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Background: Treatment of post-transplant lymphoproliferative disease (PTLD) varies, with only some patients receiving chemotherapy. Concern for chemotherapy toxicities may influence treatment decisions as little is known regarding the late effects (LE) in PTLD survivors. This report characterizes LE in PTLD survivors at our institution., Procedure: Pediatric patients (0-18 years old) diagnosed with PTLD from 1990 to 2020 were examined. All patients included survived 6 months after completing chemotherapy or were 6 months from diagnosis if received no chemotherapy. Treatment with anti-CD20 antibody (rituximab) alone was not considered chemotherapy. Toxicities were classified per Common Terminology Criteria for Adverse Events Version 5.0. Chi-square tests assessed differences between categorical groups, or Fischer's exact test or the Fischer-Freeman-Halton exact test for limited sample sizes., Results: Of the 44 patients included, 24 (55%) were treated with chemotherapy. Twenty-four (55%) were alive at last follow-up. Chemotherapy was not associated with differences in survival (odds ratio [OR] 1.40, confidence interval [CI]: 0.42-4.63; p = .31). All patients experienced LE. Grade 3 toxicity or higher was experienced by 82% of patients with no difference in incidence (OR 1.20, CI: 0.27-5.80; p > .99) or median toxicity grade (3.00 vs. 4.00, p = .21) between treatment groups. Patients who received chemotherapy were more likely to experience blood and lymphatic toxicity (58% vs. 25%, p = .03) and cardiac toxicity (46% vs. 15%, p = .03), but less likely to have infections (54% vs. 85%, p = .03)., Conclusions: Survivors of PTLD experience LE including late mortality regardless of chemotherapy exposure. Further investigation to better understand LE could optimize upfront therapy for children with PTLD and improve outcomes., (© 2023 Wiley Periodicals LLC.)

Pediatric non-Hodgkin lymphoma (NHL) includes over 30 histologies (many with subtypes), with approximately 800 cases per year in the United States. Improvements in survival in NHL over the past 5 decades align with the overall success of the cooperative trial model with dramatic improvements in outcomes. As an example, survival for advanced Burkitt lymphoma is now >95%. Major remaining challenges include survival for relapsed and refractory disease and long-term morbidity in NHL survivors. Langerhans cell histiocytosis (LCH) was added to the NHL Committee portfolio in recognition of LCH as a neoplastic disorder and the tremendous unmet need for improved outcomes. The goal of the Children' Oncology Group NHL Committee is to identify optimal cures for every child and young adult with NHL (and LCH). Further advances will require creative solutions, including engineering study groups to combine rare populations, biology-based eligibility, alternative endpoints, facilitating international collaborations, and coordinated correlative biology., (© 2023 Wiley Periodicals LLC.)

Background: We sought to estimate the frequency of hearing screening failures in pediatric cancer survivors at low risk for hearing loss and evaluate the feasibility of administering screenings in this population., Procedure: Survivors in the St. Louis Children's Hospital Late Effects Clinic were recruited. Eligibility included (a) diagnosis of a pediatric cancer treated without platinum chemotherapy or cranial radiation, (b) at least 6 months from completion of therapy, (c) between the ages of 7 and 18 years, (d) cognitively/behaviorally able to participate, and (e) English speaking. Behavioral hearing screenings from 1000 to 8000 Hz were performed by trained personnel using a calibrated audiometer. A failed screen was defined by a participant not responding to two or more of the three screening attempts for at least one frequency in at least one ear., Results: One hundred nine patients met eligibility criteria with 78 enrolled (71.5%). Diagnoses included leukemia (57.7%), sarcoma (11.5%), Wilms tumor (14.1%), lymphoma (12.8%), and other solid tumors (3.9%). The median age was 13.2 years (Q1-Q3: 9.6-15.4) and the median time from treatment completion was 3.7 years (Q1-Q3: 2.3-7.4). Eighteen patients (23%) failed the hearing screen (95% CI: 14%-34%). No demographic or treatment-related variables were significantly correlated to screening failure. Six screen failures (33%) underwent formal audiology assessments, with three demonstrating unilateral hearing loss: two conductive and one sensorineural., Conclusions: A significant fraction of pediatric cancer survivors at low risk for hearing loss failed hearing screening. Broader use of hearing screening should be considered., (© 2021 Wiley Periodicals LLC.)

