Roth, Lisa

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.

Background: cHL is one of the most curable forms of childhood cancer, but patients (pts) who have a SER to initial chemo are at high risk of relapse. The approaches currently used to treat pts with SER, such as dose intensification and radiotherapy (RT), can cause long-term toxicity.An unmet need remains to optimize treatment in pts with cHL and SER while minimizing long-term toxicity. The open-label, phase 2 KEYNOTE-667 study (NCT03407144) is being conducted to evaluate the efficacy and safety of pembro plus chemo in pediatric pts with cHL and SER to front-line chemo. Early analysis of pts in KEYNOTE-667 with high-risk cHL showed that pembro plus cyclophosphamide, vincristine, prednisone/prednisolone, and dacarbazine (COPDAC-28) consolidation had manageable safety and promising antitumor activity, with 66% of pts being spared RT. We present updated results for pts with high-risk cHL and SER. Methods: Pts eligible for the high-risk group were 3-25 y old and had newly diagnosed stage IIEB, IIIEA, IIIEB, IIIB, IVA, or IVB cHL, measurable disease per investigator assessment, and a Lansky Play-Performance Scale ≥50 (<16 y old) or a Karnofsky score ≥50 (≥16 y old). All pts received 2 cycles of induction therapy with vincristine, etoposide, prednisone/prednisolone, and doxorubicin (OEPA). After induction, response was assessed by PET/MRI/CT (early response assessment). Pts with rapid early response received nonstudy therapy. Pts with SER (Deauville score, 4 or 5) received consolidation with pembro 2 mg/kg up to 200 mg IV Q3W (3-17 y) or 200 mg IV Q3W (18-25 y) plus 4 cycles of COPDAC-28. Response was then assessed by PET/CT/MRI (late response assessment [LRA]). Pts with PET positivity at LRA (Deauville score, 4 or 5) received involved-site RT (28.8 Gy) to late PET-positive residua plus maintenance pembro Q3W for up to 17 cycles; pts with PET negativity received maintenance pembro Q3W for up to 17 cycles without RT. The primary end point was ORR by BICR per Cheson 2007 IWG criteria in pts with SER, determined at any time after starting pembro and before start of new anticancer therapy. Secondary end points included PET negativity after consolidation, EFS, OS, and safety. Results: This analysis included 62 pts with high-risk cHL and SER to frontline OEPA. The median time from enrollment to data cutoff (March 1, 2023) was 16.8 mo (range, 2.3-36.4). At the data cutoff, 34 pts (55%) had completed consolidation and maintenance therapy, 23 (37%) were ongoing on treatment, and 5 (8%) had discontinued because of adverse events (AEs; n = 1), progressive disease (n = 2), or withdrawal by pt (n = 2). Median age was 14 y (range, 5-22), 30 pts (48%) were male, 29 (47%) had bulky disease, and 41 (66%) had Ann Arbor stage IV disease. Pts had received a median of 17 administrations of pembro (range, 1-17); the median time on pembro was 11.0 mo (range, <0.1-11.8). Of 62 pts who received consolidation with pembro plus COPDAC-28, 53 (85%) had a LRA (9 are still in consolidation and have not reached the LRA time point), of whom 35 (66%) were PET negative by BICR (37 [70%] PET negative by investigator review). AEs regardless of causality that occurred during consolidation and maintenance were reported in 54 pts (87%), most commonly (≥15%) headache (n = 11; 18%), nausea (n = 11; 18%), cough (n = 10; 16%), COVID-19 (n = 10; 16%), and pyrexia (n = 10; 16%). Grade 3/4 AEs occurred in 21 pts (34%). 13 pts (21%) had a serious AE. No pts died because of AEs. Treatment-related AEs occurred in 38 pts (61%). Grade 3/4 treatment-related AEs occurred in 10 pts (16%). One pt (2%) discontinued treatment because of a treatment-related AE (grade 3 AST increased). Pembro-related AEs occurred in 23 (37%) pts; most commonly (≥5%) hypothyroidism (n = 4; 6%), nausea (n = 3; 5%), and ALT increased (n = 3; 5%). Three pts (5%) experienced grade 3/4 pembro-related AEs. One serious AE was related to pembro (abdominal pain). Six pts (10%) experienced immune-mediated AEs (hypothyroidism, n = 4 [2 grade 1, 2 grade 2]; colitis, n = 1 [grade 2]; pneumonitis, n = 1 [grade 2]). Conclusion: In this updated analysis, consolidation with pembro plus COPDAC-28 continued to have manageable safety and promising antitumor activity in pediatric pts with high-risk cHL and SER to front-line OEPA. Of pts with a LRA, 66% had a PET-negative response and were spared RT. These findings support the results of prior analyses and suggest that adding pembro to COPDAC-28 consolidation may augment responses in the high-risk cHL population.

