Acute Biphenotypic Leukemia, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Hodgkins Disease, Multiple Myeloma, Myelodysplastic Syndrome, Myeloproliferative Neoplasm, Non-Hodgkin Lymphoma
Conditions
Brief summary
This randomized clinical trial studies standard GVHD prophylaxis with tacrolimus and methotrexate compared to tacrolimus, mycophenolate mofetil and a reduced-dose methotrexate in patients with hematologic malignancies undergoing allogeneic hematopoietic cell transplant. Both mycophenolate mofetil and reduced-dose methotrexate, in combination with a calcineurin inhibitor, have been shown to be safe and effective in GVHD prevention with less toxicity than standard dose methotrexate. It is not yet known, however, whether this combination of mycophenolate mofetil and reduced-dose methotrexate with tacrolimus is more effective than tacrolimus and standard dose methotrexate in preventing GVHD.
Detailed description
Study Design This is a prospective randomized trial to determine the effectiveness of different doses of GVHD prophylaxis on mucositis, engraftment and aGVHD. Study consists of two study groups of 50 subjects each. Group A will receive Tac and MTX (15 mg/m2 day +1, 10 mg/m2 day +3, +6, +11). Group B will receive Tac, Mini-dose MTX (5 mg/m2 on day +1, +3, +6) and MMF.
Interventions
DRUGtacrolimus
Tacrolimus 0.03 mg/kg/day beginning day -1 or tacrolimus 0.03mg/kg/dose BID orally beginning on day -3. If Tac is administered intravenously, it will be given over 24 hours and will be converted to oral administration 2 times a day when the patient has engrafted and/or can tolerate oral medication. Levels of Tac will be obtained to maintain a recommended target serum level of 5-12 ng/mL
DRUGmethotrexate
MTX 15mg/m2 IV on day +1, followed by 10mg/m2 on day +3, +6, +11. If patient \< 10 kg then MTX will be given at 0.5 mg/kg IV on day +1. Then MTX will be given at 0.33 mg/kg on days +3, +6 and +11.
DRUGMycophenolate mofetil
Patients will receive Mycophenolate beginning on day +1. Patients \>40 kg will receive Mycophenolate 1000 mg twice a day. Mycophenolate should be given orally twice a day. IV formulation may be used if the patient cannot tolerate oral route. Patients \< 40 kg will receive MMF 45 mg/kg/day (15 mg/kg three times a day). MMF may be given orally or intravenously as per institutional protocol
DRUGMethotrexate (low dose)
MTX 5mg/m2 IV on day +1, +3, +6. If patient\<10 kg MTX will be given at 0.17 mg/kg on day +1, +3, and +6.
Sponsors
Case Comprehensive Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 70 Years
Healthy volunteers
No
Inclusion criteria
* Patients must have one of the following documented diseases: * Chronic myelogenous leukemia * Chronic lymphocytic leukemia * Multiple myeloma * Myelodysplasia * Myeloproliferative disorder * Non-Hodgkin's lymphoma * Hodgkin's disease * Acute myelogenous leukemia * Acute lymphoblastic leukemia * Acute biphenotypic leukemia * Patients must be undergoing a myeloablative allogeneic hematopoietic cell transplant with one of the following conditioning regimens: * Busulfan (≥ 12.8 mg/kg IV or PO) and cyclophosphamide (≥ 120 mg/kg) \--- Busulfan dose may be adjusted according to pharmacokinetics targeting a daily AUC of 5000 μmol-min/L, per institution standard of practice. * Total body irradiation (TBI) (≥ 1200 cGy) and etoposide (60 mg/kg) * TBI (≥ 1200 cGy) and cyclophosphamide (120 mg/kg) * Patient must have achieved and be in complete morphologic remission prior to starting conditioning regimen * Patient's donor must be a related or unrelated human leukocyte antigen (HLA) 8/8 allele-level match (HLA-A, B, C and DRB1) * Adult patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; pediatric patients must have Lansky score ≥ 60% * Patients must have a life expectancy of 100 days * Patients must sign written informed consent
Exclusion criteria
