A Pilot Study of Allopurinol As A Modifier of 6-MP Metabolism in Pediatric ALL

• ClinicalTrials.gov Identifier: NCT02046694
• Recruitment Status: Completed
• First Posted: January 28, 2014
• Last Update Posted: June 21, 2022
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Information provided by (Responsible Party): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study Description

Brief Summary:

This research is being done to determine if allopurinol can change the metabolism of the oral chemotherapeutic medication 6-mercaptopurine (6-MP) in children with acute lymphoblastic leukemia (ALL). 6-MP is originally started at a standard dose in children with ALL, but the dose is adjusted according to the absolute neutrophil count (ANC). Occasionally, 6-MP doses need to be increased in order to get the ANC into a specific target range. Also, increasing the 6-MP dose can lead to unwanted side effects, such as inflammation of the liver as shown by increases in laboratory values (ALT, aspartate aminotransferase (AST), bilirubin), nausea, and abdominal discomfort. Previous studies in children with inflammatory bowel disease has shown that combining allopurinol with 6-MP can decrease side effects associated with high doses of 6-MP and also increase the efficacy of 6-MP. Allopurinol is approved by the Food and Drug Administration for the treatment of tumor lysis syndrome in ALL. Through this research study, the investigators hope to show that the combination of allopurinol and 6-MP will be safe, tolerable, and effective in children with ALL.

Condition or disease	Intervention/treatment	Phase
Acute Lymphoblastic Leukemia (ALL)	Drug: Allopurinol	Early Phase 1

Detailed Description:

• Patients will have several visits to the Pediatric Oncology outpatient clinic. Each visit will consist of a physical examination and laboratory evaluation. Each laboratory evaluation will consist of taking approximately 10-15 milliliters of blood (or approximately three teaspoons). These clinic visits may actually coincide with clinic visits that were previously scheduled according to the patient's treatment protocol.
• At the first study visit, patients will have a physical examination and laboratory evaluation. At that visit, patients will be asked to stop taking 6-MP and methotrexate.
• At the second study visit, which is one week later, patients will again have a physical examination and laboratory evaluation. The investigators will prescribe allopurinol and restart 6-MP and methotrexate at half of the patient's previous doses.
• Clinic visits for physical examination and laboratory evaluation will be scheduled every 1-2 weeks for a total of 5 more visits. Doses of allopurinol, 6-MP, and methotrexate may be adjusted at these visits based on laboratory values or clinical symptoms.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 34 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Pilot Study
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study of Allopurinol As A Modifier of 6-MP Metabolism in Pediatric ALL
• Actual Study Start Date: January 6, 2014
• Actual Primary Completion Date: April 6, 2020
• Actual Study Completion Date: April 6, 2020

Arms and Interventions

Arm

Intervention/treatment

Experimental: Allopurinol; Patients will stop taking their 6-MP and methotrexate at week 0. One week later (week 1), patients will begin allopurinol daily (100 mg for weight >30 kg, 50 mg for weight ≤30 kg) and will restart 6-MP and methotrexate at 50 percent of the most recent dose. Patients will continue taking allopurinol in combination with 6-MP and methotrexate for the duration of the study (total of 8 weeks). Dose adjustments of 6-MP and methotrexate will be directed by the guidelines outlined in the study protocol.

Drug: Allopurinol; At week 1, patients will begin allopurinol daily (100 mg for weight >30 kg, 50 mg for weight ≤30 kg) and will restart 6-MP and methotrexate at 50 percent of the most recent dose. Patients will continue taking allopurinol in combination with 6-MP and methotrexate for the duration of the study (total of 8 weeks).; Other Name: Zyloprim

Outcome Measures

Primary Outcome Measures :

1. Absolute neutrophil count [ Time Frame: 8 weeks ]
   Absolute neutrophil count (ANC) measured 8 weeks after the addition of allopurinol (study week 9).

Secondary Outcome Measures :

1. Feasibility of the addition of allopurinol to ALL maintenance therapy [ Time Frame: 8 weeks ]
   Allopurinol compliance rate during ALL maintenance therapy.
2. Safety of the addition of allopurinol to ALL maintenance therapy [ Time Frame: 8 weeks ]
   Occurence of grade 4 adverse events that are possibly, probably, or definitely attributable to allopurinol.
3. Effects of allopurinol on liver function tests [ Time Frame: 8 weeks ]
   Measurement of ALT, AST, and direct bilirubin before and after adding allopurinol.
4. Alteration of 6-MP metabolism through the addition of allopurinol [ Time Frame: 8 weeks ]
   Measurement of 6-thioguanine (6-TGN) and 6-methylmercaptopurine (6-MMP) before and after adding allopurinol.

