Chronic Leukaemia (CLL & CML)

Meet the patient

A 72-year-old man is sent to you after a routine blood count shows a white-cell count of 140×10⁹/L. He feels well but has lost weight, sweats at night, and admits his abdomen feels "full after two mouthfuls". On examination his spleen reaches the umbilicus. The film shows the full granulocytic spectrum with basophilia, and the LAP score is low.[1]

A second patient — a 68-year-old woman — arrives with painless rubbery cervical nodes and a lymphocyte count of 35×10⁹/L. Her film shows smudge cells. She asks, perfectly reasonably, "when do I start chemotherapy?"[3]

Two patients, two diseases, and the exam tests hinge on the same fork every time: which chronic leukaemia is this, and — just as importantly — does this patient need treatment today? Everything below answers those two questions at consultant depth.[1][5]

Two diseases, one label — and the opposite biology that runs them

Chronic leukaemia means mature-appearing cells accumulating over months to years — not blasts over days. That single contrast with acute leukaemia is where the topic begins. Both CLL and CML are clonal marrow stem-cell disorders, but they accumulate their cells by opposite mechanisms, which is why their drugs work by opposite logic.[3]

[1]

The skill in chronic leukaemia is not making the diagnosis — a blood film, flow cytometry and a BCR-ABL1 PCR do that. The skill is recognising when NOT to treat (early CLL), picking the right first drug (TKI choice in CML, chemoimmunotherapy versus targeted therapy in CLL), staging for prognosis, monitoring the molecular response (BCR-ABL1 PCR in CML, MRD in CLL), and catching transformation early — Richter in CLL, blast crisis in CML.[1]

CML phases — the three doors the blast percentage opens

The phase decides urgency, treatment and prognosis — memorise the blast cut-offs. The phase is defined by the blast percentage in blood and marrow, the basophil percentage, and whether the disease has acquired new cytogenetic chaos.[5]

• Chronic phase — blasts under 5 percent; the patient is usually well; a TKI works beautifully.
• Accelerated phase — one or more of: blasts 10 to 19 percent; basophils at least 20 percent; therapy-resistant thrombocytopenia (under 100×10⁹/L) or thrombocytosis (over 1000×10⁹/L); clonal evolution (new chromosomal abnormalities); progressive splenomegaly or leucocytosis unresponsive to therapy.
• Blast crisis — blasts at least 20 percent (WHO), or extramedullary blasts (chloroma, skin). Usually myeloid (about 70 percent) or lymphoid (about 30 percent, B-ALL phenotype). It behaves like acute leukaemia and the prognosis is poor.[1]

Who gets it, and why

CLL is a disease of Western older adults; CML is everywhere and radiation-linked. The epidemiology is itself an exam favourite because the two diseases diverge so cleanly.[1]

CLL: the commonest leukaemia in the Western world (about 25 to 30 percent of adult leukaemias), median age 70, rare under 40, slight male predominance. It is strikingly rare in East Asia — and stays rare in Asian immigrants to the West, pointing to genetic susceptibility. First-degree relatives carry a roughly 5 to 7-fold risk, one of the strongest inherited predispositions of any adult cancer. There is no clear link to ionising radiation. Its pre-neoplastic precursor, monoclonal B-cell lymphocytosis (MBL), is found in 5 to 10 percent of people over 60 and progresses at about 1 to 2 percent per year.[1]

CML: about 15 percent of adult leukaemias, incidence 1 to 2 per 100,000 per year, median age 55 to 60. The one firmly linked exposure is ionising radiation — atomic-bomb survivors had a 5 to 10-fold risk with a 5 to 10-year latency. Most cases have no identifiable risk factor, it is not inherited, and sibling risk is only modest.[1]

Opposite biology — why CLL is slow and CML is driven

CLL is a disease of cell survival; CML is a disease of a runaway kinase. Hold that one sentence and every drug in the topic makes sense.[1]

Chronic lymphocytic leukaemia

CLL arises from a mature B-cell. Two biologically distinct subtypes share one immunophenotype: IGHV-mutated (a post-germinal-centre memory B-cell, indolent, median survival over 20 years) and IGHV-unmutated (a naive B-cell, aggressive, median survival about 8 years). The mutation status is a core prognostic test.[1]