* Patients who have undergone any prior transplant * Patients who are seropositive for human immunodeficiency virus (HIV) * Patients with any medical illness or concurrent psychiatric illness which, in the investigators' opinion, cannot be adequately controlled with appropriate therapy * Patients who are pregnant or lactating
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Incidence of Participants With Acute GVHD | Day 7- Day 100 | Acute GVHD by grade will be estimated using cumulative incidence methods and compared using the Gray test. A lower clinical grade and/or stage of GVHD corresponds to a better participant outcome and a higher grade corresponds to a worse participant outcome. Grading is as follows: Grade 0: No stage 1-4 of any organ Grade 1: Stage 1-2 skin without liver, upper GI, or lower GI involvement. Grade 2: Stage 3 rash and/or stage 1 liver and/or stage 1 upper GI and/or stage 1 lower GI. Grade 3: Stage 2-3 liver and/or stage 2-3 lower GI, with stage 0-3 skin and/or stage 0-1 upper GI. Grade 4: Stage 4 skin, liver, or lower GI involvement, with stage 0-1 upper GI. A greater stage of GVHD involves worsening end-organ involvement and worse participant outcomes based on the skin, liver, lower GI, and upper GI. |
| Percentage of Severe (Grade 3-4) Mucositis Graded According to the World Health Organization (WHO) Grading Scale | Up to day 28 | Participants (percentage of) will be graded three times per week through day 28 of the study. Incidence will be compared through Wilcoxon rank sum tests. The WHO grading scale for mucositis is scaled depending on the severity of mucositis symptoms, with a lower stage associated with a better outcome and greater stages associated with worse outcomes. The staging is as follows: Stage 0: None Stage 1 (mild): Oral soreness, erythema Stage 2 (moderate): Oral erythema, ulcers, solid diet tolerated Stage 3 (severe): Oral ulcers, liquid diet only Stage 4 (life-threatening): Oral alimentation impossible |
| Time to Neutrophil Engraftment | Up to 28 days | The number of days to reach a neutrophil count of greater than or equal to 500/ul for three consecutive laboratory values obtained on different days. The day of engraftment will be the first day of the three consecutive laboratory values. |
| Time to Platelet Engraftment | The date the participant engrafts, up to 28 days | The number of days to reach a platelet count of greater than or equal to 20,000/ul for three consecutive laboratory values obtained on different days, independent of platelet transfusions the prior 7 days. The day of engraftment will be the first day of the three consecutive laboratory values. For cases of delayed engraftment beyond 28 days, results will be recorded once the participant engrafts. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | Up to 1 year | Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test. |
| Incidence of Chronic GVHD | at 6 months | Chronic GVHD will be graded as mild, moderate, or severe based on the National Institutes of Health Consensus Development Project. The type and duration of immunosuppressive treatment given for cGVHD will be recorded. Mild grades are associated with a better participant outcome and severe corresponds to a worse participant outcome. Grading is as follows: Mild: 1 or 2 organs involved with no more than score 1 plus Lung score 0 Moderate: 3 or more organs involved with no more than score 1 OR At least 1 organ (not lung) with a score of 2 OR Lung score 1 Severe: At least 1 organ with a score of 3 OR Lung score of 2 or 3 Organ scores can range from 0 to 3, with 0 being no symptoms on the target organ and a better participant outcome while a score of 3 correlates to severe symptoms on the target organ and worse participant outcomes. Potential target organs include: skin, mouth, eyes, GI tract, liver, lungs, joint /fascia, and genital tract |
| Length of Time on Continuous Infusion Narcotics | up to +28 day | Start and stop dates for the need of continuous IV infusion of narcotics for severe mucositis pain will be recorded. Time on IV infusion will be compared between patients in groups A and B using the Wilcoxon rank sum test. |
