Review Highlights Knowledge Gaps in Lymphoma Treatment Outcomes in AYAs

Short- and long-term treatment-related outcomes are of great importance among adolescents and young adults (AYAs) with lymphoma, but crucial research gaps remain despite progress in therapeutics for this patient population, according to a review published in eJHaem.

Lymphoma is the most common cancer in AYAs, with classic Hodgkin lymphoma, diffuse large B-cell lymphoma, and primary mediastinal large B-cell lymphoma being the most common subtypes of lymphoma in AYAs aged 15 to 39 years. These subtypes are therefore the most commonly studied subtypes in AYAs, and they are typically treated with curative intent. Still, treatment-related toxicities are a concern.

Blood cells | Image credit: Катерина Євтехова - stock.adobe.com

“The clinical management of lymphoma involves balancing the risk of relapse against acute as well as late toxicity and quality of life impact,” the authors wrote. “For AYAs with lymphoma, adverse effects (AEs) of treatment are particularly relevant because they have many decades of life after cancer diagnosis and treatment in which to experience them.”

The review summarized existing evidence around short- and long-term treatment-related toxicities among AYAs and gaps in care guidelines for AYA survivors of lymphoma, to provide insight into research needs and potential strategies to improve outcomes in this patient population.

AEs related to treatment are a key area of research in the AYA population, and the review authors call for a greater focus on characterizing the tolerability of lymphoma therapies rather than the safety of treatments as defined by AE incidence. The patient perspective on tolerability is particularly important, the authors noted.

“Many reports on the safety of novel therapies for lymphoma and other cancers include phrases, such as ‘the treatment was generally well tolerated,’ yet they have not incorporated the patient perspective on treatment tolerability, nor have they accounted for the time profile of AEs or the impact of chronic, low-grade AEs,” they wrote. While there may not be obvious safety signals when the burden of low-grade AEs is high, patients’ daily lives may be impacted by those AEs.

There is also a lack of standardization in the analysis of both AE and patient-reported outcome (PRO) data, according to the review authors. Ongoing efforts by US-based and international groups aim to address this roadblock, which has been a significant gap in understanding the tolerability of lymphoma treatments in AYAs. The authors highlighted the National Cancer Institute–funded AYA PRO initiative, which aims to include study-specific symptom assessments and targeted functional domains in clinical trials.

The review also highlights that most data on outcomes among AYAs with lymphoma are sourced from clinical trials with limited follow-up. With follow-ups commonly in the 5-year range, this leaves a gap in posttrial morbidity data at 5 to 15 years or longer, the authors noted. Even registry and health care utilization databases do not typically include complete data, so estimates of outcomes among AYA survivors of lymphoma require aggregating data, the authors argued. 

Long-term complications following lymphoma treatment are often explored, but the postacute setting is an area where further research is needed to inform clinical follow-up in the real world.

Patient Experience | Photo credit: wladimir1804 - stock.adobe.com

“Future work could include how to identify the patients at the highest risk for these types of events. Importantly, the follow-up time frame in this study is postacute, and longer follow-up data are needed to determine long-term risks for patients treated over the last two decades,” the authors wrote. A main outcome of interest for AYAs in this setting is the impact of treatment on fertility, which varies depending on treatment.

In the long term, past population-based research suggests an increased risk of death due to causes aside from cancer, including from treatment-related AEs, in lymphoma survivors, according to the authors. And while many new treatments have been developed in the past 25 years, the long-term safety of these treatments and their impact on patient quality of life require further research.

“In addition to observational studies, known dose-risk relationships for long-used components of treatment (radiation, anthracyclines, and alkylating agents) can be applied to contemporary protocol exposures to model the risk of late toxicity and quantify the potential benefits of different protocol modifications,” wrote the authors.

Finally, the review authors call for evidence-based, AYA-specific guidelines for lymphoma treatment. Although 2 consensus guidelines exist—the COG Long-Term Follow-up Guidelines, and the National Comprehensive Cancer Network guidelines—they lack concordance on the link between exposure to treatment and late effects in AYAs. This includes recommendations for screening survivors for cardiac toxicity, breast cancer, and neurocognitive deficits, which vary mostly due to limited evidence to support those practices, the authors noted.

“In summary, despite significant progress in therapeutics for the treatment of lymphoma in AYAs, there remain significant deficiencies in our understanding of short- and long-term toxicities, patient experience, and impact of lymphoma therapies on different aspects of quality of life,” the authors concluded. “There is a critical need for AYA-focused survivorship care guidelines and the application of PROs, as well as novel research methodology, such as multisource data aggregation and modeling to overcome the limitations of clinical trial data, especially for non-Hodgkin lymphoma.”

Reference
Pophali PA, Morton LM, Parsons SK, et al. Critical gaps in understanding treatment outcomes in adolescents and young adults with lymphoma: A review of current data. eJHaem. Published online August 25, 2023. doi:10.1002/jha2.778