Background: Pediatric patients (pts) with low-risk cHL achieve high cure rates with standard chemo. However, those with a SER to front-line chemo are at higher risk of relapse than pts with a rapid early response (RER). Current treatment options are also associated with long-term toxicities such as secondary malignancies, cardiovascular disease, and pulmonary and gonadal toxicity. Novel treatment approaches are needed to optimize outcomes while minimizing long-term toxicity. KEYNOTE-667 (NCT03407144) is an open-label, phase 2 study that included an analysis of safety and efficacy of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) induction in pediatric pts with low-risk cHL followed by consolidation with pembro plus AVD and involved-site radiotherapy (ISRT) and pembro maintenance in those with SER to front-line ABVD. We present an interim analysis of pts with low-risk cHL enrolled in this trial. Methods: Eligible pts were 3-25 y old and had newly diagnosed stage IA, IB, or IIA cHL without bulky disease, measurable disease per investigator assessment, and a Lansky Play-Performance Scale ≥50 (aged <16 y) or a Karnofsky score of ≥50 (aged ≥16 y). Pts initially received 2 cycles of induction with ABVD. Response was then assessed by PET/MRI/CT (early response assessment). Pts with RER received nonstudy therapy per treating physician. Pts with SER (Deauville score [DS], 4 or 5) received consolidation with pembro 2 mg/kg up to 200 mg IV Q3W (3-17 y) or 200 mg IV Q3W (18-25 y) in combination with 2 cycles of AVD followed by a late response assessment (LRA) with PET/MRI/CT. All pts with a SER then received ISRT (21.6 Gy for pts with a complete PET response [DS, 1-3]; 30.6-36 Gy for pts with a partial PET response [DS, 4 or 5]) plus maintenance pembro Q3W for up to 17 cycles. Primary end point was ORR by blinded independent central review (BICR) per Cheson 2007 IWG criteria in pts with SER determined at any time after starting pembro and before start of new anticancer therapy. Secondary end points included rate of PET negativity after consolidation, EFS, OS, and safety. Results: 73 pts with low-risk cHL were enrolled, 9 of whom had SER to ABVD induction. 64 pts had a RER and received nonstudy treatment. At data cutoff (March 1, 2023), 2 of 9 pts (22%) with SER had completed consolidation and maintenance therapy, 5 (56%) were ongoing, and 2 (22%) had discontinued, both because of complete response. Median time from enrollment to data cutoff was 8.7 mo (range, 2.2-32.9). Median age was 16 y (range, 7-20), 5 pts (56%) were male, 2 (22%) had Ann Arbor stage I disease, and 7 (78%) had Ann Arbor stage II disease. Pts with SER had received a median of 8 doses of pembro (range, 1-17); median time on pembro was 4.8 mo (range, <0.1-11.3). Of 9 pts who received consolidation therapy with pembro plus AVD, 6 (67%) had a LRA (3 are still in consolidation and have not reached the LRA timepoint), of whom 3 (50%) were PET negative by BICR (2 [33%] were PET negative by investigator review). Of 73 pts who received ABVD induction, 66 (90%) had an AE regardless of causality. 33 pts (45%) experienced grade 3/4 AEs, most commonly (≥10%) neutrophil count decreased (n = 19; 26%) and neutropenia (n = 9; 12.3%). One pt experienced grade 4 febrile neutropenia. Twelve pts (16%) had serious AEs. No pts discontinued treatment or died because of AEs. Treatment-related AEs due to ABVD induction occurred in 59 pts (81%), with grade 3/4 events in 31 (42%). Of the 9 pts with SER to ABVD induction who received consolidation and maintenance therapy, 7 (78%) experienced an AE regardless of causality. Two pts (22%) had grade 3/4 AEs. No serious AEs were reported during consolidation and maintenance therapy, and no pts discontinued treatment or died because of AEs. Treatment-related AEs occurred in 6 pts (67%) who received consolidation and maintenance therapy; with grade 3/4 events in 2 pts (22%). Six pts (67%) experienced AEs related to pembro; most commonly (≥3 pts) anemia, nausea, vomiting (n = 3 each [33%]). Two pts experienced grade 3/4 AEs related to pembro (vomiting, white blood cell count decreased). One pt (11%) experienced an immune-mediated AE (grade 2 hyperthyroidism). Conclusion: Early results from the low-risk cHL cohort of KEYNOTE-667 suggest that induction therapy with ABVD and consolidation with pembro plus AVD had a manageable safety profile. Among the relatively small number of pts with a SER to ABVD, 50% with a LRA had a PET-negative response by BICR and received a reduced dose of RT.

