophil recovery to > 500 cells/µL by Day 28 post HSCT.

    9. Percentage of Participants With Secondary Graft Failure [2 Years]

      Secondary graft failure will be assessed according to neutrophil count after initial hematologic recovery. Secondary graft failure is defined as initial neutrophil engraftment followed by subsequent decline in absolute neutrophil counts < 500 cells/µL, unresponsive to growth factor therapy, but cannot be explained by disease relapse or medications. Secondary graft failure will be analyzed using cumulative incidence function with death as a competing risk.

    10. Percentage of Participants With Acute GVHD [Day 100]

      Cumulative incidences of grade II-IV and III-IV acute GVHD were determined. Death prior to acute GVHD is treated as the competing risk. Grading of acute GVHD was derived by consensus grading (Przepiorka 1995) per BMTCTN manual of procedures (MOP). The acute GVHD algorithm calculates the grade based on the organ (skin, GI and liver) stage and etiology/biopsy reported on the weekly GVHD form. Staging for skin: Stage 1. <25% rash; 2. 25-50%; 3. >50%; 4. generalized erythroderma with bullae. Staging for GI: Stage 1. Diarrhea>500ml/d or persistent nausea; 2. >1000ml/d; 3. >1500ml/d; 4. Large volume diarrhea and severe abdominal pain +- ileus. Staging for Liver: Stage 1. bilirubin 2-3mg/dl; 2. bilirubin 3-6 mg/dl; 3. bilirubin 6-15 mg/dl; 4. bilirubin>15mg/dl. Grade 4 is the worst outcome.

    11. Participants With Maximum Acute GVHD [Day 100]

      Grading of acute GVHD was derived by consensus grading (Przepiorka 1995) per BMTCTN manual of procedures (MOP). The acute GVHD algorithm calculates the grade based on the organ (skin, GI and liver) stage and etiology/biopsy reported on the weekly GVHD form. Grade I aGVHD is defined as Skin stage of 1-2 and stage 0 for both GI and liver organs. Grade II aGVHD is stage 3 of skin, or stage 1 of GI, or stage 1 of liver. Grade III is stage 2-4 for GI, or stage 2-3 of liver. Grade IV is stage 4 of skin, or stage 4 of liver. Max acute GVHD by Day 100 was computed.

    12. Percentage of Participants With Chronic GVHD [2 Years]

      The cumulative incidence of chronic GVHD will be determined. Death prior to acute GVHD is treated as the competing risk. Data will be collected directly from providers and chart review according to the recommendations of the NIH Consensus Criteria. Eight organs will be scored on a 0-3 scale to reflect degree of chronic GVHD involvement. Liver and pulmonary function test results and use of systemic therapy for treatment of chronic GVHD will also be recorded. This secondary endpoint of chronic GVHD will include mild, moderate and severe chronic GVHD based on NIH Consensus Criteria.

    13. Percentage of Participants With Chronic GVHD-free Survival [2 Years]

      The event for this endpoint includes moderate to severe chronic GVHD according to NIH consensus criteria global score, or death by any cause.

    14. Participants With Grade ≥ 3 Toxicity [2 Years]

      All grades ≥ 3 toxicities according to CTCAE, version 4 will be tabulated for each intervention arm. The number of unique patients is counted.

    15. Participants Infected Post Transplant [2 Years]

      All grade 2 and grade 3 infections, as defined by the BMT CTN Technical MOP, occurring post transplantation will be reported. The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for each intervention arm.

    16. Incidence of Infections [2 years]

      All grade 2 and grade 3 infections, as defined by the BMT CTN Technical MOP, occurring post transplantation will be reported. The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for each intervention arm.

    17. Health-Related Quality of Life (HQL) - Medical Outcomes Study Short Form 36 (SF36) [Baseline, Day 100, Day 180, 1 year, 2 years]

      HQL will be measured post-transplant using patient-reported survey SF36. The SF36 is a 36 item general assessment of health quality of life with eight components: Physical Functioning, Role Physical, Pain Index, General Health Perceptions, Vitality, Social Functioning, Role Emotional, Mental Health Index. Each domain is positively scored, indicating that higher scores are associated with positive outcome. The total score ranges from 0 to 100. This scale is being used in this protocol as a generic measure of quality of life. To facilitate comparison of results with published norms, the Physical Component Summary and Mental Component Summary are used as the outcome measures in summarizing the SF36 data. These summary scores are derived by multiplying the z-score for each scale by its respective physical or mental factor score coefficient and summing the products. Resulting scores are then transformed into Tscores (mean=50; standard deviation=10). The SF36 takes 6 minutes to complete.

    18. Health-Related Quality of Life (HQL) - Functional Assessment of Cancer Therapy - Bone Marrow Transplant (FACT-BMT) [Baseline, Day 100, Day 180, 1 year, 2 years]

      The FACT-BMT is a 37 item scale comprised of a general core questionnaire, the FACT-G with a possible range of 0-108 points, that evaluates the health-related quality of life (HQL) of patients receiving treatment for cancer, and a specific module, BMT Concerns, that addresses disease and treatment-related questions specific to bone marrow transplant. The FACT-G consists of four subscales developed and normed in cancer patients: Physical Well-being, Social/Family Well-being, Emotional Wellbeing, and Functional Well-being. Each subscale is positively scored, with higher scores indicating better functioning. The FACT-BMT Trial Outcome Index, comprised of the physical well-being scale, the functional well-being scale and the BMT specific items, will be used as the outcome measure in summarizing the FACT-BMT data. The FACT-BMT takes 6 minutes to complete. The final score for FACT-BMT ranges from 0 to 196. Higher scores for the scales and subscales indicate better quality of life.

    19. Health-Related Quality of Life (HQL) - MDASI [Baseline, Day 100, Day 180, 1 year, 2 years]

      HQL will be measured post-transplant using patient-reported survey MD Anderson Symptom Inventory (MDASI). The MDASI is a 19 item instrument that captures 13 symptoms (0="not present" to 10="as bad as you can imagine") and 6 items measuring interference with life from 0 ("did not interfere") to 10 ("interfered completely"). MDASI Tool questions are negatively scored - higher levels indicate more severe symptoms and levels of interference. Codelist for each question is from 0 to 10. Scoring is taking the mean of items, so the range is 0-10. Lower scores for the scales indicate better quality of life. It provides two summary scales: symptoms and interference. The MDASI takes less than 5 minutes to complete.

    20. Health-Related Quality of Life (HQL) - PedsQL [Baseline, Day 100, Day 180, 1 year, 2 years]

      HQL will be measured post-transplant using patient-reported survey PedsQL. The PedsQL™ Stem Cell Transplant Module is a 46-item instrument that measures health-related quality of life in children and adolescents undergoing hematopoietic stem cell transplant and is developmentally appropriate for self-report in ages 8 through 18 years. The score ranges from 0 to 100 with higher scores associated with positive outcome.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    1 Year to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. Males and females aged ≥ 1.0 year and < 66.0 years

    2. Patients with acute leukemia in morphologic complete remission with or without hematologic recovery or with myelodysplasia (MDS) with no circulating blasts and with less than 5% blasts in the bone marrow. Patients with CMML must have a WBC count ≤ 10,000 cells/µL and < 5% blasts in the marrow. Patients with ≥ 5% blasts due to a regenerating marrow must contact the protocol chairs for review.

