Kelly, Kara M.

10019 Background: The reported incidence of second malignant neoplasms (SMN) in long-term survivors of Hodgkin lymphoma (HL) is derived from patients treated with outdated radiation therapy (RT) techniques. We modeled the risk of SMN in pediatric patients with high-risk classic HL treated with modern mediastinal RT. Methods: In patients who received mediastinal RT on the Children’s Oncology Group study AHOD1331, we modeled the lifetime attributable risk (LAR) at 70 years of age of thyroid, lung, and breast carcinoma. This value indicates the absolute increased risk of SMN at 70 years of age due to RT, above the baseline population risk (mean baseline rates at 70 years of age are 0.7%, 3.3%, and 8.9% for thyroid, lung, and breast carcinoma, respectively, https://seer.cancer.gov/data/ ). Results: In 296 patients who received protocol-directed mediastinal RT, median age at diagnosis was 15.1 years, 55% were female, and 98% had large mediastinal adenopathy. Following 5 cycles of chemotherapy, patients received RT targeting the mediastinum based on criteria of this study; in addition, some patients received RT to other supradiaphragmatic sites that contained slowly responding lesions, including the axilla (n = 3, 1%), lung (n = 7, 2.4%), upper neck (n = 4, 1.3%), and lower neck (n = 8, 2.7%). The RT modality was proton therapy in 25.3%, photon intensity modulated RT (IMRT) in 45.6%, and photon 3-dimensional conformal RT (3D-CRT) in 27.7%. The RT prescription dose was 21 Gy in 83% and 30 Gy in 16% who had a partial metabolic response at the completion of chemotherapy. The mean (range) doses to the thyroid, lungs, and breasts were 12.8 Gy (0-30.3), 8.0 Gy (0.1-15.2), and 4.2 Gy (0.2-14.5), respectively. For the complete cohort, the mean LAR at 70 years of age of thyroid carcinoma was 0.063% and of lung carcinoma was 5.34%. For females, the mean LAR at 70 years of age of breast carcinoma was 2.92%. The Table summarizes the LAR for each SMN, stratified by RT modality. Conclusions: In patients treated with mediastinal RT on a recent multi-institutional study of pediatric HL, the predicted long-term risk of SMN is substantially lower than in historical cohorts. Clinicians should consider the toxicity associated with a current RT approach when selecting therapies and counseling patients. Clinical trial information: NCT02166463 , this is a post hoc modeling study that includes patients enrolled on this study. Mean [range] lifetime attributable risk (%) at an attained age of 70 years for thyroid, lung, and breast carcinoma. Thyroid Lung Breast (females) 3D-CRT 0.046 [0.002-0.332]N=81 5.07 [0.12-10.82]N=82 1.82 [0.67-5.98]N=46 IMRT 0.064 [0.001-0.386]N=135 6.24 [2.22-11.79]N=135 4.36 [0.66-8.43]N=76 Proton 0.086 [0-1.160]N=74 4.15 [0.94-7.77]N=75 1.45 [0.17-7.23]N=40

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Acute Lymphoblastic Leukemia (ALL) were developed as a result of meetings convened by a multidisciplinary panel of pediatric ALL experts, with the goal of providing recommendations on standard treatment approaches based on current evidence. The NCCN Guidelines for pediatric ALL focus on risk assessment and stratification of risk-adapted therapy; treatment strategies for BCR::ABL1 (Philadelphia chromosome [Ph])-negative and BCR::ABL1-positive B-cell lineage, T-cell lineage, and infant ALL; and supportive care considerations. This selection from the NCCN Guidelines for pediatric ALL focuses on the diagnosis of and management of pediatric T-ALL.

