Summary Background Diffuse large-B-cell lymphoma is curable, but when treatment fails, outcome is poor. Although imaging can help to identify patients at risk of treatment failure, they are often ...imprecise, and radiation exposure is a potential health risk. We aimed to assess whether circulating tumour DNA encoding the clonal immunoglobulin gene sequence could be detected in the serum of patients with diffuse large-B-cell lymphoma and used to predict clinical disease recurrence after frontline treatment. Methods We used next-generation DNA sequencing to retrospectively analyse cell-free circulating tumour DNA in patients assigned to one of three treatment protocols between May 8, 1993, and June 6, 2013. Eligible patients had diffuse large-B-cell lymphoma, no evidence of indolent lymphoma, and were previously untreated. We obtained serial serum samples and concurrent CT scans at specified times during most treatment cycles and up to 5 years of follow-up. VDJ gene segments of the rearranged immunoglobulin receptor genes were amplified and sequenced from pretreatment specimens and serum circulating tumour DNA encoding the VDJ rearrangements was quantitated. Findings Tumour clonotypes were identified in pretreatment specimens from 126 patients who were followed up for a median of 11 years (IQR 6·8–14·2). Interim monitoring of circulating tumour DNA at the end of two treatment cycles in 108 patients showed a 5-year time to progression of 41·7% (95% CI 22·2–60·1) in patients with detectable circulating tumour DNA and 80·2% (69·6–87·3) in those without detectable circulating tumour DNA (p<0·0001). Detectable interim circulating tumour DNA had a positive predictive value of 62·5% (95% CI 40·6–81·2) and a negative predictive value of 79·8% (69·6–87·8). Surveillance monitoring of circulating tumour DNA was done in 107 patients who achieved complete remission. A Cox proportional hazards model showed that the hazard ratio for clinical disease progression was 228 (95% CI 51–1022) for patients who developed detectable circulating tumour DNA during surveillance compared with patients with undetectable circulating tumour DNA (p<0·0001). Surveillance circulating tumour DNA had a positive predictive value of 88·2% (95% CI 63·6–98·5) and a negative predictive value of 97·8% (92·2–99·7) and identified risk of recurrence at a median of 3·5 months (range 0–200) before evidence of clinical disease. Interpretation Surveillance circulating tumour DNA identifies patients at risk of recurrence before clinical evidence of disease in most patients and results in a reduced disease burden at relapse. Interim circulating tumour DNA is a promising biomarker to identify patients at high risk of treatment failure. Funding National Cancer Institute and Adaptive Biotechnologies.
Abstract Since the incorporation of tyrosine kinase inhibitors into the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), the notion that all patients with ...“high-risk” ALL uniformly require allogeneic hematopoietic cell transplantation (alloHCT) has received increasing scrutiny. Although multiple studies have shown superiority of alloHCT over autologous hematopoietic cell transplantation (autoHCT) for “high-risk” patients, these findings may be explained, in part, by contamination of the peripheral blood progenitor cell (PBPC) leukapheresis product by residual leukemic cells in patients undergoing autoHCT. We retrospectively evaluated minimal residual disease (MRD) using next-generation sequencing (NGS) (Adaptive Biotechnologies Corp., South San Francisco, CA) in the PBPC leukapheresis product of 32 ALL patients who underwent autoHCT. Twenty-eight patients (88%) had diagnostic samples with quantifiable immunoreceptor rearrangements to follow for MRD. Twelve (38%) patients had Ph+ B-ALL, 12 (38%) had Ph-negative (Ph-) B-ALL, and 4 (14%) had T-cell ALL. With a median follow-up of 41 months (range 3-217), median relapse-free survival (RFS) and overall survival (OS) for the entire cohort are 3.2 and 4.2 years, respectively; at 5 years post-transplant, 42% of patients remain alive and relapse-free. Using MRD detection at a threshold of ≥1x10-6 , median RFS for patients with detectable MRD is 6.5 months, and is not reached for patients without detectable disease ( p=0.0005). In multivariate analysis, the only factor significantly associated with relapse was the presence of MRD ≥1x10-6 (OR 23.8, CI 1.8-312.9, p=0.0158). Our findings suggest that NGS for MRD detection can predict long-term RFS in patients undergoing autoHCT for high-risk ALL.
Chronic wasting disease (CWD), a prion disease affecting free-ranging and captive cervids (deer and elk), is widespread in the United States and parts of Canada. The large cervid population, the ...popularity of venison consumption, and the apparent spread of the CWD epidemic are likely resulting in increased human exposure to CWD in the United States. Whether CWD is transmissible to humans, as has been shown for bovine spongiform encephalopathy (the prion disease of cattle), is unknown. We generated transgenic mice expressing the elk or human prion protein (PrP) in a PrP-null background. After intracerebral inoculation with elk CWD prion, two lines of "humanized" transgenic mice that are susceptible to human prions failed to develop the hallmarks of prion diseases after >657 and >756 d, respectively, whereas the "cervidized" transgenic mice became infected after 118-142 d. These data indicate that there is a substantial species barrier for transmission of elk CWD to humans.
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