Understanding predictors of continued long-term pediatric cancer care across the region: A report from the Consortium for New England Childhood Cancer Survivors.

BACKGROUND: Many survivors of childhood cancer do not receive recommended longitudinal oncology care. Factors present at the time of childhood cancer diagnosis may identify patients who are vulnerable to poor adherence to follow-up. METHODS: This cohort of survivors of acute lymphoblastic leukemia (ALL) diagnosed from 1996 to 1999 at seven Consortium for New England Childhood Cancer Survivors institutions was evaluated for attendance at oncology clinics at 5 and 10 years from diagnosis. Demographic, socioeconomic, disease, and treatment characteristics were analyzed as risk factors for nonadherence to follow-up. RESULTS: Of 317 patients, 90% were alive 5 years from diagnosis and 88% of those remained in active follow-up. At 10 years from diagnosis, 88% were alive, 73% of whom continued in active follow-up. Insurance status at diagnosis was significantly associated with adherence at both 5 and 10 years. At 10 years, initial enrollment on therapeutic study was associated with increased attendance and central nervous system (CNS) leukemia with decreased attendance. In multivariable modeling of follow-up at 5 years, patients who were adults were less likely to participate and those with private insurance at diagnosis more likely to participate. At 10 years, insurance status at diagnosis remained a predictor of adherence to follow-up. CONCLUSIONS: In this regional cohort, many patients who are survivors of ALL continue to participate in oncology care at 5 and 10 years from diagnosis. Factors known at diagnosis including insurance status, CNS leukemia, older age, and enrollment on therapeutic study were associated with differential attendance to follow-up visits.

Late Effects Surveillance Recommendations among Survivors of Childhood Hematopoietic Cell Transplantation: A Children's Oncology Group Report.

Hematopoietic cell transplantation (HCT) is an important curative treatment for children with high-risk hematologic malignancies, solid tumors, and, increasingly, nonmalignant diseases. Given improvements in care, there are a growing number of long-term survivors of pediatric HCT. Compared with childhood cancer survivors who did not undergo transplantation, HCT survivors have a substantially increased burden of serious chronic conditions and impairments involving virtually every organ system and overall quality of life. This likely reflects the joint contributions of pretransplantation treatment exposures and organ dysfunction, the transplantation conditioning regimen, and any post-transplantation graft-versus-host disease (GVHD). In response, the Children's Oncology Group (COG) has created long-term follow-up guidelines (www.survivorshipguidelines.org) for survivors of childhood, adolescent, and young adult cancer, including those who were treated with HCT. Guideline task forces, consisting of HCT specialists, other pediatric oncologists, radiation oncologists, organ-specific subspecialists, nurses, social workers, other health care professionals, and patient advocates systematically reviewed the literature with regards to late effects after childhood cancer and HCT since 2002, with the most recent review completed in 2013. For the most recent review cycle, over 800 articles from the medical literature relevant to childhood cancer and HCT survivorship were reviewed, including 586 original research articles. Provided herein is an organ system-based overview that emphasizes the most relevant COG recommendations (with accompanying evidence grade) for the long-term follow-up care of childhood HCT survivors (regardless of current age) based on a rigorous review of the available evidence. These recommendations cover both autologous and allogeneic HCT survivors, those who underwent transplantation for nonmalignant diseases, and those with a history of chronic GVHD.

Evaluation and Management of Hearing Loss in Survivors of Childhood and Adolescent Cancers: A Report From the Children's Oncology Group.

Hearing loss (HL) is common in childhood cancer survivors exposed to platinum chemotherapy and/or cranial radiation and can severely impact quality of life. Early detection and appropriate management can mitigate academic, speech, language, social, and psychological morbidity resulting from hearing deficits. This review is targeted as a resource for providers involved in aftercare of childhood cancers. The goal is to promote early identification of survivors at-risk for HL, appropriate evaluation and interpretation of diagnostic tests, timely referral to an audiologist when indicated, and to increase knowledge of current therapeutic options.

Helicobacter pylori associated gastric Burkitt lymphoma.

Chronic Helicobacter pylori (H. pylori) infection has been linked to lymphoma of gastric mucosa-associated lymphoid tissue (MALT), a tumor that is typically localized at presentation. Sporadic Burkitt lymphoma (BL) frequently presents as an abdominal mass. However, primary gastric BL is unusual and the role of H. pylori in its pathogenesis is unclear. We describe a 12 year old with localized gastric BL and concurrent H. pylori infection. In this report, we discuss the potential association between H. pylori and gastric BL and also highlight certain similarities between gastric MALT lymphomas and BL arising in the stomach.

