Low Dose Induction for Pediatric Acute Myeloid Leukemia Patients

Acute myeloid leukemia (AML) accounts for 15% to 20% of all childhood leukemias. In most children, AML presents as a de novo entity, but in a minority, it is a secondary malignancy. Acute myeloid leukemia is a heterogeneous disease and its diagnosis involves a combination of diagnostic analyses including morphology, immunophenotyping, cytochemistry, and leukemic blasts derived from peripheral blood or bone marrow demonstrating cytogentic and molecular characteristics. The treatment of AML comprises induction of remission followed by intensive consolidation therapy with the use of chemotherapy alone or in combination with allogeneic hematopoietic stem cell transplantation (HSCT). The standard chemotherapy courses for remission induction and consolidation are typically accompanied by an extended period of myelosuppression during which there is significant morbidity and mortality. Treatment-related morbidity and treatment-related mortality (TRM) represents a significant challenge in pediatric AML worldwide. In low- and middle- income countries (LMICs), mortality associated with initial disease and treatment can be up to 50 %. It is now well understood and accepted that if the relapse rate with a given therapy is excessive then the treatment may need intensification; however, if toxic death rates are too high, de-intensification may save more lives, depending on the enhancement of supportive care. During tumor formation, new mutations are constantly occurring giving rise to drug resistant mutation at a very low frequency. With the pre- existence of small drug-resistant sub clones giving the current chemotherapy at the maximum tolerated dose that eliminates a dominant drug sensitive clone might allow the competitive release of resistant sub clones to undergo accelerated growth in a resource-rich environment, resulting in more rapid disease progression or relapse. Reducing chemotherapy drug dosage may be a logical way to maintain a stable population of sensitive sub clone, thereby restricting the growth of resistant cell. Intensifying the induction courses can decrease relapse rates but not improve OS. The initial concerns for offering a low dose intensity regimen for children with AML in most studies was based on the high risk of toxicity related deaths or treatment abandonment specially for children in limited resources countries. According to SIOP/PODC, patients with AML treated with low dose chemotherapy (LDC/G-CSF) receive only a two -drug regimen with 10 \& 2 times lower doses of cytrabine \& anthracyclines respectively than those given standard AML remission induction regimens. Although the mechanism \& clinical efficacy of LDC/G-CSF are still unknown, it is possible that granulocyte colony stimulating factor (G-CSF) makes leukemia cells more vulnerable to chemotherapy through sensitization or priming.G-CSF can also reduce the overall viability of AML cells when cocultured with BM stroma but not alone. G- CSF mobilizes T-regulatory cells and has other immunomodulatory effects.