Ann LaCasce, MD, MMSc
Background
Hodgkin lymphoma occurs in fewer than 9,000 individuals in the United States each year,1 but it is one of the most common types of cancer in AYAs.2 For the purposes of cHL, AYA is typically defined as an age range of 18 to 39 years, which covers the first of 2 bimodal peaks in incidence but stops short of the second.3,4 The first of these peaks occurs between the ages of 15 and 34 years, while the second begins at about age 55.5 Children younger than 15 years of age can also develop Hodgkin lymphoma, but it is less common.6
In AYAs and in adults, more than 90% of patients with Hodgkin lymphoma have cHL.7 Most AYAs present with the nodular sclerosis subtype, but cHL is managed differently in pediatric patients versus in adult centers.8,9 Evidence suggests that the specific risks of common treatment protocols, although similar, are not the same in AYAs as in adults.10,11 Even though the literature evaluating the presentation and management of AYA cHL has been growing since 2005, when the AYA Oncology Progress Review Group called for AYAs to be recognized
as a distinct group, clinical trials specific to AYA cHL remain limited.9
Major Hodgkin lymphoma guidelines only partially address AYAs as a distinct group. In guidelines issued by the National Cancer Institute, the differences in clinical presentation of AYAs are described for young children, AYAs, and older adults, but there are no treatment recommendations specific to AYAs.12 Guidelines from the EuroNet Paediatric Hodgkin Lymphoma Group offer recommendations for relapsed and refractory Hodgkin lymphoma, but do not differentiate between children and adolescents.13 The National Comprehensive Cancer Network (NCCN) provides separate treatment recommendations for patients 18 years or younger and those who are older than 18.14,15 For Hodgkin lymphoma, AYA is not addressed as a separate category even though the NCCN has provided general guidelines for treatment of malignancies in AYA.16
First-line therapies are effective in children, AYAs, and adults. Survival rates at 5 years have increased steadily, approaching or exceeding 90% across age groups even for patients with unfavorable risk characteristics.17 This success has permitted greater focus on developing strategies that preserve efficacy with lower acute and long-term risks.
Risk-Adapted Therapies
While the potential for new and novel therapies to reduce the risk of long-term toxicities continues to be explored, adjusting existing regimens to reduce these risks has proven to be a viable strategy. This adjustment is a standard of care in the pediatric setting based on results from such studies as German GPOH-HD 95, which suggested that doses of radiotherapy, a major contributor to late toxicities,18 can be omitted in patients with a complete response after chemotherapy.11 This pediatric trial contained both younger children and adolescents, but subsequent secondary analyses looking specifically at AYAs in this and other trials have suggested that efficacy is similarly preserved with risk-adapted strategies.9
However, due to AYA patients with cHL being treated using both pediatric and adult approaches, the persistent debate about optimal therapies in this age group complicates the effort to define a well-accepted strategy for risk adjustment. While risk-adapted strategies that rely on interim positron emission tomography (PET) to calibrate treatment intensity are now being used routinely across age stratifications, other initiatives are creating additional opportunities to gauge the impact on late effects in AYAs. These include strategies to improve collaboration across groups of trialists and data generated by observational cohorts, which can evaluate late effects not captured in time-limited clinical trials.
Among recent data supporting risk-adjusted therapy, the toxicity outcomes from a multicenter trial of PET-guided intensive treatment in patients with newly diagnosed advanced cHL were presented at the 2022 annual meeting of the American Society of Hematology.19 This phase 3 trial enrolled patients younger than 60 years, 79% of whom were younger than 45 years. Building on previous evidence that PET guidance improves the safety of eBEACOPP (escalated doses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), nearly 1,500 patients were randomized to this strategy or to PET-guided BrECADD, a modified eBEACOPP in which the antibody conjugate brentuximab vedotin (BV) was substituted for bleomycin. For an adjudicated endpoint of treatment-related morbidity, the experimental BrECAAD regimen reduced the risk by nearly 30% (hazard ratio [HR] 0.72). It is unclear whether this strategy will be used in the United States, where trials have been built on ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) rather than BEACOPP.
Efficacy data from this trial are not yet available, and these data will be important. There is concern that PET-directed therapy might result in lower toxicity at a cost of reduced rates of disease control. It is possible that the serious consequences of late toxicities—including infertility, compromised cardiovascular function, secondary cancers, and other organ damage—might need to be balanced against some loss of efficacy.
Novel Targeted Therapies
The goal of reducing late toxicities of cHL therapy in AYAs is also likely to be advanced by novel therapies. Research endeavors include a multicenter collaboration between US and Canadian investigators that is exploring the combination of nivolumab (a checkpoint inhibitor) plus BV.20 The trial recently completed accrual and includes both adult and pediatric patients. If novel agents prove effective for improving efficacy while reducing the risk of late complications in AYAs, they are expected to have a profound effect on clinical practice.
Arguably, the era of targeted and novel therapies in cHL was initiated more than 10 years ago with the introduction of BV for the treatment of advanced disease in older adults.21 BV was moved into the front line for patients 18 years of age or older with advanced cHL in a trial that compared the standard of ABVD to the same drugs with BV substituted for bleomycin.22 In this study, the BV-containing regimen was associated with a significantly improved progression-free survival (PFS) (P = .04) and a lower rate of adverse events, including pulmonary toxicity (1% vs 3%) after 2 years of follow-up.
A similar study recently associated a BV-containing regimen with even greater efficacy in pediatric high-risk cHL.23 In this multicenter study with 600 treatment-naïve patients ranging in age from 2 to 21 years, the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide was compared to the same regimen with BV substituted for bleomycin. With event-free survival as the primary endpoint, the experimental regimen was associated with a nearly 60% reduction in the risk of an adverse event or death (HR 0.41). However, no substantial differences were noted in toxicity after a follow-up of 42 months. It not yet clear whether the elimination of bleomycin will translate into less late toxicity, such as pulmonary or cardiovascular morbidity.
In the era of targeted therapies, the experience with BV has been a step toward more effective treatments using novel mechanisms of action to improve outcomes when used in the first-line treatment of patients with high-risk disease. Historically, many regimens and treatments that have demonstrated efficacy in relapsed and refractory cHL have found their way into the first-line setting. This trend might also be true of the checkpoint inhibitors, which have been tested extensively in relapsed/refractory cHL. In AYA patients with cHL, the rationale for these treatments might not only include a poor predicted response to current regimens, but a reduced risk of late toxicities if long-term follow-up demonstrates these treatments reduce late complications, such as secondary malignancies, which are associated with standard strategies, particularly those that include radiotherapy.
If targeted therapies do preserve efficacy and reduce risk of late complications, strategies to individualize therapy will remain relevant. Many of the emerging targeted therapies involve challenging and costly treatment protocols that demand selective application. Efforts to develop simpler and more precise biomarkers might streamline this task. Of promising developments in this area, cell-free DNA (cfDNA) appears to be near routine clinical application. A small study of cfDNA conducted in 121 patients found that minimal residual disease assessment by repeat cfDNA sequencing predicted response and PFS when performed as early as a week after treatment initiation.24 If larger studies confirm accuracy, this biomarker strategy might prove simpler and more convenient than PET imaging.
Summary
In the treatment of hematologic malignancies, cHL is widely regarded as a success story with high rates of extended survival among children, AYAs, and older adults. This level of success does not obviate the need for even more effective treatments, and also permits more attention to be directed to reducing the risk of late toxicities. For the AYA population, which represents a large group with cHL, the current directions of clinical research offer the promise of imminent changes in how the disease is controlled and a reduction in treatment-related late morbidity and mortality.