Survival of children with ALL in the 1970s was only about 50%, but today more than 90% of these children can be cured. Contributing factors include a better understanding of the immunobiology of ALL, recognition that different chemotherapy agents and intensity are required for different disease burdens, and improved supportive care.
Clinical trials have progressively refined therapy on the basis of a multitude of prognostic factors related to the host or the leukemic cell (Table 2). These factors and the heterogeneous nature of ALL have generated a variety of complex treatment protocols.[5-7] Improved treatment has eliminated previous prognostic factors like male sex and T-cell ALL. We also now understand that some treatment failures reflect suboptimal drug dosing in patients with specific genetic polymorphisms of drug-metabolizing enzymes, transporters, receptors, or drug targets. DNA microarrays for global gene-expression profiling of leukemic cells can predict immunophenotype, treatment response, and relapse and are becoming an important tool in refining the classification of ALL. Moreover, these microarrays can be used to identify novel molecular therapeutic targets, as in the case of FLT3 inhibitors.
Although very few new leukemia-specific drugs have been developed, we have learned to optimize the use of the available agents by applying pharmacokinetic and pharmacodynamic principles, by understanding the selective roles of various agents (eg, different steroids; different routes, dosages, and schedules of antimetabolites), and by developing alternative approaches to prophylaxis for the central nervous system (CNS) and other sanctuary sites. All treatment protocols now use the strategy of remission induction followed by intensification (or consolidation) therapy and continuation treatment to eliminate residual leukemia. Delayed intensification (reinduction) therapy was recently found to benefit all risk groups, and 5-year event-free-survival (EFS) was increased from 58% to 87% in the standard-risk group by double reinduction.
Early CNS prophylaxis was another breakthrough in ALL therapy, as it prevented both isolated CNS relapse and combined CNS and bone marrow relapse. Although craniospinal irradiation was effective, its acute and long-term neurocognitive impact and the risk of secondary brain tumors led to its reassessment during the past decade. With careful disease staging and modification of systemic and intrathecal chemotherapy, most cases of childhood ALL can now be effectively controlled without radiation therapy.
The most important independent predictor of treatment success is the response to therapy, measured as the level of minimal residual disease (MRD). Patients whose leukemic blasts comprise < 0.01% of nucleated bone marrow cells at the end of induction fare significantly better than others. Future protocols will individualize therapy on the basis of the leukemia' genetic signature and the patient' pharmacogenetic and pharmacodynamic characteristics and will modify ongoing therapy on the basis of MRD findings.
Finally, we must recognize the importance of supportive care in the management of childhood ALL, including routine empiric antibiotic therapy during periods of neutropenia, prophylaxis of Pneumocystis carinii pneumonia with trimethoprim(Drug information on trimethoprim)-sulfamethoxasole, and more recently, the use of uricolytics in the management of hyperuricemia and prevention of acute renal failure.
Treatment of childhood Hodgkin's lymphoma is well tolerated and highly effective. However, the morbidity and long-term sequelae of therapy are of increasing concern. In the 1970s and 1980s, growth inhibition and musculoskeletal malformations were observed after high-dose, large-field radiation therapy (35-44 Gy). Subsequently, low-dose radiotherapy (15-25 Gy) given with combination chemotherapy proved very effective, with 10-year survival rates of up to 90%. However, the alkylating agents in these regimens heightened the risk of secondary leukemias and myelodysplastic syndromes. After 10 to 15 years, survivors also developed radiation-associated tumors of the lung, skin, gastrointestinal tract, and breast. Other dose-dependent effects include an increased risk of cardiovascular disease, myocardial infarction, cardiopulmonary fibrosis, hypothyroidism, and infertility.
Most contemporary Hodgkin's lymphoma regimens use a combined-modality approach with chemotherapy and radiation. There are, however, instances in which only radiation, or chemotherapy alone may be considered. Advances in treatment have reduced the prognostic importance of age, sex, histologic subtype, stage, and B symptoms. The response to initial therapy is increasingly used to determine subsequent therapy. Diagnostic imaging advances have obviated the need for staging laparotomy and lymphangiography. High-resolution computed tomography (CT) and magnetic resonance imaging (MRI) have revolutionized staging. Positron-emission tomography (PET) scans can sensitively assess the proliferative activity in tumors through the uptake of 18-fluoro-2-deoxyglucose (FDG) and assess tumor response after treatment to help guide additional therapy. (Figure 3).[15,16] Prospective trials of FDG-PET in pediatric Hodgkin's lymphoma are ongoing.
Recurrent and refractory Hodgkin's lymphoma remain the greatest challenge. Progression of the disease during induction therapy or within 1 year after therapy predicts a 5-year disease-free survival rate < 20%.(17) Patients whose relapse occurs more than 1 year after completion of therapy have a survival rate of only 20% to 50% with conventional chemotherapy and 40% to 50% with high-dose chemotherapy and autologous stem cell rescue.
The sensitivity of Hodgkin's lymphoma to combined-modality therapy has been a great asset, but the paucity of Hodgkin and Reed-Sternberg (HRS) cells in the tumors has slowed research on the origin and biology of the disease. HRS cells were found to be monoclonal derivatives of germinal-center B cells only in the early 1990s. The role of the nuclear factor kappaB pathway in Hodgkin's lymphoma offers potential targets for novel therapies to reduce treatment sequelae and improve the survival of high-risk patients. Other novel possibilities for retrieval therapy incorporate proteasome inhibitors, monoclonal antibodies to Hodgkin's lymphoma-associated receptors (CD30, CD20, CD40), or radiolabeled immunoglobulin therapy.
Pediatric non-Hodgkin's lymphoma (NHL) is a diverse collection of lymphoid malignancies that vary in pathogenesis, natural history, and response to therapy. Pediatric NHL originates from both mature and immature cells of the B- or T-lymphocyte lineage and is typically intermediate- to high-grade, whereas adult lymphomas are more indolent. With effective combination chemotherapy and supportive care, approximately 70% to 80% of children with NHL are now cured. This progress reflects an understanding of the pathogenesis of pediatric NHL and the integration of immunophenotypic and genetic information into classification and staging so that therapy can be tailored to stage and histologic subtype.
Although the etiology of most pediatric NHL remains unknown, patients who have congenital or acquired immune deficiency are known to be at risk. Identification of the role of Epstein-Barr virus in the pathogenesis of B-cell neoplasms and the role of tumor-specific molecular lesions such as the NPM-ALK fusion product in large-cell lymphomas has offered new diagnostic tools and potential targets for therapy. We also now know that the molecular epidemiology of Burkitt' lymphoma differs across regions of the world, ie, Africa and North and South America.
Many of the principles of therapy for pediatric NHL have evolved from the treatment of childhood ALL: systemic combination chemotherapy for all patients, limited use of primary surgery, no irradiation except in life-threatening emergencies, and use of intravenous high-dose methotrexate(Drug information on methotrexate) for T-cell lymphomas. The treatment of childhood advanced-stage Burkitt' lymphoma has been a particular success. Systemic combination chemotherapy based on intensive cyclophosphamide(Drug information on cyclophosphamide), methotrexate, and cytarabine(Drug information on cytarabine) has pushed cure rates above 85%.[21,22] However, the prognosis after relapse or primary treatment failure remains poor. Further, late effects such as anthracycline-induced cardiomyopathy or secondary myeloid leukemia can be devastating. Promising new strategies include monoclonal antibody-based immunotherapy (eg, rituximab(Drug information on rituximab) [Rituxan] for CD20-positive NHL) and cellular approaches (targeted cytotoxic T cells).