Pentoxifylline In Pediatric Acute Lymphoblastic Leukemia During Induction

Study Overview
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Brief Summary
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Recent advances in acute lymphoblastic leukemia treatment are based on a cytotoxic drug combination. Measurement of minimal residual disease in bone marrow samples at day 14 of treatment is the most powerful early predictive indicator of further relapse, and it can be applied practically to all patients with acute lymphoblastic leukemia. Even more so, it has been observed that patients who present negative minimal residual disease in bone marrow samples at day 7 during induction have a better prognosis than those achieving this at day 14. Relapse represents the main cause of treatment failure that related in the extreme with resistance to apoptosis, defining the latter as the principal mechanism of programmed cell death; it is also related with the induction of leukemic cells to senescent arrest. Pentoxifylline is a methyl-xanthine byproduct considered an unspecific inhibitor of phosphodiesterase. It inhibits nuclear factor-kappa-beta activation by different mechanisms and stimulates apoptosis induced by different drugs; thus, it can optimize the antineoplastic effect of actual treatments in order to increase the apoptosis of leukemic cells. This effect might improve the prognosis of these patients. Evaluate the safety and effect of Pentoxifylline together with antineoplastic drugs in order to study increased apoptosis and decreased senescence during the remission induction phase in pediatric patients with newly diagnosed acute lymphoblastic leukemia. To achieve this propose, we will divide patients in two groups, who will receive pentoxifylline or placebo depending on the group, in addition to conventional treatment according to the protocol standard chemotherapy schema for pediatric patients with acute lymphoblastic leukemia at our institution during the remission induction phase. In addition, we will test whether the study group exerts an impact on reaching remission earlier as compared with the control group.

Detailed Description
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This study will be controlled, double-blind clinical trial versus placebo, with random assignment to evaluate the effect of pentoxifylline on apoptosis and senescence of leukemic blasts from remission induction in pediatric patients with newly diagnosed acute lymphoblastic leukemia, as well as to address pentoxifylline efficacy and safety in this group of patients.

Official Title
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SAFETY AND EFFICACY OF PENTOXIFYLLINE VERSUS PLACEBO ADMINISTERED AS APOPTOSIS INDUCTOR DURING REMISSION INDUCTION PHASE OF PEDIATRIC PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA

Conditions
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Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Pentoxifylline Plus Chemotherapy
* Drug: Placebo Plus Chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pediatric and teenaged patients of both genders ≤18 years of age with newly diagnosed acute lymphoblastic leukemia in accordance with French-American-British criteria and under immunophenotypical classification and paired within the risk-classification group. Patients with ≥20 kg of weight at the time of treatment assignment. Patients who are able to swallow the medicine Patients agreeing to enter the protocol by the signing of informed consent by the parent Patients who could give their assent to enter the protocol The parent or guardian must be able to read. Exclusion Criteria: Patients with treatment adherence of ≥80 percent Patients or their parents who decide to abandon the study or who withdraw consent for participation Patients who present grade III or higher adverse event. Patients previously treated with chemotherapy and/or radiotherapy History of peptic acid disease or gastrointestinal bleeding Known pentoxifylline intolerance and general intolerance to xanthine, caffeine or theophylline Patients in treatment with anticoagulants, Cimetidine, Ciprofloxacin, or Theophylline Patients with Down syndrome Patients with several bleeding or extensive retinal hemorrhage, several cardiac arrhythmias (paroxysmal supraventricular tachycardia, congenital atrioventricular block, arrhythmias associated with congenital heart disease, digital poisoning, and patients after cardiac surgery, hypoxia, hypercapnia, and electrolyte disturbances) Patients with hypotension Several liver failures Bleeding diathesis (for bleeding disorders or anticoagulant medication)

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 18 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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pentoxifylline Plus Chemotherapy<br>Pentoxifylline: 10-20 milligrams per kilogram, doses daily by oral, for 30 days. Chemotherapy: Prednisone, Vincristine, Daunorubicin, L-asparaginase, Cyclophosphamide, Cytarabine, 6-Mercaptopurine, Methotrexate, Hydrocortisone and Cytarabine | Drug: Pentoxifylline Plus Chemotherapy<br>* Pentoxifylline 10 to 20 milligrams per kilogram, daily, for up to 32 days Chemotherapy: Prednisone 40 milligrams per square meter per day, orally, day 5-32. Vincristine 1.5 milligrams per square meter per week, intravenously, day 5, 12, 19, 26. Daunorubicin 25 milligrams per square meter per week, intravenously, days 5; 12. L-asparaginase 10,000 units for square meter, intramuscular, days 6, 8, 10, 12, 14, 16, 19, 21, 23. Cyclophosphamide 1000 milligrams per square meter per dose intravenously, day 26. Cytarabine 75 milligrams per square meter per dose intravenously, days 27-30, 34-37. 6-Mercaptopurine 60 milligrams per square meter per dose, orally, days 26-39, Mix: Methotrexate 8-12 milligrams, Hydrocortisone 16-24 milligrams and Cytarabine 24-36 milligrams, intrathecal, day 19.<br>* Other names: Oxpentifylline;|
| Placebo Comparator: Placebo Plus Chemotherapy<br>Placebo: double blind period, one doses daily for 30 days. Chemotherapy: Prednisone, Vincristine, Daunorubicin, L-asparaginase, Cyclophosphamide, Cytarabine, 6-Mercaptopurine, Methotrexate, Hydrocortisone and Cytarabine | Drug: Placebo Plus Chemotherapy<br>* Placebo daily, for up to 32 days Chemotherapy: Prednisone 40 milligrams per square meter per day, orally, day 5-32. Vincristine 1.5 milligrams per square meter per week, intravenously, day 5, 12, 19, 26. Daunorubicin 25 milligrams per square meter per week, intravenously, days 5; 12. L-asparaginase 10,000 units for square meter, intramuscular, days 6, 8, 10, 12, 14, 16, 19, 21, 23. Cyclophosphamide 1000 milligrams per square meter per dose intravenously, day 26. Cytarabine 75 milligrams per square meter per dose intravenously, days 27-30, 34-37. 6-Mercaptopurine 60 milligrams per square meter per dose, orally, days 26-39, Mix: Methotrexate 8-12 milligrams, Hydrocortisone 16-24 milligrams and Cytarabine 24-36 milligrams, intrathecal, day 19.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Apoptosis measure by Flow Cytometry | Percentage of apoptotic cells by Flow Cytometry | Up to 28 days after initiation of chemotherapy for remission induction | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Senescence measure by Flow Cytometry | Percentage of senescent blasts by Flow Cytometry | Up to 28 days after initiation of chemotherapy for remission induction. | 
| Safety measure by Common Terminology Criteria for Adverse Events version 4.0 | Percentage of adverse events grading table is a list of common terms and severity (intensity) of parameters used to describe adverse events occurring in Common Terminology Criteria for Adverse Events version 4.0 | Evaluate frequency adverse events with pentoxifylline up to 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pediatric, apoptosis