The Pediatric Hodgkin Consortium (PHC) hypothesized that increasing chemotherapeutic dose-density for Hodgkin lymphoma (HL) they could increase the complete response rate among favorable risk patients with HL after 8 weeks of Stanford V compared to 8 weeks of VAMP. This would translate to a decrease in patients who required radiation therapy (RT) to achieve a cure. HOD08 (NCT00846742) was a phase II multicenter investigator-initiated single- arm trial for patients ≤ 21 years of age with previously untreated stage IA or IIA HL without mediastinal bulk or extranodal disease extension and fewer than three sites of disease. Treatment consisted of a modified 8-week Stanford V regimen (vinblastine, doxorubicin, vincristine, bleomycin, mechlorethamine, etoposide and prednisone). Modified tailored field RT was administered only to disease sites achieving less than a CR. The primary objective was to increase CR rate after 8 weeks of chemotherapy by at least 20% (from an estimated 44% to 64%) compared to patients treated on a previous trial (HOD99). HOD08 enrolled 85 patients with HL and 72 were evaluable for the primary objective of whom 55 (76.4%) achieved a CR at all sites and did not receive RT. The 5-year event-free survival (EFS) and overall survival (OS) rates for the entire cohort were 87.4% (95% confidence interval (CI) 80.4%-95.0%) and 98.7% (95% CI 96.2%-100%), respectively. A dose-dense modified Stanford V regimen reduced the proportion of low-risk pediatric patients with HL who received RT while maintaining excellent outcomes. NCT00846742

10018 Background: The AEPA/CAPDac (brentuximab vedotin, etoposide, prednisone, doxorubicin [cumulative dose = 160mg/m 2 ], cyclophosphamide, brentuximab vedotin, prednisone, and dacarbazine) regimen results in excellent EFS and OS rates for pediatric cHL but resulted in 65% of patients requiring RNRT using metabolic and anatomic response criteria. We aimed to determine if use of a metabolic-only response assessment would allow omission of consolidative prednisone and RNRT for the majority of high-risk patients while maintaining a high EFS. Methods: cHOD17 is an open-label, single-arm, multicenter, phase 2 trial with a stratum for patients ≤25 yrs of age at diagnosis of high-risk (stage IIB, IIIB, or IV), CD30+ cHL. 18 FDG-PET only (rather than + anatomic) was used to guide therapy following 2 cycles of AEPA [adapted from the HLHR13 trial (NCT01920932), without mandated growth factor] at the early response assessment (ERA). Complete (CMR) and inadequate metabolic responses (IR) were defined as Deauville ≤3 and ≥4, respectively. Patients in overall CMR received 4 CADac cycles without prednisone or RNRT. IR patients received 4 CAPDac (with prednisone) followed by consolidative IR site directed RNRT (25.5 Gy). The primary objective was to estimate EFS utilizing this approach. Results: 114 patients were enrolled at 7 institutions from January 2019 to February 2024. Median (range) age at diagnosis was 16.4 (6.7-24.1) yrs and follow-up 2.5 (0.4-5.7) yrs. Most (79.8%) were nodular sclerosing histology. Stages included 22.8% IIB, 16.7% IIIB, 20.2% IVA, and 40.4% IVB. One patient discontinued therapy due to treatment-related toxicity and was unavailable for response assessment. Of 113 remaining, 69 (61.1%) achieved a CMR at ERA and were spared RNRT and glucocorticoids during the CAPDac cycles. The 2-yr EFS was 94.7% (95% CI: 90.3%-99.4%) and OS 100% (95% CI: 100%-100%). Five of six relapses ( < 3 mo (N = 1), 3-12 mo (N = 2), and > 12 mos (N = 3) following therapy) occurred in individuals with an IR. The most frequent grade ≥3 toxicities were lymphopenia (84.2%) and neutropenia (91.2%). Grade 3 and 4 febrile neutropenia occurred in 21.1% and 1%, respectively. Neuropathy grade ≥3 was not observed. Serious adverse events were rare (n = 4) and included: multi-organ failure during cycle 1 that recovered (n = 2), therapy-related myeloid leukemia in remission following allotransplant (n = 1), and infection-related death during allotransplant for relapse (n = 1). Conclusions: A metabolic-only response assessment in the AEPA-CAPDac regimen results in high rates of omission of consolidative RT and glucocorticoids while limiting cumulative anthracycline exposure and maintaining excellent 2-year EFS of 94.7% and OS of 100%. Clinical trial information: NCT03755804 .

