NCI, NHLBI first international consensus conference on late effects after pediatric hematopoietic cell transplantation: etiology and pathogenesis of late effects after HCT performed in childhood--methodologic challenges.

Hematopoietic cell transplantation (HCT) is now a curative option for certain categories of patients with hematologic malignancies and other life-threatening illnesses. Technical and supportive care has resulted in survival rates that exceed 70% for those who survive the first 2 years after HCT. However, long-term survivors carry a high burden of morbidity, including endocrinopathies, musculoskeletal disorders, cardiopulmonary compromise, and subsequent malignancies. Understanding the etiologic pathways that lead to specific post-HCT morbidities is critical to developing targeted prevention and intervention strategies. Understanding the molecular underpinnings associated with graft-versus-host disease (GVHD), organ toxicity, relapse, opportunistic infection, and other long-term complications now recognized as health care concerns will have significant impact on translational research aimed at developing novel targeted therapies for controlling chronic GVHD, facilitating tolerance and immune reconstitution, reducing risk of relapse and secondary malignancies, minimizing chronic metabolic disorders, and improving quality of life. However, several methodological challenges exist in achieving these goals; these issues are discussed in detail in this paper.

Long-Term Neurocognitive and Psychosocial Outcomes After Acute Myeloid Leukemia: A Childhood Cancer Survivor Study Report.

BACKGROUND: Survivors of childhood acute myeloid leukemia (AML) are vulnerable to medical late effects of treatment; however, less is known about their psychosocial outcomes. This study evaluated neurocognitive and psychosocial outcomes in long-term AML survivors treated with bone marrow transplantation (BMT) or intensive chemotherapy (IC) without BMT. METHODS: AML survivors (N = 482; median age at diagnosis = 8 [range = 0-20] years; median age at evaluation = 30 [range = 18-49] years) treated with BMT (n = 183) or IC (n = 299) and sibling controls (N = 3190; median age at evaluation = 32 [range = 18-58] years) from the Childhood Cancer Survivor Study were compared on emotional distress (Brief Symptom Inventory-18), neurocognitive problems (Childhood Cancer Survivor Study Neurocognitive Questionnaire), health-related quality of life (SF-36), and social attainment. Outcomes were dichotomized (impaired vs nonimpaired) using established criteria, and relative risks (RRs) were estimated with multivariable Poisson regression, adjusted for age at evaluation and sex. RESULTS: AML survivors were more likely than siblings to report impairment in overall emotional (RR = 2.19, 95% confidence interval [CI] = 1.51 to 3.18), neurocognitive (RR = 2.03, 95% CI = 1.47 to 2.79), and physical quality of life (RR = 2.71, 95% CI = 1.61 to 4.56) outcomes. Survivors were at increased risk for lower education (RR = 1.15, 95% CI = 1.03 to 1.30), unemployment (RR = 1.41, 95% CI = 1.16 to 1.71), lower income (RR = 1.39, 95% CI = 1.17 to 1.65), and not being married or having a partner (RR = 1.33, 95% CI = 1.17 to 1.51). BMT-treated survivors did not differ statistically significantly from IC-treated on any outcome measure. CONCLUSIONS: AML survivors are at increased risk for psychosocial impairment compared with siblings; however, BMT does not confer additional risk for psychosocial late effects compared with treatment without BMT.

Improved outcome for patients with middle ear rhabdomyosarcoma: a children's oncology group study.

