Chronic Leukaemia and Myeloid Neoplasms — Viva Defence

Long Case Viva Defence

The scenario

A 62-year-old fit man, previously well, presents with a three-month history of progressive fatigue, drenching night sweats and a 4 kg weight loss. Full blood count shows a white cell count of 78 (absolute lymphocyte count 66), haemoglobin 104 g/L and platelets 86. The blood film shows small mature lymphocytes and smudge cells. Flow cytometry confirms a clonal B-cell population that is CD5-positive, CD19-positive, CD23-positive with restricted kappa light chain. CT shows bulky cervical, axillary and intra-abdominal lymphadenopathy with splenomegaly. IGHV mutation status is unmutated, and fluorescence in situ hybridisation detects a deletion of 17p with an accompanying TP53 mutation. His renal and hepatic function are normal, and his ECOG performance status is 1. [1] />

Opening statement (SASPOP)

"This is Mr M, a 62-year-old fit man presenting with symptomatic, active chronic lymphocytic leukaemia — Rai stage III to IV (anaemia and thrombocytopenia indicating marrow failure), Binet stage C, with bulky lymphadenopathy and B-symptoms. The immunophenotype is the classic CLL fingerprint (CD5-positive, CD19-positive, CD23-positive clonal B cells), and the molecular biology is adverse — an unmutated IGHV status and deletion of 17p with a TP53 mutation, which together predict an aggressive course and resistance to chemoimmunotherapy. His main problems are: the active CLL requiring prompt therapy; the TP53-disrupted biology that mandates a novel agent rather than chemoimmunotherapy; the tumour lysis syndrome risk if venetoclax is chosen, given his high lymphocyte count and bulk; the anticipated complications of infection, autoimmune cytopenia and Richter transformation; and the prognostic and psychosocial counselling that an incurable but controllable diagnosis demands. My priorities are to start a novel agent — ibrutinib or venetoclax with obinutuzumab — chosen with him after a shared discussion of continuous versus time-limited therapy, to manage the tumour lysis syndrome risk with the standard ramp-up and prophylaxis if venetoclax is chosen, to anticipate and prevent infection and autoimmunity, and to provide clear prognostic counselling and a named coordinator." [1] />

Problem list (numbered, prioritised)

1. Symptomatic, active CLL with TP53 disruption — the central problem; needs a novel-agent first-line therapy, not chemoimmunotherapy.
2. Tumour lysis syndrome risk — high lymphocyte count and bulky disease; mandatory ramp-up and prophylaxis if venetoclax is used.
3. Infection risk — hypogammaglobulinaemia plus therapy-related immunosuppression; needs vaccination, prompt antibiotics, and immunoglobulin consideration.
4. Anticipated autoimmune cytopenia and Richter transformation — surveillance and clear patient warnings.
5. Prognostic and psychosocial counselling — an incurable but controllable diagnosis; coordinator, written information, goals of care. [1] />

Integrated management plan

Pillar 1 — The treatment decision: "This man has active CLL (Binet C, iwCLL active-disease criteria met — progressive marrow failure, bulky lymphadenopathy, and B-symptoms), so treatment is indicated. The decisive finding is the TP53 disruption (del(17p) and TP53 mutation), which confers resistance to chemoimmunotherapy. I would therefore not offer FCR or BR, even though he is fit. The two first-line options are ibrutinib (with or without obinutuzumab) — a Bruton tyrosine kinase inhibitor given continuously, established by RESONATE-2 and active in TP53-disrupted disease [2] — and venetoclax with obinutuzumab, a BCL-2 inhibitor given as a time-limited course, with high rates of measurable residual disease negativity from the MURANO data [3]. I would present both honestly — the continuous versus time-limited nature, the atrial fibrillation and bleeding risk of ibrutinib, the tumour lysis syndrome risk of venetoclax — and make a shared decision."

