Adolescents and young adults (AYAs) with lymphoma are a unique population, with distinct biology, disparities in outcome, poorer survival compared with children and adults, and variable impacts of treatments. Ongoing research on this patient population with lymphoma will hopefully lead to improved understanding of this entity, better therapies, and improved outcomes, according to experts who spoke at the 2020 American Association for Cancer Research (AACR) Virtual Meeting: Advances in Malignant Lymphoma.1-3
Sonali M. Smith, MD, FASCO
“In general, AYAs with cancer—between the ages of 15 and 39—have an incidence of death that is six times higher than in children younger than age 14. Lymphomas in AYAs raise many challenges,” said Sonali M. Smith, MD, FASCO, Elwood V. Jensen Professor in Medicine, Interim Chief of Hematology/Oncology, and Director of the Lymphoma Program of the University of Chicago, who moderated the session.
Focusing on lymphomas in this patient population, Dr. Smith explained that the histology of Hodgkin lymphoma is different in AYAs than in children or adults, treatment regimens for lymphoma are varied, and health-related causes of mortality have not changed over recent decades. “Overall survival in AYAs with lymphoma continues to lag behind,” she stated.
According to Dr. Smith, issues to be addressed in this younger population of patients include finding opportunities for collaborative trials within the National Cancer Institute (NCI) Clinical Trials Network (NCTN), biologic differences into future clinical trials, improved understanding of lymphoma biology, and more accurate diagnoses and avoidance of overtreatment of pediatric-type peripheral lymphomas.
Awareness of Special Needs
Kara Kelly, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, New York, did a deeper dive into the special concerns of AYAs with lymphomas.1 “Many outstanding issues should be addressed, and we need increased awareness of the importance of research to improve the understanding of lymphomas in AYAs.
Several factors separate lymphomas in AYAs from those in children and adults. AYAs see less improvement in survival compared with other age groups. This has been termed the ‘AYA gap’ in survival,” Dr. Kelly stated. Factors that contribute to the AYA gap include biology of the tumor and the host, type of treatment, access to care, and toxicity.
Kara Kelly, MD
The distribution of lymphomas varies by age. Lymphomas account for about 20% of all cancers in AYAs. The most common type of lymphomas in AYA are precursor lymphomas, Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma, whereas follicular lymphoma is less common between the ages of 15 and 39.
“The survival differences in AYA lymphoma suggest differences in tumor and/or host biology,” Dr. Kelly said. “Vulnerabilities in this population extend beyond biology and can be addressed by expanding access to care and providing AYA-specific psychosocial support.”
Differences by race and age have been identified in lymphomas in AYAs. The incidence of follicular lymphoma is higher in Blacks at the younger end of the AYA spectrum, but it is significantly more prevalent in Whites at older ages. HL is more common in Whites than Hispanics in the age range of AYAs, but it is equally common in younger and older White and Hispanic patients.
“There is tremendous variation between pediatric and adult treatments for most lymphomas,” she noted. Factors that contribute to divergent paradigms for treatment include age, practice location, clinical trial participation, greater impact of survivorship research on pediatric patients, and better access to investigational agents for adults,” Dr. Kelly said. Participation in clinical trials is lower for AYAs than for those of other age groups. Reasons include concern about enrollment in trials, not enough information on the risks vs benefits for AYAs, and challenges to access.
In the past, trial options have been limited for patients younger than 18. The NCTN aims to address this problem. Currently, trials are underway in high-risk HL and primary mediastinal B-cell lymphoma.
Genomic Features of Hodgkin and Primary Mediastinal Lymphomas
Hodgkin and primary mediastinal lymphomas are the most common types of lymphoma in AYAs. Both types can present with mediastinal masses, and they have overlapping genomic features, explained Lisa Giulino-Roth, MD, of Weill-Cornell Medical Center, New York.2
“It is challenging to sequence Hodgkin lymphoma by standard methods, because the cells of interest [ie, Hodgkin Reed-Sternberg cells] are exceedingly rare in tumor biopsies.”— Lisa Giulino-Roth, MD
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“It is challenging to sequence HL by standard methods, because the cells of interest [ie, Hodgkin Reed-Sternberg cells] are exceedingly rare in tumor biopsies,” she explained.
Whole-exome sequencing has shown that the most common genetic alteration in classic HL is loss of beta-2 microglobulin (B2M), and a larger series identified B2M and HLA-B as relevant pathways. Transcriptome analysis shows that Hodgkin Reed-Sternberg cells cluster together in HL.
Primary mediastinal B-cell lymphoma is a distinct subtype that shares some features of HL. Common pathways altered in both types are associated with immune invasion; deletions in mutations on B2M; and alterations in PD-L1, PD-L2, the JAK pathway, and the nuclear factor kappa B pathway. “Some of these alterations are potentially targetable, and they may lead to opportunities to study novel agents in the AYA lymphoma population,” Dr. Giulino-Roth stated.