Background: Adolescent and young adult (AYA) survivors of cancer and central nervous system (CNS) tumors endure major life disruptions with their diagnosis, treatment, and the burden of emerging learning difficulties. Survivors and their parents often struggle to obtain more academic support as survivors transition through school. This study explored the knowledge and experience survivors and their parents need as they progress through school to college., Methods: This cross-sectional study examined childhood cancer and CNS tumor survivors, aged 11 to 21 years, with a known learning difficulty (Individual Education Plan, 504 Plan) and their parents. We assessed participants' knowledge of and experience with transition planning for postsecondary education and independent living., Results: Ninety-two AYA survivors and parents (45 survivors, 47 parents) completed the survey. High school-aged survivors described their learning difficulties better than middle school-aged survivors. Survivors estimated their abilities higher than did their parents. Despite a majority of survivors expecting to attend college, 68.5% of survivors and 57.9% of parents were not certain how to get special accommodations for standardized college entrance exams. Only 20.8% of survivors were aware of what a transition plan includes. Parents understood the transition planning process and when it should begin better than the students (P = 0.001), but many parents (40.0%) were still unsure., Conclusions: AYA survivors and parents lack knowledge necessary to successfully transition to their goals after high school. Greater education is needed., (© 2018 Wiley Periodicals, Inc.)

Background: Sickle cell disease (SCD) may cause injury to any organ, including the auditory system. Although the association of SCD and hearing loss has been described, the nature of this complication is unknown. We sought to establish the prevalence and nature of hearing loss in a referred cohort of children with SCD and to identify correlating disease- or treatment-associated factors., Procedure: We conducted a retrospective review of patients with SCD < 22 years of age who had hearing evaluations between August 1990 and December 2014. Demographics, audiograms, and disease and treatment variables were analyzed., Results: Two hundred and ten audiograms among 81 patients were reviewed, and 189 were evaluable. Seventy-two children constituted the referred cohort. Fourteen (19.4%) had hearing loss documented on at least one audiogram. Seven (9.7%) patients had only conductive hearing loss, and the loss persisted for up to 10.3 years. The median age of first identification was eight years. Six (8.3%) patients had hearing loss that was at least partially sensorineural. One patient's hearing loss was ambiguous. All sensorineural hearing losses were unilateral and 4/6 patients had prior documented normal hearing, indicating acquired loss. No correlations were identified., Conclusions: Both conductive and sensorineural hearing losses are more prevalent in our study population than those observed in the general pediatric population. In children with SCD, sensorineural hearing loss appears to be acquired and unilateral. Conductive hearing loss was identified in older children and can persist. Serial screening is needed for early detection and more prompt intervention in this population., (© 2018 Wiley Periodicals, Inc.)

Background: Ototoxicity is a significant complication of cisplatin treatment. Hearing loss can be symmetric or asymmetric, and may decline after therapy. This study examined the risks of asymmetric and late-onset hearing loss (LOHL) in cisplatin-treated pediatric patients with cancer., Methods: A retrospective review of 993 patients' medical and audiological charts from August 1990 to March 2015 was conducted using stringent criteria to characterize patients with asymmetric hearing loss (AHL) or LOHL. Audiologic data were reviewed for 248 patients that received cisplatin to assess cisplatin-induced sensorineural hearing loss and its associated risk factors., Results: Of the patients evaluable for AHL, 26% exhibited this finding. Of those evaluable for LOHL, 42% of the patients' hearing worsened more than 6 months after therapy completion. Radiation and type of cancer diagnosis were major risk factors for both AHL and LOHL. Furthermore, LOHL was linked to age of diagnosis, noncranial radiation, and longer audiologic follow-up. AHL was strongly associated with LOHL-60% of patients with AHL also had LOHL. Logistic regression analysis revealed that patients with AHL (OR 6.3, 95% CI: 2.2-17.8, P = 0.0005) or those receiving radiation (OR 3.2, 95% CI: 1.2-8.6, P = 0.02) were at greatest risk for LOHL., Conclusion: Children receiving cisplatin therapy are at risk for developing AHL and LOHL. Those that have received radiation and/or with AHL are at increased risk for further hearing decline. Long-term monitoring of these patients is important for early intervention as hearing diminishes., (© 2018 Wiley Periodicals, Inc.)

