Classical Hodgkin lymhpoma (BSH 2013, 2014 & 2022)

CD30+, CD15+

CD45-, CD20-, CD3-

epidemiology

Annual Incidence 2.7 / 100,000 in UK

Two peaks at 20-34 and >70

Initial Work-up

Bloods - FBC, ESR, U&E, LFT, Bone profile, HIV, hep B/C

Biopsy - 4 histological subtypes - Nodular sclerosis, mixed cellularity, lymphocyte-rich and lymphocyte-depleted - but no difference in outcomes

PET-CT - For staging. Detects bone involvement. BM biopsy not required.

Fertility preservation - consider prior to treatment

Staging

Early (Stage I/II)

• Favourable (GHSG) requires:

  • No large mediastinal mass

  • ESR <50 without B symptoms or ESR <30 with B symptoms

  • No extranodal disease

  • 1-2 lymph nodes involved (BSH guideline has LN chart)

• Favourable (EORTC) requires:

  • No large mediastinal mass

  • ESR <50 without B symptoms or ESR <30 with B symptoms

  • Age 50 years or younger

  • 1-3 lymph nodes involved (BSH guideline has LN chart)

• Unfavourable – Not meeting the favourable criteria

N.B. Large mediastinal mass = mediastinal thoracic ratio >0.33 (UK NCRI / GHSG) or >0.35 (EORTC)

Advanced (Stage III/IV)

Prognostic Scores

Advanced stage patients should have Hasenclever/IPS calculated.

Hogkin IPS, one point for each of:

• Serum albumin <40g/l

• Hb <105g/l

• Male sex

• Ann Arbor Stage IV

• Age 45 years or greater

• WBC 15x10e9/l or above

• Lymphocyte count 0.6x10e9/l or below

Hodgkin IPS 5-yr OS, by No. of risk factors

• 0 - 89%

• 1 - 90%

• 2 - 81%

• 3 - 78%

• 4 - 61%

• 5 or more - 56%

first line treatment

ABVD – Doxorubicin, Bleomycin, Vinblastine, Dacarbazine

escBEACOPP – Bleomycin, Etoposide,Doxorubicin, Cyclophosphamide,Vincristine, Pred, Procarbazine

escBEACOPDac - Dacarbazine instead of procarbazine —> reduced gonadal toxicity and neutropenia in paediatric randomised trials. In adult audit, reduced RBC transfusion and hospital admissions.

PET negative in Hodgkin = Deauville score 1-3

Early Stage, Favourable

• ABVD x2 —> PET-CT

  • iPET2 negative —> options: AVDx1 + RT or AVDx2 with no RT (selected pts)

  • iPET2 positive —> EscBEACOPP x2 + 20Gy RT

Early Stage, Unfavourable / Intermediate

• ABVD x2 —> PET-CT

  • iPET2 negative —> options: AVD x4 or AVD x2 + 30Gy RT

  • iPET2 positive —> EscBEACOPP x2 + RT

• (HD14+17) EscBEACOPP x2 + ABVD x2 (“2+2”) —> PET-CT

  • iPET2 negative —> Stop

  • iPET2 positive —> 30Gy RT

Advanced Disease, Age <60

• (RATHL) ABVD x2 —> PET-CT

  • iPET2 negative —> AVD x4

  • iPET2 positive —> escBEACOPP x4 +/- RT

• (HD18) escBEACOPP x2 —> PET-CT

  • iPET2 negative —> escBEACOPP x2 or AVD x4

  • iPET2 positive —> escBEACOPP x4 +/- RT

Some amalgamated ABVD / escBEACOPP stats:

• ABVD                       PFS 73%,        OS 82-90%    Fertility >30 y.o. 94%

• escBEACOPP          PFS 89%,        OS 95%          Fertility >30 y.o. 45%

• 2/3 of BEACOPP patients have grade 3-4 infections and increased hospital admissions

Supportive Care

• Life-long irradiated blood products

• GCSF not required for ABVD, do not delay for neutropenia

• GCSF for escBEACOPP / BV-AVD

• Aciclovir + Co-trimoxazole prophylaxis for escBEACOPP

HIV-related Hodgkins

• ABVD + Anti-retroviral therapy

• No data for BEACOPP

Teenage and Young Adults (TYA)

• Paediatric or adult regimens can be considered

• Late toxicities particularly important consideration

• Don’t forget fertility preservation 

Pregnancy

• Delaying chemotherapy until after delivery is not standard practice

• Consider alternative imaging – USS / MRI

• ABVD can be used in all 3 trimesters based on retrospective data, prefer to avoid in 1st

• Excellent outcomes reported

Age >60 yo

• 20% of Hodgkin Lymphoma patients

• ABVD - excellent response rates but 5% TRM (HD10 and HD11)

• BEACOPP - 21% TRM in HD9 trial – avoid

• Use standardized frailty assessment tool

• Consider limiting number of cycles / bleomycin dosing (see below)

• ‘Frail’ patients - avoid anthracyclines, e.g. conside ChlVPP

1st Line Treatment Summary

Bleomycin pulmonary Toxicity (BPT) (BSH 2024)

Intro

• Multiple pathophys: reduces expression of alveolar scaffolding proteins + causes hyperinflammatory state

