Chronic Lymphocytic Leukemia

Chronic lymphocytic leukaemia (CLL) is a clonal proliferation of mature CD5 positive B lymphocytes.

• Commonest adult leukaemia in the West; median age 70; incidence 4 per 100,000.
• Small lymphocytic lymphoma (SLL) is the nodal form.
• Prognostic markers: IGHV unmutated (poor), del(17p) and TP53 mutation (poor), del(11q), complex karyotype, trisomy 12 (intermediate), del(13q) alone (favourable); CLL-IPI.
• Complications: autoimmune haemolytic anaemia (10%), immune thrombocytopenia, hypogammaglobulinaemia with infections, Richter transformation (2 to 10%), second cancers.

• Often asymptomatic lymphocytosis.
• Lymphadenopathy, splenomegaly, fatigue, B symptoms (fever, night sweats, weight loss over 10%).
• Recurrent infections, bleeding, anaemia.
• Richter transformation: rapid node growth, LDH rise, B symptoms.

• Sustained B lymphocytosis over 5 x 10^9/L, flow cytometry (CD5, CD19, CD23, weak CD20, weak sIg, CD200), smudge cells on film.
• Before treatment: FISH (del 17p, 11q, 13q, trisomy 12), TP53 sequencing, IGHV mutation status, direct antiglobulin test, immunoglobulins, LDH, beta-2 microglobulin, hepatitis B/C and HIV.
• CT only if symptomatic or clinical trial; PET for suspected Richter (biopsy).
• Staging: Rai or Binet.

• Observation ("watch and wait") for asymptomatic early stage disease.
• Indications for treatment: progressive marrow failure, massive or progressive splenomegaly/nodes, constitutional symptoms, autoimmune cytopenia unresponsive to steroids, lymphocyte doubling under 6 months.
• Preferred therapies (all with or without TP53 aberration):
  • BTK inhibitors: acalabrutinib 100 mg twice daily, zanubrutinib 160 mg twice daily or 320 mg daily, ibrutinib 420 mg daily (continuous until progression).
  • Venetoclax 400 mg daily (ramp-up 20 to 400 mg over 5 weeks) with obinutuzumab 1000 mg (cycle 1 days 1, 2, 8, 15, then day 1 of cycles 2 to 6) for fixed 12 months.
  • Tumour lysis prophylaxis, hydration and monitoring during venetoclax ramp-up; avoid strong CYP3A inhibitors.
• Chemoimmunotherapy (FCR: fludarabine 25 mg/m2, cyclophosphamide 250 mg/m2 days 1 to 3, rituximab 375 to 500 mg/m2) limited to young fit patients with mutated IGHV and no TP53 aberration; bendamustine rituximab for older patients.
• Relapsed: switch class (BTK to venetoclax and vice versa), pirtobrutinib 200 mg daily, CAR T cell therapy, allogeneic transplant for TP53 mutated young fit patients.
• Autoimmune cytopenias: prednisolone 1 mg/kg, rituximab, ibrutinib.
• Hypogammaglobulinaemia with recurrent infections: IVIG 0.4 g/kg every 3 to 4 weeks. Prophylaxis: aciclovir, co-trimoxazole; vaccinate (inactivated), avoid live vaccines.
• Richter transformation: R-CHOP or novel agents, transplant.
• Atrial fibrillation and bleeding with BTK inhibitors need monitoring.