Mantle cell lymphoma from the image bank of the American Society of Hematology.
Several factors contribute to the higher rate of mantle cell lymphoma at the VA. One is that the patient population is primarily older and male. Further, development of MCL in veterans exposed to Agent Orange or to contaminants in the water at the Marine Corps Base at Camp Lejeune, NC, between August 1953 and December 1987 is presumed to be service connected. Even at the VA, however, choosing the right therapy for MCL poses a challenge as a result of its highly heterogeneous nature.
ST. LOUIS — As the nation’s largest integrated healthcare system, the VA provides clinicians the opportunity to diagnose and treat an unusual range of rare diseases. For oncologists, working at the VA often means exposure to types of cancer many colleagues may never encounter.
Mantle cell lymphoma is one such malignancy. Accounting for approximately 6% of all non-Hodgkin lymphomas or 0.24% of all cancers, mantle cell lymphoma has only been recognized as a separate disease in the last 25 years. While its incidence in the United States is generally estimated to be 0.5 to 0.8 in 100,000, some research indicates that the incidence may be up to four times higher in the VA.
Several factors contribute to the higher rate in the VA. Mantle cell lymphoma (MCL) primarily occurs in individuals over the age of 60, with an average age of diagnosis of 68, and three-quarters of patients are male, largely paralleling the population served by the VA. Further, development of MCL in veterans exposed to Agent Orange or to contaminants in the water at the Marine Corps Base at Camp Lejeune, NC, between August 1953 and December 1987 is presumed to be service connected.
Even at the VA, however, choosing the right therapy for MCL poses a challenge as a result of its highly heterogeneous nature. For some patients, the disease proves very aggressive, with overall survival of a few months without treatment. For patients with a low disease burden and no symptoms, who represent 10% to 15% of all cases, close observation may be sufficient for years, according to Brad Kahl, MD, professor of medicine and director of the lymphoma program at Washington University School of Medicine In St. Louis.1
The rapidly expanding number of therapies for MCL also complicates treatment. The National Comprehensive Cancer Network (NCCN) guidelines updated in March 2021 lists five preferred induction therapy regimens for aggressive treatment, four for less aggressive treatment, with another three recommended first-line regimens. In the second line, NCCN includes four preferred regimens and nine that could be useful in certain circumstances. The third line offers an additional therapy.
The last year has seen significant progress in resolving some issues in determining the aggressiveness of a patient’s MCL and the best option for treatment as a result of advances in the genomic characterization of the disease.
Defining Genomic Types
These development build on the initial recognition that overproduction of cyclin D1 (CCND1) in lymphoma cells caused by chromosomal t(11;14)(q13;q32) translocation is the primary signature of MCL. In rare cases, overproduction of cyclin D2 or cyclin D3 caused by CCND2/CCND3 rearrangements or cyclin E dysregulation may occur instead.
More recently, MCL has been seen as comprising two distinct types. The more aggressive nodal form presents with unmutated Ig heavy chain variable region (IGHV) genes and over expression of the sex-determining region Y-box 11 (SOX11) and encompasses 80% to 90% of cases. A non-nodal form, which is typically indolent, has mutated IGHV genes and does not over express SOX11.2
SOX11 expression affects B-cell receptor (BCR) signaling as well as regulation of B-cell lymphoma 6 (BCL6), paired box 5 (PAX5) and B-lymphocyte-induced maturation protein 1 (BLIMP1) expression and other pathways.
“Better understanding of the biological mechanisms of disease initiation and progression and the complex interplay of the components involved in BCR signaling lead to the detection of multiple molecules as potential druggable targets for MCL therapy and have already paved the way for the development and clinical introduction of targeted treatment alternatives such as temsirolimus, ibrutinib, lenalidomide and bortezomib,” said Elisabeth Silkenstedt, MD, of the LMU Hospital in Munich, and her colleagues in a review of recent advances in mantle cell lymphoma.
Genomic profiling has also found multiple other genetic alterations and recurrent mutations involved in cell cycle, DNA damage response, and apoptosis pathways that influence the aggressiveness of MCL. The large number of mutations is unsurprising given that “MCL has one of the highest levels of genomic instability among the malignant lymphoid neoplasms,” noted Sikenstedt and her co-authors. Further, a larger number of driver genetic alterations is associated with more aggressive MCL.
In a presentation at the 2020 American Society of Hematology annual meeting, Yuting Yan,PhD, of the City of Hope in Duarte, CA., and the National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China, and her colleagues outlined a more detailed genomic profiling of MCL.3
Their work identified four distinct subtypes of MCL based on clonal status of genetic lesions and the pattern of clonal evolution. “Patients with extreme evolution had inferior survival than those with modest and no evolution (median survival from first sampling was 47.5 months vs. not reached, p=0.041, second sampling was 17.1 months vs not reached, p=0.023),” they noted.
Each of their subtypes had its own distinct gene expression profile and clinical behavior. Cluster 1 had the previously described mutated IGHV, CCND1 mutation, amp(11q13) and active BCR signaling seen in the more indolent, non-nodal MCL. Cluster 2 “was enriched with del (11q22), del (1p21), ATM mutation and had up regulation of genes involved in the NF-kB and DNA repair pathways while C3 was characterized by mutations in SP140, NOTCH1 and NSD2 and down regulation of gene expression in the NF-kB, BCR signaling, MYC and inflammatory pathways,” Yan and colleagues said.
The last cluster displayed the greatest incidence of blastoid or pleomorphic MCL as well as del(17p), del(13q), del(9p) and mutations in TP53 and TRAF2. It also demonstrated enrichment of MYC pathway activation and hyperproliferation signatures.
Each grouping had clearly differentiated survival. Median progression free survival in cluster 1 was not reached, while it was 41.2 months for cluster 2, 30.7 months for cluster 3 and 16.1 months for cluster 4.
- Treatment Update on Mantle Cell Lymphoma (MCL). CancerCare Connect Workshop. June 4, 2020.
- Silkenstedt E, Linton K, Dreyling M. Mantle cell lymphoma – advances in molecular biology, prognostication and treatment approaches. Br J Haematol. 2021 Mar 30. doi: 10.1111/bjh.17419. Epub ahead of print. PMID: 33783838.
- Yan Y, Lv R, Xiong W, Li Z, Wang Y, Yu Y, Yu Z, Wang T, Sui W, Liu W, Zou D, Yi S, Qiu L. Genomic and Transcriptomic Profiling Reveals Distinct Subsets Associated with Outcomes in Mantle Cell Lymphoma. Blood. 2020:(136)28-29. doi:10.1182/blood-2020-139955.