Background: Improving risk stratification of patients with Hodgkin lymphoma (HL) allows for optimization of treatment allocation and minimization of late effects when possible. The Childhood Hodgkin International Prognostic Score (CHIPS) was developed as a predictive model for event-free survival (EFS) in pediatric and adolescent HL using clinical data at diagnosis from patients with intermediate-risk HL treated on Children's Oncology Group protocol AHOD0031 (NCT00025259) with doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide (ABVE-PC) chemotherapy and response-adapted radiation. Stage IV, large mediastinal mass, albumin <3.5 g/deciliter, and fever were identified as independent predictors of EFS and assigned one point each, resulting in CHIPS ranging from 0 to 4. CHIPS was highly predictive of EFS in this patient cohort, but has not been validated in high-risk patients or in patients treated with other therapeutic regimens. We aim to validate the CHIPS as a risk stratification tool for patients with intermediate or high-risk HL treated with Stanford V chemotherapy by the Pediatric Hodgkin Consortium (PHC). Methods: The PHC trial HOD99 (NCT00145600) enrolled patients on the high-risk arm with stage IIB, IIIB, or IV disease <22 years (n=123). HOD05 (NCT00352027) enrolled patients with intermediate-risk HL with stage IB, IA or IIA with “E” lesions, ≥3 nodal sites, or bulky mediastinal adenopathy, or IIIA disease <22 years (n=49). All patients received 12 weeks of Stanford V chemotherapy with doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone followed by low-dose, response-adapted radiation therapy. All patients with absent B symptoms were deemed afebrile; patients missing documentation of any elements of CHIPS were excluded from the analysis. Results: Our final analysis included a total of 164 patients, 116 with high-risk HL from HOD99 and 48 with intermediate-risk HL from HOD05. One patient was excluded for missing fever data and 7 were excluded due to missing albumin values. Patients were classified into 2 groups based on their CHIPS value: CHIPS 0-1 (n=88, 53.7%) and CHIPS 2-4 (n=76, 46.3%). The EFS for patients in the CHIPS 0-1 and CHIPS 2-4 groups was analyzed using Kaplan-Meier curves (Figure 1). The 2-year EFS estimates for patients with CHIPS 0-1 and CHIPS 2-4 were 95.5% (95% confidence interval (CI) 91.2%-99.9%) and 80.3% (95% CI 71.8%-89.7%), respectively, with a log-rank p-value of 0.003. Similarly, the 4-year EFS estimates for patients with CHIPS 0-1 and CHIPS 2-4 were 93.2% (95% CI 88.0%-98.6%) and 77.6% (95% CI 68.7%-87.6%), respectively, with a log-rank p-value of 0.004. The reduced EFS in patients with higher CHIPS is consistent across different stages and early response assessment (Table 1). Conclusions: CHIPS is highly predictive of EFS in pediatric and adolescent patients with intermediate and high-risk HL treated with Stanford V chemotherapy, as it identifies a subset (CHIPS 2-4) with significantly lower EFS compared to the other subset (CHIPS 0-1). Assessment of CHIPS alongside novel approaches such as circulating tumor DNA and total metabolic tumor volume should be analyzed across trials to allow for further enhancements to risk stratification for pediatric, adolescent and young adult HL.