Emesis predicts bacteremia in immunocompromised children with central venous catheters and fever.

BACKGROUND: The objective of this study was to determine whether vomiting at presentation of a febrile illness in immunocompromised children with central venous catheters (CVCs) predicts bacteremia. METHODS: A chart review was conducted of children who were admitted to the hospital with a diagnosis of cancer or aplastic anemia, fever, and a CVC. Data were collected on the presence or absence of vomiting, catheter type, presence or absence of severe neutropenia, C-reactive protein (Crp) value, and culture results. RESULTS: There were 143 admissions for fever among 48 children. Among 35 admissions with emesis, 19 included bacteremia; whereas, among 107 admissions without emesis, 19 included bacteremia (P < .001). There was a 5-fold greater risk of bacteremia in children with children without vomiting (odds ratio, 5.50; 95% confidence interval, 2.20-13.67). Gram-negative organisms were more likely to be associated with vomiting than Gram-positive organisms (P = .008). Children with severe neutropenia did not have a significantly higher rate of bacteremia than children who had neutrophil counts >500 cells/mm(3). Other factors that were associated with higher rates of bacteremia were underlying diagnosis and catheter type. CONCLUSIONS: Immunocompromised children with a CVC and a fever who presented with vomiting were more likely to have bacteremia than similar children who presented without vomiting. Gram-negative organisms were more likely to be associated with emesis than Gram-positive organisms. The absence of severe neutropenia was not associated with a decreased likelihood of bacteremia. These findings may be useful in identifying children who are at high risk for bacteremia and in determining initial, empiric therapy.

Inflammatory cytokines and the development of pulmonary complications after allogeneic hematopoietic cell transplantation in patients with inherited metabolic storage disorders.

Patients with inherited metabolic storage disorders are at a higher risk of developing pulmonary complications after hematopoietic cell transplantation (HCT). This single-center prospective study of 48 consecutive inherited metabolic storage disorder patients was performed to identify risk factors for the development of pulmonary complications after HCT. Before HCT, subjects underwent bronchoalveolar lavage (BAL) for cell count, culture, nitrite levels, and analysis of proinflammatory cytokines and chemokines. The overall incidence of pulmonary complications was 52% (infectious, 23%; noninfectious, 29%) over a period of 4 years. Diffuse alveolar hemorrhage was the most frequent noninfectious complication and occurred in 19% of patients, all of whom had a diagnosis of mucopolysaccharidosis (Hurler and Maroteaux-Lamy syndromes). Levels of interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor alpha, macrophage inflammatory protein 1alpha, and granulocyte colony-stimulating factor in BAL fluid samples obtained before HCT were higher in patients with mucopolysaccharidoses than in patients with leukodystrophies. In addition, levels of IL-1beta, IL-6, IL-8, and granulocyte colony-stimulating factor were increased in the BAL fluid of patients who developed noninfectious pulmonary complications compared with those who did not develop pulmonary complications. It is interesting to note that most noninfectious pulmonary complications occurred in patients with mucopolysaccharidoses, especially diffuse alveolar hemorrhage, which occurred exclusively in patients with mucopolysaccharidoses. Higher levels of bronchial proinflammatory cytokines and chemokines may be predictive of the development of subsequent posttransplantation noninfectious complications in patients with mucopolysaccharidoses, especially those with Hurler syndrome. Larger studies will be required to further elucidate etiologic mechanisms and predictive factors.

Safety and efficacy of enzyme replacement therapy in combination with hematopoietic stem cell transplantation in Hurler syndrome.

PURPOSE: Hurler syndrome is a debilitating genetic disease with a typical life span of 5 to 8 years. Early hematopoietic stem cell transplantation (HSCT) mitigates disease symptoms and improves survival. However, morbidity and mortality associated with HSCT can limit its success. We describe the initial experience with combined use of enzyme replacement therapy (ERT, laronidase) and HSCT in Hurler syndrome. METHODS: Thirteen transplants were performed in 12 patients. ERT was given at a standard dose of 0.58 mg/kg per week. Transplant conditioning regimen and donor graft source were determined by institutional protocol. RESULTS: The median age at initiation of ERT was 12 months (range, 8 to 18 months). The median duration of pre-HSCT ERT was 12 weeks (range, 4 to 28). All but 1 patient tested showed decrease in urinary GAG excretion during ERT. ERT infusion-related toxicity was limited to mild reactions. Development of antibodies to laronidase did not correlate with infusion reactions or responses in urinary GAG excretion. ERT was given for a median of 7 weeks (range, 3 to 20) after HSCT. After transplantation, eight patients demonstrated complete donor engraftment and four suffered graft failure. Two patients required ventilator support and three developed acute GVHD. Eleven of the 12 patients are surviving with a median follow-up of 3 months (range, 1 to 7 months). CONCLUSIONS: In children with Hurler syndrome, ERT with HSCT is feasible and well tolerated. Development of antibodies against exogenous enzyme does not appear to correlate with infusion reactions or response to ERT. A prospective study is needed to determine the effect of concomitant ERT on transplant outcomes.

