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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
SUPPORTIVE_CARE
Masking
NONE
Enrollment
101
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
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.
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
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.
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
Cleveland, Ohio, United States
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
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
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
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
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
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
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
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
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
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
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Time frame: at 12 months
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
Incidence of Infection
100-day incidence of infection will be compared using a the Gray test.
Time frame: Up to day +100
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
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
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
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
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
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
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