43  Hodgkin Lymphoma

Key Points

• cHL is highly curable; balance efficacy w/ late toxicity
• RT ↓ relapse in early-stage but ↑ long-term toxicity risk
• Frontline BV improves OS in newly diagnosed advanced-stage
• PD-1 blockade active across HL; FDA-approved for R/R only
• BV maintenance post-auto-SCT prolongs PFS in high-risk
• NLPHL treated as indolent NHL; rare transformation to THRLBCL

43.1 Overview

• HL ~10% lymphomas (US); cHL 95%, NLPHL 5%
• Median age 39 y, bimodal (20s, >70 y)
• ~8,830 new cases/yr; ~900 deaths/yr

43.2 Pathology & Immunophenotype

Classical Hodgkin Lymphoma (cHL) - 95% cases; does not affect prognosis/treatment - Subtypes: NS (most common), MC, LR, LD - Key cells: Reed-Sternberg (HRS) & variants; minority population - Immunophenotype: CD15+, CD30+, CD20−/weak, CD19− - CD25, PAX-5 weak, CD79b weak - Distinct from other B-cell malignancies - EBV+ 40%: LMP-1 → PD-L1 via AP-1 & JAK-STAT (immune evasion) - Microenvironment: Eosinophils, small lymphs, histiocytes w/ HRS cells

Nodular Lymphocyte-Predominant HL (NLPHL) - ~5% cases; CD20+, CD30−, CD15− - See section below

43.3 Classical Hodgkin Lymphoma

43.3.1 Presentation & Workup

Presentation - Painless lymphadenopathy (most common) - Mediastinal involvement in 40% - B symptoms (fever >38°C, drenching night sweats, ≥10% wt loss in 6 mo) in ~25%

Diagnosis & Staging - Biopsy: Excisional or core > FNA (few HRS cells, need architecture) - Labs: CBC, CMP, LDH (prognostic), HIV, ESR - PET/CT: Deauville scale (1–3 = CMR, >3 = active disease) - Residual mass >5–7 cm may have similar prognosis to FDG+ despite PET− - More accurate than conventional imaging - Bone marrow: Only if clinical suspicion; core biopsy if done - Staging: Ann Arbor classification; bulky = >10 cm node or >1/3 thoracic diameter

Ann Arbor staging for Hodgkin lymphoma

Stage	Definition
I	Single node region or contiguous nodes, 1 side diaphragm
II	≥2 node regions, 1 side diaphragm
III	Node involvement both sides diaphragm ± spleen
IV	Extranodal involvement (except contiguous)

43.3.2 Response Assessment & Prognosis

Response Criteria - PET/CT Deauville scale: 1–3 = CMR; >3 = active disease - Residual masses >5–7 cm common post-tx; use DS to discriminate FDG− from + - ctDNA not validated; not recommended routinely

Risk Factors (Early-Stage) - EORTC: Mediastinal mass (>1/3 thorax), ESR >50 (no B-sx), ESR >20 (w/ B-sx) - GHSG: + above + extranodal extension, ≥3 node groups - NCCN: + above + any bulk >10 cm

International Prognostic Score (Advanced-Stage) - Age, male, ≥4 node groups, bulky mediastinal mass, extranodal sites, ↓ Hgb, ↓ albumin

43.3.3 Early-Stage Disease (I–II)

Favorable-Risk (no risk factors) - GHSG HD10: ABVD × 2 + IFRT 20 Gy (combined modality standard) - 10-y PFS ~95%; RT required (RT alone inferior) - Chemotherapy-only w/ PET-adaptation: ABVD × 3 + PET3 - DS 1–2 at PET3: ±IFRT 30 Gy (3-y PFS 94% either way; borderline NI) - Standard: ABVD × 2–3 + IFRT 20–30 Gy

Unfavorable-Risk (≥1 risk factor) - Preferred: ABVD × 4 + IFRT 30 Gy - HD17: eBEACOPP × 2 + ABVD × 2 (2+2) + PET3-adapted RT → noninferior - Bulky disease: 6 cycles ABVD ± PET4-adapted IFRT - ECHELON-1: ABVD × 6 + consolidation RT (3-y PFS 93% PET2−, 90% PET2+)