The driving defect is BCL2 over-expression: deletion of miR-15a/16-1 at 13q14.3 removes the brake on the anti-apoptotic BCL2 protein, so lymphocytes survive without dividing rapidly. They accumulate in marrow, blood, nodes and spleen. That is exactly why BCL2-targeted venetoclax is so effective — the drug restores the cell death the clone has been refusing.[1]

The Döhner cytogenetic hierarchy — read on interphase FISH on blood, with the worst lesion governing prognosis — is one of the most reproduced ladders in haematology exams:[2]

• del(17p13.1) / TP53 — worst; chemo-refractory, median survival about 30 months. Steers you to targeted agents, never chemoimmunotherapy.
• del(11q) / ATM — adverse; bulky nodes, faster progression.
• Trisomy 12 — intermediate; atypical morphology, higher Richter risk.
• Normal karyotype — intermediate.
• del(13q14.3) as the sole abnormality — best; median over 15 years.[2]

The B-cell receptor signalling pathway that sustains the clone is the target of the BTK inhibitors (ibrutinib, acalabrutinib) and PI3K-δ inhibitors (idelalisib, duvelisib).[1]

Chronic myeloid leukaemia

CML is defined by the Philadelphia chromosome — a balanced t(9;22)(q34;q11.2) that fuses ABL1 (chromosome 9) with BCR (chromosome 22) on the derivative chromosome 22. The fusion gene makes a constitutively active tyrosine kinase (p210) that fires RAS–RAF–MEK–ERK (proliferation), PI3K–AKT (survival) and STAT5 (transcription).[4]

This single lesion explains every feature of CML: massive granulocytic expansion with the full maturation spectrum, basophilia (essentially pathognomonic for a myeloproliferative neoplasm), a low LAP score (the kinase suppresses LAP — the discriminator from leukemoid reaction), splenomegaly from extramedullary haematopoiesis, and progression to blast crisis as genomic instability layers on TP53, RUNX1 and ABL1 kinase-domain mutations.[1]

The discovery that CML ran on one oncogenic kinase made it the paradigm of targeted therapy — imatinib, a small molecule that jams the ATP pocket of ABL1, turned a near-fatal disease into a chronic one with near-normal life expectancy.[4]

Etymology for viva gold: the Philadelphia chromosome was first spotted in 1960 in — yes — Philadelphia, by Nowell and Hungerford. It was the first specific chromosomal abnormality ever linked to a human cancer, two decades before anyone knew it made a kinase. The name stuck even after the mechanism was solved.[4]

How they walk into clinic

CLL is usually an incidental finding; CML usually has symptoms. That difference is itself an exam discriminator.[3]

Chronic lymphocytic leukaemia

About 70 percent of CLL patients are asymptomatic at diagnosis — picked up on a routine count showing lymphocytosis. When symptomatic, expect:[1]

• Constitutional "B" symptoms — fatigue (commonest), weight loss over 10 percent in 6 months, drenching night sweats, fever without infection (38°C or higher for at least 2 weeks).
• Lymphadenopathy — painless, symmetrical, rubbery, mobile; cervical, supraclavicular, axillary, inguinal.
• Splenomegaly or hepatomegaly — usually mild to moderate.
• Infections — recurrent bacterial (sinopulmonary, zoster) from hypogammaglobulinaemia and T-cell dysfunction.
• Autoimmune cytopenias — warm-antibody AIHA in 10 to 15 percent, ITP, pure red-cell aplasia; Evans syndrome is AIHA plus ITP together.[1]

The classic trap — autoimmune cytopenia is NOT marrow failure. The Coombs-positive haemolysis or the ITP does not count toward Binet stage C and is treated in its own right (steroids, rituximab), not with CLL-directed therapy. Confusing the two is a recurring trainee error.[1]

The Richter alarm bell: a known CLL patient with a rapidly enlarging node, a rising LDH and new B-symptoms is transforming into diffuse large B-cell lymphoma — about a 2 to 10 percent lifetime risk, median survival under a year. PET-CT (SUV max over 5) and a node biopsy confirm it.[2]

