Mantle cell lymphoma (MCL) is biologically and clinically heterogeneous and would benefit from prognostic biomarkers to guide management. Circulating tumor DNA (ctDNA) is a novel prognostic biomarker in diffuse large B-cell lymphoma that may have applicability in MCL. We analyzed ctDNA dynamics in previously untreated patients with MCL who received induction therapy with bortezomib and DA-EPOCH-R for 6 cycles followed by random assignment to observation or bortezomib maintenance in responding patients in a prospective phase 2 study. Most patients also underwent initial treatment window of bortezomib alone prior to induction. Serum was collected pretreatment, after the window, after cycles 1 and 2, at the end of induction, and at each follow-up visit along with restaging computed tomography scans. Next-generation sequencing was used to identify and quantify ctDNA encoding the immunoglobulin receptor sequences in serum as markers of minimal residual disease. Fifty-three patients were enrolled, with a median follow-up of 12.7 years. Patients without detectable ctDNA after 2 cycles of induction had longer progression-free survival (PFS) and overall survival (OS) compared with those with detectable ctDNA (median PFS, 2.7 vs 1.8 years; overall P = .005; median OS, 13.8 vs 7.4 years; overall P = .03). Notably, in vivo assessment of ctDNA dynamics during the bortezomib window was not prognostic, and there was no difference in PFS or OS with bortezomib maintenance. ctDNA monitoring after induction showed that molecular relapse preceded clinical relapse in some cases. In conclusion, interim ctDNA negativity strongly correlates with improved survival and supports the investigation of response-adapted strategies. This trial was registered at www.clinicaltrials.gov as #NCT00114738.
In recent years, advances have been made in methods to assess response to therapy in lymphoma. Ideally, response assessment tools should be highly sensitive and specific for identifying a disease, should carry a minimal risk of harm to the patient, and should provide reproducible results. Traditional surveillance methods have included clinical assessment and, in many cases, routine surveillance imaging. Minimal residual disease (MRD) refers to the detection of disease level below that of these traditional surveillance methods. Either circulating tumor cells or their nucleic acid fragments released from necrotic/apoptotic cells can be measured in circulating peripheral blood, referred to as circulating tumor DNA (ctDNA). ctDNA can be detected with allele-specific polymerase chain reaction (ASO-PCR) or with next-generation sequencing (NGS) techniques. The use of ctDNA as a monitoring strategy in lymphoma can aid in assessment of disease burden, as well as prognostication, customization of therapy ("risk-adapted" strategies), monitoring for relapse, and consideration of early intervention ("preemptive" strategies), while reducing radiation exposure from surveillance imaging modalities that are presently used. In this review, we discuss the current state of the art in ctDNA measurement, as well as the clinical data supporting its potential utility in the management of lymphoma patients.
Background: Benign ethnic neutropenia (BEN), defined by neutrophil count less than 1·5 k/uL in the absence of other causes, is an asymptomatic condition more commonly observed in individuals of African ancestry. However, the natural history of this condition has been less well described. Methods: Individuals with BEN were retrospectively identified by chart review or referral to hematology clinics. They were then invited to enroll in a prospective natural history study. Retrospective and prospective clinical and laboratory data were combined for descriptive analyses. Findings: 46 participants, younger and older adults from 2 institutions, had BEN. Hypertension was reported in 30%, musculoskeletal disorders in 15%, and upper respiratory infection in 33% of these adults. Their leukopenia resulted from isolated neutropenia, ranging from 1000 and 1500 cells/uL. The severity of infections was mild and the frequency was similar to other healthy individuals in the ambulatory clinic. Interpretation: In this group of BEN participants, their leukopenia was stable over time, and they had low rates of infections or common medical disorders, confirming the benign nature of this condition. The presence of BEN in children, younger adults, and older adults suggest a hereditary pattern for BEN. Funding Statement: This work is supported in part by the intramural research program of the National Institute of Diabetes, Digestive, and Kidney Diseases and the National Heart, Lung, and Blood Institute.Declaration of Interests:Rahul Lakhotia – noneAnita Aggarwal - noneMary E Link - noneGriffin P Rodgers - noneMatthew M Hsieh – noneEthics Approval Statement: Both studies were approved by local institutional review boards, and all patients gave informed consent (clinicaltrials.gov, NCT00059423). Retrospective and prospective laboratory data, testing results, and clinical history were then combined for descriptive analysis.
'%3e%3ccircle r='20' fill='%23008'/%3e%3ccircle r='17.5' fill='%23fff'/%3e%3ccircle r='3.5' fill='%23008'/%3e%3cg id='d'%3e%3cg id='c'%3e%3cg id='b'%3e%3cg id='a' fill='%23008'%3e%3ccircle r='.875' transform='rotate(7.5 -8.75 133.5)'/%3e%3cpath d='M0 17.5.6 7 0 2l-.6 5L0 17.5z'/%3e%3c/g%3e%3cuse xlink:href='%23a' transform='rotate(15)'/%3e%3c/g%3e%3cuse xlink:href='%23b' transform='rotate(30)'/%3e%3c/g%3e%3cuse xlink:href='%23c' transform='rotate(60)'/%3e%3c/g%3e%3cuse xlink:href='%23d' transform='rotate(120)'/%3e%3cuse xlink:href='%23d' transform='rotate(-120)'/%3e%3c/g%3e%3c/svg%3e)