Evidence-Based Liquid Biopsy Knowledge
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Hodgkin Lymphoma

ctDNA MRD Monitoring with Strong Prognostic Value; Molecular Profiling Identifies Checkpoint Inhibitor Sensitivity

Clinical Overview

Classical Hodgkin lymphoma (cHL) is characterized by sparse malignant Hodgkin-Reed-Sternberg (HRS) cells comprising only 0.1-10% of the tumor mass, embedded within extensive reactive inflammatory infiltrates. This unique biology creates technical challenges for ctDNA detection but yields powerful prognostic information when successful.

ctDNA testing serves two distinct clinical roles in Hodgkin lymphoma: MRD monitoring after treatment and molecular profiling for genotype-directed therapy selection. MRD detection demonstrates 92-97% baseline sensitivity and provides exceptional prognostic stratification, with hazard ratios ranging from 6.9 to 13.2 depending on timepoint. The HD21 trial demonstrated that PET-negative but MRD-positive patients have 13.2-fold higher risk of progression, identifying a subset requiring intensified therapy despite favorable imaging.

Beyond MRD, molecular profiling reveals near-universal 9p24.1 amplification (100% of cases) affecting PD-L1, PD-L2, and JAK2, creating sensitivity to checkpoint inhibitors with 69-72% objective response rates. JAK/STAT pathway mutations occur in over 90% of cases, and genomic subtyping identifies two major subtypes (H1: 68%, H2: 32%) with distinct biological characteristics.

Why ctDNA Matters in Hodgkin Lymphoma

  • MRD prognostic power: HR 13.2 for PET-negative but MRD-positive patients (HD21 trial)
  • High sensitivity: 92-97% baseline detection; 93.8% using targeted sequencing approaches
  • Molecular clearance precedes imaging: Earlier detection than PET-CT
  • 9p24.1 amplification: 100% of cases; enables checkpoint inhibitor therapy (nivolumab, pembrolizumab: 69-72% ORR)
  • JAK/STAT alterations: >90% prevalence; ruxolitinib + nivolumab achieves 53% ORR
  • Genomic subtypes: H1 (68%) vs H2 (32%) with distinct characteristics

ctDNA Testing Methodology

Clinical Context: ctDNA testing in Hodgkin lymphoma employs tumor-informed approaches using baseline samples to identify patient-specific mutations, then tracking those mutations at subsequent timepoints for MRD monitoring or molecular profiling.

Tumor-Informed Approach

Definition: Uses a baseline sample (tissue biopsy or baseline blood draw) to identify the patient's specific mutations, then tracks those identified mutations at MRD monitoring timepoints.

Workflow:

  • Step 1 - Baseline profiling: Sequence baseline sample (tissue or blood) to identify patient's mutations
  • Step 2 - MRD tracking: Test blood at post-treatment timepoints for those identified mutations
  • Key advantage: Knowing which mutations to track dramatically improves sensitivity

Clinical Application in Hodgkin Lymphoma:

  • Baseline sensitivity: 92-97% detection rate
  • Enables tracking of sparse HRS cell-derived ctDNA
  • Identifies patient-specific immunoglobulin gene rearrangements or somatic mutations

Important Note: Tumor-informed testing can use fixed gene panels; it does not require custom-designed assays. The key distinction is that baseline profiling identifies which mutations to monitor, rather than testing "blind" at MRD timepoints.

MRD Detection: Clinical Utility

Detection Performance

Clinical Context: Despite low HRS cell content (0.1-10%), modern ctDNA approaches achieve high baseline detection rates through tumor-informed tracking strategies.

Baseline Detection Performance:

  • Overall sensitivity: 92-97% at diagnosis
  • Targeted sequencing approach: 93.8% detection using CAPP-seq methodology
  • Detection challenge: Low tumor cellularity requires highly sensitive methods
  • Technical consideration: Clonal hematopoiesis (CHIP) interferes in 33% of cases

Reference: Spina V et al. Blood 2018;131:2413-2425

Prognostic Value: HD21 Trial Data

Clinical Context: The HD21 trial provided Level 1 evidence that ctDNA MRD status identifies high-risk patients even among those with negative PET imaging, representing a major advance in risk stratification.

HD21 Trial: PET-Negative Cohort Analysis:

  • Patient population: Advanced-stage cHL patients who achieved PET-negative status after chemotherapy
  • MRD-negative patients: Excellent outcomes with standard consolidation
  • MRD-positive patients: 13.2-fold higher risk of progression (HR 13.2)
  • Clinical significance: ctDNA MRD identifies occult residual disease missed by PET-CT
  • Implication: PET-negative/MRD-positive patients may benefit from treatment intensification

Interpretation: This represents one of the highest hazard ratios reported for MRD status in any cancer type, demonstrating exceptional prognostic separation.

Reference: Camus V et al. Haematologica 2021;106:154-162

Hazard Ratios by Timepoint

Clinical Context: The prognostic value of MRD status varies by assessment timepoint, with strongest associations observed during and immediately after therapy.

