Chronic Leukaemia and Myeloid Neoplasms — Written Clinical Reasoning

SAQ 1 — Symptomatic CLL with TP53 disruption: the novel-agent decision (15 marks, 30 minutes)

Prompt: Outline your staging synthesis, the treatment decision and its justification, the approach to prognostic counselling, and the anticipated complications and their management. [1] />

Model Answer

Step 1 — The staging synthesis (3 marks): [1]

This man has symptomatic, active chronic lymphocytic leukaemia. By the Rai system he is stage III to IV (anaemia with Hb of 104, and thrombocytopenia with platelets of 86 — both indicating marrow failure); by the Binet system he is stage C (anaemia and thrombocytopenia with widespread lymphoid involvement). The iwCLL criteria for active disease are clearly met — progressive marrow failure (worsening anaemia and thrombocytopenia), massive and progressive lymphadenopathy, and disease-related B-symptoms (fevers, drenching night sweats, weight loss) [4]. This is not a watch-and-wait situation; the disease is active and treatment is indicated.

The immunophenotype is the classic CLL fingerprint: CD5-positive, CD19-positive, CD23-positive clonal B cells with restricted light chain. The two molecular findings are pivotal and define his prognosis and therapy: an unmutated IGHV status (aggressive biology) and deletion of 17p with a TP53 mutation (chemoresistance). TP53 disruption is the single most adverse prognostic feature in CLL. [1] />

Step 2 — The treatment decision and its justification (5 marks): [1] />

Because of the TP53 disruption (del(17p) and TP53 mutation), this patient must not receive chemoimmunotherapy. FCR (fludarabine, cyclophosphamide, rituximab) and BR (bendamustine, rituximab) both produce poor and short-lived responses in TP53-disrupted disease and would expose him to toxicity with little benefit. The evidence-based approach is a novel agent targeting the B-cell receptor pathway or apoptosis [2][3].

The two first-line options are: [1]

• Ibrutinib (with or without obinutuzumab) — an irreversible Bruton tyrosine kinase (BTK) inhibitor that blocks B-cell receptor signalling. The RESONATE-2 trial established first-line ibrutinib in older patients, and its activity extends to TP53-disrupted and unmutated-IGHV disease [2]. It is given continuously until progression. Characteristic toxicities are bleeding (antiplatelet effect), atrial fibrillation, hypertension, infection and rash.
• Venetoclax with obinutuzumab — a BCL-2 inhibitor that restores the intrinsic apoptotic pathway, given as a time-limited course (typically 12 months in the first-line combination). The MURANO trial (venetoclax-rituximab in relapsed disease) showed high rates of measurable residual disease negativity and durable progression-free survival [3].

For this otherwise fit 62-year-old, both are reasonable; I would discuss the trade-offs — continuous (ibrutinib) versus time-limited (venetoclax), the atrial fibrillation and bleeding risk of ibrutinib, and the tumour lysis syndrome risk of venetoclax — and make a shared decision. I would explicitly not offer FCR here, even though he is fit, because the TP53 disruption makes chemoimmunotherapy ineffective. The key teaching point: always test IGHV mutation status and TP53 (FISH del(17p) plus sequencing) at CLL diagnosis, because they direct the first treatment decision. [1] />

Step 3 — Venetoclax tumour lysis syndrome precaution (2 marks): [1] />

If venetoclax is chosen, the mandatory tumour lysis syndrome (TLS) precaution is central. This patient is high-risk for TLS by virtue of a high lymphocyte count (over 25) and bulky lymphadenopathy. The protocol is the 5-week ramp-up dosing schedule (20, 50, 100, 200, then 400 mg), aggressive hydration, allopurinol (or rasburicase for the highest risk), and frequent monitoring of potassium, phosphate, calcium, creatinine and uric acid during the ramp-up. Failing to use the ramp-up and TLS prophylaxis can precipitate fatal TLS. [1] />

Step 4 — Prognostic counselling (2 marks): [1]

I would be honest but hopeful. The TP53 disruption and unmutated IGHV predict a more aggressive course than the average CLL, and historically the prognosis was poor with chemoimmunotherapy. However, the novel agents (ibrutinib, venetoclax) have transformed the outlook for TP53-disrupted disease, with durable disease control in a majority. I would explain that the disease 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 relapse is likely to require an alternative novel agent or a clinical trial. I would provide written information and introduce a cancer nurse coordinator. [1] />

