Radiological follow-up of osteonecrosis lesions in children and adolescents with Hodgkin lymphoma.

Osteonecrosis (ON) is a common complication of glucocorticoid-based Hodgkin lymphoma (HL) treatment, but the natural evolution and prognosis of ON lesions remain poorly understood. We describe the radiological evolution of ON lesions identified in a Nordic population-based cohort of paediatric HL patients. Magnetic resonance images of suspected ON lesions were centrally reviewed to confirm ON diagnosis and grade the ON lesions according to the Niinimäki classification. The study included 202 ON lesions in 46 patients, of which 77 were joint lesions. Follow-up images were available for 146/202 lesions, with a mean follow-up time of 28 months. During follow-up, 71% of the lesions remained stable, 26% improved or resolved, and 3% progressed. A higher ON grade at diagnosis was associated with a lower likelihood of spontaneous resolution. The likelihood for resolution of ON decreased by 50% for each year of added patient age, when adjusted for sex, ON location, and symptoms. Hip ON showed less spontaneous improvement compared with other joints, and the risk for surgery was 13-fold in hip ON. Grades 3-4 joint ON has the potential to either progress or resolve, warranting follow-up in patients with severe symptoms. Research on secondary prevention should be directed at grade 3-4 joint ON.

Symptomatic osteonecrosis in children treated for Hodgkin lymphoma: A population-based study in Sweden, Finland, and Denmark.

BACKGROUND: Osteonecrosis (ON) is a potentially disabling skeletal complication of cancer treatment. Although symptomatic osteonecrosis (sON) is well-known in acute lymphoblastic leukemia (ALL), with an incidence around 6%, studies on sON in pediatric Hodgkin lymphoma (HL) are scarce. The aim of this study was to examine the incidence, risk factors, and outcome of sON in children treated for HL. PROCEDURE: A total of 490 children under 18, diagnosed with HL between 2005 and 2019 in Sweden, Finland, and Denmark were eligible for the study. Data on patient characteristics, HL treatment, and development of sON were collected from patients' medical records. Magnetic resonance imaging scans were used to establish ON diagnosis and grade ON according to the Niinimäki grading system. RESULTS: Cumulative 2-year incidence of sON among the 489 included patients was 5.5% (n = 30). The risk for developing sON was higher for those with older age (odds ratio [OR] 1.25, 95% confidence interval [CI]: 1.05-1.49, p < .010), female sex (OR 4.45, CI 1.87-10.58, p < .001), high total cumulative glucocorticoid (GC) doses (OR 1.76, 95% CI: 1.21-2.56, p = 0.003), and advanced HL (OR 2.19, 95% CI: 1.03-4.65, p = .042). Four (13.3%) patients underwent major surgical procedures and 13 (43.3%) had persistent symptoms due to ON at follow-up. CONCLUSIONS: This study shows that sON is as common in pediatric HL as in pediatric ALL, with risk factors such as older age, female sex, high cumulative GC doses, and advanced HL. Future HL protocol development should aim to reduce the burden of ON by modifying GC treatment.

Successful treatment of paediatric refractory Hodgkin lymphoma with immunotherapy - A case report and literature review.

AIM: To describe a rare case of primary refractory Hodgkin lymphoma nodular sclerosis syncytial variant in a child and review immunotherapy in relapsed/refractory Hodgkin lymphoma. METHODS: We described the treatment course of a child with primary refractory classic Hodgkin lymphoma and discussed different options for salvage therapy, with an emphasis on immunotherapy. We searched PubMed for all published clinical trials investigating immunotherapy in classic Hodgkin lymphoma written in English until 31 June, 2023. The reference list of each identified paper was searched for additional publications. RESULTS: Our patient was salvaged with anti-programmed cell death 1 (PD-1) antibody therapy followed by high-dose chemotherapy with autologous stem cell rescue. Radiotherapy was avoided. We identified five one-armed phase II trials investigating anti-PD-1 therapy in first relapse/refractory disease in a total of 254 patients aged 9-71 years, of which one included 31 children. The complete remission rate before high-dose chemotherapy was 59%-95% overall and 67%-89% among those with refractory disease. CONCLUSION: Although it remains to be proven in randomised trials, anti-PD-1 therapy may provide higher complete response rates than traditional chemotherapy. Anti-PD-1 therapy has the potential to increase the chance of cure while decreasing the risk of late effects from chemotherapy and radiotherapy.