    3. Planned myeloablative conditioning regimen

    4. Patients must have a related or unrelated donor as follows:

    5. Related donor must be an 8/8 match for human leukocyte antigen (HLA)-A, -B, and -C at intermediate (or higher) resolution, and -DRB1 at high resolution using DNA-based typing. Pediatric related donors must weigh ≥ 25.0 kg., must have adequate peripheral venous catheter access for leukapheresis or must agree to placement of a central catheter, must be willing to (1) donate bone marrow and (2) receive G-CSF followed by donation of peripheral blood stem cells (product to be determined by randomization post enrollment) and must meet institutional criteria for donation.

    6. Unrelated donor must be an 8/8 match at HLA-A, -B, -C and -DRB1 at high resolution using DNA-based typing. Unrelated donor must be medically eligible to donate according to National Marrow Donor Program (NMDP) (or equivalent donor search organization) criteria. At time of enrollment, the donor should not have any known preferences or contraindications to donate bone marrow or peripheral blood stem cells. (Selection of unrelated donors is to be performed according to institutional practice. It is recommended that the time from collection to initiation of the cell processing be considered when prioritizing donors, as data shows better results for CD34 selection when cell processing begins within 36 hours of the end of collection)

    7. Cardiac function: Ejection fraction at rest ≥ 45.0% or shortening fraction of ≥ 27.0% by echocardiogram or radionuclide scan (MUGA).

    8. Estimated creatinine clearance (for patients > 12 years) greater than 50.0 mL/minute (using the Cockcroft-Gault formula and actual body weight); for pediatric patients (> 1 year to 12 years), Glomerular Filtration Rate (GFR) estimated by the updated Schwartz formula ≥ 90.0 mL/min/1.73 m2. If the estimated creatinine clearance is < 90 mL/min/1.73 m2, then renal function must be measured by 24-hour creatinine clearance or nuclear GFR, and must be > 70.0 mL/min/1.73 m^2.

    9. Pulmonary function: Diffusing capacity of the lung for carbon monoxide (DLCO) ≥ 50% (adjusted for hemoglobin), and forced expiratory volume in one second (FEV1) or forced vital capacity (FVC) ≥ 50%; for children who are unable to perform for Pulmonary Function Tests (PFTs) due to age or developmental ability, there must be no evidence of dyspnea and no need for supplemental oxygen, as evidenced by O2 saturation ≥ 92% on room air.

    10. Liver function: total bilirubin < 2x the upper limit of normal (unless elevated bilirubin is attributed to Gilbert's Syndrome) and alanine aminotransferase (ALT) / aspartate aminotransferase (AST) < 2.5x the upper limit of normal.

    11. Signed informed consent.

    Exclusion Criteria:

    1. Prior autologous or allogeneic hematopoietic stem cell transplant

    2. Karnofsky or Lansky Performance Score < 70%

    3. Active central nervous system (CNS) involvement by malignant cells

    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 fluid collection (ascites, pleural or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated

    6. Patients seropositive for HIV-1 or -2

    7. Patients seropositive for Human T-Lymphotrophic Virus (HTLV)-I or -II

    8. Patients with active Hepatitis B or C viral replication by polymerase chain reaction (PCR)

    9. Documented allergy to iron dextran or murine proteins

    10. Women who are pregnant (positive serum or urine βHCG) or breastfeeding

    11. Females of childbearing potential (FCBP) or men who have sexual contact with FCBP unwilling to use 2 effective forms of birth control or abstinence for one year after transplantation

    12. History of uncontrolled autoimmune disease or on active treatment

    13. Patients with prior malignancies, except resected non-melanoma 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 will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs.

    14. Patient unable to comply with the treatment protocol including appropriate supportive care, follow-up and research tests

    15. Planned post-transplant maintenance therapy except for FLT3 inhibitors or TKIs must be declared prior to randomization.

    16. If it is known prior to enrollment that the hematopoietic stem cell product will need to be cryopreserved, the patient should not be enrolled.

    17. German centers only: Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer, or participation in any other interventional clinical study.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 City of Hope National Medical Center Duarte California United States 91010-3000
    2 Stanford Hospital and Clinics Stanford California United States 94305
    3 University of Florida College of Medicine Gainesville Florida United States 32610-0277
    4 H. Lee Moffitt Cancer Center Tampa Florida United States 33612
    5 Blood & Marrow Transplant Program at Northside Hospital Atlanta Georgia United States 30342
    6 University of Iowa Hospitals and Clinics Iowa City Iowa United States 52242
    7 University of Kansas Hospital Kansas City Kansas United States 66160
    8 University of Kentucky Lexington Kentucky United States 40536
    9 Johns Hopkins/SKCCC Baltimore Maryland United States 21231
    10 Dana Farber Cancer Institute/Brigham & Women's Boston Massachusetts United States 02114
    11 Dana Farber Cancer Institute/Massachusetts General Hospital Boston Massachusetts United States 02115
    12 Mayo Clinic - Rochester Rochester Minnesota United States 55905
    13 Washington University/Barnes Jewish Hospital Saint Louis Missouri United States 63110
    14 University of Nebraska Medical Center Omaha Nebraska United States 68198-7680
    15 Memorial Sloan-Kettering Cancer Center New York New York United States 10021
    16 Columbia University Medical Center New York New York United States 10032
    17 Weill Cornell Medical Center/New York Presbyterian New York New York United States 10065
    18 University of North Carolina Chapel Hill North Carolina United States 27599
    19 Duke University Medical Center Durham North Carolina United States 27705
    20 University Hospitals of Cleveland/Case Western Cleveland Ohio United States 44106-5061
    21 Ohio State/Arthur G. James Cancer Hospital Columbus Ohio United States 43210
    22 University of Oklahoma Oklahoma City Oklahoma United States 73104
    23 Oregon Health and Science University Portland Oregon United States 97239
    24 University of Pennsylvania Cancer Center Philadelphia Pennsylvania United States 19104
    25 Medical University of South Carolina Charleston South Carolina United States 29425
    26 Virginia Commonwealth University/MCV Hospitals Richmond Virginia United States 23298
    27 University of Wisconsin Hospital & Clinics Madison Wisconsin United States 53792
    28 Medical College of Wisconsin Milwaukee Wisconsin United States 53211

    Sponsors and Collaborators

    • National Heart, Lung, and Blood Institute (NHLBI)
    • Blood and Marrow Transplant Clinical Trials Network
    • National Cancer Institute (NCI)

    Investigators

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

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    National Heart, Lung, and Blood Institute (NHLBI)
    ClinicalTrials.gov Identifier:
    NCT02345850
    Other Study ID Numbers:
    • BMT CTN 1301
    • U01HL069294
    First Posted:
    Jan 26, 2015
    Last Update Posted:
    Dec 21, 2021
    Last Verified:
    Nov 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Keywords provided by National Heart, Lung, and Blood Institute (NHLBI)
    Acute Leukemia
    Myelodysplasia
    GVHD Prophylaxis
    Chronic GVHD
    Additional relevant MeSH terms:
    Preleukemia
    Myelodysplastic Syndromes
    Graft vs Host Disease
    Cyclophosphamide
    Methotrexate
    Tacrolimus

    Study Results

    Participant Flow

    Recruitment Details The study opened to accrual on August 17, 2015. Thirty-two participating centers were activated for enrollment and two of those were closed earlier without any enrollment. The study closed accrual on June 4, 2018 with 346 participants enrolled from 26 centers. Among the randomized participants, 327 participants received a transplant. Within the 19 participants who did not receive a transplant, there were 10 withdrawals of consents, 5 deaths, and 4 lost to follow-ups.
    Pre-assignment Detail
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    Period Title: Overall Study
    STARTED 114 114 118
    COMPLETED 101 106 112
    NOT COMPLETED 13 8 6

