SUMMARY: The American Cancer Society estimates that in 2021, about 81,560 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,720 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphoma’s in the United States, and the incidence has steadily increased 3-4% each year. More than half of patients are 65 or older at the time of diagnosis and the incidence is likely to increase with the aging of the American population. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), UltraViolet radiation, pesticides, hair dyes, and diet.
DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using gene expression profiling: Germinal Center B-Cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher five year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless, R-CHOP regimen (RITUXAN®-Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL, regardless of molecular subtype.
MYC is a proto-oncogene and transcription factor and is rearranged in up to 15% of patients with DLBCL. MYC activation is an important adverse prognostic feature and results in aggressive cellular proliferation associated with DNA replication and transcription, protein synthesis, and altered cellular metabolism. BCL2 is a potent anti-apoptotic factor and dual rearrangement of MYC with BCL2 and less commonly, BCL6, occurs in 5% to 7% of cases of DLBCL. Further, both MYC and BCL2 proteins can be overexpressed, either with or without the underlying respective chromosomal rearrangements, in about 30% of patients with DLBCL.
The combination of MYC activation and anti-apoptosis (BCL2) results in a clinically aggressive phenotype called Double-Hit Lymphoma (DHL), which is associated with poor long-term survival after standard chemoimmunotherapy. Similar poor outcomes have been noted in patients with MYC activation along with BCL2, and BCL6 rearrangement, known as Triple Hit Lymphoma (THL).
The long term survival for patients with DHL or THL treated with R-CHOP is less than 20%. Patients are therefore often treated with more intensive regimens such as R-EPOCH (Rituximab, Etoposide, Prednisone, Vincristine, Cyclophosphamide, and Doxorubicin), although prospective data supporting the use of one regimen over another are limited.
The present study was conducted to compare Overall Survival of patients with advanced stage MYC-rearranged DLBCL and DHL/THL who were treated with R-CHOP versus R-EPOCH. The researchers analyzed de-identified data from a nationwide Flatiron Health Electronic Health Record database on patients diagnosed with DLBCL at 280 cancer clinics in the U.S. between January 2011, and June 2020. Among 6,809 total DLBCL patients, 443 (6.5%) were found to have MYC-rearranged DLBCL. Among these, 218 patients had advanced Stage (III/IV) disease at diagnosis, 64 patients had MYC-rearranged DLBCL only, and 117 and 37 had DHL or THL, respectively. Among those patients with DHL/THL, 43 patients (median age 73 years) were treated with R-CHOP and 111 patients (median age 67 years) received R-EPOCH. Among those with MYC-rearranged DLBCL only, 36 received R-CHOP (median age 70 years), and 28 received R-EPOCH (median age 61 years).
The investigators found no difference in the 4-year Overall Survival rates between the R-CHOP and R-EPOCH treatment arms in different patient groups. Among the MYC-rearranged DLBCL cohort, the 4-year Overall Survival rates were 32.8% with R-CHOP versus 30.4% with R-EPOCH regimens. In the DHL/THL group of patients, the 4-year Overall Survival rates were 54.5% with R-CHOP versus 49.6% with R-EPOCH. Among DHL/THL patient group, 89% of deaths occurred within 2 years of diagnosis, and among MYC- rearranged DLBCL, 78% of deaths occurred in the first 2 years. ECOG Performance Status score of 2 or more and elevated LDH were independently associated with worse mortality for these patients, by multivariate analysis.
It was concluded from this analysis that Overall Survival outcomes were similar between patients with MYC-rearranged Diffuse Large B-Cell Lymphoma and Double-Hit lymphoma/Triple-Hit Lymphoma (THL) who were treated with R-CHOP versus R-EPOCH. The authors suggested that further studies are needed to better risk stratify patients with DLBCL, for optimizing outcomes.
No difference in overall survival between R-CHOP and R-EPOCH among patients with advanced stage MYC-rearranged, double hit, or triple hit diffuse large B-cell lymphoma. Magnusson T, Narkhede M, Mehta A, et al. Abstract #S224. Presented at the EHA2021 Virtual Congress, June 9-17, 2021.