PURPOSE: The goal of this study was to define the clinical features and optimal therapy for children and adolescents with middle ear (ME) rhabdomyosarcoma (RMS). PATIENTS AND METHODS: We reviewed demographic data, clinical features, therapy (including chemotherapy, surgery, and radiation), and outcome for the 179 eligible patients with ME RMS who were enrolled onto Intergroup Rhabdomyosarcoma Studies (IRS) I through IV or pilot studies between November 1972 and December 1997. RESULTS: Most patients were younger than 10 years old (90%), and 63% were male. Because of the parameningeal location, most tumors were not resected before chemotherapy (group I, < 1%; group II, 4%; group III, 84%; group IV, 12%). Although most tumors were locally invasive (T2, 89%), the majority were small (< or = 5 cm, 66%), lacked nodal metastases (N0, 86%), and had embryonal histology (85%). The 5-year failure-free survival (FFS) and overall survival (OS) estimates were 67% and 72%, respectively. Both FFS and OS improved significantly over the course of IRS I through IV (3-year FFS and OS: IRS-I, 42% and 42%; IRS-II, 70% and 74%; IRS-III, 65% and 72%; IRS-IV pilot, 81% and 96%; IRS-IV, 88% and 88%, P <.001). Lower clinical group or stage and smaller tumor size were associated with better outcome. Age, sex, tumor invasiveness, and nodal metastases were not predictive of outcome. CONCLUSION: Patients with ME RMS generally present with small, unresectable, invasive tumors at a site traditionally considered prognostically unfavorable. Nevertheless, such patients have benefited markedly from improvements in multimodal, risk-based therapy during the course of IRS I through IV, and with contemporary therapy, most are cured.

Busulfan in infant to adult hematopoietic cell transplant recipients: a population pharmacokinetic model for initial and Bayesian dose personalization.

PURPOSE: Personalizing intravenous busulfan doses to a target plasma concentration at steady state (Css) is an essential component of hematopoietic cell transplantation (HCT). We sought to develop a population pharmacokinetic model to predict i.v. busulfan doses over a wide age spectrum (0.1-66 years) that accounts for differences in age and body size. EXPERIMENTAL DESIGN: A population pharmacokinetic model based on normal fat mass and maturation based on postmenstrual age was built from 12,380 busulfan concentration time points obtained after i.v. busulfan administration in 1,610 HCT recipients. Subsequently, simulation results of the initial dose necessary to achieve a target Css with this model were compared with pediatric-only models. RESULTS: A two-compartment model with first-order elimination best fit the data. The population busulfan clearance was 12.4 L/h for an adult male with 62 kg normal fat mass (equivalent to 70 kg total body weight). Busulfan clearance, scaled to body size-specifically normal fat mass, is predicted to be 95% of the adult clearance at 2.5 years postnatal age. With a target Css of 770 ng/mL, a higher proportion of initial doses achieved the therapeutic window with this age- and size--dependent model (72%) compared with dosing recommended by the U.S. Food and Drug Administration (57%) or the European Medicines Agency (70%). CONCLUSION: This is the first population pharmacokinetic model developed to predict initial i.v. busulfan doses and personalize to a target Css over a wide age spectrum, ranging from infants to adults.

White versus gray matter function as seen on neuropsychological testing following bone marrow transplant for acute leukemia in childhood.

Current theory suggests that neurocognitive late effects of treatments for childhood cancer such as difficulties with attention, processing speed and visual-motor ability are the result of white matter damage. Neuroimaging studies have produced a variety of white matter findings. However, although white matter is thought to be differentially affected, previous studies have not demonstrated a discrepancy between white and gray matter function. The present study included 36 children treated for childhood leukemia with hematopoietic stem cell transplant (HCT). Their performance on neurocognitive measures traditionally thought to measure white matter was compared to performance on measures thought to measure gray matter function. Composite white and gray matter standard scores were created based on neuropsychological measures that individuals with known white or gray matter damage perform poorly. As predicted, composite white matter scores (mean = 98.1) were significantly lower (t = 2.26, p = 0.03) than composite gray matter scores (mean = 102.5). Additionally, as gray matter performance increased, the difference between gray and white matter scores increased (R = 0.353, p = 0.035). Overall, the results of this study support the current theory that white matter damage is responsible for the more subtle neurocognitive late effects resulting from treatment for childhood leukemia.