Pillar 2 — Tumour lysis syndrome: "If venetoclax is chosen, he is high-risk for tumour lysis syndrome (lymphocyte count over 25, bulky disease). I would use the mandatory 5-week ramp-up dosing (20 then 50 then 100 then 200 then 400 mg), aggressive hydration, allopurinol or rasburicase for the highest risk, and frequent electrolyte and renal monitoring during the ramp-up. Failing to use the ramp-up can precipitate fatal tumour lysis syndrome." [1] />

Pillar 3 — Infection and supportive care: "I would ensure vaccination before therapy (influenza, pneumococcal, COVID-19, with live vaccines avoided during immunosuppression), provide prompt antibiotic access for febrile episodes, and consider intravenous immunoglobulin for recurrent bacterial infection with a low serum IgG. I would screen for hepatitis B reactivation risk before anti-CD20 therapy." [1] />

Pillar 4 — Complication surveillance: "I would warn him to report rapid lymph-node enlargement, new B-symptoms, or a rapid clinical change — any of which would prompt an urgent node biopsy and a lactate dehydrogenase for Richter transformation, which complicates 2 to 10 percent of CLL. I would also watch for autoimmune haemolytic anaemia and immune thrombocytopenia, treated first-line with corticosteroids." [1] />

Pillar 5 — Counselling: "I would explain that CLL with TP53 disruption is currently incurable except by allogeneic stem cell transplant (which is not first-line here), that therapy is aimed at long disease control, and that the novel agents have transformed the outlook for his biology. I would introduce a cancer nurse coordinator and provide written information." [1] />

Probing questions the examiner would ask

Q: Why would you not offer this fit man FCR — is fitness not the main criterion? [1] />

A: "Fitness is necessary but not sufficient. FCR is the gold standard for fit patients with favourable biology — a mutated IGHV status and intact TP53 — in whom the CLL8 trial showed a survival benefit and a subset achieves durable remission consistent with cure [1]. But the TP53 disruption (del(17p) and TP53 mutation) confers resistance to chemoimmunotherapy: FCR and BR both produce poor and short-lived responses in TP53-disrupted disease. So the treatment decision is driven by the molecular biology, not by fitness alone. This is exactly why every patient with newly diagnosed CLL must have IGHV mutation status and TP53 (FISH del(17p) plus sequencing) tested at diagnosis — they direct the first treatment decision toward a novel agent when disrupted [4]."

Q: What is the mechanism of ibrutinib, and what toxicities must you warn the patient about? [1] />

A: "Ibrutinib is an irreversible covalent inhibitor of Bruton tyrosine kinase (BTK), a key node in the B-cell receptor signalling pathway that CLL cells depend on. Blocking BTK disrupts the survival and proliferation signals, and traps CLL cells in the lymph node and marrow microenvironments, releasing them into the blood (producing a transient lymphocytosis that is not progression). It is given continuously until progression. The toxicities I would warn about are bleeding (an antiplatelet effect that matters with anticoagulants and around procedures), atrial fibrillation (which may require dose modification and a cardiology assessment), hypertension, infection (with opportunistic prophylaxis), and a rash. It is generally well tolerated, which is why it has displaced chemoimmunotherapy in many settings [2]."

Q: If he were in deep molecular response and his CLL were replaced by CML, how would you approach stopping therapy? [1] />

A: "That is the treatment-free remission question. Treatment-free remission is attempted only in chronic-phase CML, after at least three years of tyrosine kinase inhibitor therapy and a sustained deep molecular response (MR4 or deeper for over two years). The STIM trial was the proof of concept that around 40 to 60 percent of well-selected patients maintain a molecular remission off therapy, with relapse (when it occurs) usually within six months and reliably regained on restarting [1] />. After stopping, BCR-ABL1 is monitored monthly for six months then less frequently, with re-initiation if loss of major molecular response. It is a shared decision weighing freedom from lifelong therapy against the monitoring burden. This principle does not yet apply to CLL, where novel agents are generally given either continuously (ibrutinib) or as a defined course (venetoclax combinations) within a treatment paradigm rather than a discontinuation one."