Abstract BACKGROUND: Burkitt lymphoma (BL) represents approximately 40% of all childhood and adolescent non-Hodgkin lymphoma (Miles/Cairo, BJH, 2012). Children with relapsed or progressive BL develop chemotherapy-resistant disease and can rarely be cured with salvage therapy (Cairo et al, JCO, 2012). Bruton's tyrosine kinase (BTK) is a regulator of normal B-cell development and is activated upon B-cell receptor (BCR) stimulation. Chronic active BCR signaling through BTK activation can be inhibited by the selective and covalent BTK inhibitor, ibrutinib (Young et al, Nat Rev, 2013). Ibrutinib has been highly effective in the treatment of refractory patients with CLL and MCL and has been approved by the FDA for patients with CLL or MCL who have received at least one prior therapy (USPI) (Byrd et al, NEJM, 2013 and Wang et al, NEJM, 2013). BL, however, is associated with tonic or possibly chronic active BCR signaling; while, both CLL and MCL have chronic active BCR signaling. We have previously demonstrated ibrutinib significantly decrease BL proliferation and viability in vitro (Lee/Cairo et al, ASH, 2014) OBJECTIVE: We hypothesize that ibrutinib may be a potential adjuvant agent in the treatment of BL. Therefore, we investigated the in vivo anti-tumor activity of ibrutinib in BL xenografted NOD/SCID (NSG) mice. METHODS: The luciferase expression plasmid (ffluc-Zeo), kindly provided by L. Cooper, MD) was transfected into Raji cells. Cells were subcutaneously injected into NSG mice (6-8wks old, NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ, Jackson lab). Tumor cells engraftment and progression were examined by Bioluminescent Imaging using the Xenogen IVIS-200 (Caliper Life Sciences). Mice were orally gavaged with vehicle control or Ibrutinib (1.25, 12.5 and 25mg/kg/day, generously provided by Janssen R&D, LLC) for 10 days. Statistical probability of survival and curve were determined by Kaplan Meier method. RESULTS: We observed a significant decrease in tumor luminescence intensity following ibrutinib treated BL xenografted NSG mice at day 20 (12.5mg/kg, p<0.001 and 25mg/kg, p<0.05) and at day 25 (12.5mg/kg, p<0.05 and 25mg/kg, p<0.05) compared to vehicle control. Furthermore, ibrutinib (12.5 mg/kg) treated mice significantly prolonged survival compared to vehicle control mice (p<0.05). The median survival of mice following ibrutinib treatment (1.25, 12.5 and 25 mg/kg) were 31.5, 37.5 and 22.5 days, respectively, compared to control (24 days). CONCLUSIONS: Ibrutinib significantly decreased tumor progression and significantly increased the survival in BL xenografted NSG mice following 12.5mg/kg ibrutinib treatment. These results indicate that ibrutinib may be a potential adjuvant agent therapy in the treatment of BL. Future directions will be investigated the efficacy of ibrutinib in combination with dexamethasone in BL xenografted NSG mice. Citation Format: Sanghoon Lee, Changhong Yin, Timmy O'Connell, Matthew Barth, Janet Ayello, Lauren Harrison, Carmella van de Ven, Rodney Miles, Paul Galardy, Stanton C. Goldman, Megan Lim, Michelle Hermiston, Linda McAllister-Lucas, Lisa G. Roth, Sherrie L. Perkins, Mitchell S. Cairo. Ibrutinib significantly improves survival in a human Burkitt lymphoma (BL) xenograft NSG mouse model: Ibrutinib may be a potential adjuvant agent in the treatment of BL. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2608. doi:10.1158/1538-7445.AM2015-2608