The management and outcome of chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a common complication following allogeneic haematopoietic cell transplantation (HCT). It is the leading cause of non-relapse mortality in transplant survivors and has a significant impact upon their functional status and quality of life. Despite significant advances being made in the field of HCT over the past 25 years, there has been little change in the incidence, morbidity and mortality of cGVHD. This is partly because of a lack of understanding about the pathogenesis of the disorder but also because a lack of well validated grading systems and outcome measures has hindered clinical research. Strategies for prophylaxis have largely been unsuccessful and may compromise the graft-versus-leukaemia (GVL) effect. Standard primary treatment remains a combination of corticosteroids and calcineurin inhibitors. There is no standard therapy for those who fail to respond to corticosteroids. Many agents have been studied but there is an urgent need for systematic research to compare the efficacy of different approaches. Infection is the leading cause of death among patients with cGVHD so antimicrobial prophylaxis is mandatory. A multidisciplinary approach to the care of patients with cGVHD is essential to adequately address its effects on both physical and psychological functioning.

Physical impairment and social adaptation in adult survivors of childhood and adolescent rhabdomyosarcoma: A report from the Childhood Cancer Survivors Study.

BACKGROUND: Despite interest in the well-being of adult survivors of childhood rhabdomyosarcoma (RMS), few studies have examined their health-related quality of life (HRQOL). This study evaluated physical and social aspects of HRQOL among long-term childhood RMS survivors relative to a sibling comparison group, and assessed whether physical impairment among RMS survivors adversely affected their ability to achieve adult life goals. METHODS: Using baseline data from the Childhood Cancer Survivor Study, we evaluated self-reported physical impairment and social adaptation among 417 survivors of childhood RMS and 2685 siblings > or =18 years of age at survey completion. RESULTS: Survivors were more likely than siblings to report physical impairment, characterized by: at least one medically diagnosed condition, limitations in the performance of routine activities, a health-related inability to work or attend school, cancer-related pain. Survivors were less likely than siblings to have completed high school, ever worked a job, or ever been married. The odds of completing high school were lower among survivors with performance limitations, a health-related inability to work or attend school, or moderate to high levels of cancer-related pain. Survivors who reported cancer-related pain had an increased likelihood of ever being married. CONCLUSIONS: The majority of adult survivors of pediatric RMS are successful in attaining adult life goals despite higher reported occurrence of physical impairment than their sibling counterparts. Additional studies are needed to advance our understanding of other aspects of HRQOL in this population of pediatric cancer survivors.

Autoimmune haemolytic anaemia complicating haematopoietic cell transplantation in paediatric patients: high incidence and significant mortality in unrelated donor transplants for non-malignant diseases.

Haemolytic anaemia is a recognized complication of haematopoietic cell transplantation (HCT) and can result from alloimmune- or autoimmune-derived antibodies. Unlike alloimmune haemolytic anaemia, autoimmune haemolytic anaemia (AIHA) is poorly understood, particularly in the paediatric population where only case reports have been published. Between January 1995 and July 2001, 439 consecutive allogeneic HCT were performed in paediatric patients at the University of Minnesota, 31% (n = 136) from related donors (RD) and 69% (n = 303) from unrelated donors (URD). Nineteen cases of AIHA were identified with documented significant haemolysis and a positive direct antiglobulin test. All cases of AIHA occurred in URD transplants, yielding a cumulative incidence of AIHA post-transplant of 6% at 1 year. Patients transplanted for non-malignant disease, particularly metabolic diseases, had a higher incidence of AIHA post-HCT when compared with patients transplanted for malignancies (RR 4.2 95% CI 1.2-15.4, P = 0.01). Mortality was high in our series of 19 patients with 10 (53%) dying following the onset of AIHA, three as a direct consequence of haemolysis. Fifty per cent of deaths occurred from infection while on immunosuppressive therapy to treat haemolysis. Alternative treatment strategies were employed, with the majority of patients demonstrating disease refractory to traditional steroid therapy.