Positive PET2 - Favorable-risk: Biopsy; if + → salvage; if − → continue ABVD - Unfavorable-risk: Consider intensification (eBEACOPP per RATHE trial)

43.3.4 Advanced-Stage (III–IV)

Standard Options (>90% 10-y OS w/ modern regimens) - eBEACOPP × 4 or 2+2 ABVD (Standard in Europe & NCCN) - eBEACOPP × 2 → ABVD × 2 + PET3-adapted IFRT (HD21/HD17) - eBEACOPP superior PFS vs ABVD in prospective trials - ABVD × 6 alternative in USA - BV-AVD × 6 (brentuximab vedotin + ADM/vinblastine/daca) - ECHELON-1: Improves 4-y OS vs ABVD alone - Preferred if high risk (bulky, advanced IPS) - Nivo-AVD (nivolumab + AVD) - SWOG S1826: Comparable to BV-AVD; good tolerability

Consolidation - PET3/PET4-adapted IFRT 30 Gy if residual disease

Older Patients (Age ≥60y) - ↑ Bleomycin toxicity (lung 13% vs <2% young) - Preferred: N-AVD or ABVD ± BV - Avoid eBEACOPP/iBEACOPP if comorbid - BV × 6 alone: 3-y PFS/OS 84%/90%

43.3.5 Relapsed/Refractory (R/R) HL

Salvage Strategy - 80% CR w/ initial therapy; 10–30% relapse - PD-1 blockade (nivo/pembro) first-line (high RR; only FDA-approved for R/R) - High response rates; minimal toxicity vs chemo - Brentuximab vedotin (CD30 antibody–drug conjugate) - Highly effective; standard option - Salvage chemo (DHAP, GVD) if PD-1/BV unavailable - Lower use in modern era

Consolidation - Auto-SCT after PD-1 or BV response (standard of care) - 2-y PFS ~70% post-transplant - Maintenance BV post-auto-SCT prolongs PFS (not prospectively studied w/ prior BV/PD-1)

Allogeneic HCT (AlloHCT) - Indicated: Refractory to auto-SCT or 2nd relapse - Post-PD-1 blockade: ↓ relapse 14–18% @ 2 y (vs 40–60% historical) - Grade 3–4 aGVHD 15%; chronic 34% - 2-y OS ~60–70% - Myeloablative preferred over reduced-intensity

43.4 Nodular Lymphocyte-Predominant HL (NLPHL)

Overview - ~5% of HL; distinct biology & prognosis - Immunophenotype: CD20+, CD30−, CD15− (opposite of cHL) - Median age 35 y; 78% male; 69% early-stage - Lower grade (indolent); risk of transformation to THRLBCL (~1%)

Prognosis & Risk Stratification - 10-y OS ~92% (cHL ~90% but different risk trajectory) - Lymphocyte-predominant IPS (LIPS) - Age >50, male, ESR >30, stage III/IV, Hgb <10.5, splenic involvement - Predicts ↑ risk of transformation & worse OS - EBV status also prognostic

Treatment - Early-stage (IA–IIA): RT alone or ABVD ± RT (good outcomes) - Advanced-stage: Treat as indolent B-cell NHL - Rituximab-based regimens (R-CHOP, I-CHOP) - Response rates >90%; watch & wait option for select patients - Watch & wait: Observation in asymptomatic early-stage (10 of 37 progression over 60 mo)

43.5 Surveillance & Late Toxicity

43.5.1 Surveillance

• No survival benefit from routine PET/CT post-CR
• Relapse risk ↓ sharply after 5 y
• Recommend symptom-directed imaging; imaging every 6 mo × 2 y optional
• Exam + labs (CBC, ESR, LDH) q 3 mo × 2 y, then q 6–12 mo × 3 y

43.5.2 Late Therapy-Related Toxicity (≥40 y follow-up risk)

Secondary Malignancies - ↑ Risk w/ RT (esp. mediastinal) > chemo alone - Lung cancer: Mediastinal RT + doxorubicin - Breast cancer: Mediastinal RT, age <30 y at treatment (highest risk) - AML: Pediatric cHL post-mediastinal RT + anthracycline-based chemo - Minimize radiation dose & field