Q: What is the role of allogeneic stem cell transplant in CLL today? [1] />

A: "Transplant is the only potentially curative modality for CLL, but it is not first-line in the era of effective novel agents. It is reserved for the small subset of patients whose disease is refractory to or relapses after both a BTK inhibitor and a BCL-2 inhibitor, or who have a particularly poor-risk biology with transplant-eligible fitness. It carries substantial treatment-related mortality and chronic graft-versus-host disease, so for most patients long disease control on sequential novel agents is preferable. I would not discuss transplant first-line for this patient; I would revisit it only if he exhausted the novel agents." [1] />

Q: How would you recognise and manage Richter transformation? [1] />

A: "Richter transformation is the transformation of CLL into an aggressive diffuse large B-cell lymphoma (rarely Hodgkin lymphoma), complicating 2 to 10 percent of patients. I would suspect it with a discordant, rapid change — rapid lymph-node enlargement at one site, new or worsening B-symptoms (fever, sweats, weight loss), a rising lactate dehydrogenase, or a PET-avid node. The diagnosis requires a node biopsy (not the blood count) showing diffuse large B-cell lymphoma. Treatment is with aggressive chemoimmunotherapy such as R-CHOP, with a consideration of allogeneic transplant in responders. The prognosis is poor, with a median survival under a year in many series, so early recognition and biopsy are essential. I would never assume a rapid clinical change is simple disease progression without biopsying." [1] />

Communication and shared decision-making

"Mr M, you have a type of leukaemia called chronic lymphocytic leukaemia, and the tests show it is now active and causing your symptoms, so we need to start treatment. The important result from the molecular tests is a change in a gene called TP53, which means the standard chemotherapy-based approach is unlikely to work well for you — but we have newer, highly effective targeted drugs that work in a different way and are specifically suited to your type of disease. I would like to discuss two options with you. The first is a tablet called ibrutinib that you take every day — it works very well but it is a long-term treatment, and it can cause some bleeding tendency, a racing heart, and a higher blood pressure. The second is a combination including a drug called venetoclax that you take for a fixed period of about a year — it can also work very well, but because your lymphocyte count is high we have to start it slowly and monitor you closely to avoid a complication called tumour lysis syndrome, where the breaking-down leukaemia cells upset the blood salts. Neither approach will cure the leukaemia, but both can control it for a long time. I will give you written information, introduce you to a cancer nurse coordinator who will be your consistent point of contact, and we will review your progress closely. There are some things I want you to watch for and tell us about straight away — new fevers and sweats, rapidly enlarging glands, or any new symptoms — because they may mean the disease has changed and we need to re-biopsy. Do you have questions, and which of the two approaches would you like to discuss further?" [1] />

Short Case Discussion — Lymphadenopathy and Splenomegaly

Instruction: "Examine this patient's abdomen and the lymph nodes, and comment on the relevant general signs." [1] />

Systematic examination routine

1. End of bed — observe for cachexia (advanced malignancy), pallor (anaemia from marrow infiltration or autoimmunity), bruising or petechiae (thrombocytopenia), and jaundice (haemolysis or hepatic infiltration). Look for scratch marks (pruritus in polycythaemia vera or lymphoma).
2. Hands and arms — pallor of the palmar creases and conjunctivae, koilonychia, peripheral stigmata, and palpable axillary, supraclavicular and epitrochlear nodes.
3. Neck — systematically palpate the cervical chains (submental, submandibular, upper cervical, lower cervical, posterior triangle, supraclavicular), noting the size, consistency, mobility and whether they are matted or tender. A Virchow (left supraclavicular) node suggests abdominal malignancy.
4. Abdomen — inspect for distension (splenomegaly, hepatomegaly, ascites), then palpate lightly then deeply for the spleen (start in the right iliac fossa and move toward the left upper quadrant on inspiration) and the liver. Percuss for splenic dullness and shifting dullness (ascites).
5. Examine the rest — for lymphoma, examine the oropharynx (Waldeyer ring) and the skin; for an MPN, look for plethoric facies (polycythaemia vera) and gouty tophi. [1] />

