Optimizing 6-mercaptopurine Therapy in Pediatric Acute Lymphoblastic Leukemia by Using Allopurinol

Study Overview
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Brief Summary
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The study will investigate, in children with acute lymphoblastic leukemia during maintenance treatment, if addition of allopurinol to conventional oral 6-mercaptopurine and methotrexate therapy, affects erythrocyte concentrations of 6-thioguanine and 6 methylmercaptopurine. The effect on hematological and liver toxicity parameters in blood will also be investigated as well as clinical toxicity.

Detailed Description
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After one month of conventional maintenance therapy (MT) children and adolescents, treated for acute lymphoblastic leukemia on Nordic protocols and with wild type thiopurine methyltransferase (TPMT) are eligible for the study. They will first receive a 12 week phase with normal MT during which time repeated sampling of 6-mercaptopurine (6MP) metabolite levels and other laboratory parameters will be performed. After 12 weeks, allopurinol at a dose of 50 mg/sqm is added (simultaneously reducing the dose of 6MP by 50%) and during the next 12 weeks patients are monitored closely for toxicity and samples for determination of metabolite levels and hematological and liver toxicity are obtained regularly. If, after 4 weeks of allopurinol treatment, the levels of 6-thioguanine are below 200 nmol/mmol hemoglobin, the dose of allopurinol will be increased to 100 mg/sqm. Allopurinol treatment is continued for 12 weeks after which the patients switch to their original maintenance therapy.

Official Title
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Optimizing 6-mercaptopurine Therapy in Pediatric Acute Lymphoblastic Leukemia by Using Allopurinol Clinical Study in Children 1-19 Years on Maintenance Therapy for Acute Lymphoblastic Leukemia.

Conditions
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Lymphoblastic Leukemia, Acute, Childhood

Intervention / Treatment
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* Drug: Allopurinol
* Drug: Standard treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of acute lymphoblastic leukemia Treatment according to Nordic Society for pediatric hematology/oncology (NOPHO) ALL2008 based protocols Age 0-18y at time of initial diagnosis TPMT wild type Written informed consent Exclusion Criteria: Mature B cell lymphoblastic leukemia t(9;22) positive acute lymphoblastic leukemia Unknown TPMT status or presence of TPMT mutation (both heterozygous and homozygous) Known intolerance to any of the chemotherapeutic drugs in the protocol Major organ failure precluding administration of planned chemotherapy Severe liver toxicity defined as persistent (≥ two weeks) elevation of either S-bilirubin > 50 μmol/l or S-GPT > 20 x Upper normal limit (UNL) or P-Prothrombin complex > 1.5. Reduced kidney function defined as S-creatinine ≥ 1.5 x UNL. Lactating female or female of childbearing potential not using adequate contraception.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard maintenance therapy<br>Standard maintenance therapy with 6 mercaptopurine and methotrexate | Drug: Standard treatment<br>* Oral 6-mercaptopurine and methotrexate<br>|
| Experimental: Allopurinol treatment<br>The second 12 week phase during which allopurinol is added to oral 6-mercaptopurine and methotrexate therapy | Drug: Allopurinol<br>* Allopurinol is added to standard oral 6-mercaptopurine and methotrexate<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-thioguanine (6TG) levels in erythrocytes | The fraction of patients with 6TG levels over 200 nmol/mmol Hb at week 13 and 25 (ie after 12 weeks standard and allopurinol treatment respectively) | Up to week 25 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean level of 6-thioguanine | The mean level of 6TG at week 13 and 25 | Up to week 25 | 
| Mean level of DNA-incorporated thioguanine (DNA-TGN) | The mean level of DNA-TGN at week 13 and 25 | Up to week 25 | 
| Mean level of 6-methylmercaptopurine (6MMP) | The mean level of 6MMP at week 13 and 25 | Up to week 25 | 
| Mean levels of platelets | Comparison of weighted mean of platelets in the treatment phases | Up to week 25 | 
| Mean levels of hemoglobin | Comparison of weighted mean of hemoglobin in the treatment phases | Up to week 25 | 
| Mean levels of absolute neutrophil count (ANC) | Comparison of weighted mean of ANC in the treatment phases | Up to week 25 | 
| Mean levels of white blood cells (WBC) | Comparison of weighted mean of WBC in the treatment phases | Up to week 25 | 
| Glutamate pyruvate transaminase (GPT) | Comparison of weighted means of serum GPT in the treatment phases | Up to week 25 | 
| Bilirubin | Comparison of weighted means of serum bilirubin in the treatment phases | Up to week 25 | 
| Hypoglycemia | Comparison of incidence of hypoglycemia and laboratory measures of metabolic disturbance during the treatment phases | Up to week 25 | 
| Metabolic disturbance | Comparison of incidence of laboratory measures of metabolic disturbance during the treatment phases | Up to week 25 | 
| Incidence of serious adverse events (SAE) | Comparison of the frequency of SAE in the treatment phases | Up to week 29 | 
| Cumulative dose of 6-mercaptopurine and methotrexate | Comparison of the cumulative dose of 6MP and methotrexate and days with treatment interruption in the two treatment arms | Up to week 29 |