SUMMARY: The American Cancer Society estimates that in 2018, about 74,680 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,910 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.
Approximately 30-40% of patients experience disease progression or relapse, during the first 2 years and it is important to be able to predict which patients will need more aggressive intervention earlier. Circulating tumor DNA (ctDNA) is being increasingly used as a biomarker across various tumor types and the researchers have previously shown that ctDNA levels can predict tumor recurrence weeks or months before clinical symptoms arise, in patients with lung cancer.
The use of International Prognostic Index (IPI) and interim Positron Emission Tomography (PET) to select patients for intensified therapy, has failed to improve Overall Survival in patients with DLBCL. Several recent studies have suggested that for patients with DLBCL, the addition of pretreatment tumor genomic information to the established clinical prognostic tools such as the International Prognostic Index (IPI) score and interim positron emission tomography (PET) may greatly improve risk stratification. However, the association between the use of this risk stratification to select patients for more aggressive therapy and improvement in outcomes has remained unclear.
The authors in this study evaluated whether dynamic and serial measurements of circulating tumor DNA (ctDNA) from plasma of DLBCL patients had additional prognostic value for predicting patient outcomes, before and during therapy of Diffuse Large B-Cell Lymphoma, as the existing methods are unable to consistently predict treatment failure, given the heterogeneity of DLBCL.
The researchers measured ctDNA from 217 patients with DLBCL or Primary Mediastinal B-cell Lymphoma at six centers in the US and Europe using CAPP-Seq (Cancer Personalized Profiling by deep sequencing ) methodology and compared levels of ctDNA before treatment with levels after the first and second cycles of conventional chemotherapy for each patient. CAPP-Seq is a form of targeted deep next-generation sequencing invented by these authors. They applied deep sequencing of genes for mutational genotyping and tracking of mutations before and during therapy for predicting Event Free Survival (EFS) at 24 months as well as Overall Survival (OS). Using this method, 99% of patients had at least one tumor-specific alteration detected for monitoring, and 98% had ctDNA prior to therapy. Further, the researchers also assessed the prognostic value of ctDNA in the context of established risk factors, including the International Prognostic Index and interim Positron Emission Tomography/Computed Tomography scans.
It was noted that Pretreatment ctDNA levels were prognostic in both the frontline and the relapsed setting. A two-log (i.e., 100-fold) decrease in ctDNA between pretreatment samples and end of cycle 1 of therapy (Early Molecular Response-EMR) or a 2.5-log drop in ctDNA between pretreatment samples and end of cycle 3 of therapy (Major Molecular Response-MMR) was associated with a substantially higher likelihood of cure, independent of the IPI score, in the multivariate analysis. Early Molecular Response and Major Molecular Response were concordant in 92% of patients in whom both were evaluable.
The 24-month Event Free Survival among patients receiving frontline therapy who experienced an Early Molecular Response was 83% vs. 50% (P=0.0015) and for those who experienced a Major Molecular Response was 82% vs. 46% (P<0.001). Early Molecular Response also predicted superior 24-month EFS among patients receiving salvage therapy (100% vs. 13%; P =0.011).
The molecular responses as defined by the drop in ctDNA levels, when correlated with established risk factors such as IPI and interim PET/CT scans, remained prognostic for EFS and OS in patients with low or high IPI, as well as in the context of interim PET/CT. It was noted that patients with favorable results for both molecular response and interim PET had excellent outcomes, whereas those with a combination of a positive interim PET scan and no molecular response were at extremely high risk for treatment failure.
It was concluded that pretreatment ctDNA levels and molecular responses are independently prognostic of outcomes in DLBCL. ctDNA could be used as a risk stratification tool and those who do not have a rapid drop in the ctDNA levels ( within 21 days after the initiation of treatment) may be candidates for more aggressive or novel therapies. More importantly standardization of the available assays for molecular monitoring in DLBCL will be necessary. Circulating Tumor DNA Measurements As Early Outcome Predictors in Diffuse Large B-Cell Lymphoma. Kurtz DM, Scherer F, Jin MC, et al. J Clin Oncol. 2018 Oct 1;36(28):2845-2853. doi: 10.1200/JCO.2018.78.5246. Epub 2018 Aug 20.