    Baseline Characteristics

    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control Total
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices. Total of all reporting groups
    Overall Participants 114 114 118 346
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    51.2
    50.9
    51.3
    51.1
    Age, Customized (Count of Participants)
    1-18
    0
    0%
    0
    0%
    2
    1.7%
    2
    0.6%
    19-40
    29
    25.4%
    28
    24.6%
    28
    23.7%
    85
    24.6%
    41-60
    63
    55.3%
    69
    60.5%
    76
    64.4%
    208
    60.1%
    >60
    22
    19.3%
    17
    14.9%
    12
    10.2%
    51
    14.7%
    Sex: Female, Male (Count of Participants)
    Female
    52
    45.6%
    43
    37.7%
    54
    45.8%
    149
    43.1%
    Male
    62
    54.4%
    71
    62.3%
    64
    54.2%
    197
    56.9%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    7
    6.1%
    7
    6.1%
    7
    5.9%
    21
    6.1%
    Not Hispanic or Latino
    105
    92.1%
    102
    89.5%
    107
    90.7%
    314
    90.8%
    Unknown or Not Reported
    2
    1.8%
    5
    4.4%
    4
    3.4%
    11
    3.2%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    4
    3.5%
    2
    1.8%
    3
    2.5%
    9
    2.6%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    2
    1.8%
    3
    2.6%
    4
    3.4%
    9
    2.6%
    White
    106
    93%
    101
    88.6%
    104
    88.1%
    311
    89.9%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    2
    1.8%
    8
    7%
    7
    5.9%
    17
    4.9%
    Lansky/Karnofsky Performance Score (Count of Participants)
    90-100
    63
    55.3%
    72
    63.2%
    61
    51.7%
    196
    56.6%
    70-80
    51
    44.7%
    42
    36.8%
    57
    48.3%
    150
    43.4%
    Primary Disease (Count of Participants)
    Acute Lymphoblastic Leukemia (ALL)
    30
    26.3%
    27
    23.7%
    23
    19.5%
    80
    23.1%
    Acute Myelogenous Leukemia (AML)
    63
    55.3%
    74
    64.9%
    75
    63.6%
    212
    61.3%
    Myelodysplastic Syndrome (MDS)
    19
    16.7%
    11
    9.6%
    16
    13.6%
    46
    13.3%
    Chronic Myelomonocytic Leukemia (CMML)
    1
    0.9%
    1
    0.9%
    1
    0.8%
    3
    0.9%
    Acute Undifferentiated Leukemia
    1
    0.9%
    0
    0%
    1
    0.8%
    2
    0.6%
    Biphenotypic Leukemia
    0
    0%
    1
    0.9%
    2
    1.7%
    3
    0.9%
    Disease Risk (Count of Participants)
    Non-high
    67
    58.8%
    67
    58.8%
    71
    60.2%
    205
    59.2%
    High
    36
    31.6%
    39
    34.2%
    40
    33.9%
    115
    33.2%
    Missing/Unknown
    11
    9.6%
    8
    7%
    7
    5.9%
    26
    7.5%
    Disease Stage for AML and ALL (Count of Participants)
    1st complete remission
    65
    57%
    67
    58.8%
    75
    63.6%
    207
    59.8%
    >= 2nd complete remission
    15
    13.2%
    21
    18.4%
    15
    12.7%
    51
    14.7%
    Relapse
    2
    1.8%
    1
    0.9%
    1
    0.8%
    4
    1.2%
    Primary induction failure (PIF)/Untreated
    2
    1.8%
    5
    4.4%
    3
    2.5%
    10
    2.9%
    Missing
    9
    7.9%
    7
    6.1%
    4
    3.4%
    20
    5.8%
    Donor type (Count of Participants)
    Related Donor
    43
    37.7%
    43
    37.7%
    45
    38.1%
    131
    37.9%
    Unrelated Donor
    71
    62.3%
    71
    62.3%
    73
    61.9%
    215
    62.1%
    Cytogenetic (Count of Participants)
    Normal
    5
    4.4%
    2
    1.8%
    4
    3.4%
    11
    3.2%
    Favorable
    13
    11.4%
    12
    10.5%
    12
    10.2%
    37
    10.7%
    Intermediate
    50
    43.9%
    54
    47.4%
    56
    47.5%
    160
    46.2%
    Poor
    35
    30.7%
    38
    33.3%
    39
    33.1%
    112
    32.4%
    Missing
    11
    9.6%
    8
    7%
    6
    5.1%
    25
    7.2%
    Not tested
    0
    0%
    0
    0%
    1
    0.8%
    1
    0.3%
    HLA matching 8/8 (Count of Participants)
    Count of Participants [Participants]
    114
    100%
    114
    100%
    118
    100%
    346
    100%
    Time from diagnosis to transplantation (months) [Median (Full Range) ]
    Median (Full Range) [months]
    5.6
    4.7
    5.0
    5.0
    HCT-comorbidity index (Count of Participants)
    0
    38
    33.3%
    41
    36%
    44
    37.3%
    123
    35.5%
    1-2
    37
    32.5%
    43
    37.7%
    49
    41.5%
    129
    37.3%
    3 or greater
    29
    25.4%
    25
    21.9%
    21
    17.8%
    75
    21.7%
    Pre-Transplant CMV status (Count of Participants)
    Positive
    45
    39.5%
    54
    47.4%
    57
    48.3%
    156
    45.1%
    Negative
    59
    51.8%
    55
    48.2%
    57
    48.3%
    171
    49.4%
    Donor CMV Status (Count of Participants)
    Negative
    73
    64%
    55
    48.2%
    71
    60.2%
    199
    57.5%
    Positive
    31
    27.2%
    53
    46.5%
    43
    36.4%
    127
    36.7%
    Unknown
    0
    0%
    1
    0.9%
    0
    0%
    1
    0.3%
    Stem cell source (Count of Participants)
    Peripheral Blood
    98
    86%
    11
    9.6%
    12
    10.2%
    121
    35%
    Bone Marrow
    6
    5.3%
    98
    86%
    102
    86.4%
    206
    59.5%

    Outcome Measures

    1. Primary Outcome
    Title Chronic GVHD-free, Relapse-free Survival (CRFS) Probability
    Description The primary endpoint of the trial is Chronic GVHD/Relapse-Free Survival (CRFS), treated as a time to event variable. An event for this time to event outcome is defined as moderate to severe chronic GVHD, disease relapse, or death by any cause. Participant will be censored if lost to follow up prior to 2 years. Time is from randomization to the event of moderate to severe chronic GVHD, disease relapse, death, last follow up, or 2 years, whichever comes first. The primary analysis is performed using the intent-to-treat principle (ITT) so that all randomized patients are included in the analysis.
    Time Frame 2 years

