Acute Lymphoblastic Leukemia
Conditions
Keywords
pediatric, apoptosis
Brief summary
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
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.
Interventions
DRUGPentoxifylline Plus Chemotherapy
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.
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.
Sponsors
Instituto de Investigacion en Cancer de la Infancia y la Adolescencia
Hospital Civil Juan I. Menchaca
Centro de Investigacion Biomedica de Occidente
Ramón Óscar González-Ramella, Ph.D
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
1 Years to 18 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apoptosis measure by Flow Cytometry | Up to 28 days after initiation of chemotherapy for remission induction | Percentage of apoptotic cells by Flow Cytometry |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Senescence measure by Flow Cytometry | Up to 28 days after initiation of chemotherapy for remission induction. | Percentage of senescent blasts by Flow Cytometry |
| Safety measure by Common Terminology Criteria for Adverse Events version 4.0 | Evaluate frequency adverse events with pentoxifylline up to 6 weeks | 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Gene expression measure by Microarray and Semi-quantitative Polymerase Chain Reaction. | Up to 28 days after initiation of chemotherapy for remission induction. | Fold change by microarray and Semi-quantitative Polymerase Chain Reaction. |
Countries
Mexico
Contacts
Primary ContactMonzerrat Pardo Zepeda, MD
Backup ContactFernando A. Sanchez Zubieta, MD
Outcome results
None listed