Abstract
Remarkable progress has been made in the past decade in the treatment and in the understanding of the biology of childhood lymphoid and myeloid leukemias. With contemporary improved risk assessment, chemotherapy, hematopoietic stem cell transplantation and supportive care, approximately 80% of children with newly diagnosed acute lymphoblastic leukemia and 50% of those with myeloid neoplasm can be cured to date. Current emphasis is placed not only on increased cure rate but also on improved quality of life.
In Section I, Dr. Ching-Hon Pui describes certain clinical and biologic features that still have prognostic and therapeutic relevance in the context of contemporary treatment programs. He emphasizes that treatment failure in some patients is not due to intrinsic drug resistance of leukemic cells but is rather caused by suboptimal drug dosing due to host compliance, pharmacodynamics, and pharmacogenetics. Hence, measurement of minimal residual disease, which accounts for both the genetic (primary and secondary) features of leukemic lymphoblasts and pharmacogenomic variables of the host, is the most reliable prognostic indicator. Finally, he contends that with optimal risk-directed systemic and intrathecal therapy, cranial irradiation may be omitted in all patients, regardless of the presenting features.
In Section II, Dr. Martin Schrappe performs detailed analyses of the prognostic impact of presenting age, leukocyte count, sex, immunophenotype, genetic abnormality, early treatment response, and in vitro drug sensitivity/resistance in childhood acute lymphoblastic leukemia, based on the large database of the Berlin-Frankfurt-Münster consortium. He also succinctly summarizes the important treatment components resulting in the improved outcome of children and young adolescents with this disease. He describes the treatment approach that led to the improved outcome of adolescent patients, a finding that may be applied to young adults in the second and third decade of life. Finally, he believes that treatment reduction under well-controlled clinical trials is feasible in a subgroup of patients with excellent early treatment response as evidenced by minimal residual disease measurement during induction and consolidation therapy.
In Section III, Dr. Raul Ribeiro describes distinct morphologic and genetic subtypes of acute myeloid leukemia. The finding of essentially identical gene expression profiling by DNA microarray in certain specific genetic subtypes of childhood and adult acute myeloid leukemia suggests a shared leukemogenesis. He then describes the principles of treatment as well as the efficacy and toxicity of various forms of postremission therapy, emphasizing the need of tailoring therapy to both the disease and the age of the patient. Early results suggest that minimal residual disease measurement can also improve the risk assessment in acute myeloid leukemia, and that cranial irradiation can be omitted even in those with central-nervous-system leukemia at diagnosis.
In Section IV, Dr. Charlotte Niemeyer describes a new classification of myelodysplastic and myeloproliferative diseases in childhood, which has greatly facilitated the diagnosis of myelodysplastic syndromes and juvenile myelomonocytic leukemia. The recent discovery of somatic mutations in PTPN11 has improved the understanding of the pathobiology and the diagnosis of juvenile myelomonocytic leukemia. Together with the findings of mutations in RAS and NF1 in the other patients, she suggests that pathological activation of RAS-dependent pathways plays a central role in the leukemogenesis of this disease. She then describes the various treatment approaches for both juvenile myelomonocytic leukemia and myelodysplastic syndromes in the US and Europe, emphasizing the differences between childhood and adult cases for the latter group of diseases. She also raises some controversial issues regarding treatment that will require well-controlled international clinical trials to address.
Juvenile Myelomonocytic Leukemia (JMML): A Mimicker of KMT2A-Rearranged Acute Myeloid Leukemia (AML)