Chronic myeloid leukaemia

CML presents insidiously but with more symptoms than CLL, because the white-cell count is typically much higher:[1]

• Fatigue, weight loss, early satiety (the spleen), low-grade fever, night sweats — the metabolic cost of a huge granulocyte mass.
• Splenomegaly in over 90 percent — often massive, reaching below the umbilicus; left-upper-quadrant fullness or pain from infarction.
• Hypermetabolism and leucostasis — gout or hyperuricaemia from cell turnover; priapism (leucostasis in the corpora — rare but classic); visual disturbance, headache and confusion when the WBC exceeds about 200×10⁹/L.
• Asymptomatic detection on a routine count in 40 to 50 percent of modern cases.[1]

The differential — what it is NOT

An asymptomatic lymphocytosis is not always CLL, and a marked granulocytosis is not always CML. Name the mimic and the single discriminator.[1]

The CLL differential: [1]

• Reactive lymphocytosis — atypical lymphocytes, an acute viral illness (EBV, CMV, HIV), pertussis (marked lymphocytosis with a paroxysmal cough), toxoplasmosis. Flow cytometry is polyclonal and CD5-negative, and it resolves.
• Mantle-cell lymphoma (leukaemic phase) — the exam trap. It is CD5+ like CLL but CD23-negative, cyclin D1-positive, t(11;14). If the stem says "CD5-positive" and you reach for CLL, check CD23 and cyclin D1 first.
• Hairy-cell leukaemia — pancytopenia (not lymphocytosis), monocytopenia, dry tap, TRAP-positive cells, BRAF V600E, splenomegaly without nodes.[10]

The CML differential: [1]

• Leukemoid reaction — the classic mimic. Distinguishing features: toxic granulation and Döhle bodies, left shift but no basophilia, a HIGH LAP score, an underlying infection or inflammation, usually no splenomegaly, and no BCR-ABL1. The single best discriminator is the LAP score.
• Other myeloproliferative neoplasms — polycythaemia vera, essential thrombocythaemia, primary myelofibrosis — all BCR-ABL1-negative.[1]

The face-off — leukemoid reaction versus CML: [1]

[1]

The discriminator line: a low LAP score with basophilia points to CML; a high LAP score with toxic changes points to a leukemoid reaction. Send the BCR-ABL1 PCR to settle it. [1]

For splenomegaly in general, add portal hypertension, visceral leishmaniasis (kala-azar) in an Indian exam stem, malaria, Felty syndrome (rheumatoid arthritis plus splenomegaly plus neutropenia) and myelofibrosis.[1]

The bedside round

Examination rarely makes the diagnosis — that is the laboratory's job — but it stages, finds complications, and catches the emergencies.[1]

Run it in order: general (pallor, bruising, cachexia, fever); all lymph-node regions including epitrochlear (note size, consistency — rubbery in lymphoma, hard in carcinoma — mobility, matting); abdomen for spleen and liver, grading splenomegaly with the Hackett scale (1 just palpable, 3 to the umbilicus, 5 into the pelvis, 6 across the midline); sternal tenderness (marrow infiltration); the skin (chloroma, leukaemia cutis); and signs of haemolysis or hyperviscosity.[1]

Bedside red flags that demand action now: WBC over 100×10⁹/L with leukostasis symptoms; suspected blast crisis (new cytopenia, rising blasts); suspected Richter transformation; impending tumour lysis at treatment initiation; severe autoimmune haemolysis with a falling haemoglobin.[1]

Making the diagnosis — flow for CLL, BCR-ABL1 for CML

Chronic lymphocytic leukaemia

The iwCLL 2018 diagnostic criterion requires all three:[3]

1. Peripheral-blood B-lymphocyte count at least 5×10⁹/L, sustained at least 3 months.
2. Clonality on flow cytometry (kappa or lambda light-chain restriction).
3. The characteristic immunophenotype (Matutes score at least 3): CD5+, CD19+/CD20 dim, CD23+, surface Ig dim, CD79b/CD22 dim, FMC7 negative. A score of 4 or 5 confirms CLL; a score of 3 is equivocal and needs cyclin D1 and t(11;14) testing to exclude mantle-cell lymphoma.[1]