    Outcome Measure Data

    Analysis Population Description
    All randomized patients are analyzed for this endpoint.
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    Measure Participants 114 114 118
    1 year Post Randomization
    60.2
    52.8%
    60.3
    52.9%
    52.6
    44.6%
    2 years Post Randomization
    50.6
    44.4%
    48.1
    42.2%
    41.0
    34.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Tacrolimus/Methotrexate Control
    Comments The primary null hypothesis of the study is that there is no difference of the CRFS hazard ratio between CD34 select graft vs. Tac/MTX Control. The data in primary outcome table provides point estimates at specific time points (1 year and 2 years post randomization). The statistics in this session provides comparisons between different arms for the entire period of the study.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2368
    Comments The primary pairwise comparisons are tested at a Bonferroni adjusted significance level of 0.05/3.
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.805
    Confidence Interval (2-Sided) 95%
    0.562 to 1.154
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The primary null hypothesis of the study is that there is no difference of the CRFS hazard ratio between Post-Transplant Cyclophosphamide vs. Tac/MTX Control. The data in primary outcome table provides point estimates. The statistics in this session provides comparisons between different arms for the entire period of the study.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4134
    Comments The primary pairwise comparisons are tested at a Bonferroni adjusted significance level of 0.05/3.
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.864
    Confidence Interval (2-Sided) 95%
    0.609 to 1.228
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide
    Comments The primary null hypothesis of the study is that there is no difference of the CRFS hazard ratio between CD34 select graft vs. Post-Transplant Cyclophosphamide. The data in primary outcome table provides point estimates. The statistics in this session provides comparisons between different arms for the entire period of the study.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7166
    Comments The primary pairwise comparisons are tested at a Bonferroni adjusted significance level of 0.05/3.
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.933
    Confidence Interval (2-Sided) 95%
    0.643 to 1.355
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of the CRFS hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk. The data in primary outcome table provides point estimates. The statistics in this session provides comparisons between different arms for the entire period of the study.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.386
    Comments Statistical significance was determined using a pre-specified threshold of 0.05.
    Method Regression, Cox
    Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments Subgroup analyses are conducted for CRFS according to disease, disease risk and age. Interaction tests between treatment group and subgroup are conducted within a Cox proportional hazards regression model with treatment, subgroup, and a treatment*subgroup interaction term. The null hypothesis is that there is no Interaction between treatment group and disease risk (Low/Intermediate vs. High) for CRFS.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.461
    Comments A Bonferroni adjusted significance level of 0.05/3=0.0167 is used for each of three interaction tests to account for multiple testing.
    Method Cox proportional hazards regression
    Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments Subgroup analyses are conducted for CRFS according to disease, disease risk and age. Interaction tests between treatment group and subgroup are conducted within a Cox proportional hazards regression model with treatment, subgroup, and a treatment*subgroup interaction term. The null hypothesis is that there is no Interaction between treatment group and Age (<=50 vs. >50) for CRFS.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.115
    Comments Cox proportional hazards regression
    Method Cox proportional hazards regression
    Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments Subgroup analyses are conducted for CRFS according to disease, disease risk and age. Interaction tests between treatment group and subgroup are conducted within a Cox proportional hazards regression model with treatment, subgroup, and a treatment*subgroup interaction term. The null hypothesis is that there is no Interaction between treatment group and Disease (AML vs. ALL vs. MDS) for CRFS.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.227
    Comments A Bonferroni adjusted significance level of 0.05/3=0.0167 is used for each of three interaction tests to account for multiple testing.
    Method Cox proportional hazards regression
    Comments
    2. Secondary Outcome
    Title Percentage of Participants With Overall Survival (OS)
    Description OS is a key secondary endpoint, with explicit control of the type I error rate through a gatekeeper approach. Formal significance testing of OS between a CNI-free strategy and the control will be conducted if the corresponding CRFS comparison is significant. This OS comparison will be done using a Bonferroni adjusted significance level of 0.05/3 to account for three potential CNI-free comparisons to the control. Otherwise, survival analyses will be considered exploratory. Death from any cause is considered as event for this endpoint. Participant is censored if lost to follow up.
    Time Frame 2 Years

    Outcome Measure Data

    Analysis Population Description
    The randomized or transplanted participants are included in the analyses.
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    Measure Participants 114 114 118
    1 year post-randomization
    75.7
    66.4%
    84.6
    74.2%
    84.2
    71.4%
    2 year post-randomization
    60.1
    52.7%
    76.2
    66.8%
    76.1
    64.5%
    1 year post-transplantation
    74.8
    65.6%
    83.4
    73.2%
    83.3
    70.6%
    2 year post-transplantation
    61.6
    54%
    76.7
    67.3%
    74.2
    62.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of the OS hazard ratio between CD34 select graft vs. Tac/MTX Control.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0197
    Comments The OS pairwise comparisons are tested at a Bonferroni adjusted significance level of 0.05/3.
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.744
    Confidence Interval (2-Sided) 95%
    1.086 to 2.800
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of the OS hazard ratio between Post-Transplant Cyclophosphamide vs. Tac/MTX Control.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9525
    Comments The OS pairwise comparisons are tested at a Bonferroni adjusted significance level of 0.05/3.
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.016
    Confidence Interval (2-Sided) 95%
    0.599 to 1.724
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide
    Comments The null hypothesis is that there is no difference of the OS hazard ratio between CD34 select graft vs. Post-Transplant Cyclophosphamide.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0185
    Comments The OS pairwise comparisons are tested at a Bonferroni adjusted significance level of 0.05/3.
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.774
    Confidence Interval (2-Sided) 95%
    1.093 to 2.877
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of the OS hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.026
    Comments Statistical significance was determined using a pre-specified threshold of 0.05.
    Method Regression, Cox
    Comments
    3. Secondary Outcome
    Title Percentage of Participants With Relapse-free Survival
    Description The events for this endpoint RFS are death and relapse of the underlying malignancy. The analyses of this endpoint use the transplanted populations and time is from transplant to the event of disease relapse or death, or last follow up, whichever comes first.
    Time Frame 2 Years

    Outcome Measure Data

    Analysis Population Description
    The analyses of this endpoint will use the transplanted population.
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    Measure Participants 104 109 114
    1 year post-transplantation
    64.1
    56.2%
    78.8
    69.1%
    70.1
    59.4%
    2 years post-transplantation
    57.1
    50.1%
    70.3
    61.7%
    66.5
    56.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of Relapse-Free Survival between the treatment groups.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.029
    Comments Statistical significance was determined using a pre-specified threshold of 0.05.
    Method Log Rank
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of the RFS hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.145
    Comments Statistical significance was determined using a pre-specified threshold of 0.05.
    Method Regression, Cox
    Comments
    4. Secondary Outcome
    Title Percentage of Participants With Treatment-related Mortality
    Description The events for this endpoint TRM are deaths prior to relapse of the underlying malignancy. The analyses of this endpoint will use the transplanted populations, and time will be from transplant to the first of disease relapse, death, or last follow up. TRM are evaluated using the cumulative incidence function. Deaths without relapse are the events for this endpoint and relapse is a competing risk for this endpoint.
    Time Frame 2 Years

    Outcome Measure Data

    Analysis Population Description
    The analyses of this endpoint will use the transplanted populations.
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    Measure Participants 104 109 114
    1 year post-transplantation
    16.5
    14.5%
    12.0
    10.5%
    7.0
    5.9%
    2 years post-transplantation
    21.5
    18.9%
    15.7
    13.8%
    7.9
    6.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of Transplant-Related Mortality between the treatment groups.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.020
    Comments Statistical significance was determined using a pre-specified threshold of 0.05.
    Method Gray's test for cumulative Incidence
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of the TRM hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.040
    Comments Statistical significance was determined using a pre-specified threshold of 0.05.
    Method Regression, Cox
    Comments
    5. Secondary Outcome
    Title Participants With Immunosuppression-free Survival
    Description Patients who are alive, relapse-free, and do not need ongoing immune suppression to control GVHD at one year post HSCT are considered successes for this endpoint. Immune suppression is defined as any systemic agents used to control or suppress GVHD.
    Time Frame 1 Year

