Lymphoma — Written Clinical Reasoning

SAQ 1 — Newly diagnosed bulky stage IIB classical Hodgkin lymphoma in a young man (20 marks, 30 minutes)

Prompt: Outline your staging, prognostic assessment, the fertility discussion, the choice of frontline regimen, the role of PET-adapted therapy, and the structured survivorship plan. Justify each decision with reference to the evidence. [1]

Model Answer

Step 1 — Confirm stage and prognostic group (3 marks): [1]

By the Lugano classification, this patient has Ann Arbor stage IIBX (bulky) classical Hodgkin lymphoma — bulky mediastinal and bilateral cervical disease (the bulky modifier X applies because the mass is over a third of the internal thoracic diameter or 10 cm, and here the largest mass is 9 cm which is borderline; many centres would stage this as bulky IIB or even advanced based on the bulk). PET-CT has supplanted CT alone for staging Hodgkin lymphoma and can replace bone marrow biopsy when clearly negative [5][6]. His marrow is clear and there is no extranodal disease. The International Prognostic Score (IPS, Hasenclever 1998) is calculated from seven adverse factors [1]: his albumin and haemoglobin are normal, he is male (1 point), under 45, not stage IV, white cell count likely normal, lymphocyte count normal — his IPS is 1 (low risk), which predicts a favourable outcome. The bulk and B symptoms place him in an unfavourable early-stage or limited advanced-stage category, which guides therapy intensity.

Step 2 — Fertility preservation before chemotherapy (3 marks): [1]

Before any chemotherapy, I would urgently refer him for sperm cryopreservation — alkylating agents (particularly procarbazine in escalated BEACOPP, and dacarbazine in ABVD to a lesser extent) and anthracyclines cause gonadal toxicity and risk permanent infertility. Sperm cryopreservation is rapid (a single sample, ideally two), low-cost, and should be arranged within days so that chemotherapy is not delayed. I would document the discussion and the patient's decision. If he has a partner and they wish, embryo cryopreservation is an option. The fertility specialist and the haematologist should coordinate timing — for a young man with Hodgkin lymphoma, the standard is to bank sperm before cycle 1. [1]

Step 3 — Frontline therapy — ABVD versus A+AVD (4 marks): [1]

For bulky stage IIB Hodgkin lymphoma, the standard is 6 cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). ABVD is given every 28 days with doxorubicin and dacarbazine and bleomycin and vinblastine on days 1 and 15. The modern alternative is brentuximab vedotin plus AVD (A+AVD) — the ECHELON-1 trial showed a modified progression-free survival advantage over ABVD in stage III to IV classical Hodgkin lymphoma, with less pulmonary toxicity (no bleomycin) but more neuropathy and neutropenia [3]. For a young man with asthma (which increases the risk of bleomycin pulmonary toxicity), A+AVD is a particularly attractive option. The shared decision with the patient weighs the pulmonary risk of ABVD (bleomycin lung is more common in patients over 40, smokers, and those with pre-existing lung disease — asthma is a relative consideration) against the neuropathy and neutropenia of A+AVD. Both achieve excellent outcomes — 5-year progression-free survival over 80 per cent.

Step 4 — PET-adapted therapy (3 marks): [1]

I would use interim PET after 2 cycles to guide subsequent therapy, scored by the Deauville 5-point scale [6]. The RATHL trial showed that patients who are PET-negative (Deauville 1 to 3) after 2 cycles of ABVD can safely de-escalate to AVD (omitting bleomycin) without loss of efficacy, while PET-positive patients (Deauville 4 to 5) are escalated to BEACOPP [4]. For this patient, if the interim PET shows a complete metabolic response (Deauville 1 to 3), I would continue ABVD or de-escalate to AVD for the remaining cycles; if PET-positive, I would escalate to escalated BEACOPP or switch to a salvage-based approach. The end-of-treatment PET determines whether consolidative involved-site radiotherapy (ISRT) is needed for bulky residual or PET-positive sites — for a bulky mediastinal mass, ISRT is often considered even after a complete metabolic response, because the relapse risk in bulky mediastinal disease with chemotherapy alone is higher.

Step 5 — Supportive care and comorbidity (3 marks): [1]

I would optimise his asthma before chemotherapy (peak flow, spirometry, review of inhaler technique, consider a course of oral corticosteroid if poorly controlled). I would prescribe antiemetics for the dacarbazine and doxorubicin (5-HT3 antagonist plus dexamethasone plus aprepitant for the highly emetogenic dacarbazine), pegfilgrastim if neutropenia develops, PJP prophylaxis (co-trimoxazole) during corticosteroid-containing cycles, and tumour lysis prophylaxis (hydration, allopurinol) given the bulk. Bleomycin pulmonary toxicity must be monitored — baseline pulmonary function tests (spirometry and DLCO), counsel the patient to report cough or exertional dyspnoea immediately, and hold bleomycin if there is significant decline in DLCO or clinical suspicion of pneumonitis. Hepatitis B serology (surface antigen, core antibody), HIV serology, and echocardiogram (baseline before doxorubicin) are part of the pretreatment workup. [1]

