S8 EXABS-108-LYM Treatment Approach to AYA Patients With Lymphoma Ann LaCasce, MD, MMSc1,* 1Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, USA *Corresponding author: Ann_LaCasce@dfci.harvard.edu Keywords Classic Hodgkin lymphoma, primary mediastinal large B-cell lymphoma Introduction Although rare diseases, classic Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma (PMBCL) frequently present in adolescents and young adults (AYA). Given the long life expectancy for the majority of these patients, the efficacy of therapy must be balanced with risk of late toxicity. In addition, AYAs face unique challenges during their disease trajectory, including important psychosocial stressors that are critical to address. Classic Hodgkin Lymphoma CHL is most frequently diagnosed in patients between the ages of 20-34 with an overall incidence of approximately 8,500 cases per year.1 The therapy for classic Hodgkin lymphoma has evolved dramatically over the years from the use of primary radiotherapy, particularly in early-stage disease, to the introduction of combination chemotherapy and more recently to the incorporation of novel agents including brentuximab vedotin and PD-1 inhibitors. CHL is uniquely sensitive to PD-1 inhibition given the disease is characterized by copy gain and amplification of chromosome 9p24, leading to the overexpression of PDL-1 and PDL-2.2 Early-Stage Hodgkin Lymphoma In patients with stage I and II disease, PET (positron emission tomography) adapted approaches have facilitated the omission of radiotherapy in patients who achieve favorable early response. Late effects of radiotherapy include risk of second cancers, particularly breast cancer in young women under the age of 30 who receive mediastinal RT.3 In addition, radiotherapy is associated with cardiovascular disease including accelerated coronary artery, valvular and pericardial disease, as well as conduction system abnormalities.3 With novel radiotherapy approaches, including smaller fields and lower doses delivered using modern machines, the risks may decline over time, though several decades of follow-up will be necessary to assess the true impact. For patients with early-stage disease, including patients with unfavorable and even bulky disease, outcomes are excellent using PET adapted approaches. The vast majority of patients are PET 2 negative (Deauville scores of 1–3) after 2 cycles of ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine). Adult trials have studied various approaches, and in general, 2–4 additional cycles of ABVD or 4 cycles of AVD result in more than 90% of patients being disease free at 3 years.4–6 Outcomes in patients who are PET2 positive (Deauville 4–5) are less favorable, though escalation to BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) with the addition of radiotherapy results in improved progression free survival (PFS) compared to continuation of ABVD plus RT.4 A US and Canadian Intergroup trial led by the Children’s Oncology Group using a PET adapted approach after 2 cycles of ABVD recently opened and will randomize patients to standard therapy versus BV plus nivolumab. Advanced Stage Hodgkin Lymphoma In the US, over the past several decades until recently, ABVD in the adult setting and ABVEPC in the pediatric setting were standard of care. With the introduction of brentuximab vedotin (BV), BV-AVD is superior to ABVD in terms of progression free and overall survival.7,8 The recently published COG study AHOD 1331, BV-AVEPC yielded improved PFS compared to ABVEPC.9 Approximately 50% of patients, however, including those who had bulky disease or slow early response by PET, received consolidation with RT. In the combined US and Canadian adult and pediatric cooperative study comparing nivolumab plus AVD versus BV-AVD, early results demonstrate 1-year PFS of 94% vs 86% respectively in patients > age 12. Fewer than 1 % of patients received RT.10 This will likely become the standard of care in adult and pediatric patients with advanced stage disease in North America. Relapsed/Refractory Hodgkin Lymphoma With improvements in upfront therapy, the number of patients needing therapy for relapsed/refractory disease is declining from historical rates of 25-30%. Second line therapeutic options are moving away from standard chemotherapy to regimens incorporating PD-1 inhibitors with or without BV. For patients who are BV naïve, brentuximab plus nivolumab is highly active with high overall and complete response rates.11 More recently, a phase 2 study demonstrated excellent outcomes in patients treated with pembrolizumab plus gemcitabine/vinorelbine/doxil.12
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