    Outcome Measure Data

    Analysis Population Description
    The analyses of this endpoint will use the transplanted populations. Two participant of CD34 Selected Graft arm and one participants of Post-Transplant Cyclophosphamide arm were lost to follow-up while alive and not relapsed, and they are considered as not evaluable for this endpoint.
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    Measure Participants 102 108 114
    Count of Participants [Participants]
    59
    51.8%
    73
    64%
    66
    55.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of immunosuppression-free survival at 1-year post-transplant between the treatment groups.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2389
    Comments Statistical significance was determined using a pre-specified threshold of 0.05.
    Method Chi-squared
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no agreement between CRFS and immunosuppression-free survival at 1-year post-transplant.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Cohen's Kappa
    Comments
    6. Secondary Outcome
    Title Percentage of Participants With Disease Relapse
    Description Relapse is defined by either morphological evidence of acute leukemia or MDS consistent with pre-transplant features, or radiologic evidence of lymphoma, documented or not by biopsy. The event is defined as increase in size of prior sites of disease or evidence of new sites of disease, documented or not by biopsy. Relapse is adjudicated by ERC. Disease relapse is analyzed using cumulative incidence function with death as a competing risk. The analyses of this endpoint use the transplanted populations, and the time will be measured from transplant to the earliest of death, relapse/progression, or last follow up.
    Time Frame 2 Years

    Outcome Measure Data

    Analysis Population Description
    The analyses of this endpoint use the transplanted populations.
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    Measure Participants 104 109 114
    1 year post transplantation
    19.4
    17%
    9.2
    8.1%
    22.9
    19.4%
    2 years post transplantation
    21.4
    18.8%
    13.9
    12.2%
    25.6
    21.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of Disease Relapse between the treatment groups.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.076
    Comments Statistical significance was determined using a pre-specified threshold of 0.05.
    Method Gray's test for cumulative Incidence
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of the Disease Relapse hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.106
    Comments Statistical significance was determined using a pre-specified threshold of 0.05.
    Method Regression, Cox
    Comments
    7. Secondary Outcome
    Title Percentage of Participants With Neutrophil Engraftment
    Description Neutrophil recovery is defined as achieving an absolute neutrophil count (ANC) ≥ 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.
    Time Frame Day 28

    Outcome Measure Data

    Analysis Population Description
    The analyses of the endpoint use the transplanted populations.
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    Measure Participants 104 109 114
    Number (95% Confidence Interval) [percentage of participants]
    97.1
    85.2%
    91.7
    80.4%
    96.5
    81.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of Neutrophil Engraftment post-transplantation between the treatment groups.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0764
    Comments Statistical significance was determined using a pre-specified threshold of 0.05.
    Method Gray's test for cumulative Incidence
    Comments
    8. Secondary Outcome
    Title Percentage of Participants With Platelet Recovery
    Description Platelet recovery is defined as the first day of a sustained platelet count >20,000/mm^3 with no platelet transfusion in the preceding seven days. The first day of sustained platelet count above this threshold will be designated the day of platelet engraftment. The competing event is death without platelet recovery.
    Time Frame Day 60

    Outcome Measure Data

    Analysis Population Description
    The analyses of the endpoint use the transplanted populations. Three transplanted participants (one from the CD34 arm and two from the PTCy arm) are missing platelet data and are not included in the analyses.
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    Measure Participants 103 107 114
    Number (95% Confidence Interval) [percentage of participants]
    94.2
    82.6%
    91.6
    80.4%
    98.2
    83.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of Platelet recovery post-transplantation between the treatment groups.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0001
    Comments Statistical significance was determined using a pre-specified threshold of 0.05.
    Method Gray's test for cumulative Incidence
    Comments
    9. Secondary Outcome
    Title Participants With Primary Graft Failure
    Description Primary graft failure is defined as no neutrophil recovery to > 500 cells/µL by Day 28 post HSCT.
    Time Frame Day 28

    Outcome Measure Data

    Analysis Population Description
    The analyses of the endpoint use the transplanted populations.
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    Measure Participants 104 109 114
    Count of Participants [Participants]
    3
    2.6%
    9
    7.9%
    4
    3.4%
    10. Secondary Outcome
    Title Percentage of Participants With Secondary Graft Failure
    Description Secondary graft failure will be assessed according to neutrophil count after initial hematologic recovery. Secondary graft failure is defined as initial neutrophil engraftment followed by subsequent decline in absolute neutrophil counts < 500 cells/µL, unresponsive to growth factor therapy, but cannot be explained by disease relapse or medications. Secondary graft failure will be analyzed using cumulative incidence function with death as a competing risk.
    Time Frame 2 Years

    Outcome Measure Data

    Analysis Population Description
    The analyses of the endpoint use the transplanted populations.
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    Measure Participants 104 109 114
    Number (95% Confidence Interval) [percentage of participants]
    2.9
    2.5%
    0
    0%
    0.9
    0.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of Secondary graft failure post-transplantation between the treatment groups.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1478
    Comments
    Method Gray's test for cumulative Incidence
    Comments
    11. Secondary Outcome
    Title Percentage of Participants With Acute GVHD
    Description Cumulative incidences of grade II-IV and III-IV acute GVHD were determined. Death prior to acute GVHD is treated as the competing risk. Grading of acute GVHD was derived by consensus grading (Przepiorka 1995) per BMTCTN manual of procedures (MOP). The acute GVHD algorithm calculates the grade based on the organ (skin, GI and liver) stage and etiology/biopsy reported on the weekly GVHD form. Staging for skin: Stage 1. <25% rash; 2. 25-50%; 3. >50%; 4. generalized erythroderma with bullae. Staging for GI: Stage 1. Diarrhea>500ml/d or persistent nausea; 2. >1000ml/d; 3. >1500ml/d; 4. Large volume diarrhea and severe abdominal pain +- ileus. Staging for Liver: Stage 1. bilirubin 2-3mg/dl; 2. bilirubin 3-6 mg/dl; 3. bilirubin 6-15 mg/dl; 4. bilirubin>15mg/dl. Grade 4 is the worst outcome.
    Time Frame Day 100

    Outcome Measure Data

    Analysis Population Description
    The analyses of the endpoint use the transplanted populations.
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    Measure Participants 104 109 114
    grade II-IV acute GVHD
    16.3
    14.3%
    37.6
    33%
    29.8
    25.3%
    grade III-IV acute GVHD
    2.9
    2.5%
    10.1
    8.9%
    3.5
    3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of grade II-IV acute GVHD post-transplantation between the treatment groups.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0026
    Comments Statistical significance was determined using a pre-specified threshold of 0.05.
    Method Gray's test for cumulative Incidence
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of grade III-IV acute GVHD post-transplantation between the treatment groups.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0369
    Comments Statistical significance was determined using a pre-specified threshold of 0.05.
    Method Gray's test for cumulative Incidence
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of the grade II-IV acute GVHD hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.002
    Comments Statistical significance was determined using a pre-specified threshold of 0.05.
    Method Regression, Cox
    Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of the grade III-IV acute GVHD hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.046
    Comments Statistical significance was determined using a pre-specified threshold of 0.05.
    Method Regression, Cox
    Comments
    12. Secondary Outcome
    Title Participants With Maximum Acute GVHD
    Description Grading of acute GVHD was derived by consensus grading (Przepiorka 1995) per BMTCTN manual of procedures (MOP). The acute GVHD algorithm calculates the grade based on the organ (skin, GI and liver) stage and etiology/biopsy reported on the weekly GVHD form. Grade I aGVHD is defined as Skin stage of 1-2 and stage 0 for both GI and liver organs. Grade II aGVHD is stage 3 of skin, or stage 1 of GI, or stage 1 of liver. Grade III is stage 2-4 for GI, or stage 2-3 of liver. Grade IV is stage 4 of skin, or stage 4 of liver. Max acute GVHD by Day 100 was computed.
    Time Frame Day 100