First-line tests: FBC and film (lymphocytosis, smudge cells, spherocytes if AIHA); flow cytometry on peripheral blood — a marrow sample is not required to make the diagnosis; a direct Coombs test; serum immunoglobulins; LDH and beta-2 microglobulin (prognosis); CT only for bulky or symptomatic disease.[1]

Before any treatment, send the prognostic battery: interphase FISH for the Döhner lesions, TP53 sequencing, IGHV mutational status, and a targeted NGS panel (NOTCH1, SF3B1, BIRC3). Bone marrow and node biopsy are reserved for cytopenia of unclear cause or suspected Richter.[2]

Chronic myeloid leukaemia

Diagnosis requires demonstration of BCR-ABL1 — there is no diagnosis without it.[1]

The FBC shows marked leucocytosis (median about 100×10⁹/L, sometimes over 500×10⁹/L) with the full granulocytic spectrum and basophilia — the single most useful film clue. The LAP score is low (under 20). Marrow shows hypercellularity, granulocytic hyperplasia with full maturation, and small "dwarf" megakaryocytes. Cytogenetics shows t(9;22) in over 90 percent; the rest need FISH or quantitative RT-PCR for BCR-ABL1 transcripts (p210) to catch a cryptic translocation.[1]

Staging — Rai and Binet for CLL, Sokal/ELTS for CML

The scores are reproduced verbatim because the examiner does. Know the cut-offs cold.[3]

Rai staging of CLL (original 5-tier): [3]

[1]

Binet staging (3-tier, European): [3]

[1]

Each nodal region (cervical, axillary, inguinal) counts as one whether unilateral or bilateral; spleen and liver make five. Note again: autoimmune cytopenias do not count toward Binet C.[3]

For CML, the risk score at diagnosis is the ELTS score (age, spleen size, blast percent, platelet count) — now preferred by the ELN because it is superior to the older Sokal score for predicting CML-related mortality. The Sokal score (cut-offs: under 0.8 low, 0.8 to 1.2 intermediate, over 1.2 high) is still examined, but name the ELTS score as the modern tool.[11]

Monitoring the molecular response in CML — the milestones that drive every decision

The BCR-ABL1 transcript PCR on the International Scale is the single most important monitoring test in CML. Fail a milestone and you switch the TKI.[5]

[1]

Failure to reach EMR at 3 months or MMR by 12 months triggers an ABL1 kinase-domain mutation test and a TKI switch.[5]

The emergencies — leukostasis, tumour lysis, Richter, blast crisis

[1]

Chronic leukaemias rarely present as emergencies — but four scenarios need immediate recognition:[1]

1. Leukostasis (CML with WBC over about 200×10⁹/L, or very high-count CLL) — headache, visual disturbance, confusion, dyspnoea, priapism, stroke. Treat with aggressive hydration, hydroxycarbamide 50 to 100 mg/kg/day orally to drop the count fast, leukapheresis in extreme cases, and prompt disease-directed therapy.
2. Tumour lysis syndrome — at the start of therapy in bulky disease (high WBC, bulky nodes, high LDH). Prophylaxis: aggressive IV hydration, rasburicase 0.15 to 0.2 mg/kg/day (or a single 3 to 6 mg fixed dose) for high-risk or allopurinol 300 mg/day orally for moderate risk; monitor potassium, phosphate, calcium, urate and creatinine every 4 to 6 hours for 24 to 48 hours.
3. Severe autoimmune haemolysis or ITP in CLL — prednisolone 1 mg/kg/day orally (methylprednisolone 1 g/day IV if severe), rituximab 375 mg/m² IV weekly for 4 for refractory disease, transfuse for symptomatic anaemia, IVIG 0.4 g/kg/day for 5 days if still refractory.
4. Sepsis in the immunosuppressed patient — neutropenic sepsis gets blood cultures and broad-spectrum piperacillin-tazobactam 4.5 g IV 6-hourly within one hour, plus CMV/HSV/EBV checks and PCP prophylaxis (co-trimoxazole 480 mg daily) on BTK therapy.[1]