In 2007, the Pediatric Hodgkin Consortium (PHC) published the results of a trial using combined modality therapy with vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) and involved-fi eld radiation (IFRT) for pediatric patients with low-risk Hodgkin lymphoma (HL) between 1990 and 2000. 1 This trial (HOD90) included both patients with classical HL (cHL) and those with nodular lymphocyte – predominant Hodgkin lymphoma (NLPHL). Analysis of event-free survival (EFS) rate was performed based on the number of sites of disease at diagnosis. This revealed an inferior 10-year EFS rate of 80% for patients with ≥ 3 sites of disease compared with a 10-year EFS rate of 92.7% for patients with <3 sites of disease. 1 These data formed the basis for risk strati fi cation in subsequent PHC trials, which incorporated a restriction of <3 sites of disease for patients at low risk. 2 However, evolution in our understanding of the biology of NLPHL and increasing use of targeted therapies has led to the exclusion of patients with NLPHL from contemporary frontline clinical trials for cHL. 3 Given the superior outcomes for patients with NLPHL compared with those with cHL on HOD90 (10-year EFS of 100% for the NLPHL cohort vs 85.4% for those with cHL) 1 and the preponderance of patients with NLPHL with 1 or 2 sites of disease, 1 we hypothesized that the number of sites may be less predictive of the outcome among patients with cHL who otherwise met the criteria for low-risk disease. We performed an analysis of HOD90 trial data to assess for the prognostic signi fi cance of the number of sites of disease in cHL

Introduction - Treatment abandonment contributes significantly to poor survival of children with cancer in low-middle-income countries (LMICs). In order to inform an approach to this problem at our Cancer Unit, we investigated why caregivers withdraw their children from treatment. Methods – In a qualitative study, in-depth interviews were conducted with caregivers of children who had abandoned cancer treatment at the Paediatric Cancer Unit (PCU) of Mbarara Regional Referral Hospital (MRRH) in South Western Uganda, between May 2017 and September 2020. Recorded in-depth interviews with caregivers were transcribed and analyzed to identify themes of caregiver self-reported reasons for treatment abandonment. Results - Seventy-seven out of 343 (22.4%) children treated for cancer at MRRH abandoned treatment during the study period; 20 contactable and consenting caregivers participated in the study. The median age of children’s caregivers was 37 years and most (65%) were mothers. At the time of this study, eight (40%) children were alive and 5 (62.5%) were males; with a median age of 6.5 years. Financial difficulties, other obligations, the child falsely appearing cured, preference for alternative treatments, belief that cancer was incurable, fear that the child’s death was imminent and chemotherapy side-effects were the caregivers’ reasons for treatment abandonment. Conclusions and Recommendation – Treatment abandonment among children with cancer in Uganda is, most times, as a result of difficult conditions beyond the caregivers’ control and needs to be approached with empathy and support.

The successful use of bone marrow transplantation is dependent upon several interrelated features: control of graft-vs-host disease, sufficient immunosuppression to prevent graft rejection, and adequate cytotoxicity to eradicate the malignancy. Eradication of the malignancy depends primarily on the conditioning regimen, but recent evidence supports the possibility that T cells in the graft mediate a graft-vs-leukemia reaction that is an important adjunct to the cytotoxic effects of chemotherapy and radiation. A comparison of treated and control bone marrow cells was used to evaluate efficacy of T cell depletion. PHA at a final concentration of 0.5% was added, and varying numbers of treated and control bone marrow cells were titered in. Since the immunotoxin does not kill the cells immediately, FACS analysis was performed after a 5-day incubation in phytohemagglutinin and interleukin 2. Increasing the intensity of the conditioning regimen is an important component of a bone marrow transplant protocol that uses T cell depletion.