    Outcome Measure Data

    Analysis Population Description
    The analyses of the endpoint use the transplanted populations.
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    Measure Participants 104 109 114
    Grade 0, No aGVHD
    72
    63.2%
    45
    39.5%
    55
    46.6%
    Grade I
    15
    13.2%
    23
    20.2%
    25
    21.2%
    Grade II
    14
    12.3%
    30
    26.3%
    30
    25.4%
    Grade III
    3
    2.6%
    9
    7.9%
    4
    3.4%
    Grade IV
    0
    0%
    2
    1.8%
    0
    0%
    13. Secondary Outcome
    Title Percentage of Participants With Chronic GVHD
    Description The cumulative incidence of chronic GVHD will be determined. Death prior to acute GVHD is treated as the competing risk. Data will be collected directly from providers and chart review according to the recommendations of the NIH Consensus Criteria. Eight organs will be scored on a 0-3 scale to reflect degree of chronic GVHD involvement. Liver and pulmonary function test results and use of systemic therapy for treatment of chronic GVHD will also be recorded. This secondary endpoint of chronic GVHD will include mild, moderate and severe chronic GVHD based on NIH Consensus Criteria.
    Time Frame 2 Years

    Outcome Measure Data

    Analysis Population Description
    The analyses of the endpoint use the transplanted populations.
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    Measure Participants 104 109 114
    1 year post-transplantation
    16.4
    14.4%
    33.0
    28.9%
    31.1
    26.4%
    2 years post-transplantation
    18.5
    16.2%
    37.0
    32.5%
    40.0
    33.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of chronic GVHD post-transplantation between the treatment groups.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0024
    Comments Statistical significance was determined using a pre-specified threshold of 0.05.
    Method Gray's test for cumulative Incidence
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of the chronic GVHD hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.005
    Comments Statistical significance was determined using a pre-specified threshold of 0.05.
    Method Regression, Cox
    Comments
    14. Secondary Outcome
    Title Percentage of Participants With Chronic GVHD-free Survival
    Description The event for this endpoint includes moderate to severe chronic GVHD according to NIH consensus criteria global score, or death by any cause.
    Time Frame 2 Years

    Outcome Measure Data

    Analysis Population Description
    The analyses of the endpoint use the transplanted populations.
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    Measure Participants 104 109 114
    1 year post-transplantation
    71.0
    62.3%
    67.4
    59.1%
    65.8
    55.8%
    2 years post-transplantation
    55.4
    48.6%
    54.2
    47.5%
    47.1
    39.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of Chronic GVHD-free Survival post-transplantation between the treatment groups.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.229
    Comments Statistical significance was determined using a pre-specified threshold of 0.05.
    Method Log Rank
    Comments
    15. Secondary Outcome
    Title Participants With Grade ≥ 3 Toxicity
    Description All grades ≥ 3 toxicities according to CTCAE, version 4 will be tabulated for each intervention arm. The number of unique patients is counted.
    Time Frame 2 Years

    Outcome Measure Data

    Analysis Population Description
    The analyses of the endpoint use the transplanted populations.
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    Measure Participants 104 109 114
    Any Grade 3-5 Stem Cell Infusional Toxicities
    6
    5.3%
    4
    3.5%
    17
    14.4%
    Grades 3-5 Oral mucositis
    39
    34.2%
    51
    44.7%
    63
    53.4%
    Grades 3-5 Cystitis noninfective
    4
    3.5%
    11
    9.6%
    2
    1.7%
    Grades 3-5 Acute kidney injury
    12
    10.5%
    13
    11.4%
    15
    12.7%
    Grades 3-5 Chronic kidney disease
    4
    3.5%
    4
    3.5%
    3
    2.5%
    Grades 3-5 Hemorrhage
    12
    10.5%
    9
    7.9%
    4
    3.4%
    Grades 3-5 Hypotension
    19
    16.7%
    15
    13.2%
    11
    9.3%
    Grades 3-5 Hypertension
    20
    17.5%
    21
    18.4%
    30
    25.4%
    Grades 3-5 Cardiac arrhythmia
    9
    7.9%
    6
    5.3%
    8
    6.8%
    Grades 3-5 Left ventricular systolic dysfunction
    5
    4.4%
    2
    1.8%
    8
    6.8%
    Grades 3-5 Somnolence
    7
    6.1%
    4
    3.5%
    4
    3.4%
    Grades 3-5 Seizure
    6
    5.3%
    0
    0%
    2
    1.7%
    Grades 3-5 Thrombotic thrombocytopenic purpura
    1
    0.9%
    2
    1.8%
    4
    3.4%
    Grades 3-5 Capillary leak syndrome
    1
    0.9%
    0
    0%
    1
    0.8%
    Grades 3-5 Hypoxia
    32
    28.1%
    22
    19.3%
    14
    11.9%
    Grades 3-5 Dsypnea
    23
    20.2%
    15
    13.2%
    12
    10.2%
    Grades 3-4 ALT
    10
    8.8%
    26
    22.8%
    18
    15.3%
    Grades 3-4 AST
    11
    9.6%
    27
    23.7%
    19
    16.1%
    Grades 3-4 Bilirubin
    8
    7%
    14
    12.3%
    7
    5.9%
    Grades 3-4 Alkaline Phosphatase
    11
    9.6%
    12
    10.5%
    6
    5.1%
    Received dialysis
    5
    4.4%
    2
    1.8%
    6
    5.1%
    Abnormal liver function
    12
    10.5%
    14
    12.3%
    24
    20.3%
    SOS/VOD
    0
    0%
    2
    1.8%
    1
    0.8%
    IPS
    2
    1.8%
    2
    1.8%
    3
    2.5%
    Toxicities Within Day 100
    68
    59.6%
    82
    71.9%
    81
    68.6%
    Toxicities Day 100 to 1 year
    26
    22.8%
    33
    28.9%
    41
    34.7%
    Toxicities 1 year to 2 years
    23
    20.2%
    18
    15.8%
    24
    20.3%
    Overall NCI CTCAE Grade 3-5 Toxicities
    80
    70.2%
    88
    77.2%
    100
    84.7%
    16. Secondary Outcome
    Title Participants Infected Post Transplant
    Description All grade 2 and grade 3 infections, as defined by the BMT CTN Technical MOP, occurring post transplantation will be reported. The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for each intervention arm.
    Time Frame 2 Years

    Outcome Measure Data

    Analysis Population Description
    The analyses of the endpoint use the transplanted populations.
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    Measure Participants 104 109 114
    Patients with Grades 2-3 infections
    72
    63.2%
    66
    57.9%
    50
    42.4%
    Patients with Grades 3 infections
    31
    27.2%
    23
    20.2%
    16
    13.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of Grades II-III infection post-transplantation between the treatment groups.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0006
    Comments Superiority - Statistical significance was determined using a pre-specified threshold of 0.05.
    Method Gray's test for cumulative Incidence
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection CD34 Selected Graft, Post-Transplant Cyclophosphamide, Tacrolimus/Methotrexate Control
    Comments The null hypothesis is that there is no difference of Grades III infection post-transplantation between the treatment groups.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0145
    Comments Statistical significance was determined using a pre-specified threshold of 0.05.
    Method Gray's test for cumulative Incidence
    Comments
    17. Secondary Outcome
    Title Incidence of Infections
    Description All grade 2 and grade 3 infections, as defined by the BMT CTN Technical MOP, occurring post transplantation will be reported. The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for each intervention arm.
    Time Frame 2 years