Background: Sensorineural hearing loss due to ototoxic cancer therapy is well established; effects on the vestibular system are unknown. We examined the feasibility of implementing vestibular screens for pediatric cancer survivors exposed to ototoxic agents. The prevalence of screening failures is reported., Methods: Cancer survivors who were 6-17 years, at least 1-month posttreatment, and received ototoxic therapy (radiation to the head/neck, cisplatin, carboplatin) were eligible. Screening measures included (1) Pediatric Vestibular Symptom Questionnaire, (2) Modified Clinical Test of Sensory Interaction on Balance, and (3) Dynamic Visual Acuity., Results: Vestibular screening failures were observed in 30 participants (60%). Patients with a brain tumor diagnosis were at increased risk for failures compared to nonbrain tumor patients (74.2% vs. 36.8%, P = 0.009). Patients who underwent brain surgery were at increased risk for failures compared to patients without brain surgery (71% vs. 42%, P = 0.043). Patients with a longer duration between end of treatment and vestibular screening had a reduced risk of failures, with an almost 20% decrease for each year between the time points (odds ratio = 0.812; 95% confidence interval: 0.683-0.964, P = 0.018). Receiving carboplatin correlated with a decreased risk of failure (P = 0.016), due to a negative correlation with other clinical risk factors (diagnosis of a brain tumor, major brain surgery) that are associated with vestibular screening failure., Conclusion: Vestibular screening failures are highly prevalent in childhood cancer survivors who received ototoxic therapy. Broad screening of this population and further characterization of these patients are warranted., (© 2018 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.)

Background: Children and adolescents with sickle cell disease (SCD) are at high risk of strokes and are frequently treated with red blood cell (RBC) transfusions. The goal is to suppress hemoglobin (Hb) S while minimizing transfusion-induced iron overload. RBCs may be given via simple transfusion, manual exchange transfusion (MET), or erythrocytapheresis (aRBCX). Chronic transfusion practices vary among institutions., Methods: This single-institution, retrospective cohort study compares Hb S control and therapy complication rates between MET and aRBCX in a cohort of children and adolescents with SCD and stroke during a 5-year period from 2008 through 2012. Duration and mode of transfusion therapy, achievement of Hb S suppression goal, iron burden by ferritin levels, and catheter complications were evaluated., Results: Thirty-seven children were included in analysis. The prevalence of catheter complications was 75% in aRBCX recipients compared with 0% in MET recipients (P < 0.001). There was no significant difference between modalities in achieving Hb S suppression or ferritin goals, but those receiving aRBCX had a greater likelihood of discontinuing chelation therapy. Among aRBCX recipients, adherence to >90% of transfusion appointments was associated with achieving Hb S suppression goals., Conclusion: aRBCX may have increased complication risks compared with MET for chronic transfusion therapy in SCD. Risks and benefits of aRBCX and MET should be considered when selecting a chronic transfusion modality. Transfusion therapy modalities should be compared in prospective studies for stroke prevention in children with SCD., (© 2017 Wiley Periodicals, Inc.)

