CLL Flashcards
CLL is the most common leukaemia in adults over 55. What is the aetiology and pathophysiology of this?
Chronic proliferation of a single type of well differentiated lymphocyte, usually B-lymphocytes
Genetic alterations
TP53 mutation: major tumour suppressor gene, linked to a poor response to treatment.
11q and 13q14 deletions
Trisomy 12: presence of an extra 12th chromosome
Overexpression of BCL2 proto-oncogene
NOTCH1 mutation
What is the natural disease history of CLL?
RELAPSING AND REMITTING
Initial event or abnormal reaction to an antigen leads to genetic alterations that allow the formation of a clone of B lymphocytes. This is a premalignant disorder, monoclonal B cell lymphocytosis (MBL)
Overtime, further genetic mutations and bone marrow microenvironment changes promote the progression to CLL. This transformation from MBL to CLL occurs at a rate of 1% per year
May remain asymptomatic for many years. The symptomatic stage of CLL is characterised by progressive lymphadenopathy, which includes splenomegaly and hepatomegaly, that occurs due to the accumulation of incompetent lymphocytes.
How does CLL present?
Lymphadenopathy: hallmark feature due to infiltration of malignant B-lymphocytes
Asymptomatic: detected on routine blood tests
Recurrent infections: due to low IgG
What investigations are done to diagnose CLL? (different to other leukaemias)?
DO NOT NEED BONE MARROW ASSESSMENT
FBC: persistent lymphocytosis and normocytic anaemia
Cytogenetics and Immunophenotyping: done by flow cytometry, proves lymphocytes are clonal. Can also look for mutations like TP53
Blood film: smear or ‘smudge’ cells. These are artefacts due to damaged lymphocytes
What are some further investigations you should do with a diagnosis of CLL and why?
Routine biochemistry: U&E, bone profile, LFTs
Haemolysis screen (at risk of AIHA): Direct antiglobulin test (DAT), haptoglobin, LDH, unconjugated bilirubin, reticulocytes
Immunoglobulins: at risk of secondary hypogammglobulinaemia
CXR: look for pulmonary lymphadenopathy.
Lymph node biopsy: if concern about lymphomatous transformation.
Virology: important prior to initiation of treatment. Hepatitis B, hepatitis C, HIV,CMV
How is CLL staged?
Binet or Rai
Binet staging
Lymphoid sites are cervical nodes, axillary nodes, inguinal nodes, spleen, and liver
Stage A: <3 lymphoid sites
Stage B: ≥3 lymphoid sites
Stage C: presence of anaemia (<100 g/L) and/or thrombocytopaenia (<100 x10^9/L)
Rai staging
Based on natural progression of CLL
Stage 0 (lymphocytosis): 25% at initial diagnosis
Stage I-II (lymphocytosis + lymphadenopathy + organomegaly): 50% at initial diagnosis
Stage III-IV (lymphocytosis + anaemia or thrombocytopaenia +/- lymphadenopathy/ organomegaly): 25% at initial diagnosis
What are some prognostic indicator in CLL?
Binet and Rai stage
Lymphocyte doubling time
Genetic abnormalities on cytogenetics: TP53, del(11q), trisomy 12, and del(13q)
Beta-2-microglobulin: correlates with disease stage and tumour burden
If patients with CLL are asymptomatic how are they treated?
Watch and wait
If asymptomatic, indolent disease without poor prognostic factors and Binet stage A/B or Rai stage <3
Full blood count at 3 monthly intervals
At 12 months, treatment decisions can be decided based on the trajectory of the condition or develop of active/symptomatic disease
What are indications for treatment with CLL?
Need active disease. Need one of iwCLL criteria:
Bone marrow failure (Hb < 100 g/L, plts <100 x10^9/L)
Massive, progressive or symptomatic splenomegaly (≥6 cm)
Massive, progressive or symptomatic lymphadenopathy (≥10 cm)
Progressive lymphocytosis (≥50% over 2 months or doubling time < 6 months)
Autoimmune complications not responsive to steroids (e.g. ITP/AIHA)
Symptomatic/functional extranodal sites (e.g. skin, kidney, lung, spine)
Disease-related symptoms (e.g. significant weight loss, severe fatigue, >2 weeks of fever or ≥1 month of night sweats without infection)
What does treatment depend on in CLL?
Patient fitness and performance status
Co-morbidities
Mutational analysis (e.g. TP53 mutations)
First-line treatment or treating relapse/refractory disease
How is active CLL treated medically/surgically?
Pharmacotherapy
Chemotherapy
Chlorambucil: cross-links DNA leading to damage and apoptosis.
Fludarabine: purine analog that inhibits DNA synthesis
Bendamustine: alkylating agent that cross-links DNA
Small molecule inhibitors
Ibrutinib: tyrosine kinase inhibitor. TP53 mutations
Idelalisib: phosphoinositide 3-kinase inhibitor.
Venetoclax: BCL2 inhibitor
Monoclonal antibodies
Rituximab/Obinutuzumab/Ofatumumab: Anti-CD20 antibodies that target B lymphocytes
Other
Corticosteroids: in extremely frail patients or to treat autoimmune complications including haemolytic anaemia and immune thrombocytopaenia
Allogenic stem cell transplantation
If fail chemotherapy and BCR inhibitor therapy
TP53 mutations that do not respond to treatment or relapse
Richter’s transformation
What supportive care is done in CLL?
Vaccination: influenza, pneumococcal
Antibiotics for infections
Consider IVIG: treatment of secondary hypogammaglobulinaemia (i.e. IgG < 5g/L)
Consider (PJP) and herpes zoster prophylaxis: in patients on treatment for relapsed CLL
What autoimmune complications are patients with CLL at risk of?
AIHA
ITP
What are some of the complications of CLL?
Histological transformation
Richter transformation: aggressive lymphoma, 5-8 month survival
Prolymphocytic leukemia
Hodgkin lymphoma
Multiple myeloma
Other complications
Secondary infections: herpes zoster, PJP, bacterial infections
Autoimmune complications: AIHA, immune thrombocytopaenia
Hyperviscosity syndrome
Secondary malignancies
How may you know that Richter’s transformation has happened in CLL?
Ritcher’s transformation occurs when leukaemia cells enter the lymph node and change into a high-grade, fast-growing non-Hodgkin’s lymphoma
Ritcher’s transformation is indicated by one of the following symptoms:
lymph node swelling
fever without infection
weight loss
night sweats
nausea
abdominal pain