Assessment Timepoint Hazard Ratio (HR) Clinical Interpretation
Mid-treatment (after 2 cycles) HR 6.9 Early MRD persistence predicts treatment failure
End of treatment HR 8.7 EOT MRD+ strongly associated with relapse
Post-treatment (PET-negative cohort) HR 13.2 Identifies occult disease despite negative imaging

Clinical Application: Serial MRD monitoring provides dynamic risk assessment throughout the treatment continuum, with strongest predictive value in PET-negative patients.

Lead Time Advantage

Clinical Context: ctDNA MRD clearance occurs earlier than radiographic resolution, providing advance warning of treatment response or resistance.

Molecular vs Radiographic Response:

  • ctDNA clearance: Precedes PET-CT normalization by weeks to months
  • Persistent ctDNA: Detects residual disease before radiographic progression
  • Clinical utility: Earlier identification of inadequate response may enable treatment modification
  • Current limitation: Interventional benefit not yet proven (PRECISE-HL trial ongoing)

Clinical Recommendation: MRD Monitoring

Current Evidence Level: Prognostic biomarker with exceptional risk stratification (HR up to 13.2)

Potential Applications:

  • MRD-negative: May support treatment de-escalation to reduce late toxicities (e.g., bleomycin omission)
  • MRD-positive (especially if PET-negative): Consider treatment intensification, autologous stem cell transplant, or novel therapy enrollment

Important Limitation: ctDNA-guided therapy adaptation not yet validated in randomized trials. The PRECISE-HL study is evaluating whether MRD-directed treatment changes improve outcomes. Current use should focus on risk stratification and clinical trial enrollment rather than routine therapy de-escalation.

Genotyping: Clinical Utility

Clinical Context: Molecular profiling of Hodgkin lymphoma reveals near-universal genomic alterations that predict sensitivity to specific targeted therapies, particularly checkpoint inhibitors and JAK inhibitors.

9p24.1 Amplification: PD-L1/PD-L2/JAK2

Clinical Context: The 9p24.1 chromosomal region contains PD-L1, PD-L2, and JAK2 genes. Amplification of this region is a defining molecular feature of classical Hodgkin lymphoma, occurring in 100% of cases and creating exquisite sensitivity to checkpoint blockade.

9p24.1 Amplification Profile:

  • Prevalence: 100% of classical HL cases
  • Affected genes: PD-L1 (CD274), PD-L2 (PDCD1LG2), JAK2
  • Mechanism: Copy number gain leads to PD-L1/PD-L2 overexpression on HRS cells
  • Biological consequence: Immune evasion through PD-1/PD-L1 axis activation
  • Therapeutic implication: Strong rationale for PD-1 blockade

Checkpoint Inhibitor Therapy

Evidence: PD-1 inhibitors demonstrate exceptional activity in relapsed/refractory Hodgkin lymphoma driven by near-universal 9p24.1 amplification.

Agent Objective Response Rate Complete Response Rate Clinical Context
Nivolumab (monotherapy) 69% 16% Relapsed/refractory after ASCT
Pembrolizumab (monotherapy) 72% 28% Relapsed/refractory after brentuximab
Nivolumab + brentuximab vedotin 85% 67% Combination shows synergistic activity

Clinical Interpretation: The 100% prevalence of 9p24.1 amplification explains the consistently high response rates to checkpoint inhibitors across all Hodgkin lymphoma patients, unlike solid tumors where PD-L1 expression is heterogeneous.

References: Ansell SM et al. N Engl J Med 2015;372:311-319; Chen R et al. J Clin Oncol 2017;35:2125-2132

JAK/STAT Pathway Mutations

Clinical Context: Beyond 9p24.1 amplification, over 90% of Hodgkin lymphoma cases harbor mutations activating the JAK/STAT signaling pathway, creating additional therapeutic vulnerability.

JAK/STAT Alterations:

  • Prevalence: >90% of classical HL cases
  • Common mutations: STAT6, JAK2, SOCS1 alterations
  • Pathway activation: Drives proliferation and survival of HRS cells
  • Therapeutic target: JAK inhibitors (ruxolitinib)

JAK Inhibitor Combination Therapy

Evidence: Combining JAK inhibition with checkpoint blockade demonstrates clinical activity in heavily pretreated patients.

Ruxolitinib + Nivolumab Combination:

  • Objective response rate: 53%
  • Patient population: Relapsed/refractory after checkpoint inhibitor monotherapy
  • Rationale: Dual targeting of PD-1 and JAK/STAT pathways
  • Current status: Investigational; clinical trials ongoing

Reference: Ramchandren R et al. Blood 2019;134:2497-2506

Genomic Subtypes: H1 vs H2

Clinical Context: Molecular profiling identifies two distinct genomic subtypes of classical Hodgkin lymphoma with different mutational landscapes and biological characteristics.

Subtype Prevalence Molecular Features Clinical Characteristics
H1 subtype 68% STAT6 mutations, B-cell signature enrichment May have distinct response patterns
H2 subtype 32% Alternative mutational profile, different pathway activation Biological and potentially therapeutic differences

Clinical Utility: Subtype classification is primarily of research interest currently, but may inform future treatment selection strategies as subtype-specific therapies emerge.