Treating CLL — the skill is knowing when NOT to treat

Early-stage inactive CLL is watched, not treated. Multiple randomised trials showed no survival benefit to early treatment with chlorambucil or even modern agents. The patient is followed 6 to 12-monthly, and therapy is reserved for active disease. This single fact — that doing nothing is correct for Binet A / Rai low disease — is the most tested idea in the topic.[3]

The iwCLL 2018 indications for treatment (any one): progressive marrow failure (Hb under 10 g/dL or Plt under 100×10⁹/L); massive, progressive or symptomatic splenomegaly or lymphadenopathy; a lymphocyte doubling time under 6 months; refractory autoimmune cytopenia; symptomatic extranodal disease; or disease-related B-symptoms.[3]

First-line therapy is risk-adapted to fitness, IGHV status and TP53:[1]

• Fit, TP53-wildtype, IGHV-mutated → FCR (fludarabine 25 mg/m² days 1 to 3; cyclophosphamide 250 mg/m² days 1 to 3; rituximab 375 mg/m² cycle 1 then 500 mg/m²) for 6 cycles — potentially curative in this subset. CLL8 established FCR over FC.[1]
• Unfit or comorbid → BR (bendamustine 90 mg/m² days 1 and 2 plus rituximab).
• TP53-mutated / del(17p), or unfit, or preferred oral therapy → BTK inhibitor — ibrutinib 420 mg orally daily continuously (RESONATE-2), or acalabrutinib 100 mg twice daily.[6]
• OR BCL2 inhibition → venetoclax plus obinutuzumab, fixed-duration 12 months — CLL14 showed durable MRD-negative responses at 6 years.[12]
• Elderly or frail without access to targeted therapy → chlorambucil plus obinutuzumab.[1]

Relapsed or refractory CLL → venetoclax plus rituximab for 24 months — the MURANO standard — or a BTK/PI3K inhibitor.[7]

Supportive care is non-negotiable: IVIG for recurrent infection with hypogammaglobulinaemia; vaccination (influenza, pneumococcal, recombinant zoster — no live vaccines); hepatitis B reactivation prophylaxis (entecavir or tenofovir) before any anti-CD20 therapy in HBsAg-positive or anti-HBc-positive patients.[1]

Treating CML — an oral TKI from day 1

The treatment of chronic-phase CML is an oral TKI, started within days of diagnosis and usually continued for life. Imatinib 400 mg once daily is the standard; the second-generation TKIs achieve faster, deeper responses and are first-line options, especially in higher-risk disease.[1]

[1] [8]

Treatment-free remission — patients on dasatinib or nilotinib (and increasingly imatinib) in a sustained deep molecular response (MR4 or MR4.5 for at least 2 years) may stop the TKI under monitoring; about 40 to 60 percent stay in remission, with BCR-ABL1 PCR checked monthly then 2-monthly and the TKI restarted on loss of MMR.[5]

Accelerated phase — switch to a second-generation TKI and proceed to allogeneic stem-cell transplant once back in second chronic phase. Blast crisis is treated as AML (myeloid) or B-ALL (lymphoid) plus a TKI, bridging to allogeneic transplant in responders; prognosis remains poor.[1]

The subtypes that bite

• Hairy-cell leukaemia — pancytopenia with monocytopenia, splenomegaly without nodes, a dry tap, TRAP-positive hairy cells, BRAF V600E, annexin A1-positive. First-line cladribine 0.09 mg/kg/day IV for 7 days (a single course) gives long-lasting complete remission in over 80 percent.[10]
• T-cell prolymphocytic leukaemia — aggressive; marked lymphocytosis, hepatosplenomegaly, skin and serous effusions; CD3+, TCL1+. Treat with alemtuzumab (anti-CD52).
• Large granular lymphocytic leukaemia — indolent; chronic neutropenia with recurrent oral ulcers, pure red-cell aplasia, rheumatoid arthritis (Felty-like). Often watch-and-wait; low-dose methotrexate or ciclosporin for symptomatic cytopenias.
• CML in pregnancy — interferon-alfa is the only agent considered safe; avoid TKIs, especially in the first trimester. Use leukapheresis and hydroxycarbamide for short-term cytoreduction.[1]