ImportanceRetrieval strategies for children, adolescents, and young adults with relapsed classic Hodgkin lymphoma (cHL) aim to maintain efficacy while minimizing long-term toxic effects. Children, adolescents, and young adults with low-risk, relapsed cHL may benefit from replacing high-dose chemotherapy and autologous stem cell transplant with less intensive involved-site radiotherapy (ISRT).ObjectiveTo evaluate a risk-stratified, response-adapted, transplant-free approach for treatment of children, adolescents, and young adults with low-risk relapsed cHL with nivolumab plus brentuximab vedotin (BV) followed by BV plus bendamustine for patients with suboptimal response and ISRT (30.0 to 30.6 Gy).Design, Setting, and ParticipantsCheckMate 744 (R1 cohort) was a phase 2, nonrandomized, single-arm study enrolling children, adolescents, and young adults aged 5 to 30 years with low-risk cHL between September 25, 2017, and December 16, 2020, across the US, Canada, and Europe. Data were analyzed from September 2017 to November 2022.ExposuresPatients received 4 cycles of nivolumab plus BV induction; patients with complete metabolic response (CMR) received an additional 2 cycles of nivolumab plus BV while patients with suboptimal response received 2 cycles of BV plus bendamustine intensification. Patients with CMR after induction or intensification received ISRT consolidation.Main Outcomes and MeasuresPrespecified coprimary end points were CMR rate (Lugano 2014 classification) any time before ISRT and 3-year event-free survival (EFS) rate, per blinded independent central review (BICR).ResultsOf 28 included patients treated in the low-risk cohort, 18 (64%) were female, and the median (range) age was 17 (6-27) years. At a median (range) follow-up of 31.9 (2.2-55.3) months, CMR per BICR any time before ISRT was 93% (26 of 28; 90% CI, 79.2-98.7; objective response rate [ORR], 100%), and 23 of 28 (82%) achieved CMR per BICR after 4 cycles of nivolumab plus BV (ORR, 96.4%). Kaplan-Meier estimates of EFS and progression-free survival rates at 3 years were 87% (3 of 18; 90% CI, 69.5-94.7) and 95% (1 of 18; 90% CI, 76.7-99.0), respectively. During induction, 22 patients (79%) had treatment-related adverse events, including 7 with grade 3 or 4 adverse events, 2 with anemia, 1 with neutropenia, and 6 with immune-mediated adverse events. Serious adverse events leading to discontinuation occurred in 2 patients.Conclusions and RelevanceThis nonrandomized clinical trial found that for children, adolescents, and young adults with low-risk, relapsed cHL, a transplant-free, risk-adapted, response-based approach with nivolumab plus BV and ISRT offered high CMR rates and high 3-year EFS rate, with a safety profile consistent with that of each agent used.Trial RegistrationClinicalTrials.gov Identifier: NCT02927769

This nonrandomized clinical trial reports outcomes for children with low-risk relapsed Hodgkin lymphoma treated with second-line chemotherapy and involved-field radiotherapy without autologous stem cell transplant.

Purpose In lymphomas, the Deauville score (DS) standardizes 18F-FDG PET treatment response assessments. We assessed interobserver agreement of the DS and developed a quantitative PET-based parameter to minimize subjectivity of response assessments. Methods PET scans performed within the Children’s Oncology Group AHOD0831 study were analyzed. One hundred one scans obtained after the first cycle of chemotherapy (PET1) and 83 obtained after the second cycle (PET2) were eligible for inclusion. Each scan was assigned a DS by 2 nuclear medicine radiologists and a Hodgkin lymphoma index (HLI), defined as the ratio of the tumor’s SUVmax or SUVpeak to the liver’s SUVmean. Cohen κ coefficient measured the rate of agreement of the DS assigned by the 2 radiologists. Receiver operating characteristic curves and the Youden index were used with the consensus DS to identify an optimal HLI cutoff value to distinguish PET-negative from PET-positive images. For each HLI cutoff value, sensitivity, specificity, and accuracy were calculated. Results Interobserver agreement in DS was moderate (PET1: κ = 0.480, P < 0.001; PET2: κ = 0.428, P < 0.001). On PET1, the optimal cutoff values for HLImax were 1.19 for DS2/DS3 and 1.78 for DS3/DS4, and for HLIpeak were 1.19 for DS2/DS3 and 1.44 for DS3/DS4. On PET2 images, the corresponding values were 1.18, 1.58, 0.94, and 1.26. The most accurate predictor was HLImax on PET2 when scans were dichotomized as DS1–DS3 versus DS4–DS5 (accuracy, 92.8%; sensitivity, 100%; specificity, 91.8%). Conclusion The HLI provides an objective, quantitative measure of disease response and thus may improve interreader agreement for lymphoma response assessments.

PURPOSE Lymphomas are a heterogeneous group of diseases that develop in individuals of all ages and have variable prognoses. Improved survival resulting from therapy advances has led to the emergence of diverse late effects. Although several (US)–based organizations have developed survivorship guidelines, the distinct features of lymphoma subtypes and diverse therapies used raise concerns regarding their applicability to lymphoma survivors. We compared survivorship recommendations (outside primary disease monitoring) between US clinical guidelines. METHODS We extracted information from 17 guidelines from five US-based organizations: ASCO (n = 11), American Cancer Society (n = 1), Children's Oncology Group (n = 1), Center for International Blood and Marrow Transplant Research (n = 1), and the National Comprehensive Cancer Network (n = 3). Guidelines were evaluated to determine whether they offer recommendations on physical effects , psychosocial and quality of life ( QOL ), and health promotion and prevention . Comparisons were focused on second primary malignancy, cardiovascular complications, and vaccination. RESULTS Survivorship recommendations on physical effects and psychosocial and QOL mainly differ in the timing and approaches for screening. Vaccination recommendations were primarily derived from other cancer populations. Identified research gaps were a lack of understanding of the risk of late effects across lymphoma subtypes, the role of social determinants of health in survivorship, and the lack of a survivorship care model that integrates lymphoma subtypes and treatment exposures. CONCLUSION This study raises awareness about the complexity and challenges of managing survivors under the umbrella diagnosis of lymphoma. The inconsistency and incompleteness of existing guidelines may lead to suboptimal survivorship care. We propose expert-based research priorities to address gaps and unmet needs to help develop risk-based follow-up recommendations to optimize survivorship care for lymphoma survivors.