Step 5 — Anticipated complications and their management (3 marks): [1] />

• Infection — from hypogammaglobulinaemia and treatment-related immunosuppression. I would ensure vaccination before therapy, provide prompt antibiotic access for febrile episodes, and consider intravenous immunoglobulin for recurrent bacterial infection with a low IgG.
• Autoimmune cytopenias — autoimmune haemolytic anaemia and immune thrombocytopenia complicate CLL in 5 to 10 percent. I would treat with corticosteroids first-line and rituximab for steroid-refractory disease.
• Richter transformation — transformation to diffuse large B-cell lymphoma in 2 to 10 percent. I would warn the patient to report rapid lymph-node enlargement, new B-symptoms, or a rapid clinical change; any such change warrants an urgent node biopsy and a raised LDH. [1] />

SAQ 2 — Chronic myeloid leukaemia in chronic phase: monitoring milestones, resistance and pregnancy (10 marks, 20 minutes)

Prompt: A 36-year-old woman is diagnosed with chronic-phase chronic myeloid leukaemia (BCR-ABL1 positive). She is started on dasatinib and achieves a major molecular response by 12 months. She now, at 18 months, wishes to plan a pregnancy, and a repeat BCR-ABL1 has risen from a stable major molecular response. Discuss the molecular monitoring milestones, the interpretation of the rising transcript, the management of the T315I mutation if found, and the approach to pregnancy. [1] />

Model Answer

Step 1 — The molecular monitoring milestones (3 marks): [1] />

The cornerstone of CML monitoring is serial quantitative RT-PCR for BCR-ABL1 on the International Scale, measured at 3, 6, 12 and 18 months and then periodically. The milestones are: the early molecular response (EMR), a BCR-ABL1 transcript under 10 percent at 3 months; the major molecular response (MMR), under 0.1 percent (typically by 12 months, which this patient achieved on dasatinib); and the deep molecular response (DMR), MR4 (under 0.01 percent) or MR4.5 (under 0.0032 percent), sustained for over 2 years, which is the prerequisite for considering treatment-free remission [7]. Dasatinib achieves faster and deeper responses than imatinib (the DASISION trial) [5].

Step 2 — The rising transcript — interpretation (3 marks): [1] />

A confirmed rise in BCR-ABL1 (a one-log rise with loss of MMR) is loss of response and mandates a structured assessment. The first steps are to confirm adherence (prescription records, patient history) and to review drug interactions — particularly CYP3A4 inhibitors and inducers, which markedly affect dasatinib levels. Non-adherence and drug interactions are the commonest causes of loss of response before acquired resistance. After excluding these, the next step is BCR-ABL1 kinase domain mutation testing to identify the resistance mechanism and guide the switch to the appropriate tyrosine kinase inhibitor. [1] />

Step 3 — The T315I mutation and ponatinib (2 marks): [1]

If mutation testing reveals the T315I gatekeeper mutation, only ponatinib is active — imatinib, dasatinib, nilotinib and bosutinib all fail against T315I. The PACE trial established ponatinib's activity in heavily pretreated and T315I-positive disease [6]. Ponatinib carries a significant risk of arterial and venous thromboembolism, so I would perform a cardiovascular risk assessment and use dose optimisation. Allogeneic stem cell transplant is reserved for failure of all available tyrosine kinase inhibitors, including ponatinib, or for progression to accelerated or blast phase.

Step 4 — Management in pregnancy (2 marks): [1]

Tyrosine kinase inhibitors (dasatinib included) are teratogenic and must be stopped before conception and throughout pregnancy and breastfeeding. The safe agent in pregnancy is interferon-alpha, which does not cross the placenta. If she is in a stable deep molecular response, she may be managed off therapy with close molecular monitoring during pregnancy, reserving interferon for any loss of response. Leukapheresis is reserved for symptomatic leucostasis. Management requires a joint haematology and obstetric plan, with counselling that pregnancy is possible but must be carefully planned around her disease control [7]. I would not recommend allogeneic stem cell transplant to facilitate pregnancy.