| Incidence of Infection | Up to day +100 | 100-day incidence of infection will be compared using a the Gray test. |
| Incidence of Hepatotoxicity as Measured by Elevated Liver Enzymes | Up to day +100 | 100-day incidence of hepatotoxicity will be compared using a Gray test. Percentage of patients with elevated Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), and alkaline phosphatase and a 95% confidence interval |
| Incidence of Hepatotoxicity as Measured by Bilirubin | Up to day +100 | 100-day incidence of hepatotoxicity will be compared using a Gray test. Median and range of largest total bilirubin (mg/dL), |
| Incidence of Nephrotoxicity | Up to day +100 | 100-day incidence of nephrotoxicity will be compared using a Chi-squared test. Percentage of patients requiring dialysis and those with elevated creatinine using a 95% confidence interval |
| Incidence of Pulmonary Toxicity Measured by Pulmonary Hemorrhage | Up to day +180 | 180-day incidence of pulmonary toxicity will be compared using the Gray test. Percentage of patients with pulmonary hemorrhage and 95% confidence interval |
| Incidence of Pulmonary Toxicity Measured by Pulmonary Edema | Up to day +180 | 180-day incidence of pulmonary toxicity will be compared using the Gray test. Percentage of patients with pulmonary edema and 95% confidence interval |
| Incidence of Pulmonary Toxicity Measured by Respiratory Failure | Up to day +180 | 180-day incidence of pulmonary toxicity will be compared using the Gray test. Percentage of patients with respiratory failure and 95% confidence interval |
| Incidence of Hepatotoxicity as Measured by Veno-occlusive Disease (VOD) | Up to day +100 | 100-day incidence of hepatotoxicity will be compared using the Gray test. Percentage of patients with VOD and 95% confidence interval |
| Length of Hospitalization | Date of transplant to date of discharge, assessed up to 1 year | Hospital stay will be compared between patients in groups A and B using the Wilcoxon rank sum test. |
| Percentage of Participants Using Total Parenteral Nutrition (TPN) Within 100 Days | Up to day 100 | TPN use will be compared using the Chi-square test. |
| Overall Survival | Up to 1 year | Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Chimerism Results | Up to one year | Donor chimerism will be assessed by analysis of single-tandem repeats on whole marrow and in lymphocyte enriched or sorted CD3+ T cells and CD33+ granulocytes. Blood will be obtained for donor chimerism Bone Marrow Engraftment analysis at approximately 1, 2, 3, 6, 9 and 12 months or as clinically indicated. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from local hospital from July 2014 thru July 2020
Participants by arm
| Arm | Count |
|---|---|
| Group A (Tacrolimus, Methotrexate) Participants receive tacrolimus IV over 24 hours beginning on day -1 (or tacrolimus orally beginning on day -3) and then PO BID after engraftment with a taper from day 100 to day 180 (in the absence of GVHD). Patients also receive methotrexate IV on days 1, 3, 6, and 11.
tacrolimus: Tacrolimus 0.03 mg/kg/day beginning day -1 or tacrolimus 0.03mg/kg/dose BID orally beginning on day -3. If Tac is administered intravenously, it will be given over 24 hours and will be converted to oral administration 2 times a day when the patient has engrafted and/or can tolerate oral medication. Levels of Tac will be obtained to maintain a recommended target serum level of 5-12 ng/mL
methotrexate: MTX 15mg/m2 IV on day +1, followed by 10mg/m2 on day +3, +6, +11. If patient \< 10 kg then MTX will be given at 0.5 mg/kg IV on day +1. Then MTX will be given at 0.33 mg/kg on days +3, +6 and +11. | 50 |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) Patients receive tacrolimus as in group A and methotrexate (low dose) IV on days 1, 3, and 6. Patients also receive oral mycophenolate mofetil BID beginning on day 1, with a taper from day 45 to day 100 (in the absence of GVHD).