Background Fever and neutropenia is a common reason for nonelective hospitalization of pediatric oncology patients. Herein we report nearly five years of experience with a clinical pathway designed to guide outpatient management for patients who had low-risk features. Procedures Through a multidisciplinary collaboration, we implemented a clinical pathway at our institution using established low-risk criteria to guide outpatient management of pediatric oncology patients. Comprehensive chart review of all febrile neutropenia episodes was conducted to characterize outcomes of patients with low-risk febrile neutropenia following clinical pathway implementation. Results Between April 1, 2013, and October 1, 2017, there were 169 cases of febrile neutropenia managed in our Pediatric Oncology Unit. Sixty-seven (40%) of these episodes were defined as low risk and managed either entirely in the outpatient setting (41 episodes, 24%) or with a step-down strategy involving a very brief inpatient stay (26 episodes, 15%). There were no intensive care unit admissions or deaths among the low-risk patients. Of those identified as low risk, seven patients (10%) required subsequent hospitalization during the follow-up period, two for inadequate oral intake, two for persistent fevers, one for cellulitis, one for seizure unrelated to the febrile episode, and one for a positive blood culture. Conclusions Following implementation of a clinical pathway, the majority of patients designated as low risk were managed primarily in the outpatient setting without major morbidity or mortality, suggesting that carefully selected low-risk patients can be successfully treated with outpatient management and subsequent admission if warranted.

Burkitt lymphoma (BL) is the most common Non-Hodgkin lymphoma (NHL) in children, representing 40–50% of paediatric NHL (Cairo et al, 2012). BL is frequently advanced, involving the bone marrow (BM), central nervous system (CNS) or both, which requires aggressive therapy. BL is also the most frequently CNS-positive (CNS) paediatric NHL (9–13% of cases) (Cairo et al, 2007, 2012; Patte et al, 2007; Gerrard et al, 2008). Trials have strived to improve outcomes in CNS BL and other mature B cell NHL (B-NHL), where prognoses are inferior (Salzburg et al, 2007). Specifically, CNS patients who were also BM-positive (BM) had the worst outcomes on the French-American-British (FAB)/Lymphome Malins B (LMB)96 trial (Cairo et al, 2012). Yet most patients do achieve long-term survival, so studies also aim to reduce therapy-induced sequelae. The international FAB/ LMB96 cooperative group trial previously demonstrated that CNS B-NHL patients treated with intensified CNS-directed systemic and intrathecal (IT) therapies had similar event-free and overall survival (EFS, OS) to prior CNS radiotherapycontaining regimens (Cairo et al, 2007). Besides altering CNS-directed treatment, FAB/LMB96 also randomized standardversus reduced-intensity arms: reduced-intensity was proven inferior (72% vs. 84% EFS) (Cairo et al, 2007). Here, we focus CNS patients treated on the standard FAB/LMB96 C1-arm. Rituximab has proven beneficial in adult B-NHL, so shortly after FAB/LMB96, we investigated adding rituximab to the C1-regimen in the Children’s Oncology Group (COG)ANHL01P1 trial (Goldman et al, 2014). Here, we present high-risk CNS patient data from both the FAB/LMB96 C1arm and COG-ANHL01P1 and compare them to prior LMB89 results. Overall, excellent EFS and OS were achieved, with further improvement with rituximab. Clinical trial information and approvals, CNS-defining criteria, chemotherapy details and statistical methods are listed in Data S1. Forty-four CNS mature B-NHL patients were treated on FAB/LMB96-C1 (Cairo et al, 2007), with 84% having BL or BL-like histology and 52% dually CNS/BM. Fifteen COGANHL01P1 patients were CNS, 100% with BL and 53% CNS/BM. Thus, these results pertain to BL, because 88% of patients shared this pathological diagnosis (P = 0 45). No significant differences in age, gender, or BM/CNS status were seen between the patient groups (Table I and data not shown), with both cohorts mostly male (83%) and aged ≤14 years (88%). The types of CNS patients on both trials were also similar, with 55% (FAB/LMB96-C1) vs. 53% (COG-ANHL01P1) cerebrospinal fluid-positive (CSF), 36% vs. 33% isolated CSF, and 36% vs. 33% dually BM/CSF. Each group also contained ~13% of patients with isolated cranial nerve palsies. After correcting for the inferior arm of the FAB/LMB96 CNS patients, estimated 4-year EFS was 75 4 5% (FAB/ LMB96-C1; Table II); versus 93 3% on COG-ANHL01P1, with EFS in BM/CNS and BM/CSF subgroups likewise similar (data not shown). Overall, both trials illustrate that children, adolescents and young adults with high-risk CNS mature B-NHL have outstanding outcomes when CNS radiation is replaced with CNS-directed systemic and IT chemotherapy (Cairo et al, 2007; Goldman et al, 2014). Prior studies like LMB89 used similar regimens, but with cranial radiation in CNS patients. These results in CNS patients show that CNS-directed systemic (high dose methotrexate, high dose cytarabine) and IT therapy (13 doses) can limit neurotoxicity by eliminating irradiation, yet still offer superior EFS and OS. The COG-ANHL01P1 study added rituximab to therapy that was almost identical to FAB/LMB96-C1, but reduced the doxorubicin infusion time. Despite an estimated 20% improvement in 4-year EFS in CNS patients on COGANHL01P1 versus FAB/LMB96, this was not statistically significant due to the small sample size of COG-ANHL01P1. However, directly comparing these trials is complex, because these studies had key differences: (i) FAB/LMB96 randomized patients after the cytoreduction and induction cycles, thus excluding refractory/progressing patients and those who died of toxicity prior to randomization. This over-estimates FAB/LMB96 outcomes. (ii) Conversely, the reduced therapy arm of FAB/LMB96 demonstrated inferior outcome. Therefore, it would be inappropriate to compare the addition of rituximab to standardversus reduced-intensity chemotherapy of FAB/LMB96. The actual 4-year EFS of all CNS patients enrolled (not just randomized) on FAB/LMB96 was 70 4 3%. Statistical analysis of FAB/LMB96, once corrected for the inferior arm of therapy, estimated the 4-year