Two clinical trials have been developed for AYAs with lymphoma. One (study S1826) is evaluating nivolumab plus doxorubicin, vinblastine, and dacarbazine (AVD) vs brentuximab vedotin plus AVD in patients aged 12 and older with newly diagnosed advanced-stage classical HL. The other is COG ANHL 1931, a randomized phase III trial of nivolumab in combination with chemoimmunotherapy in newly diagnosed patients with primary mediastinal B-cell lymphoma with no age restriction.
Pediatric-Type Follicular Lymphoma
Follicular lymphoma typically occurs in the sixth or seventh decade of life, often with low-grade histology, although it can also present with high-grade histology. This type of lymphoma is much less common during childhood and young adulthood, explained Abner Louissaint, Jr, MD, PhD, of Massachusetts General Hospital, Boston.3
Pediatric-type follicular lymphoma is now a recognized—but uncommon—clinical entity. Over the past few years, common features of this type of lymphoma have been defined: It tends to occur more often in males, and it peaks in the second decade but can occur in 30- and 40-year-olds. Pediatric-type follicular lymphoma is limited stage, usually localized to the head and neck. It often appears to be of higher histologic grade than is typically seen in adults and lacks BCL2 expression.
“Pediatric-type follicular lymphoma stays localized. It mainly occurs on the head and neck and tends not to affect internal chains of lymph.”— Abner Louissaint, Jr, MD, PhD
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Since the original designation of pediatric-type follicular lymphoma as a clinical entity in 2008, further analyses of small series of patients showed it has an excellent prognosis with durable remissions regardless of the type of therapy, including excision alone. Pediatric-type follicular lymphoma is characterized by a high proliferation index and absence of BCL2/BCL6 and IRF4 rearrangements, Dr. Louissaint continued.
“It is important to be able to identify cases of pediatric-type follicular lymphoma to manage it appropriately,” he added.
Further studies characterized the molecular landscape of pediatric-type follicular lymphoma vs that of conventional follicular lymphoma. “Pediatric-type follicular lymphoma is genetically distinct from conventional follicular lymphoma in adults. The major distinction between the two is the presence of MAP kinase mutations in young adults and older patients with pediatric-type follicular lymphoma identical to those reported in Langerhans cell histiocytosis and melanoma,” explained Dr. Louissaint.
Other genetic abnormalities found in pediatric-type follicular lymphoma include deletions at 1p36 as well as at the TNFRSF14 gene locus. “These findings suggest that loss of TNFRSF14 function plays an important role in pediatric-type follicular lymphoma. The alterations seen in pediatric-type follicular lymphoma do not represent an early stage of conventional follicular lymphoma,” Dr. Louissaint said.
“Cases often have a blastoid appearance and appear to be of high grade, but grading is not used in cases of pediatric-type follicular lymphoma. When the diagnostic criteria for pediatric-type follicular lymphoma are met, we can be confident the outcome will be good and excision alone is all that is needed,” he continued.
During the discussion after his presentation, Dr. Louissaint said that, thus far, there have been no reports of pediatric-type follicular lymphoma transformation or progressive disease. “Pediatric-type follicular lymphoma stays localized. It mainly occurs on the head and neck and tends not to affect internal lymph node chains,” he noted.
There has been some suggestion that pediatric-type follicular lymphoma may be hereditary, but there are no data to support this theory. This is another area of potential interest for collaborative studies, commented Dr. Louissaint.
DISCLOSURE: Dr. Smith has served as a consultant or advisor to AbbVie/Genentech, Bayer, Celgene, Janssen Oncology, Kite Pharma, Seattle Genetics, and TG Therapeutics; has received research funding from Acerta Pharma/AstraZeneca, Celgene, Forty Seven, Novartis, Pharmacyclics/Janssen, Portola Pharmaceuticals, and TG Therapeutics; and has held other relationships with Karyopharm Therapeutics. Dr. Kelly has received institutional research funding from Merck and has been reimbursed for institutional travel, accommodations, or other expenses by Bristol Myers Squibb. Drs. Giulino-Roth and Louissaint reported no conflicts of interest.
1. Kelly K: AYA lymphomas: Bridging the divide. 2020 AACR Virtual Meeting: Advances in Malignant Lymphoma. Session 3. Presented August 17, 2020.
2. Giulino-Roth LG: Genomics of common AYA lymphomas: Hodgkin lymphoma and primary mediastinal B-cell lymphoma. 2020 AACR Virtual Meeting: Advances in Malignant Lymphoma. Session 3. Presented August 17, 2020.
3. Louissaint A: Unique features of pediatric-type familial lymphoma. 2020 AACR Virtual Meeting: Advances in Malignant Lymphoma. Session 3. Presented August 17, 2020.