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PA18.1-2 | Chronic Leukaemias — CML & CLL — Part 3

CLL: Rai and Binet Staging, and Richter Transformation

⚑ AI image — pending faculty review (auto-QA score 7/10; best of 3 attempts)

Infographic comparing Rai and Binet staging of chronic lymphocytic leukemia and illustrating Richter transformation into aggressive diffuse large B-cell lymphoma. — **Panel A:** Rai Stage 0: lymphocytosis only; Stage I: lymphadenopathy; Stage II: splenomegaly/hepatomegaly; Stage III: anaemia, Hb <11 g/dL; Stage IV: thrombocytopenia, platelets <100 x 10^9/L. **Panel B:** Binet Stage A: fewer than 3 lymphoid areas involved, no anaemia or thrombocytopenia; Stage B: 3 or more lymphoid areas involved, no anaemia or thrombocytopenia; Stage C: anaemia and/or thrombocytopenia regardless of lymphoid areas. **Panel C:** Richter transformation: CLL clone evolves into aggressive diffuse large B-cell lymphoma; sudden rapid lymph node enlargement; markedly elevated LDH; constitutional symptoms; median survival less than 1 year.

Rai Staging (USA):
• Stage 0: Lymphocytosis only
• Stage I: + Lymphadenopathy
• Stage II: + Splenomegaly/hepatomegaly
• Stage III: + Anaemia (Hb <11 g/dL)
• Stage IV: + Thrombocytopenia (platelets <100 × 10⁹/L)

Binet Staging (Europe — simpler for MCQs):
• Stage A: <3 lymphoid areas involved, no anaemia/thrombocytopenia
• Stage B: ≥3 lymphoid areas involved, no anaemia/thrombocytopenia
• Stage C: Anaemia and/or thrombocytopenia (regardless of lymphoid areas)

Prognosis correlates with stage: Stage 0/A → median survival >10 years; Stage III-IV/C → 2-3 years.

Richter transformation: In ~5-10% of CLL cases, the clone transforms into an aggressive large B-cell lymphoma (diffuse large B-cell lymphoma — DLBCL). This presents as sudden rapid enlargement of a lymph node, markedly elevated LDH, and constitutional symptoms. Prognosis after Richter transformation is very poor (median survival <1 year). It represents clonal evolution — similar in concept to blast crisis in CML.

CML vs CLL: A Direct Comparison

A side-by-side medical diagram compares CML and CLL by cell of origin, age group, mutations, blood film findings, LAP score, splenomegaly, immune dysfunction, and complications. — **Panel A:** Hematopoietic stem cell, myeloid stem cell, mature B lymphocyte, CML origin, CLL origin. **Panel B:** CML blood film with full myeloid spectrum, basophilia, Philadelphia chromosome t(9;22), BCR-ABL1 fusion, low LAP score, massive splenomegaly, blast crisis. **Panel C:** CLL blood film with mature lymphocytosis, smudge cells, del13q, del17p, TP53 abnormalities, normal LAP score, moderate splenomegaly, hypogammaglobulinaemia, AIHA, recurrent infections, Richter transformation.

Feature	CML	CLL
Cell of origin	Myeloid stem cell	Mature B lymphocyte
Age	Middle-aged (40-60 yr)	Elderly (>60 yr)
Key mutation	BCR-ABL1 / t(9;22)	del13q, del17p, TP53, etc.
Blood film	Full myeloid spectrum + basophilia	Mature lymphocytosis + smudge cells
LAP score	Low	Normal
Splenomegaly	Massive	Moderate
Immune dysfunction	Rare	Common (hypogammaglobulinaemia, AIHA)
Key complication	Blast crisis (→ AML/ALL)	Richter transformation (→ DLBCL)
Targeted therapy	Imatinib (TKI)	Ibrutinib (BTK inhibitor), venetoclax

For the exam: CML = myeloid + low LAP + BCR-ABL1 + massive spleen. CLL = mature lymphocytes + smudge cells + immune dysfunction + elderly.

Other Chronic Myeloproliferative Neoplasms and JAK2 V617F

A four-panel infographic compares PV, ET, and PMF as JAK2 V617F-associated chronic myeloproliferative neoplasms distinct from BCR-ABL1-positive CML. — **Panel A:** CMPN pathway showing BCR-ABL1-negative testing, JAK2 V617F gain-of-function, constitutive cytokine-receptor signalling, and contrast with CML = BCR-ABL1 / Philadelphia chromosome. **Panel B:** Polycythaemia vera showing clonal erythroid proliferation, increased RBC mass, raised Hb, raised haematocrit, hyperviscosity, thrombosis, plethora, headache, and pruritus after hot bath. **Panel C:** Essential thrombocythaemia showing clonal megakaryocyte proliferation, very high platelet count, thrombosis, bleeding, and platelet dysfunction. **Panel D:** Primary myelofibrosis showing fibrotic marrow, massive splenomegaly from extramedullary haematopoiesis, nucleated RBCs, immature granulocytes, and teardrop RBCs / dacrocytes.