Fertility - iBEACOPP: High risk infertility; counsel re: sperm banking/reproductive Hx - ABVD: Minimal effect on male fertility; safe for female fertility - Alkylating agents: Significant risk; counseling essential

Cardiac & Pulmonary - Hypothyroidism: Up to 50% post-RT - Lung fibrosis: 5–10% post-RT - Cardiotoxicity: Monitor smoking, HTN, DM, lipids; baseline stress test ± echo

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43.6 Clinical Pearls

• Early-stage w/ risk: ABVD × 4 + IFRT 30 Gy; PET-adapted RT-sparing in favorable-risk a/w ≥3 cycles
• Advanced-stage: eBEACOPP × 4 or 2+2 ABVD ± BV; N-AVD in older (>60 y); >90% 10-y OS
• R/R HL: PD-1 (nivo/pembro) → BV if needed; auto-SCT post-response; allo-SCT for refractory/2nd relapse
• NLPHL: Treat as indolent; RT or R-regimens early-stage; watch & wait option
• Avoid RT if possible: ↑ late toxicity (malignancy, cardiac, pulmonary); PET-adapted de-escalation preferred
• Fertility: Counsel iBEACOPP pts; ABVD safe; banking before treatment if possible

43.7 Bibliography

Adl AM, Horning SJ, Hoppe RT et al. Mature results of a phase II study of rituximab monotherapy for nodular lymphocyte-predominant Hodgkin lymphoma. J Clin Oncol. 2013;31(20):2512-2518.

Behringer K, Mueller H, Goergen H et al. Gonadal function and fertility in survivors after Hodgkin lymphoma treatment within the German Hodgkin Study Group HD13 to HD15 trials. J Clin Oncol. 2013;31(2):231-239.

Birkely MS, Raff MS, Molina SJ et al. NCCN Hodgkin lymphoma. Version 2. 2024. https://www.nccn.org/professionals/physician_gls/pdf/hodgkins.pdf

Dastos Oteiro M, Martin R, Gomez P et al. SEGHI study: defining therapy strategy in Hodgkin lymphoma after first-line treatment. Cancers (Basel). 2021;13(10):2412.

Eichendauer DA, Thielen I, Livorkamp LI, et al. Therapy-related acute myeloid leukemia and myelodysplastic syndromes in patients with Hodgkin lymphoma: a report from the German Hodgkin Study Group. Blood. 2014;123(11):1658-1664.

Evens AM, Advani RH, Helenowski IB, et al. Multicenter phase II study of sequential brentuximab vedotin & doxorubicin, bleomycin, vinblastine, & dacarbazine chemotherapy for stage III/IV classical Hodgkin lymphoma. Blood. 2022;139(12):3365-3616.

Gopal AK, Chen R, Smith SE, et al. Doxorubicin, bleomycin, vinblastine, & dacarbazine as frontline therapy with brentuximab vedotin and nivolumab in newly diagnosed Hodgkin lymphoma. Blood Adv. 2022;6(11):3290-3295.

Hornick JL, Colby TV, Rice A et al. Encouraging activity for I-CHOP in advanced stage nodular lymphocyte-predominant Hodgkin lymphoma. Leuk Lymphoma. 2017;58(7):1636-1644.

Johnson FF, Everton M, Kirkwood MC et al. Allogeneic transplantation after PD-1 blockade for relapsed Hodgkin lymphoma. Blood. 2023;142(4):191-192.

Mariotti A, Blyth S, Colon S et al. Surveillance computed tomography imaging & detection of relapse in intermediate- & advanced-stage pediatric Hodgkin lymphoma: a report from the Children’s Oncology Group. J Clin Oncol. 2012;30(21):2635-2640.

Mei MC, Lee HL, Palmer JM, et al. Response-adapted anti-PD-1-based salvage therapy for Hodgkin lymphoma w/ brentuximab vedotin & rituximab alone or in combination w/ ICE. Blood. 2022;139(12):3365-3616.

Moskowitz AJ, Nch C, Schächter JL. et al. Triple progression of relapsed or refractory classical Hodgkin lymphoma, J Clin Oncol. 2020;38(24):3170-3177.

Ng AK. Current survivorship recommendations for patients w/ Hodgkin lymphoma: focus on late effects. Blood. 2014;124(23):3373-3379.