Background: Hematopoietic cell transplantation (HCT) is curative in patients with severe aplastic anemia (SAA). HCT is considered at presentation when a HLA-matched related donor (MRD) is available and has a high success rate. Unrelated donor (URD) transplants are typically undertaken if immunosuppressive therapy fails. Increased toxicity and graft rejection are often encountered in this setting., Procedure: We report a prospective multi-center trial of HCT in 17 children with SAA following novel reduced intensity conditioning with alemtuzumab, fludarabine and melphalan, and the best available donor. Nine were URD transplants matched at 7-8/8 loci, and performed following failure of immune suppression. Median follow up was 61 months (range 6-128)., Results: All patients engrafted. Estimated 5 year event-free and overall-survival was 88% (95%CI 65.7-96.7). Five year overall survival for MRD and URD transplants was 100% and 78% (95%CI 45-93.6) respectively. Median times to neutrophil and platelet engraftment was 14 (range 10-27) and 23.5 (range 11-65) days respectively. Treatment related mortality was 12%. The incidence of grade II-IV and III-IV acute graft-versus-host disease was 29% and 18% respectively. At two years, all but one patient discontinued immunosuppression successfully. Laboratory measures of immune reconstitution normalized at one year and infection rates were low in the latter part of the first year., Conclusions: HCT using this RIC approach was well tolerated and successful in achieving donor engraftment and early immune reconstitution with good quality of life free of immune suppression. Children with SAA can be successfully transplanted using alemtuzumab based conditioning., (© 2015 Wiley Periodicals, Inc.)

Background: The differential effects of cranial radiotherapy (CRT), spinal radiotherapy (SRT), and total body irradiation (TBI) on growth and endocrine outcomes have rarely been examined in combination among childhood acute leukemia survivors., Procedure: Self-reported height/weight, hypothyroidism, and pregnancy/live birth were determined among acute lymphoblastic and myeloid leukemia survivors (n = 3,467) participating in the Childhood Cancer Survivor Study, an ongoing cohort study of 5-year survivors of pediatric cancers diagnosed from 1970 to 1986., Results: Compared with no radiotherapy, risk estimates were consistent across outcomes (adult short stature, hypothyroidism, absence of pregnancy/live birth) with CRT treatment associated with 2-3-fold increased risks, TBI associated with 5-10 fold increased risks, and CRT + TBI associated with >10 fold increased risks. Exposure to any SRT further increased risk of these outcomes 2-3-fold. Changes in body composition were more nuanced as CRT only was associated with an increased risk of being overweight/obese (OR 1.6, 95% CI 1.3-1.9) whereas TBI only was associated with an increased risk of being underweight (OR 6.0, 95% CI 2.4-14.9)., Conclusions: Although patients treated with CRT + TBI were at greatest risk for short stature, hypothyroidism, and a reduced likelihood of pregnancy/live birth, those treated with either modality alone had significantly increased risks as well, including altered body composition. Any SRT exposure further increased risk in an independent fashion., (Copyright © 2012 Wiley Periodicals, Inc.)

Purpose: To determine the safety, efficacy, and PK profile of intravenous busulfan (Bu) in the context of a Bu and cyclophosphamide (IVBuCy) preparative regimen in children undergoing allogeneic hematopoietic stem cell transplantation (HSCT)., Methods: Twenty-four children were enrolled in an open-label, multicenter trial of IVBuCy as the preparative regimen for HLA-matched sibling allogeneic HSCT. IVBu was administered q6 hr for 16 doses with a targeted area under the curve (AUC) of 900-1,350 microMol-min. The initial dose was 0.8 mg/kg for children >4 years of age and 1 mg/kg for those <4 years of age. PK of the first dose IVBu was determined to calculate a single dosage adjustment, and with the 9th and 13th doses to confirm steady-state PK., Results: The targeted AUC was achieved with the first dose in 17/24 (71%) of the children using the age-adjusted dosing approach. Dosing was increased in five patients, and reduced in two patients to achieve target values. After dose adjustment based on PK, 91% of the children had an AUC within the target range at steady state (AUCss). Median final dosing and clearance (CL) of IVBu were 1.1 mg/kg and 4.1 ml/min/kg in patients < or =4 years, and 0.9 mg/kg and 2.9 ml/min/kg in patients >4 years. All children were engrafted with documented donor chimerism. No late rejections or graft failures occurred. Four patients had veno-occlusive disease, three of which resolved within 2 weeks of onset. Two children died from transplant-related causes unrelated to Bu., Conclusion: IVBu is a safe and effective and offers the benefit of predictable and consistent systemic exposure., ((c) 2009 Wiley-Liss, Inc.)