Tac, Mini-MTX, MMF Versus Tac, MTX for GVHD Prevention

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• Leukemia, Myelogenous, Chronic, BCR-ABL Positive 982
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive

982 studies on the registry are indexed under Leukemia, Myelogenous, Chronic, BCR-ABL Positive; 109 are open to participants now.

This study's enrollment of 101 is above the median of 43 across 755 interventional studies indexed under Leukemia, Myelogenous, Chronic, BCR-ABL Positive.

Lead sponsor

Case Comprehensive Cancer Center is the lead sponsor of 493 studies on the registry; 59 are open to participants now.

Of its 75 completed or terminated interventional studies of FDA-regulated products, 46 (61%) have results posted.

Study arms

• Active comparator
  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.

  Drug: tacrolimus · Drug: methotrexate

• Experimental
  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).

  Drug: tacrolimus · Drug: Mycophenolate mofetil · Drug: Methotrexate (low dose)

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

  Also known as: FK 506, Prograf

• 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.

  Also known as: amethopterin, Folex, methylaminopterin, Mexate, MTX

• 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

  Also known as: Cellcept, MMF

• 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.

  Also known as: amethopterin, Folex, methylaminopterin, Mexate, MTX

Primary outcomes

1. 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

2. 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

3. 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

4. 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

Secondary outcomes

1. 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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. Incidence of Infection

   100-day incidence of infection will be compared using a the Gray test.

   Time frame: Up to day +100

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

Other outcomes

1. 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

Baseline characteristics

Publications

• Hamilton BK, Rybicki LA, Li H, Lucas T, Corrigan D, Kalaycio M, Sobecks R, Hanna R, Rotz SJ, Dean RM, Gerds AT, Jagadeesh D, Brunstein C, Sauter CS, Copelan EA, Majhail NS. Tacrolimus/methotrexate vs tacrolimus/reduced-dose methotrexate/mycophenolate for graft-versus-host disease prevention. Blood Adv. 2023 Aug 22;7(16):4505-4513. doi: 10.1182/bloodadvances.2023010310. PubMed 37352262 ↗

Study documents

• Protocol and statistical analysis plan · Jun 28, 2022
• Informed consent form · May 4, 2022

Documents are hosted by the registry — open the source record to download them.