Step 6 — Structured survivorship plan (2 marks): [1]

After treatment, I would institute a structured late-effects surveillance plan: annual TSH (cervical radiotherapy risk of hypothyroidism), echocardiographic surveillance at 2 and 5 years (anthracycline cardiomyopathy), pulmonary function if symptomatic (bleomycin), psychological support and screening for anxiety and depression, return-to-work plan, vaccination review (re-vaccinate after anti-CD20 therapy if applicable — not relevant for ABVD), and cancer screening (smoking cessation counselling, skin cancer surveillance). For young women treated for Hodgkin (not this patient), breast MRI from 8 years post-treatment or age 40, whichever comes first, is standard. The survivorship plan is a long-case archetype and should be documented and communicated to the general practitioner. [1]

Step 7 — Communication and shared decision-making (2 marks): [1]

I would sit with the patient and his partner in a quiet room with the haematologist and a clinical nurse specialist. I would explain in plain language that Hodgkin lymphoma is highly curable (5-year survival over 85 per cent), acknowledge the shock, and set out the two frontline options (ABVD with PET-adapted de-escalation, or A+AVD) honestly — weighing pulmonary risk against neuropathy. I would address fertility (sperm banking before cycle 1), the impact on his work and young family, and the long-term plan. I would document the shared decision, provide written information and a named contact, and arrange follow-up within days. [1]

SAQ 2 — Relapsed diffuse large B-cell lymphoma and CAR-T cell therapy (10 marks, 20 minutes)

Prompt: A 58-year-old man with DLBCL relapses 8 months after R-CHOP with Deauville 5 disease. After three cycles of R-ICE salvage, a repeat PET shows persistent metabolically active disease (Deauville 4). Outline the role of CAR-T cell therapy, its mechanism, its principal toxicities, and the shared decision-making framework. [1]

Model Answer

Step 1 — Define the clinical problem (2 marks): [1]

This patient has relapsed DLBCL that is refractory to platinum-based salvage chemotherapy (persistent Deauville 4 disease after R-ICE). Historically, primary refractory or relapsed DLBCL after autologous stem cell transplant had a median overall survival under 6 months. The introduction of CAR-T cell therapy has transformed this group from incurable to potentially curable. [1]

Step 2 — Mechanism of CAR-T cell therapy (2 marks): [1]

Chimeric antigen receptor (CAR) T-cell therapy involves collecting the patient's T lymphocytes by leucapheresis, genetically engineering them ex vivo to express a receptor targeting CD19 (a B-cell antigen expressed on DLBCL), expanding the engineered T cells, and reinfusing them after lymphodepleting chemotherapy (typically fludarabine plus cyclophosphamide). The CAR-T cells recognise and kill CD19-positive lymphoma cells, persist as a living drug, and provide ongoing immunosurveillance. The approved products for DLBCL are axicabtagene ciloleucel (ZUMA-1), tisagenlecleucel (JULIET), and lisocabtagene maraleucel. [1]

Step 3 — Evidence and indication (2 marks): [1]

The ZUMA-1 trial of axicabtagene ciloleucel in refractory DLBCL showed an objective response rate of 82 per cent and a complete response rate of 54 per cent, with durable remissions at 5 years in about 40 per cent of patients [12]. CAR-T is indicated for primary refractory DLBCL (progressive disease during or within 12 months of R-CHOP), relapsed DLBCL within 12 months of autologous stem cell transplant, relapsed DLBCL refractory to salvage chemotherapy (this patient), and as second-line therapy in primary refractory or early-relapsing disease. Bridging chemotherapy may be needed during the 3 to 4 week manufacturing period to control rapidly progressive disease.

Step 4 — Principal toxicities (2 marks): [1]

The two principal toxicities are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). CRS presents with fever, hypotension, hypoxia, and multi-organ dysfunction, driven by IL-6 and other cytokines; treatment is tocilizumab (anti-IL-6 receptor) for grade 2 or higher, with corticosteroids for severe or refractory cases. ICANS presents with confusion, aphasia, tremor, seizures, and obtundation; treatment is corticosteroids (dexamethasone) and supportive care. Both require management in a specialised centre with ICU access. Prolonged cytopenias, B-cell aplasia (requiring immunoglobulin replacement), and infections are longer-term complications. [1]

Step 5 — Shared decision-making (2 marks): [1]

I would sit with the patient and his family with the haematologist and a clinical nurse specialist. I would frame CAR-T as the best available option for his refractory disease with a realistic chance of long-term remission (perhaps 40 per cent durable complete response), but would honestly explain the toxicity risk (CRS, ICANS, prolonged cytopenias, weeks in hospital, possible ICU admission) and the alternative of best supportive care or palliative radiotherapy. I would discuss the logistics (leucapheresis, 3 to 4 week manufacturing period, bridging chemotherapy, admission to a CAR-T centre, 4 to 6 weeks away from home), the financial and family impact, and the survivorship plan if CAR-T succeeds. I would document the shared decision and respect the patient's choice. [1]