SUMMARY Background Diffuse large-B-cell lymphoma (DLBCL) is curable but when treatment fails, outcome is poor. Imaging scans help identify patients at risk of treatment failure but are often imprecise, and the radiation exposure is a potential health risk. Specific, sensitive and readily available biomarkers of treatment failure are needed. Methods We retrospectively analyzed cell-free circulating tumor DNA (ctDNA) in patients treated on one of 3 treatment protocols using quantitative next-generation DNA sequencing. Eligible patients had DLBCL, no evidence of indolent lymphoma and were previously untreated. Serial serum samples and concurrent computed tomography scans were obtained at specified times during most treatment cycles and 5-years of follow-up. VDJ gene segments of the rearranged immunoglobulin receptor genes were amplified and sequenced from pre-treatment specimens and serum ctDNA encoding the VDJ rearrangements was quantitated. Findings Tumor clonotype(s) were identified in pretreatment specimens from 126 patients who were followed for a median (interquartile range) of 11 (6.8 to 14.2) years. Interim ctDNA monitoring at the end of 2 treatment cycles in 108 patients showed a time to progression (TTP) of 41.7% (95% Confidence Interval (CI): 22.2% to 60.1%) and 80.2% (95% CI: 69.6% to 87.3%), at 5-years (p<0.0001) in patients with and without detectable ctDNA, respectively, and a positive and negative predicative value (PPV and NPV) of 63% and 80%, respectively. Surveillance ctDNA monitoring was performed in 107 patients who achieved complete remission. A Cox proportional hazards model showed patients who developed detectable ctDNA during surveillance had a hazard ratio 228 times that of patients with undetectable ctDNA for clinical disease progression (95% CI: 51 to 1022) (p<0.0001). Surveillance ctDNA had a PPV and NPV of 88% and 98%, respectively, and identified recurrence a median (range) of 3.5 months (0 to 200) before evidence of clinical disease. Interpretation Surveillance ctDNA identifies patients at risk of recurrence before clinical evidence of disease in most patients and results in lower disease burden at relapse. Interim ctDNA is a promising biomarker to identify patients at high risk of treatment failure.

Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed distinct molecular subtypes that include germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. ABC DLBCL has a worse survival after upfront chemotherapy and is characterized by constitutive activation of the antiapoptotic nuclear factor-kappa B (NF-B) pathway, which can inhibit chemotherapy. We hypothesized that inhibition of NF-B might sensitize ABC but not GCB DLBCL to chemotherapy and improve outcome.As the proteasome inhibitor bortezomib can inhibit NF-B through blocking IB␣ degradation, we investigated bortezomib alone followed by bortezomib and doxorubicin-based chemotherapy in recurrent DLBCL. Tumor tissue was analyzed by gene expression profiling and/or immunohistochemistry to identify molecular DLBCL subtypes. As a control, we showed that relapsed/refractory ABC and GCB DLBCL have equally poor survivals after upfront chemotherapy. Bortezomib alone had no activity in DLBCL, but when combined with chemotherapy, it demonstrated a significantly higher response (83% vs 13%; P < .001) and median overall survival (

BACKGROUND Burkitt’s lymphoma is an aggressive B-cell lymphoma that occurs in children and adults and is largely curable with the use of intensive and toxic chemotherapy. Current treatments are less effective and have more severe side effects in adults and patients with immunodeficiency than in children. METHODS We studied low-intensity treatment consisting of infused etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (EPOCH-R) in patients with untreated Burkitt’s lymphoma. Two EPOCH-R regimens were tested: a standard dose-adjusted combination in human immunodeficiency virus (HIV)–negative patients (DA-EPOCH-R group) and a lower-dose short-course combination with a double dose of rituximab in HIV-positive patients (SC-EPOCH-RR group). RESULTS A total of 30 consecutive patients were treated; 19 patients were in the DA-EPOCH-R group, and 11 in the SC-EPOCH-RR group. The overall median age of the patients was 33 years, and 40% were 40 years of age or older; 73% of the patients had intermediate-risk disease, and 10% had high-risk disease. The principal toxic events, fever and neutropenia, were observed during 22% of the DA-EPOCH-R treatment cycles and 10% of the SC-EPOCH-RR treatment cycles. The tumor lysis syndrome developed in 1 patient; no treatment-related deaths occurred. The median cumulative doses of doxorubicin–etoposide and cyclophosphamide administered in the SC-EPOCH-RR group were 47% and 57% lower, respectively, than those administered in the DA-EPOCH-R group. With median follow-up times of 86 months in the DA-EPOCH-R group and 73 months in the SC-EPOCH-RR group, the rates of freedom from progression of disease and overall survival were, respectively, 95% and 100% with DA-EPOCH-R and 100% and 90% with SC-EPOCH-RR. None of the patients died from Burkitt’s lymphoma. CONCLUSIONS In this uncontrolled prospective study, low-intensity EPOCH-R–based treatment was highly effective in adults with sporadic or immunodeficiency-associated Burkitt’s lymphoma. (Funded by the National Cancer Institute; ClinicalTrials.gov numbers, NCT00001337 and NCT00006436.)