tacrolimus: Tacrolimus 0.03 mg/kg/day beginning day -1 or tacrolimus 0.03mg/kg/dose BID orally beginning on day -3. If Tac is administered intravenously, it will be given over 24 hours and will be converted to oral administration 2 times a day when the patient has engrafted and/or can tolerate oral medication. Levels of Tac will be obtained to maintain a recommended target serum level of 5-12 ng/mL
Mycophenolate mofetil: Patients will receive Mycophenolate beginning on day +1. Patients \>40 kg will receive Mycophenolate 1000 mg twice a day. Mycophenolate should be given orally twice a day. IV formulation may be used if the patient cannot tolerate oral route. Patients \< 40 kg will receive MMF 45 mg/kg/day (15 mg/kg three times a day). MMF may be given orally or intravenously as per institutional protocol
Methotrexate (low dose): MTX 5mg/m2 IV on day +1, +3, +6. If patient\<10 kg MTX will be given at 0.17 mg/kg on day +1, +3, and +6. | 51 |
| Total | 101 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | ineligible after experiencing cardiac issues | 0 | 1 |
| Overall Study | ineligible due to a change in conditioning regimen | 0 | 1 |
| Overall Study | ineligible due to a change in donor | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Group A (Tacrolimus, Methotrexate) | Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Total |
|---|---|---|---|
| Age, Customized 0-9 years old | 1 Participants | 1 Participants | 2 Participants |
| Age, Customized 10-19 years old | 0 Participants | 3 Participants | 3 Participants |
| Age, Customized 20-29 years old | 10 Participants | 7 Participants | 17 Participants |
| Age, Customized 30-39 years old | 9 Participants | 8 Participants | 17 Participants |
| Age, Customized 40-49 years old | 11 Participants | 12 Participants | 23 Participants |
| Age, Customized 50-59 years old | 19 Participants | 15 Participants | 34 Participants |
| Age, Customized 60-69 years old | 0 Participants | 5 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 48 Participants | 48 Participants | 96 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 47 Participants | 51 Participants | 98 Participants |
| Region of Enrollment United States | 50 participants | 51 participants | 101 participants |
| Sex: Female, Male Female | 28 Participants | 18 Participants | 46 Participants |
| Sex: Female, Male Male | 22 Participants | 33 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 25 / 50 | 15 / 51 |
| other Total, other adverse events | 49 / 50 | 47 / 51 |
| serious Total, serious adverse events | 13 / 50 | 3 / 51 |
Outcome results
Primary
Cumulative Incidence of Participants With Acute GVHD
Acute GVHD by grade will be estimated using cumulative incidence methods and compared using the Gray test. A lower clinical grade and/or stage of GVHD corresponds to a better participant outcome and a higher grade corresponds to a worse participant outcome. Grading is as follows: Grade 0: No stage 1-4 of any organ Grade 1: Stage 1-2 skin without liver, upper GI, or lower GI involvement. Grade 2: Stage 3 rash and/or stage 1 liver and/or stage 1 upper GI and/or stage 1 lower GI. Grade 3: Stage 2-3 liver and/or stage 2-3 lower GI, with stage 0-3 skin and/or stage 0-1 upper GI. Grade 4: Stage 4 skin, liver, or lower GI involvement, with stage 0-1 upper GI. A greater stage of GVHD involves worsening end-organ involvement and worse participant outcomes based on the skin, liver, lower GI, and upper GI.
Time frame: Day 7- Day 100
Population: participants who completed the study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A (Tacrolimus, Methotrexate) | Cumulative Incidence of Participants With Acute GVHD | Grade 1-4 | 37 percentage of participants |
| Group A (Tacrolimus, Methotrexate) | Cumulative Incidence of Participants With Acute GVHD | Grade 2-4 | 27 percentage of participants |
| Group A (Tacrolimus, Methotrexate) | Cumulative Incidence of Participants With Acute GVHD | Grade 3-4 | 4 percentage of participants |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Cumulative Incidence of Participants With Acute GVHD | Grade 1-4 | 47 percentage of participants |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Cumulative Incidence of Participants With Acute GVHD | Grade 2-4 | 28 percentage of participants |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Cumulative Incidence of Participants With Acute GVHD | Grade 3-4 | 13 percentage of participants |
p-value: <0.05Log Rank
Primary
Percentage of Severe (Grade 3-4) Mucositis Graded According to the World Health Organization (WHO) Grading Scale
Participants (percentage of) will be graded three times per week through day 28 of the study. Incidence will be compared through Wilcoxon rank sum tests. The WHO grading scale for mucositis is scaled depending on the severity of mucositis symptoms, with a lower stage associated with a better outcome and greater stages associated with worse outcomes. The staging is as follows: Stage 0: None Stage 1 (mild): Oral soreness, erythema Stage 2 (moderate): Oral erythema, ulcers, solid diet tolerated Stage 3 (severe): Oral ulcers, liquid diet only Stage 4 (life-threatening): Oral alimentation impossible
Time frame: Up to day 28
Population: participants that completed study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A (Tacrolimus, Methotrexate) | Percentage of Severe (Grade 3-4) Mucositis Graded According to the World Health Organization (WHO) Grading Scale | 81.6 percentage of participants |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Percentage of Severe (Grade 3-4) Mucositis Graded According to the World Health Organization (WHO) Grading Scale | 57.4 percentage of participants |
p-value: 0.05Wilcoxon (Mann-Whitney)
Primary
Time to Neutrophil Engraftment
The number of days to reach a neutrophil count of greater than or equal to 500/ul for three consecutive laboratory values obtained on different days. The day of engraftment will be the first day of the three consecutive laboratory values.