Successful hematopoietic stem cell transplantation for Fanconi anemia from an unaffected HLA-genotype-identical sibling selected using preimplantation genetic diagnosis.

The only proven cure for Fanconi anemia (FA)-associated bone marrow failure is successful allogeneic hematopoietic stem cell transplantation (HSCT). However, HSCT with donors other than HLA-identical siblings is associated with high morbidity and poor survival. Therefore, we used preimplantation genetic diagnosis (PGD) to select an embryo produced by in vitro fertilization (IVF) that was unaffected by FA and was HLA-identical to the proband. The patient was a 6-year-old girl with FA and myelodysplasia previously treated with oxymetholone and prednisone. After her parents underwent 5 cycles of IVF with intrauterine transfer of 7 embryos over a span of 4 years, successful pregnancy ensued. Twenty-eight days after delivery, the patient underwent transplantation with her newborn sibling donor's HLA-identical umbilical cord blood hematopoietic stem cells (HSCs). Neutrophil recovery occurred on day 17 without subsequent acute or chronic graft-versus-host disease. Currently, 2.5 years after transplantation, the patient is well and hematopoiesis is normal. In summary, we have described the first successful transplantation, using IVF and PGD, of HSCs from a donor selected on the basis of specific, desirable disease and HLA characteristics. The medical, legal, and ethical issues involved with this approach are discussed.

Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999.

Cerebral X-linked adrenoleukodystrophy (X-ALD) is a disorder of very-long-chain fatty acid metabolism, adrenal insufficiency, and cerebral demyelination. Death occurs within 2 to 5 years of clinical onset without hematopoietic cell transplantation (HCT). One hundred twenty-six boys with X-ALD received HCT from 1982 to 1999. Survival, engraftment, and acute graft-versus-host disease were studied. Degree of disability associated with neurologic and neuropsychological function and cerebral demyelination were evaluated before and after HCT. Complete data were available and analyzed for 94 boys with cerebral X-ALD. The estimated 5- and 8-year survival was 56%. The leading cause of death was disease progression. Donor-derived engraftment occurred in 86% of patients. Demyelination involved parietal-occipital lobes in 90%, leading to visual and auditory processing deficits in many boys. Overall 5-year survival of 92% in patients with 0 or 1 neurologic deficits and magnetic resonance imaging (MRI) severity score less than 9 before HCT was superior to survival for all others (45%; P <.01). Baseline neurologic and neuropsychological function, degree of disability, and neuroradiologic status predicted outcomes following HCT. In this first comprehensive report of the international HCT experience for X-ALD, we conclude that boys with early-stage disease benefit from HCT, whereas boys with advanced disease may be candidates for experimental therapies.

Effective treatment of alpha-mannosidosis by allogeneic hematopoietic stem cell transplantation.

OBJECTIVES: To study the efficacy of hematopoietic stem cell transplantation (HCT) for ameliorating the clinical manifestations of alpha-mannosidosis. STUDY DESIGN: Four patients with alpha-mannosidosis underwent allogeneic HCT at the University of Minnesota. Diagnosis was established by assay of leukocyte alpha-mannosidase activity level. Physical features, donor engraftment, leukocyte alpha-mannosidase activity, neuropsychologic function, and hearing were monitored before and after transplantation, with follow-up ranging from 1 to 6 years. RESULTS: All 4 patients showed slowing of their neurocognitive development and sensorineural hearing loss before HCT. All patients are alive, with normalization of leukocyte enzyme activity after HCT. Intellectual function has stabilized, with improvement in adaptive skills and verbal memory function in 3 of 4 patients. Hearing has improved to normal or near normal for speech frequencies in 3 patients. No new skeletal abnormalities have developed. CONCLUSIONS: HCT can halt the progressive cognitive loss in patients with alpha-mannosidosis. Early diagnosis and treatment with HCT is critical for optimal results.