Bleeding phenotype according to factor level in 825 children with nonsevere hemophilia: data from the PedNet cohort.

BACKGROUND: Information on bleeding phenotype in nonsevere hemophilia may be used to determine target factor levels for prophylaxis or gene therapy in severe hemophilia. OBJECTIVES: To assess the association between endogenous factor level and bleeding phenotype in children with nonsevere (factor [F]VIII/FIX activity 1%-25%) hemophilia A (HA) and B without prophylaxis. METHODS: Data on annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR), and onset of bleeding were extracted from the international PedNet cohort including children born since 2000. Mean ABR and AJBR were modeled and compared according to FVIII/FIX endogenous activity (1%-2%, 3%-5%, 6%-10%, 11%-15%, 16%-20%, and 21%-25%) using negative binomial regression. Onset of bleeding was analyzed using Kaplan-Meier survival curves. RESULTS: Eight hundred twenty-five children (40% with moderate hemophilia; 87% with HA) with median follow-up of 7.4 years/child were included. The median age at onset of bleeding and median bleeding rates changed with increasing endogenous activity. From endogenous FVIII 1% to 2% to 21% to 25%, the age at onset of bleeding changed from a median of 1.4 to 14.2 years, ABR from 1.6 to 0.1/y, and AJBR from 0.5 to 0.0/y. From endogenous FIX 1% to 2% to 16% to 25%, the onset of bleeding changed from a median of 1.7 to 6.1 years, ABR from 0.5 to 0.1/y, and AJBR from 0.1 to 0.0/y. The negative correlation between AJBR and factor level was most strongly pronounced up to a factor level of 6% in HA and hemophilia B. CONCLUSION: Endogenous factor activity of >5% was identified as a threshold to significantly lower joint bleeding rate, while FVIII levels >15% and FIX levels >10% were sufficient to achieve the goal of 0 bleeds in this pediatric cohort.

Global Hemostatic Methods to Tailor Treatment With Bypassing Agents in Hemophilia A With Inhibitors- A Single-Center, Pilot Study.

For patients with hemophilia A and high-titer inhibitors treated with bypassing agents there are no reliable methods to assess treatment effect. We investigated the utility of global hemostatic methods in assessing treatment with bypassing agents (rFVIIa or activated prothrombin complex [aPCC]). All patients with hemophilia A and inhibitors followed at the Coagulation Unit or the Pediatric Coagulation Unit at Karolinska University Hospital aged 6 years and above were eligible for this noninterventional study. Baseline plasma samples were spiked with bypassing agents in increasing concentrations (aPCC 50 U/kg, 100 U/kg, 150 U/kg, and rFVIIa 90 µg/kg and 270 µg/kg) in vitro. For patients treated with factor concentrates or bypassing agents follow-up samples were collected (in vivo tests). The samples were analyzed using overall hemostatic potential (OHP), and calibrated automated thrombogram, Calibrated Automated Thrombogram (CAT). Nine patients with hemophilia A with inhibitors were included. Spiking with rFVIIa normalized the coagulation potential in 6/8 samples, in 3 only with high dose. Only one sample did not improve adequately after spiking with aPCC. The improvement in hemostasis was reliably shown by both CAT and OHP. The baseline potential was, however, more often measurable by OHP compared to CAT. Factor concentrate had been administered to 5 patients normalizing the hemostatic potential in vivo in 2 (without spiking). The hemostatic improvement induced by spiking with rFVIIa or aPCC is shown by OHP and CAT, but the results have to be evaluated in larger cohorts.