The introduction of JAK inhibitors into clinical practice has improved outcomes for patients with myeloproliferative neoplasms (MPNs). Ruxolitinib, the only approved JAK inhibitor for MPN patients, has demonstrated an ability to decrease splenomegaly and relieve constitutional symptoms.[1][1]–[3][

Specialist physicians have an important role in addressing ED utilization, especially at tertiary medical centers that treat highly specialized patients. We analyzed if reporting of ED utilization to pediatric specialist physicians can decrease ED visits. We analyzed if reporting of ED utilization rates of patients followed by pediatric specialists resulted in decreased ED use. Different pediatric specialist division received and discussed individualized ED use reports. Using control charts, we examined if our intervention decreased the rate of ED utilization. Pediatric neurology, hematology/oncology, infectious diseases and pulmonary received their ED use reports. Overall, for the four divisions specialty-related ED utilization decreased significantly during all hours, weekdays, and office hours. This was in the setting of ED utilization increasing for all diagnoses ED visits. Pediatric ED volume did not change during the study period. Physician-level reporting of ED utilization was associated with a reduction in ED use by patients followed by our pediatric specialists.

OBJECTIVESEmergency department (ED) utilization is a major driver of cost. Specialist physicians have an important role in addressing ED utilization, especially at tertiary medical centers that treat highly specialized patients. We analyzed if reporting of ED utilization to pediatric specialist physicians can decrease ED visits.METHODSPhysicians within pediatric neurology, hematology and oncology, infectious diseases, and pulmonary divisions received their ED use reports. By using control charts, we examined if this intervention decreased the rate of ED utilization.RESULTSOverall, for the 4 divisions, specialty-related ED utilization decreased significantly during all hours, weekdays, and office hours. This was in the setting of ED utilization increasing for all diagnoses ED visits. Pediatric ED volume did not change during the study period.CONCLUSIONSPhysician-level reporting of ED utilization was associated with a reduction in ED use by patients managed by our pediatric specialists.