Time frame: Up to 28 days
Population: participants that were able to engraft neutrophils
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Tacrolimus, Methotrexate) | Time to Neutrophil Engraftment | 17 days |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Time to Neutrophil Engraftment | 15 days |
Primary
Time to Platelet Engraftment
The number of days to reach a platelet count of greater than or equal to 20,000/ul for three consecutive laboratory values obtained on different days, independent of platelet transfusions the prior 7 days. The day of engraftment will be the first day of the three consecutive laboratory values. For cases of delayed engraftment beyond 28 days, results will be recorded once the participant engrafts.
Time frame: The date the participant engrafts, up to 28 days
Population: participants that were able to engraft platelets
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Tacrolimus, Methotrexate) | Time to Platelet Engraftment | 27 days |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Time to Platelet Engraftment | 23 days |
Secondary
Incidence of Chronic GVHD
Chronic GVHD will be graded as mild, moderate, or severe based on the National Institutes of Health Consensus Development Project. The type and duration of immunosuppressive treatment given for cGVHD will be recorded. Mild grades are associated with a better participant outcome and severe corresponds to a worse participant outcome. Grading is as follows: Mild: 1 or 2 organs involved with no more than score 1 plus Lung score 0 Moderate: 3 or more organs involved with no more than score 1 OR At least 1 organ (not lung) with a score of 2 OR Lung score 1 Severe: At least 1 organ with a score of 3 OR Lung score of 2 or 3 Organ scores can range from 0 to 3, with 0 being no symptoms on the target organ and a better participant outcome while a score of 3 correlates to severe symptoms on the target organ and worse participant outcomes. Potential target organs include: skin, mouth, eyes, GI tract, liver, lungs, joint /fascia, and genital tract
Time frame: at 12 months
Population: participants who completed the study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A (Tacrolimus, Methotrexate) | Incidence of Chronic GVHD | any chronic GVHD | 25 percentage of participants |
| Group A (Tacrolimus, Methotrexate) | Incidence of Chronic GVHD | moderate-severe chronic GVHD | 20 percentage of participants |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Incidence of Chronic GVHD | any chronic GVHD | 36 percentage of participants |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Incidence of Chronic GVHD | moderate-severe chronic GVHD | 23 percentage of participants |
Secondary
Incidence of Chronic GVHD
Chronic GVHD will be graded as mild, moderate, or severe based on the National Institutes of Health Consensus Development Project. The type and duration of immunosuppressive treatment given for cGVHD will be recorded. Mild grades are associated with a better participant outcome and severe corresponds to a worse participant outcome. Grading is as follows: Mild: 1 or 2 organs involved with no more than score 1 plus Lung score 0 Moderate: 3 or more organs involved with no more than score 1 OR At least 1 organ (not lung) with a score of 2 OR Lung score 1 Severe: At least 1 organ with a score of 3 OR Lung score of 2 or 3 Organ scores can range from 0 to 3, with 0 being no symptoms on the target organ and a better participant outcome while a score of 3 correlates to severe symptoms on the target organ and worse participant outcomes. Potential target organs include: skin, mouth, eyes, GI tract, liver, lungs, joint /fascia, and genital tract