Eligibility Criteria

• Ages Eligible for Study: up to 30 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Currently being treated in the maintenance phase of therapy for pediatric ALL
• Age ≤30 years
• 6-MMP:6-TGN ratio ≥40 within 21 days prior to enrollment
• 6-MMP ≥12,000/8x108 red blood cells (RBC) within 21 days prior to enrollment

• One of the following within 21 days prior to enrollment:

  1. ANC persistently ≥1500/mm3 (as measured by 3 CBCs done over 6 weeks or 2 successive monthly complete blood counts (CBCs) despite 6-MP ≥150% of Children's oncology group (COG) dosing OR

  2. Evidence of ≥ Grade 3 hepatotoxicity with one of the following:

     ALT ≥5x upper limit of normal (based on institutional standards) AST ≥5x upper limit of normal (based on institutional standards) Direct bilirubin ≥5x upper limit of normal (based on institutional standards) OR

  3. Evidence of ≥ Grade 2 gastrointestinal toxicity (including, but not limited to: nausea, vomiting, anorexia, gastrointestinal pain)

Exclusion Criteria:

• Allergy to allopurinol
• Active relapse of ALL or lymphoblastic lymphoma
• Currently enrolled on any therapeutic research study for the treatment of ALL or lymphoblastic lymphoma
• Known history of chronic liver disease (other than Gilbert's syndrome)
• Pregnant or breastfeeding females

Contacts and Locations

Locations

United States, Maryland

Johns Hopkins Hospital

Baltimore, Maryland, United States, 21287

United States, Texas

Texas Children's Cancer and Hematology Centers

Houston, Texas, United States, 77030

United States, Washington

Seattle Children's Hospital

Seattle, Washington, United States, 98105

Sponsors and Collaborators

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Investigators

• Principal Investigator: Stacy Cooper, MD; Johns Hopkins University

More Information

Publications:

Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006 Jan 12;354(2):166-78. doi: 10.1056/NEJMra052603. No abstract available.

Ansari A, Elliott T, Baburajan B, Mayhead P, O'Donohue J, Chocair P, Sanderson J, Duley J. Long-term outcome of using allopurinol co-therapy as a strategy for overcoming thiopurine hepatotoxicity in treating inflammatory bowel disease. Aliment Pharmacol Ther. 2008 Sep 15;28(6):734-41. doi: 10.1111/j.1365-2036.2008.03782.x.

Rahhal RM, Bishop WP. Initial clinical experience with allopurinol-thiopurine combination therapy in pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2008 Dec;14(12):1678-82. doi: 10.1002/ibd.20522.

Sparrow MP, Hande SA, Friedman S, Lim WC, Reddy SI, Cao D, Hanauer SB. Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine. Aliment Pharmacol Ther. 2005 Sep 1;22(5):441-6. doi: 10.1111/j.1365-2036.2005.02583.x.

Sparrow MP, Hande SA, Friedman S, Cao D, Hanauer SB. Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine. Clin Gastroenterol Hepatol. 2007 Feb;5(2):209-14. doi: 10.1016/j.cgh.2006.11.020.

Koren G, Ferrazini G, Sulh H, Langevin AM, Kapelushnik J, Klein J, Giesbrecht E, Soldin S, Greenberg M. Systemic exposure to mercaptopurine as a prognostic factor in acute lymphocytic leukemia in children. N Engl J Med. 1990 Jul 5;323(1):17-21. doi: 10.1056/NEJM199007053230104.

Balis FM, Holcenberg JS, Poplack DG, Ge J, Sather HN, Murphy RF, Ames MM, Waskerwitz MJ, Tubergen DG, Zimm S, Gilchrist GS, Bleyer WA. Pharmacokinetics and pharmacodynamics of oral methotrexate and mercaptopurine in children with lower risk acute lymphoblastic leukemia: a joint children's cancer group and pediatric oncology branch study. Blood. 1998 Nov 15;92(10):3569-77.

Pui CH, Mullighan CG, Evans WE, Relling MV. Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? Blood. 2012 Aug 9;120(6):1165-74. doi: 10.1182/blood-2012-05-378943. Epub 2012 Jun 22.

Zimm S, Collins JM, O'Neill D, Chabner BA, Poplack DG. Inhibition of first-pass metabolism in cancer chemotherapy: interaction of 6-mercaptopurine and allopurinol. Clin Pharmacol Ther. 1983 Dec;34(6):810-7. doi: 10.1038/clpt.1983.254.

Elion GB. The purine path to chemotherapy. Science. 1989 Apr 7;244(4900):41-7. doi: 10.1126/science.2649979.

Brackett J, Schafer ES, Leung DH, Bernhardt MB. Use of allopurinol in children with acute lymphoblastic leukemia to reduce skewed thiopurine metabolism. Pediatr Blood Cancer. 2014 Jun;61(6):1114-7. doi: 10.1002/pbc.24913. Epub 2013 Dec 27.

Jharap B, Seinen ML, de Boer NK, van Ginkel JR, Linskens RK, Kneppelhout JC, Mulder CJ, van Bodegraven AA. Thiopurine therapy in inflammatory bowel disease patients: analyses of two 8-year intercept cohorts. Inflamm Bowel Dis. 2010 Sep;16(9):1541-9. doi: 10.1002/ibd.21221.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT02046694
• Other Study ID Numbers: J1357; J1357 ( Other Identifier: SKCCC at Johns Hopkins ); NA_00084984 ( Other Identifier: JHMIRB )
• First Posted: January 28, 2014
• Last Update Posted: June 21, 2022
• Last Verified: June 2022

Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:

acute lymphoblastic leukemia; ALL; pediatric; maintenance; allopurinol; 6-MP; 6-mercaptopurine

Additional relevant MeSH terms:

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Allopurinol; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gout Suppressants; Antirheumatic Agents; Free Radical Scavengers; Antioxidants; Protective Agents; Physiological Effects of Drugs