• —> Organising pneumonia, usual interstitial pneumonitis, non-specific interstitial pneumonia, diffuse alveolar damage and eosinophilic pneumonia

• Morbidity may be increased by smoking, pre-existing lung disease

• Mortality increases with age and poor renal function

Clinical Presentation

• Early signs include SOB with normal O2 sats and minimal radiological findings

• Severe signs include hypoxia at rest with markedly abnormal radiological findings (often fatal)

Prevention

• Avoid routine use of GCSF with ABVD

• Adjust dose is CrCl <50ml/min

• <60yo: Omit after 2nd cycle if in CMR on interim PET-CT

• >60yo: Max. 2 cycles of bleomycin

• >70yo: Omit bleomycin

Treatment

• CT chest when diagnosis suspected. Lung function tests not required

• Prednisolone 0.5-1mg/kg/day

• Urgent respiratory referral

Relapse / Refractory treatment

1o Resistant = Progression or non-response during induction treatment or within 90 days of completion

Relapse = Occurring >90 days from completion of induction treatment (early <12 mo, late >12 mo)

Poor outcomes

• Resistant worse than relapse

• Limited prognostic models – PET-CT probably the most informative

• Salvage followed by Autograft if fit patients (about 1/3 of patients make it to transplant)

Palliative regimens

• Single agent – vinblastine, etoposide, gemcitabine

• Multi-agent – PECC, ChlVPP

Novel Therapies

• Brentuximab – Anti-CD30 + Anti-microtubulin agent.

  • Current NICE approval for relapse after 2 prior therapies or relapse after autograft (as of April 2019)

• Pembrolizumab & Nivolumab – Anti-programmed death 1 (PD-1) pathway antibodies

  • Pembrolizumab - via cancer drugs fund

  • Nivolumab - Current NICE approval for relapse post autograft + brentuximab (as of April 2019)

• Avelumab - Anti-programmed death ligand 1 (PD-L1) antibody

Long-term Follow-Up

Minimum 2 years clinic follow-up from 1st line treatment

Irradiated blood products for life

No role for routine radiological surveillance

Lifestyle advice

Late Effects

• Radiotherapy

  • Breast cancer - breast screening if received RT under age 36

  • Thyroid cancer and hypothyroidism - lifelong increased risk

• Chemotherapy/Radiotherapy

  • Cardiac disease - lifelong increased risk of MI, valve disease, heart failure

  • Respiratory toxcity - breathlessness, firbosis, pneumonitis

  • Second cancers - e.g. 0.4% MDS/AML post escBEACOPP

  • Reduced fertility (see above)

  • Chronic fatigue

  • Anxiety / depression

• These late effects have driven the many de-escalation trials mentioned above and highlight need to involve patients in discussions about their priorities / attitudes to risk.

Relevant trials

Early Stage, Favourable

Overall: RT improved PFS, but OS gain not yet demonstrated. iPET pos pts had higher relapse risk.

HD16 trial 2019

• Early stage, favourable only

• ABVD x2 —> no RT if iPET2 negative (non-inferiorty design)

H10 trial 2017

• Early stage (subdivided favourable or unfavourable).

• Experimental arm: ABVD x2 —> no RT if iPET2 negative (non-inferiorty design)

RAPID 2015

• Early stage, favourable or unfavourable

• Experimental arm: ABVD x3 —> no RT if iPET2 negative (non-inferiorty design)

Early Stage, Unfavourable / Intermediate

HD17 trial 2021

• PET-adapted 2+2, confirmed omitting RT if PET negative is non-inferior.

HD14 trial 2012

• ABVD x4 vs escBEACOPP x2 + ABVD x2 (‘2+2’)

• All patient also got RT

HD11 trial 2010

• ABVD x4 vs escBEACOPP x4 and 30Gy vs 20Gy RT

Advanced Disease

HD21 trial 2024

• BrECADD vs escBEACOPP for adults <60yo

• 1500 patients. PET-guided 4-6 cycles. 4yr est. PFS 94% BrECADD vs 90.9% eBEACOPP

S1826 Trial 2024

• Nivolumab-AVD vs Brentuximab-AVD for Adolescents and adults (any age)

• 1000 patients. 6 cycles. 2-yr PFS 92% for N-AVD, vs 83% for BV-AVD

• <1% patients required end of treatment radiotherapy. 7% hypothyroidism with N-AVD

US SWOG S0816 2019

• ABVD x2 —> iPET2 —> Switch to EscBEACOPP if postive

AHL2011 trial 2019

• EscBEACOPP x2 —> iPET2 —> if neg then ABVD x4.

• Not so commonly used in UK

ECHELON1 trial 2018

• ABVD vs BV-AVD (Brentuximab vedotin). (5yr f/up)

HD18 trial 2017

• EscBEACOPP x2 —> iPET2 —> if neg then x2 vs x4 vs x6 further cycles.

• Total of 4 cycles is non-inferior and less toxic (+ shorter total treatment length).

UK RATHL 2016

• ABVD x2 —> iPET2 —> Switch to EscBEACOPP if postive (16% of pts). Established non-inferiority of further AVD x4 vs ABVD x4 with less lung toxicity. IPS 3 & 4 pts higher relapse rates.

HD15 trial 2012:

• EscBEACOPP x6 vs x8 (non-inferiority design)

HD9 trial 2009

• Baseline vs escalated dosing of BEACOPP