When it goes wrong — complications and the traps that cost marks

CLL complications: infection (the leading cause of death, from hypogammaglobulinaemia and treatment); autoimmune cytopenias; Richter transformation to DLBCL (rising LDH, rapid node, new B-symptoms — PET-CT and biopsy); second cancers (skin, lung, GI); and tumour lysis at treatment initiation.[1]

CML complications: progression through the phases (the natural history of 3 to 5 years is now near-normal with a TKI); drug-specific toxicities — dasatinib and pleural effusion, nilotinib and QT or sudden death, ponatinib and arterial thrombosis, imatinib and fluid retention; and ABL1 kinase-domain resistance, the most infamous being T315I (the "gatekeeper" mutation), sensitive only to ponatinib and asciminib.[1]

The classic diagnostic pitfalls: [1]

• Diagnosing mantle-cell lymphoma as CLL — both CD5-positive, but MCL is CD23-negative, cyclin D1-positive, t(11;14).
• Treating a leukemoid reaction as CML — check the LAP score and BCR-ABL1 before starting a TKI.
• Treating early-stage CLL — early chemo does not improve survival; watch-and-wait is correct.[3]
• Missing Richter transformation in a CLL patient with new B-symptoms and a rising LDH.
• Forgetting HBV reactivation prophylaxis before rituximab or obinutuzumab.[1]

How chronic-leukaemia patients come to harm — the preventable list

• A septic CLL patient on BTK therapy given no PCP prophylaxis, dying of Pneumocystis pneumonia.[1]
• An HBsAg-positive patient given rituximab without antiviral prophylaxis — fatal HBV reactivation.
• A TP53-mutated CLL given chemoimmunotherapy instead of ibrutinib or venetoclax — chemo-refractory progression.[2]
• A leukemoid reaction treated with imatinib because the LAP score was never checked.[1]
• A CML patient on nilotinib with no ECG monitoring dying of a sudden cardiac event.[9]
• A T315I-mutant CML kept on imatinib instead of switched to ponatinib or asciminib.[5]
• Richter transformation in a stable CLL patient missed because the rising LDH was attributed to "the disease".

Prognosis and disposition

CLL prognosis is highly heterogeneous, governed by stage, IGHV status, TP53/del(17p), beta-2 microglobulin, LDH and the Döhner hierarchy: median overall survival runs from over 15 years (del 13q, Binet A, IGHV-mutated) to under 3 years (del 17p/TP53, refractory). Modern targeted therapy has improved even TP53-mutated disease.[2][3]

CML prognosis in the TKI era is near-normal for chronic-phase patients reaching optimal molecular response — annual mortality has fallen from 10 to 20 percent pre-imatinib to under 2 percent. Adverse features are a high ELTS score, failed molecular milestones, accelerated or blast phase at diagnosis, clonal evolution, and poor adherence.[5][11]

Most chronic-phase CML and early-stage CLL patients are managed as outpatients. Admission is for impending leukostasis or tumour lysis, severe autoimmune haemolysis, neutropenic sepsis, suspected Richter, or blast crisis.[1]

Special populations

• Young, fit, TP53-wildtype IGHV-mutated CLL — FCR offers a chance of long-term MRD-negative remission; allogeneic SCT only for very high-risk disease.
• Elderly or comorbid CLL — prefer oral targeted therapy (ibrutinib, acalabrutinib, venetoclax-obinutuzumab) over chemoimmunotherapy.
• TP53-mutated or del(17p) CLL — never chemoimmunotherapy; first-line ibrutinib or venetoclax-obinutuzumab.[2]
• Pregnancy and CML — interferon-alfa is safe; avoid TKIs in the first trimester; leukapheresis and hydroxycarbamide for short-term control.[5]
• HBsAg-positive or anti-HBc-positive patient — antiviral prophylaxis (entecavir 0.5 mg daily or tenofovir 300 mg daily) throughout and for at least 12 months after anti-CD20 therapy.[1]

The trials that changed practice

[1]

