In-depth cell-free DNA sequencing reveals genomic landscape of Hodgkin’s lymphoma and facilitates ultrasensitive residual disease detection

Abstract

Background: Individualization of treatment in Hodgkin's lymphoma is necessary to improve cure rates and reduce treatment side effects. Currently, it is hindered by a lack of genomic characterization and sensitive molecular response assessment. Sequencing of cell-free DNA is a powerful strategy to understand the cancer genome and can be used for extremely sensitive disease monitoring. In Hodgkin's lymphoma, a high proportion of cell-free DNA is tumor-derived, whereas traditional tumor biopsies only contain a little tumor-derived DNA. Methods: We comprehensively genotype and assess minimal residual disease in 121 patients with baseline plasma as well as 77 follow-up samples from a subset of patients with our targeted cell-free DNA sequencing platform. Findings: We present an integrated landscape of mutations and copy number variations in Hodgkin's lymphoma. In addition, we perform a deep analysis of mutational processes driving Hodgkin's lymphoma, investigate the clonal structure of Hodgkin's lymphoma, and link several genotypes to Hodgkin's lymphoma phenotypes and outcome. Finally, we show that minimal residual disease assessment by repeat cell-free DNA sequencing, as early as a week after treatment initiation, predicts treatment response and progression-free survival, allowing highly improved treatment guidance and relapse prediction. Conclusions: Our targeted cell-free DNA sequencing platform reveals the genomic landscape of Hodgkin's lymphoma and facilitates ultrasensitive detection of minimal residual disease.

Controversies in the Interpretation of Liquid Biopsy Data in Lymphoma

“…Alternative bioinformatic approaches utilizing unique molecular identifiers in combination with bioinformatic error reduction using individual base error likelihoods as well as error likelihoods in base triplets have been proposed. 51 In the context of MRD study where tumor fraction is low, deep sequencing methods with limited genomic targets have been applied. However, many patients with radiologically evident disease after treatment do not show detectable ctDNA.…”

“…Alternative bioinformatic approaches utilizing unique molecular identifiers in combination with bioinformatic error reduction using individual base error likelihoods as well as error likelihoods in base triplets have been proposed. 51 …”

“… 32 Another study in 121 patients showed in a cohort consisting of early and advanced stage classical HL patients that MRD measured by ctDNA reduction can differentiate good and bad outcomes to treatment as early as 1 week after initiation of treatment. 51 ctDNA is being investigated in lymphoma and in particular in DLBCL and HL as a tool that could allow early and accurate identification of chemorefractory patients who are candidates for treatment intensification, or the identification of good-risk patients, for treatment de-escalation.…”

Navigating increasingly individualised Hodgkin lymphoma treatments to optimally balance risks and benefits

“…Given the high overall treatment success rate further individualisation to optimally balance risks and benefits is desirable. By incorporating patient‐associated factors such as age, sex, comorbidities, and preferences with disease localisation and spread, as well as more sophisticated biomarkers such as circulating tumour DNA 14 or metabolic tumour volume, 15 both at baseline and on treatment, modern HL treatment truly tailored to each individual patient is achievable. By accurately determining individual risk of treatment failure and treatment‐related side‐effects, such approaches would allow further reduction of intensity while adequately addressing the remaining high‐risk patients to prevent refractory disease.…”

Blood-based Monitoring of Relapsed/Refractory Hodgkin Lymphoma Patients Predict Responses to Anti-PD-1 Treatment

“…Current cfDNA studies of cHL revolve around the detection of minimal residual disease (MRD) on the basis of mutational profiling of ctDNA. 1 , 2 We and others have shown that detection of genome-wide chromosomal copy number alterations (CNAs) by next generation sequencing (NGS) from ctDNA is relatively straightforward and could serve as a cost and labor attractive alternative to mutational profiling for disease monitoring. 3 , 4 Extracellular vesicle associated microRNAs (EV-miRNAs) are described as potential monitoring strategy in cHL and reflect FDG-PET status.…”