Keller, Frank G.

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second malignant neoplasms (SMN) in long-term survivors of Hodgkin lymphoma (HL) is derived from patients treated with outdated radiation therapy (RT) techniques.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

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.

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 <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.

Background: Cure rates for children, adolescents, and young adults with cHL are high, but patients with a slow early response (SER) to front-line chemotherapy are at an increased risk of relapse compared with patients who have a rapid early response (RER). To avoid long-term toxicity while optimizing outcomes, treatment for pediatric cHL is now shifting to a response-adapted approach. KEYNOTE-667 (NCT03407144) is an open-label phase 2 study designed to evaluate the efficacy and safety of pembrolizumab plus chemotherapy consolidation with or without radiotherapy (RT) followed by pembrolizumab maintenance in patients with cHL and SER to front-line chemotherapy. The study includes 2 groups of patients: those with low-risk cHL (stage IA, IB, and IIA without bulky disease) and those with high-risk cHL (stage IIEB-IVB cHL). Prior analysis of the low-risk group showed that consolidation with pembrolizumab plus doxorubicin, vinblastine, and dacarbazine (AVD) and RT followed by maintenance pembrolizumab had manageable safety and promising antitumor activity in patients with low-risk cHL and SER to front-line doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). We present updated results for patients with low-risk cHL and SER to ABVD. Methods: Patients eligible for the low-risk group were aged 3-25 years and had newly diagnosed stage IA, IB, or IIA cHL without bulky disease, measurable disease, and a Lansky Play-Performance Scale score of ≥50 (aged <16 years) or a Karnofsky Performance Status score of ≥50 (aged ≥16 years). All patients in the low-risk group received 2 cycles of ABVD followed by early response assessment (PET and CT/MRI). Patients with a RER (ie, Deauville score [DS] 1-3) received nonstudy therapy. Patients with SER (ie, DS 4 or 5) received consolidation with pembrolizumab 2 mg/kg up to 200 mg (aged 3-17 years) or 200 mg (aged 18-25 years) IV Q3W plus 2 cycles of AVD. Patients then underwent late response assessment (LRA; PET and MRI/CT). All patients with SER received involved-site RT: 21.6 Gy for complete PET response (ie, DS 1-3) or 30.6-36 Gy for partial PET response (ie, DS 4 or 5). 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 PET negativity after consolidation and safety. Results: 78 patients with low-risk cHL received front-line ABVD. As of the data cutoff date (February 29, 2024), 10 of 78 patients had SER to ABVD and received consolidation with pembrolizumab plus AVD; 4 had completed consolidation and maintenance, 1 was continuing to receive treatment, and 5 had discontinued because of complete response (CR). Median time from allocation to data cutoff was 19.9 months (range, 5.6-44.8). Patients had received a median of 11.5 doses of pembrolizumab (range, 5-17) and the median time on pembro was 7.4 months (range, 3.5-11.3). The median age of patients was 16 years (range, 7-20), 6 (60%) were male, and 8 (80%) had Ann Arbor stage II disease. Of 10 patients who received consolidation, all (100%) had an LRA. The ORR was 100% (95% CI, 69-100; 9 CR and 1 partial response). Six patients (60%) were PET negative by BICR. Seven patients (70%) were PET negative by investigator review, all of whom received a reduced dose of RT. During consolidation, treatment-related adverse events (AEs) were reported in 8 patients (80%); grade 3 or 4 treatment-related AEs occurred in 4 patients (40%). No patients discontinued or died due to treatment-related AEs. Seven patients (67%) had pembrolizumab-related AEs, 3 of whom (30%) had a grade 3 event (vomiting, lymphocyte count decreased, white blood cell count decreased). Immune-mediated AEs occurred in 3 patients (30%; all grade 1 or 2 hypothyroidism). Conclusion: After additional follow-up, consolidation withpembrolizumab plus AVD and RT followed by pembrolizumab maintenance continued to demonstrate promising activity and manageable safety in patients with low-risk cHL and SER to ABVD. Of patients with a LRA, 60% were PET negative by BICR; 70% of patients were PET negative by investigator review and received a reduced dose of RT. These results support further evaluation of pembrolizumab plus AVD consolidation as a treatment option for patients with low-risk CHL and SER to front-line ABVD.

Background: Chemotherapy in combination with radiotherapy (RT) is the standard for early-stage (ES) Hodgkin lymphoma (cHL). Despite high cure rates (12-year overall survival (OS) >93%), there is room to improve short and long-term outcomes for children and adults with ES cHL. Incorporation of immunotherapy (IO) into front line treatment of ES cHL is an opportunity to both improve progression-free survival (PFS) and maintain OS, while minimizing long-term morbidity and mortality by reducing exposure to RT and high-dose chemotherapy. Study Design and Methods: HL leaders of the NCTN groups, expert HL researchers and physicians, and representatives from the Cancer Therapy Evaluation Program (CTEP) formed a working group in April 2020 with the goals of harmonizing treatment approaches for ES cHL across pediatric and adult patients and reaching consensus regarding the optimal study design for incorporating IO therapy into frontline treatment. Study champions identified from each of the North American cooperative groups [Children's Oncology Group (COG), SWOG, ECOG-ACRIN, Alliance, NRG] and experts in imaging, radiation oncology, lymphoma biology and patient-reported outcomes (PROs) were included. The resulting COG-led clinical trial, AHOD2131, represents the largest ES cHL trial in the history of North American cooperative groups and the first to enroll patients across the age continuum. AHOD2131 (NCT05675410; Figure) is a randomized, phase 3 trial enrolling patients ages 5 to 60 years with newly diagnosed, previously untreated stage I and II cHL and will investigate the addition of the CD30-antibody drug conjugate brentuximab vedotin (Bv) with PD-1 blockade (nivolumab) compared to standard chemotherapy +/- RT. Since the April 2023 activation, 97 North American sites have activated the trial, and 21 participants have enrolled. Target enrollment is 1875 patients over 5 years of accrual, for an estimated 1782 eligible and evaluable patients. The primary objective is to compare the 3-year PFS of patients with ES cHL treated through a response-adapted, superiority design with either standard therapy or with an IO approach (BV + nivolumab). All patients will be stratified as favorable or unfavorable based on disease risk features at enrollment. Based on initial response assessment by PET/CT (via central review) after 2 cycles of ABVD, patients were classified to PET2 positive (SER, defined as 5 Point Score 4 or 5, ~15% of patients) and PET negative (RER). Those who are PET positive will receive involved site RT (ISRT). The SER and RER patients will be randomized to standard chemotherapy vs. IO therapy respectively. In addition to the primary outcome of PFS, there are 11 secondary and 10 exploratory aims. The secondary aims focus on OS, PFS of subgroups, and event-free survival at 12 years, physician-reported treatment-related adverse event (AE) rates, patient-reported AE using pediatric and adult versions of Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and the capture of representation by self-report and the use of electronic PRO data collections. The exploratory aims include the assessment of imaging central review as compared to local institutional review and the use of convolutional neural networks through artificial-intelligence machine learning. The study will examine the effect of therapy on acute and long-term adverse effects including health-related quality of life (HRQoL) and OS for up to 12 years. The study will compare patient self-report and provider AE reports and evaluate the associations of self-reported race/ethnicity and social determinants of health (SDOH)and post-progression/post-relapse OS. AHOD2131 strengthens the effort between the North American cooperative groups to conduct collaborative clinical trials and aims to harmonize an improved standard of care for ES cHL across the age continuum.