Key physical signs the patient demonstrates (for this case)

• Painless, rubbery, mobile cervical and axillary lymphadenopathy (CLL or lymphoma).
• A firm, non-tender spleen palpable below the costal margin (CLL, CML, myelofibrosis, lymphoma).
• Conjunctival pallor and bruising (marrow failure from infiltration or autoimmunity). [1] />

Presentation template

"I examined Mr M, who appears pale at the end of the bed. The hands show no peripheral stigmata of chronic disease. There is shotty, mobile, non-tender cervical lymphadenopathy, with a 2 cm rubbery node in the left axilla. The spleen is palpable 4 cm below the left costal margin with a firm, non-tender edge; the liver is not enlarged. There is no ascites. These findings — painless lymphadenopathy with splenomegaly and pallor — are consistent with a lymphoproliferative disorder such as chronic lymphocytic leukaemia or lymphoma. I would like to check the full blood count and film, perform flow cytometry on the peripheral blood to characterise any clonal lymphocyte population, and arrange cross-sectional imaging to stage the disease." [1] />

Discussion questions

Q: How do you distinguish CML from a leukaemoid reaction? [1] />

A: "Both produce a high neutrophil count with a left shift, but the leucocyte alkaline phosphatase (LAP) score separates them — it is low in CML and high in a leukaemoid reaction. CML also shows characteristic basophilia and the full spectrum of myeloid maturation, and is confirmed by demonstrating the BCR-ABL1 fusion by cytogenetics, FISH or quantitative PCR. A leukaemoid reaction is reactive, driven by infection, inflammation or a tumour, and lacks the Philadelphia chromosome." [1] />

Q: What is the differential of massive splenomegaly? [1] />

A: "The causes of a spleen palpable into the right iliac fossa include chronic myeloid leukaemia, myelofibrosis (with a leucoerythroblastic film of teardrop cells and nucleated red cells), chronic malaria, visceral leishmaniasis (kala-azar), Gaucher disease, and massive lymphomatous or portal-hypertensive splenomegaly. The blood film and count point the way: a left-shifted neutrophilia with basophilia suggests CML; a leucoerythroblastic film suggests myelofibrosis; pancytopenia with a dry marrow tap suggests myelofibrosis or infiltration." [1] />

Q: When would you test for the JAK2 V617F mutation? [1]

A: "I would test for JAK2 V617F in any patient with a suspected myeloproliferative neoplasm — polycythaemia vera (raised haematocrit), essential thrombocythaemia (sustained high platelet count), or primary myelofibrosis (leucoerythroblastic film with splenomegaly) — and crucially in any patient with splanchnic vein thrombosis (Budd-Chiari syndrome, portal vein thrombosis) even when the blood count is normal, because an occult myeloproliferative neoplasm is a leading cause and the clone may be present before the count rises." [1] />

Q: What is the principle of watch and wait in CLL, and when do you treat? [1] />

A: "Watch and wait is the standard for asymptomatic early-stage CLL (Binet A, Rai 0), because early treatment confers no overall survival advantage and only adds toxicity. Treatment begins when an iwCLL active-disease criterion is met — progressive marrow failure (anaemia or thrombocytopenia), massive or progressive splenomegaly or lymphadenopathy, a rapidly rising lymphocyte count, autoimmune cytopenias poorly responsive to steroids, or symptomatic disease-related features. The lymphocyte count alone is never an indication [4]. This is one of the most important and most frequently tested principles in the chronic leukaemia topic."