Time frame: at 6 months
Population: participants who completed the study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A (Tacrolimus, Methotrexate) | Incidence of Chronic GVHD | any chronic GVHD | 16 percentage of participants |
| Group A (Tacrolimus, Methotrexate) | Incidence of Chronic GVHD | moderate-severe chronic GVHD | 12 percentage of participants |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Incidence of Chronic GVHD | any chronic GVHD | 15 percentage of participants |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Incidence of Chronic GVHD | moderate-severe chronic GVHD | 11 percentage of participants |
Secondary
Incidence of Hepatotoxicity as Measured by Bilirubin
100-day incidence of hepatotoxicity will be compared using a Gray test. Median and range of largest total bilirubin (mg/dL),
Time frame: Up to day +100
Population: participants that completed the study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Tacrolimus, Methotrexate) | Incidence of Hepatotoxicity as Measured by Bilirubin | 1.5 mg/dL |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Incidence of Hepatotoxicity as Measured by Bilirubin | 1.1 mg/dL |
p-value: <0.05Gray Test
Secondary
Incidence of Hepatotoxicity as Measured by Elevated Liver Enzymes
100-day incidence of hepatotoxicity will be compared using a Gray test. Percentage of patients with elevated Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), and alkaline phosphatase and a 95% confidence interval
Time frame: Up to day +100
Population: participants that completed the study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A (Tacrolimus, Methotrexate) | Incidence of Hepatotoxicity as Measured by Elevated Liver Enzymes | AST | 29 percentage of participants |
| Group A (Tacrolimus, Methotrexate) | Incidence of Hepatotoxicity as Measured by Elevated Liver Enzymes | ALT | 33 percentage of participants |
| Group A (Tacrolimus, Methotrexate) | Incidence of Hepatotoxicity as Measured by Elevated Liver Enzymes | Alkaline Phosphatase | 2 percentage of participants |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Incidence of Hepatotoxicity as Measured by Elevated Liver Enzymes | AST | 15 percentage of participants |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Incidence of Hepatotoxicity as Measured by Elevated Liver Enzymes | ALT | 28 percentage of participants |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Incidence of Hepatotoxicity as Measured by Elevated Liver Enzymes | Alkaline Phosphatase | 2 percentage of participants |
p-value: <0.05Chi-squared
Secondary
Incidence of Hepatotoxicity as Measured by Veno-occlusive Disease (VOD)
100-day incidence of hepatotoxicity will be compared using the Gray test. Percentage of patients with VOD and 95% confidence interval
Time frame: Up to day +100
Population: participants that completed the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A (Tacrolimus, Methotrexate) | Incidence of Hepatotoxicity as Measured by Veno-occlusive Disease (VOD) | 8 percentage of participants |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Incidence of Hepatotoxicity as Measured by Veno-occlusive Disease (VOD) | 2 percentage of participants |
p-value: <0.05Gray Test
Secondary
Incidence of Infection
100-day incidence of infection will be compared using a the Gray test.