Epstein-Barr virus-related lymphoproliferative disease (EBV-LPD) rarely occurs in patients with acute lymphoblastic leukemia (ALL), who have not received hematopoietic transplantation. We describe EBV-LPD manifesting as facial lesions in two children with ALL in remission. One patient was a 16-year-old male with T-cell ALL with an EBV-positive angiocentric polymorphous lip lesion presenting as right-sided facial swelling. The other patient was a 12-year-old male with B-cell ALL with an EBV-positive polymorphous lymphoplasmacytic infiltrate presenting as bilateral dacryoadenitis. Neither patient had known primary immunodeficiencies. Both cases improved with immunosuppressant de-escalation. These cases suggest that immunosuppression induced by maintenance chemotherapy is sufficient to promote EBV-LPD.

AIM: To describe our preliminary experience with simultaneous whole body 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography and magnetic resonance imaging (PET-MRI) in the evaluation of pediatric oncology patients. METHODS: This prospective, observational, single-center study was Health Insurance Portability and Accountability Act-compliant, and institutional review board approved. To be eligible, a patient was required to: (1) have a known or suspected cancer diagnosis; (2) be under the care of a pediatric hematologist/oncologist; and (3) be scheduled for clinically indicated 18F-FDG positron emission tomography-computed tomography (PET-CT) examination at our institution. Patients underwent PET-CT followed by PET-MRI on the same day. PET-CT examinations were performed using standard department protocols. PET-MRI studies were acquired with an integrated 3 Tesla PET-MRI scanner using whole body T1 Dixon, T2 HASTE, EPI diffusion-weighted imaging (DWI) and STIR sequences. No additional radiotracer was given for the PET-MRI examination. Both PET-CT and PET-MRI examinations were reviewed by consensus by two study personnel. Test performance characteristics of PET-MRI, for the detection of malignant lesions, including FDG maximum standardized uptake value (SUVmax) and minimum apparent diffusion coefficient (ADCmin), were calculated on a per lesion basis using PET-CT as a reference standard. RESULTS: A total of 10 whole body PET-MRI exams were performed in 7 pediatric oncology patients. The mean patient age was 16.1 years (range 12-19 years) including 6 males and 1 female. A total of 20 malignant and 21 benign lesions were identified on PET-CT. PET-MRI SUVmax had excellent correlation with PET-CT SUVmax for both benign and malignant lesions (R = 0.93). PET-MRI SUVmax > 2.5 had 100% accuracy for discriminating benign from malignant lesions using PET-CT reference. Whole body DWI was also evaluated: the mean ADCmin of malignant lesions (780.2 + 326.6) was significantly lower than that of benign lesions (1246.2 + 417.3; P = 0.0003; Student’s t test). A range of ADCmin thresholds for malignancy were evaluated, from 0.5-1.5 × 10-3 mm2/s. The 1.0 × 10-3 ADCmin threshold performed best compared with PET-CT reference (68.3% accuracy). However, the accuracy of PET-MRI SUVmax was significantly better than ADCmin for detecting malignant lesions compared with PET-CT reference (P < 0.0001; two-tailed McNemar’s test). CONCLUSION: These results suggest a clinical role for simultaneous whole body PET-MRI in evaluating pediatric cancer patients.

Patient-specific primers from 10 children/adolescents with Burkitt leukaemia (BL) ± central nervous system disease who were treated with French-British-American/Lymphome Malins de Burkitt 96 C1 plus rituximab were developed from diagnostic blood/bone marrow. Minimal residual disease (MRD) was assessed by real-time polymerase chain reaction at the end of induction (EOI) and consolidation (EOC). Seventy per cent (7/10) and 71% (5/7) were MRD-positive at EOI and EOC, respectively, with no disease recurrences. MRD after induction and consolidation did not predict relapse and subsequent therapy appeared to eliminate MRD. Thus, assessing MRD at a later time point is warranted in future trials to determine its clinical significance.