Regional deltas. CLL is rare in South and East Asia (including India); CML incidence is similar worldwide. In resource-limited settings, chlorambucil plus rituximab remains a reasonable first-line for elderly CLL, and generic imatinib is the workhorse first-line for CML, with the costlier second- and third-generation TKIs restricted by funding. Treatment-free-remission programmes need standardised BCR-ABL1 PCR on the International Scale, a prerequisite not available everywhere.[1]

The mantra, and the mnemonics

[1] [1]

The mantra: CLL is watched until it is active; CML is treated with a TKI from day 1 — and in both, the molecular test tells you what to do next.[3][5]

[1]

Ward-round test — three stems, thirty seconds each

Stem 1 — the man from the top of the topic (answer)

The 72-year-old with a WBC of 140×10⁹/L, massive splenomegaly, basophilia and a low LAP score. What is the diagnosis, and what single test confirms it? Model: This is CML — granulocytic leucocytosis with the full maturation spectrum, basophilia (pathognomonic for a myeloproliferative neoplasm) and a low LAP score that separates it from a leukemoid reaction. Confirm with a quantitative BCR-ABL1 transcript PCR (or FISH for BCR-ABL1) showing the t(9;22) Philadelphia chromosome / p210 fusion. First treatment is imatinib 400 mg orally daily, started within days, with BCR-ABL1 PCR monitored for EMR (at most 10 percent) at 3 months and MMR (at most 0.1 percent) at 12 months.[1][4]

Stem 2 — the CLL patient the registrar wants to treat (answer)

The 68-year-old with painless cervical nodes, a lymphocyte count of 35×10⁹/L and smudge cells on the film. Flow cytometry shows CD5+ CD23+ dim CD20. She is Binet A. The registrar wants to start FCR. What do you say? Model: This is early-stage (Binet A) CLL — confirmed by the CD5+ CD23+ immunophenotype and the Matutes score. Watch-and-wait is correct. Randomised trials show no survival benefit to early treatment. She is followed 6 to 12-monthly with a count and examination, and treatment is reserved for active disease — progressive marrow failure, bulky or progressive nodes or spleen, a lymphocyte doubling time under 6 months, refractory autoimmune cytopenia, or disease-related B-symptoms. Reach for the cytogenetics (FISH for del 17p/TP53) and IGHV status before you ever need them, so the right first-line agent is ready.[3]

Stem 3 — the CLL patient who deteriorates suddenly (answer)

A known CLL patient on watch-and-wait develops a rapidly enlarging supraclavicular node, night sweats and a rising LDH. What happened, and what is the next step? Model: This is Richter transformation — CLL transforming into diffuse large B-cell lymphoma, carrying a median survival under a year. Confirm with a PET-CT (an SUV max over 5 is suspicious) and an excisional node biopsy. Treat as DLBCL (R-CHOP or R-EPOCH), with consideration of allogeneic SCT in responders. This is the single high-yield emergency in CLL and the reason a rising LDH in a previously stable patient is never "just the disease".[2]

References

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2. [2]Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia N Engl J Med, 2000.PMID 11136261
3. [3]Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL Blood, 2018.PMID 29540348
4. [4]O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia N Engl J Med, 2003.PMID 12637609
5. [5]Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia Leukemia, 2020.PMID 32127639
6. [6]Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia N Engl J Med, 2015.PMID 26639149
7. [7]Seymour JF, Kipps TJ, Eichhorst B, et al. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab Blood, 2022.PMID 35605176
8. [8]Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia N Engl J Med, 2010.PMID 20525995
9. [9]Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia N Engl J Med, 2010.PMID 20525993
10. [10]Tiacci E, Trifonov V, Schiavoni G, et al. BRAF mutations in hairy-cell leukemia N Engl J Med, 2011.PMID 21663470
11. [11]Pfirrmann M, Baccarani M, Saussele S, et al. The EUTOS long-term survival (ELTS) score is superior to the Sokal score for predicting survival in chronic myeloid leukemia Leukemia, 2020.PMID 32601376
12. [12]Al-Sawaf O, Zhang S, Hallek M, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized phase 3 CLL14 study Blood, 2024.PMID 39082668