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

Vastra Gotaland Region

Status and phase: Unknown; Phase 2

Conditions: Lymphoblastic Leukemia, Acute, Childhood

Treatments: Drug: Allopurinol; Drug: Standard treatment

Study type: Interventional

Funder types: Other

Identifiers

NCT03022747

Allopurinol Study V3.0

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 60 estimated patients

Sex: All

Ages: 6 months to 19 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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60 participants in 2 patient groups

Standard maintenance therapy

Active Comparator group

Description:

Standard maintenance therapy with 6 mercaptopurine and methotrexate

Treatment:

Drug: Standard treatment

Allopurinol treatment

Experimental group

Description:

The second 12 week phase during which allopurinol is added to oral 6-mercaptopurine and methotrexate therapy

Treatment:

Drug: Allopurinol