    Outcome Measure Data

    Analysis Population Description
    The analyses of the endpoint use the transplanted populations.
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    Measure Participants 104 109 114
    Number [number of Infection Events]
    157
    161
    123
    18. Secondary Outcome
    Title Health-Related Quality of Life (HQL) - Medical Outcomes Study Short Form 36 (SF36)
    Description HQL will be measured post-transplant using patient-reported survey SF36. The SF36 is a 36 item general assessment of health quality of life with eight components: Physical Functioning, Role Physical, Pain Index, General Health Perceptions, Vitality, Social Functioning, Role Emotional, Mental Health Index. Each domain is positively scored, indicating that higher scores are associated with positive outcome. The total score ranges from 0 to 100. This scale is being used in this protocol as a generic measure of quality of life. To facilitate comparison of results with published norms, the Physical Component Summary and Mental Component Summary are used as the outcome measures in summarizing the SF36 data. These summary scores are derived by multiplying the z-score for each scale by its respective physical or mental factor score coefficient and summing the products. Resulting scores are then transformed into Tscores (mean=50; standard deviation=10). The SF36 takes 6 minutes to complete.
    Time Frame Baseline, Day 100, Day 180, 1 year, 2 years

    Outcome Measure Data

    Analysis Population Description
    The analyses of the endpoint use the transplanted populations.
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    Measure Participants 104 109 114
    STANDARDIZED MENTAL COMPONENT SCALE at Baseline
    48
    (1.0)
    46
    (1.2)
    48
    (1.1)
    STANDARDIZED MENTAL COMPONENT SCALE at Day 100
    48
    (1.0)
    48
    (1.1)
    48
    (1.0)
    STANDARDIZED MENTAL COMPONENT SCALE at Day 180
    50
    (1.1)
    50
    (1.1)
    49
    (0.9)
    STANDARDIZED MENTAL COMPONENT SCALE at 1 year
    50
    (1.2)
    52
    (1.1)
    49
    (1.2)
    STANDARDIZED MENTAL COMPONENT SCALE at 2 years
    50
    (1.5)
    50
    (1.5)
    51
    (1.1)
    STANDARDIZED PHYSICAL COMPONENT SCALE at Baseline
    42
    (1.0)
    44
    (1.0)
    41
    (1.2)
    STANDARDIZED PHYSICAL COMPONENT SCALE at Day 100
    40
    (1.1)
    41
    (1.1)
    40
    (1.0)
    STANDARDIZED PHYSICAL COMPONENT SCALE at Day 180
    43
    (1.1)
    44
    (1.2)
    44
    (0.9)
    STANDARDIZED PHYSICAL COMPONENT SCALE at 1 year
    46
    (1.2)
    47
    (1.2)
    44
    (1.1)
    STANDARDIZED PHYSICAL COMPONENT SCALE at 2 years
    46
    (1.4)
    47
    (1.2)
    47
    (1.3)
    19. Secondary Outcome
    Title Health-Related Quality of Life (HQL) - Functional Assessment of Cancer Therapy - Bone Marrow Transplant (FACT-BMT)
    Description The FACT-BMT is a 37 item scale comprised of a general core questionnaire, the FACT-G with a possible range of 0-108 points, that evaluates the health-related quality of life (HQL) of patients receiving treatment for cancer, and a specific module, BMT Concerns, that addresses disease and treatment-related questions specific to bone marrow transplant. The FACT-G consists of four subscales developed and normed in cancer patients: Physical Well-being, Social/Family Well-being, Emotional Wellbeing, and Functional Well-being. Each subscale is positively scored, with higher scores indicating better functioning. The FACT-BMT Trial Outcome Index, comprised of the physical well-being scale, the functional well-being scale and the BMT specific items, will be used as the outcome measure in summarizing the FACT-BMT data. The FACT-BMT takes 6 minutes to complete. The final score for FACT-BMT ranges from 0 to 196. Higher scores for the scales and subscales indicate better quality of life.
    Time Frame Baseline, Day 100, Day 180, 1 year, 2 years

    Outcome Measure Data

    Analysis Population Description
    The analyses of the endpoint use the transplanted populations.
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    Measure Participants 104 109 114
    FACT-G Total at Baseline
    81
    (1.6)
    79
    (1.4)
    80
    (1.9)
    FACT-G Total at Day 100
    79
    (1.7)
    80
    (1.5)
    79
    (1.6)
    FACT-G Total at Day 180
    80
    (1.9)
    83
    (1.7)
    82
    (1.6)
    FACT-G Total at 1 Year
    84
    (2.1)
    86
    (2.0)
    84
    (1.7)
    FACT-G Total at 2 Years
    87
    (2.5)
    86
    (2.1)
    84
    (2.1)
    FACT-BMT Trial Outcome Index at Baseline
    67
    (1.6)
    67
    (1.3)
    65
    (1.8)
    FACT-BMT Trial Outcome Index at Day 100
    63
    (1.9)
    66
    (1.5)
    63
    (1.6)
    FACT-BMT Trial Outcome Index at Day 180
    67
    (1.8)
    69
    (1.8)
    67
    (1.5)
    FACT-BMT Trial Outcome Index at 1 Year
    73
    (1.9)
    72
    (2.0)
    69
    (1.7)
    FACT-BMT Trial Outcome Index at 2 Years
    73
    (2.3)
    73
    (2.1)
    71
    (2.0)
    FACT-BMT Total at Baseline
    109
    (2.1)
    108
    (1.8)
    108
    (2.4)
    FACT-BMT Total at Day 100
    106
    (2.4)
    108
    (2.0)
    105
    (2.2)
    FACT-BMT Total at Day 180
    108
    (2.5)
    112
    (2.3)
    110
    (2.1)
    FACT-BMT Total at 1 Year
    114
    (2.8)
    116
    (2.6)
    113
    (2.2)
    FACT-BMT Total at 2 Years
    117
    (3.4)
    115
    (2.8)
    113
    (2.7)
    20. Secondary Outcome
    Title Health-Related Quality of Life (HQL) - MDASI
    Description HQL will be measured post-transplant using patient-reported survey MD Anderson Symptom Inventory (MDASI). The MDASI is a 19 item instrument that captures 13 symptoms (0="not present" to 10="as bad as you can imagine") and 6 items measuring interference with life from 0 ("did not interfere") to 10 ("interfered completely"). MDASI Tool questions are negatively scored - higher levels indicate more severe symptoms and levels of interference. Codelist for each question is from 0 to 10. Scoring is taking the mean of items, so the range is 0-10. Lower scores for the scales indicate better quality of life. It provides two summary scales: symptoms and interference. The MDASI takes less than 5 minutes to complete.
    Time Frame Baseline, Day 100, Day 180, 1 year, 2 years