Background: Overall survival rates now exceed 90% for children, adolescents, and young adults with cHL, but patients with slow early response (SER) to front-line chemotherapy are at an increased risk of relapse. The approaches used historically to treat patients with SER included dose intensification and radiotherapy (RT), which can be associated with long-term toxicity. The open-label, phase 2 KEYNOTE-667study (NCT03407144) is designed to evaluate the efficacy and safety of consolidation with pembrolizumab plus chemotherapy with or without RT followed by pembrolizumab maintenance in patients with cHL and SER to front-line chemotherapy. The study includes 2 groups: patients with low-risk cHL (stage IA, IB, or IIA without bulky disease) and patients with high-risk cHL (stage IIEB-IVB). Prior analysis of the high-risk group showed that consolidation with pembrolizumab plus cyclophosphamide, vincristine, prednisone/prednisolone, and dacarbazine (COPDAC-28) followed by pembrolizumab maintenance had manageable safety and promising activity in patients with high-risk cHL and SER to front-line vincristine, etoposide, prednisone/prednisolone, and doxorubicin (OEPA). Here, we present updated results for patients with high-risk cHL and SER to OEPA. Methods: Patients eligible for the high-risk group were aged 3-25 years and had newly diagnosed stage IIEB, IIIEA, IIIEB, IIIB, IVA, or IVB cHL; measurable disease; and a Lansky Play-Performance Scale (aged &lt;16 years) or a Karnofsky Performance Status (aged ≥16 years) score of ≥50. All patients in the high-risk group received 2 cycles of OEPA followed by early response assessment (PET and CT/MRI). Patients with a rapid early response (ie, Deauville score [DS] 1-3) received nonstudy therapy. Patients with a SER (ie, DS 4 or 5) received consolidation therapy with pembrolizumab 2 mg/kg up to 200 mg (aged 3-17 years) or 200 mg (aged 18-25 years) IV Q3W plus COPDAC-28 for 4 cycles. Patients then underwent late-response assessment (LRA; PET and CT/MRI). Patients with PET-positive disease at LRA (ie, DS 4 or 5) received RT (28.8 Gy) to late PET-positive residua. Patients with PET-negative disease (ie, DS 1-3) received no RT. All patients received maintenance pembrolizumab for up to 17 cycles. The primary end point was objective response rate (ORR) by blinded independent central review (BICR) per Cheson 2007 IWG criteria. Secondary end points included the rate of PET negativity after consolidation and safety. Results: 84 patients with high-risk cHL and SER to front-line OEPA received consolidation with pembrolizumab plus COPDAC-28. Median time from treatment allocation to data cutoff (Feb 29, 2024) was 24.3 months (range, 5.7-48.4). As of the data cutoff, 55 patients had completed consolidation and maintenance therapy, 20 were ongoing, and 9 had discontinued treatment (due to adverse events [AE], n = 3; progressive disease, n = 2; withdrawal by patient, n = 2; complete response [CR], n = 1; physician decision, n = 1). Patients received a median of 17 doses of pembrolizumab (range, 2-17) and the median time on pembrolizumab was 11.1 months (range, 0.5-11.8). The median age of patients was 14 years (range, 4-22), 78 (93%) were aged 3-17 years, 45 (54%) were male, 44 (52%) had bulky disease, and 53 (63%) had Ann Arbor stage IV disease. Of 84 patients who received consolidation, 80 (95%) had an LRA. The ORR among these patients was 99% (95% CI, 93-100; 57 CR and 22 partial response). 56 patients (70%) with a LRA were PET negative by BICR; 55 (69%) were PET negative by investigator review and did not receive RT. Treatment-related AEs were reported in 61 patients (73%); grade 3 or 4 treatment-related AEs occurred in 16 patients (19%). Three patients (4%) discontinued treatment due to treatment-related AEs. No patients died due to treatment-related AEs. Immune-mediated AEs occurred in 10 patients (12%). Conclusion: After additional follow up, consolidation with pembrolizumab plus COPDAC-28 with or without RT followed by pembrolizumab maintenance continued to demonstrate promising activity and manageable safety in patients with high-risk cHL and SER to front-line OEPA. Among the 80 patients with an LRA, 70% were PET negative by BICR and 69% were PET negative by investigator review and were spared RT. These results continue to support pembrolizumab plus COPDAC-28 consolidation as a treatment option that may augment response in patients with high-risk CHL and SER to front-line OEPA.