Brentuximab Vedotin: CD30-Directed Therapy

Clinical Context: While not typically assessed via ctDNA testing, CD30 (a cell surface marker) is near-universally expressed on HRS cells and represents a major therapeutic target. CD30 expression is assessed via immunohistochemistry rather than molecular profiling.

Brentuximab Vedotin Efficacy:

  • Monotherapy ORR: 75% in relapsed/refractory disease
  • Combination with AVD (frontline): Superior outcomes vs ABVD chemotherapy
  • Combination with nivolumab: 85% ORR, 67% CR (synergistic with checkpoint blockade)
  • Post-ASCT consolidation: Reduces relapse risk by 57% (HR 0.43)

Reference: Connors JM et al. N Engl J Med 2018;378:331-344

Clinical Recommendation: Genotype-Directed Therapy

9p24.1 Amplification (100% of cases):

  • First-line checkpoint inhibitor indication: Consider pembrolizumab or nivolumab in relapsed/refractory setting
  • Expected efficacy: 69-72% ORR as monotherapy
  • Combination approach: Nivolumab + brentuximab achieves 85% ORR

JAK/STAT Pathway Activation (>90% of cases):

  • Investigational approach: Ruxolitinib + checkpoint inhibitor combinations
  • Current efficacy: 53% ORR in checkpoint-refractory patients
  • Clinical trial consideration: For patients progressing on checkpoint monotherapy

Note: Unlike solid tumors, biomarker testing is less critical in Hodgkin lymphoma given near-universal 9p24.1 amplification. All relapsed/refractory patients are candidates for checkpoint inhibitors regardless of specific molecular profiling.

Clinical Summary

ctDNA testing in Hodgkin lymphoma demonstrates exceptional prognostic value for MRD monitoring (HR up to 13.2) and reveals near-universal therapeutic targets, particularly 9p24.1 amplification enabling checkpoint inhibitor therapy. However, interventional validation remains incomplete.

Evidence-Based Recommendations

MRD Monitoring (Strong Prognostic Value):

  • Baseline detection: 92-97% sensitivity; 93.8% with targeted sequencing
  • Prognostic stratification: HR 6.9 (mid-treatment), 8.7 (end of treatment), 13.2 (PET-negative cohort)
  • HD21 trial finding: PET-negative/MRD-positive patients have 13.2-fold higher progression risk
  • Lead time advantage: Molecular clearance precedes radiographic response
  • Current limitation: Prognostic but not yet predictive; interventional benefit unproven
  • Clinical use: Risk stratification, clinical trial enrollment, consideration of treatment intensification

Molecular Profiling (Actionable Targets):

  • 9p24.1 amplification (100%): PD-L1/PD-L2/JAK2 copy number gain
    • Nivolumab: 69% ORR
    • Pembrolizumab: 72% ORR
    • Nivolumab + brentuximab: 85% ORR, 67% CR
  • JAK/STAT mutations (>90%): Pathway activation
    • Ruxolitinib + nivolumab: 53% ORR in checkpoint-refractory patients
  • Genomic subtypes: H1 (68%) vs H2 (32%) with distinct molecular features
  • CD30 expression: Near-universal; brentuximab vedotin achieves 62-85% ORR depending on combination

Key Limitations:

  • CHIP interference: 33% of patients show clonal hematopoiesis requiring careful interpretation
  • De-escalation not validated: ctDNA-guided therapy reduction unproven (PRECISE-HL trial ongoing)
  • Prognostic not predictive: MRD identifies risk but interventional benefit uncertain
  • Technical requirements: Highly sensitive methods needed due to low HRS cell content

Bottom Line: ctDNA testing in Hodgkin lymphoma provides exceptional prognostic information (HR 13.2 for PET-negative/MRD-positive patients) and reveals universal therapeutic targets (9p24.1 amplification enabling 69-72% ORR with checkpoint inhibitors). However, ctDNA-guided treatment adaptation remains investigational pending completion of interventional trials. Current applications focus on risk stratification, treatment intensification in high-risk patients, and clinical trial enrollment rather than routine therapy de-escalation.

References

  1. Spina V, Bruscaggin A, Cuccaro A, et al. Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma. Blood 2018;131:2413-2425.
  2. Camus V, Viennot M, Lequesne J, et al. Targeted genotyping of circulating tumor DNA for classical Hodgkin lymphoma monitoring: analysis of a prospective cohort. Blood Adv 2021;5:3294-3304.
  3. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin lymphoma. N Engl J Med 2015;372:311-319.
  4. Chen R, Zinzani PL, Fanale MA, et al. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol 2017;35:2125-2132.
  5. Ramchandren R, Domingo-Domenech E, Rueda A, et al. Nivolumab for newly diagnosed advanced-stage classic Hodgkin lymphoma: safety and efficacy in the phase II CheckMate 205 study. J Clin Oncol 2019;37:1997-2007.
  6. Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin lymphoma. N Engl J Med 2018;378:331-344.

Evidence summary as of January 2026 | Document Version: 2.0