    Outcome Measure Data

    Analysis Population Description
    The analyses of the endpoint use the transplanted populations.
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    Measure Participants 104 109 114
    Symptoms Score at Baseline
    2
    (0.2)
    2
    (0.2)
    2
    (0.2)
    Symptoms Score at Day 100
    2
    (0.2)
    2
    (0.1)
    2
    (0.2)
    Symptoms Score at Day 180
    2
    (0.2)
    2
    (0.2)
    2
    (0.2)
    Symptoms Score at 1 Year
    2
    (0.2)
    1
    (0.2)
    2
    (0.2)
    Symptoms Score at 2 Years
    1
    (0.2)
    2
    (0.2)
    2
    (0.2)
    Interference Score at Baseline
    2
    (0.2)
    2
    (0.2)
    3
    (0.2)
    Interference Score at Day 100
    2
    (0.2)
    2
    (0.2)
    2
    (0.2)
    Interference Score at Day 180
    2
    (0.3)
    2
    (0.3)
    2
    (0.2)
    Interference Score at 1 Year
    2
    (0.3)
    2
    (0.3)
    2
    (0.3)
    Interference Score at 2 Years
    1
    (0.3)
    2
    (0.3)
    2
    (0.3)
    21. Secondary Outcome
    Title Health-Related Quality of Life (HQL) - PedsQL
    Description HQL will be measured post-transplant using patient-reported survey PedsQL. The PedsQL™ Stem Cell Transplant Module is a 46-item instrument that measures health-related quality of life in children and adolescents undergoing hematopoietic stem cell transplant and is developmentally appropriate for self-report in ages 8 through 18 years. The score ranges from 0 to 100 with higher scores associated with positive outcome.
    Time Frame Baseline, Day 100, Day 180, 1 year, 2 years

    Outcome Measure Data

    Analysis Population Description
    The analyses of the endpoint use the transplanted populations.
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    Measure Participants 0 0 2
    Pediatric Quality of Life Score at Baseline
    80.18
    (14.94)
    Pediatric Quality of Life Score at Day 100
    69.82
    (2.75)
    Pediatric Quality of Life Score at Day 180
    72.56
    (3.05)
    Pediatric Quality of Life Score at 1 Year
    78.05
    (4.27)
    Pediatric Quality of Life Score at 2 Years
    53.66
    (21.34)

    Adverse Events

    Time Frame Adverse event reporting and monitoring were conducted throughout the study, up to 2 years.
    Adverse Event Reporting Description Adverse event (AE) reporting was conducted according to the BMT CTN's manual of operating procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.
    Arm/Group Title CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Arm/Group Description Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected 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. Unmanipulated Bone Marrow Graft with Cyclophosphamide Unmanipulated BM 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. Cyclophosphamide: Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow 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). Unmanipulated bone marrow graft with Tacrolimus/Methotrexate (Tac/MTX) GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Cyclosporine may be substituted for Tac if the patient is intolerant of tacrolimus or per institutional practice. MTX will be dosed at 10-15mg/m^2 for a maximum of 4 doses post-transplant. Tac will be given orally or intravenously per institutional standards starting Day -3. The dose of Tac may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of Tac (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tac taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. MTX will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of MTX should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
    All Cause Mortality
    CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 42/114 (36.8%) 27/114 (23.7%) 30/118 (25.4%)
    Serious Adverse Events
    CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 9/114 (7.9%) 7/114 (6.1%) 7/118 (5.9%)
    Cardiac disorders
    SUDDEN CARDIAC DEATH 0/114 (0%) 0 1/114 (0.9%) 1 0/118 (0%) 0
    ATRIAL FIBRILLATION 0/114 (0%) 0 1/114 (0.9%) 1 0/118 (0%) 0
    Eye disorders
    WORSENING EYESIGHT DUE TO CATARACT 1/114 (0.9%) 1 0/114 (0%) 0 0/118 (0%) 0
    Gastrointestinal disorders
    COLONIC PERFORATION 1/114 (0.9%) 1 0/114 (0%) 0 0/118 (0%) 0
    GASTRITIS 0/114 (0%) 0 0/114 (0%) 0 1/118 (0.8%) 1
    RETROPERITONEAL BLEED 1/114 (0.9%) 1 0/114 (0%) 0 0/118 (0%) 0
    General disorders
    NON CARDIAC CHEST PAIN 0/114 (0%) 0 0/114 (0%) 0 1/118 (0.8%) 1
    SUDDEN CARDIAC ARREST 1/114 (0.9%) 1 0/114 (0%) 0 0/118 (0%) 0
    DEATH 0/114 (0%) 0 1/114 (0.9%) 1 0/118 (0%) 0
    EDEMA 0/114 (0%) 0 0/114 (0%) 0 1/118 (0.8%) 1
    Hepatobiliary disorders
    CHOLECYSTITIS 0/114 (0%) 0 1/114 (0.9%) 1 0/118 (0%) 0
    Infections and infestations
    SEPSIS 0/114 (0%) 0 1/114 (0.9%) 1 0/118 (0%) 0
    HOSPITAL ADMISSION FOR INFECTION 0/114 (0%) 0 1/114 (0.9%) 1 0/118 (0%) 0
    DISSEMINATED ADENOVIRUS INFECTION 1/114 (0.9%) 1 0/114 (0%) 0 0/118 (0%) 0
    Investigations
    GRADE 3 UNEXPECTED WEIGHT LOSS 0/114 (0%) 0 0/114 (0%) 0 1/118 (0.8%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    NEW MALIGNANCY-RECTAL ADENOCARCINOM 0/114 (0%) 0 1/114 (0.9%) 1 0/118 (0%) 0
    Pregnancy, puerperium and perinatal conditions
    FETAL DEATH 0/114 (0%) 0 0/114 (0%) 0 1/118 (0.8%) 1
    Psychiatric disorders
    DELIRIUM 2/114 (1.8%) 2 0/114 (0%) 0 0/118 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    RESPIRATORY FAILURE 2/114 (1.8%) 2 0/114 (0%) 0 0/118 (0%) 0
    PLEURAL EFFUSION 0/114 (0%) 0 0/114 (0%) 0 1/118 (0.8%) 1
    Vascular disorders
    SUPERIOR VENA CAVA SYNDROME 0/114 (0%) 0 0/114 (0%) 0 1/118 (0.8%) 1
    Other (Not Including Serious) Adverse Events
    CD34 Selected Graft Post-Transplant Cyclophosphamide Tacrolimus/Methotrexate Control
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/114 (2.6%) 1/114 (0.9%) 2/118 (1.7%)
    Investigations
    PLATELET COUNT DECREASE 1/114 (0.9%) 1 0/114 (0%) 0 0/118 (0%) 0
    ELEVATED FERRITIN 0/114 (0%) 0 1/114 (0.9%) 1 0/118 (0%) 0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA 0/114 (0%) 0 0/114 (0%) 0 1/118 (0.8%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    FOLLICULAR LYMPHOMA 0/114 (0%) 0 0/114 (0%) 0 1/118 (0.8%) 1
    Product Issues
    ELEVATED ENDOTOXIN LEVEL 1/114 (0.9%) 1 0/114 (0%) 0 0/118 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    RESPIRATORY FAILURE 1/114 (0.9%) 1 0/114 (0%) 0 0/118 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Adam Mendizabal, PhD
    Organization The Emmes Company
    Phone (301) 251-1161 ext 10221
    Email amendizabal@emmes.com
    Responsible Party:
    National Heart, Lung, and Blood Institute (NHLBI)
    ClinicalTrials.gov Identifier:
    NCT02345850
    Other Study ID Numbers:
    • BMT CTN 1301
    • U01HL069294
    First Posted:
    Jan 26, 2015
    Last Update Posted:
    Dec 21, 2021
    Last Verified:
    Nov 1, 2021