Beyond CML, three other chronic myeloproliferative neoplasms (CMPNs) share the theme of clonal myeloid proliferation but affect different lineages:

Polycythaemia vera (PV): Clonal erythroid (RBC) proliferation. Presents with hyperviscosity symptoms (headache, plethora, thrombosis, pruritus after hot bath). Raised Hb, raised haematocrit, raised RBC mass.

Essential thrombocythaemia (ET): Clonal megakaryocyte/platelet proliferation. Presents with thrombosis and paradoxically also bleeding (platelet dysfunction). Very high platelet count.

Primary myelofibrosis (PMF): Clonal proliferation with reactive fibrosis of the marrow. Presents with massive splenomegaly (extramedullary haematopoiesis), leucoerythroblastic blood picture (nucleated RBCs + immature granulocytes), and teardrop-shaped red cells (dacrocytes).

The unifying molecular lesion in PV (>95%), ET (~60%), and PMF (~60%) is the JAK2 V617F point mutation — a gain-of-function mutation in the Janus kinase 2 signalling protein that mimics constitutive cytokine-receptor stimulation. Testing for JAK2 V617F is the first-line molecular test when a CMPN is suspected and BCR-ABL1 is negative.

Key memory hook: CML = BCR-ABL1 (Ph chromosome). All other CMPNs = JAK2 V617F.

SELF-CHECK

A 65-year-old woman has haematocrit 58%, splenomegaly, and pruritus after a warm bath. BCR-ABL1 PCR is negative. Which molecular test should be ordered next?

A. TP53 sequencing

B. JAK2 V617F mutation analysis

C. FISH for t(15;17) PML-RARA

D. del(13q) by FISH

Reveal Answer

Answer: B. JAK2 V617F mutation analysis

The raised haematocrit, splenomegaly, and aquagenic pruritus strongly suggest polycythaemia vera (PV). PV is BCR-ABL1-negative (ruling out CML). The next step is JAK2 V617F mutation testing, positive in >95% of PV cases. PML-RARA is the APL translocation. del(13q) is associated with CLL and myeloma. TP53 sequencing is relevant in CLL with high-risk features or therapy planning.

CLINICAL PEARL

The aquagenic pruritus of PV — itching triggered specifically by warm water or bathing — is caused by histamine release from the increased mast cells and basophils in the skin. It is one of the most specific symptoms in haematology. If a patient says they itch after a shower but not from dry skin, think polycythaemia vera and check the haematocrit.

Putting It Together: A Diagnostic Framework

A stepwise flowchart shows how leucocytosis is classified by cell lineage, tested with LAP score, BCR-ABL1 and CD markers, staged for prognosis, and linked to targeted therapy. — **Panel A:** Leucocytosis on blood film; neutrophils/myeloid series; mature lymphocytes; CML; Leukaemoid Reaction; AML; CLL; reactive lymphocytosis; viral infection. **Panel B:** Low LAP score; CML; BCR-ABL1 confirmation; high LAP score; Leukaemoid Reaction; sepsis; TB; carcinoma; increased blasts; AML. **Panel C:** Mature lymphocytes; smudge cells; CD5 positive; CD19 positive; CLL; reactive lymphocytes; viral lymphocytosis. **Panel D:** CML blast percentage ladder; chronic phase; accelerated phase; blast crisis; CLL Rai staging; CLL Binet staging; low-risk; intermediate; high-risk. **Panel E:** BCR-ABL1 TKI therapy; imatinib first-line; PCR monitoring; CLL watch-and-wait; BTK inhibitor ibrutinib; BCL-2 inhibitor venetoclax; symptomatic/high-risk disease.

When you encounter leucocytosis on a blood film, use this stepwise approach:

Step 1 — What type of cells are increased?
• Neutrophils/myeloid series → CML vs Leukaemoid Reaction vs AML
• Mature lymphocytes → CLL vs Reactive lymphocytosis vs Viral infection

Step 2 — Apply the discriminating tests:
• LAP score low → CML (check BCR-ABL1 to confirm)
• LAP score high → Leukaemoid Reaction (find the cause: sepsis, TB, carcinoma)
• Smudge cells + mature lymphocytes + CD5/CD19 co-expression → CLL

Step 3 — Assess phase/stage for prognosis:
• CML: Blast percentage → Chronic / Accelerated / Blast crisis
• CLL: Rai or Binet staging → low-risk / intermediate / high-risk

Step 4 — Targeted therapy:
• CML → BCR-ABL1 TKI (imatinib first-line, monitor by PCR)
• CLL → Watch-and-wait if asymptomatic; BTK inhibitor (ibrutinib) or BCL-2 inhibitor (venetoclax) for symptomatic/high-risk disease