Time frame: Up to day +100
Population: participants that completed the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A (Tacrolimus, Methotrexate) | Incidence of Infection | 63 percentage of participants |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Incidence of Infection | 53 percentage of participants |
p-value: <0.05Gray Test
Secondary
Incidence of Nephrotoxicity
100-day incidence of nephrotoxicity will be compared using a Chi-squared test. Percentage of patients requiring dialysis and those with elevated creatinine using a 95% confidence interval
Time frame: Up to day +100
Population: participants that completed the study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A (Tacrolimus, Methotrexate) | Incidence of Nephrotoxicity | Participants requiring dialysis | 12 percentage of participants |
| Group A (Tacrolimus, Methotrexate) | Incidence of Nephrotoxicity | Participants with elevated creatinine | 27 percentage of participants |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Incidence of Nephrotoxicity | Participants requiring dialysis | 4 percentage of participants |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Incidence of Nephrotoxicity | Participants with elevated creatinine | 2 percentage of participants |
Secondary
Incidence of Pulmonary Toxicity Measured by Pulmonary Edema
180-day incidence of pulmonary toxicity will be compared using the Gray test. Percentage of patients with pulmonary edema and 95% confidence interval
Time frame: Up to day +180
Population: participants that completed the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A (Tacrolimus, Methotrexate) | Incidence of Pulmonary Toxicity Measured by Pulmonary Edema | 14 percentage of participants |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Incidence of Pulmonary Toxicity Measured by Pulmonary Edema | 4 percentage of participants |
p-value: <0.05Gray Test
Secondary
Incidence of Pulmonary Toxicity Measured by Pulmonary Hemorrhage
180-day incidence of pulmonary toxicity will be compared using the Gray test. Percentage of patients with pulmonary hemorrhage and 95% confidence interval
Time frame: Up to day +180
Population: participants that completed the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A (Tacrolimus, Methotrexate) | Incidence of Pulmonary Toxicity Measured by Pulmonary Hemorrhage | 2 percentage of participants |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Incidence of Pulmonary Toxicity Measured by Pulmonary Hemorrhage | 2 percentage of participants |
p-value: <0.05Gray Test
Secondary
Incidence of Pulmonary Toxicity Measured by Respiratory Failure
180-day incidence of pulmonary toxicity will be compared using the Gray test. Percentage of patients with respiratory failure and 95% confidence interval
Time frame: Up to day +180
Population: participants that completed the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A (Tacrolimus, Methotrexate) | Incidence of Pulmonary Toxicity Measured by Respiratory Failure | 9 percentage of participants |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Incidence of Pulmonary Toxicity Measured by Respiratory Failure | 6 percentage of participants |
p-value: <0.05Gray Test
Secondary
Length of Hospitalization
Hospital stay will be compared between patients in groups A and B using the Wilcoxon rank sum test.
Time frame: Date of transplant to date of discharge, assessed up to 1 year
Population: participants who completed the study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Tacrolimus, Methotrexate) | Length of Hospitalization | 31 days |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Length of Hospitalization | 27 days |
p-value: 0.05Wilcoxon (Mann-Whitney)
Secondary
Length of Time on Continuous Infusion Narcotics
Start and stop dates for the need of continuous IV infusion of narcotics for severe mucositis pain will be recorded. Time on IV infusion will be compared between patients in groups A and B using the Wilcoxon rank sum test.
Time frame: up to +28 day
Population: Participants that were on continuous infusion narcotics
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Tacrolimus, Methotrexate) | Length of Time on Continuous Infusion Narcotics | 10 days |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Length of Time on Continuous Infusion Narcotics | 9 days |
p-value: <0.05Wilcoxon (Mann-Whitney)
Secondary
Overall Survival
Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test.
Time frame: Up to 1 year
Population: participants who completed the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A (Tacrolimus, Methotrexate) | Overall Survival | 71 percentage of participants |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Overall Survival | 72 percentage of participants |
p-value: <0.05Log Rank
Secondary
Percentage of Participants Using Total Parenteral Nutrition (TPN) Within 100 Days
TPN use will be compared using the Chi-square test.
Time frame: Up to day 100
Population: participants who completed the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A (Tacrolimus, Methotrexate) | Percentage of Participants Using Total Parenteral Nutrition (TPN) Within 100 Days | 41 percentage of participants |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Percentage of Participants Using Total Parenteral Nutrition (TPN) Within 100 Days | 38 percentage of participants |
p-value: <0.05Chi-squared
Secondary
Progression-free Survival
Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test.
Time frame: Up to 1 year
Population: participants who completed the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A (Tacrolimus, Methotrexate) | Progression-free Survival | 59 percentage of participants |
| Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil) | Progression-free Survival | 68 percentage of participants |
p-value: <0.05Log Rank
Other Pre-specified
Chimerism Results
Donor chimerism will be assessed by analysis of single-tandem repeats on whole marrow and in lymphocyte enriched or sorted CD3+ T cells and CD33+ granulocytes. Blood will be obtained for donor chimerism Bone Marrow Engraftment analysis at approximately 1, 2, 3, 6, 9 and 12 months or as clinically indicated.
Time frame: Up to one year