Chronic Leukaemias Flashcards Preview

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Flashcards in Chronic Leukaemias Deck (29):
1

What are the different types of leukaemia?

Acute
Chronic

2

Give examples of acute leukaemias

Acute Myeloblastic Leukaemia (AML)
Acute Lymphoblastic Leukaemia (ALL)

3

Give examples of chronic leukaemias

Chronic Lymphocytic Leukaemia (CLL)
Hairy cell leukaemia
Prolymphocytic leukaemia
Adult T-cell lymphoma-leukaemia
Chronic Myeloid Leukaemia (CML)
Chronic myelomonocytic Leukaemia (CMML)

4

What is Chronic Lymphocytic Leukaemia (CLL)?

A clonal low grade lymphoproliferative disorder in which there is a build-up of long lived, apparently mature small lymphocytes in the blood, bone marrow and lymphoid
tissues.

5

Describe the epidemiology of CLL

98% are B cell lineage, 2% T cell.
Most Common leukaemia in the West (30%)
Very rare in China /Japan.
Approx. 1,500 new cases per year in UK.
Incidence age related
- 50-60yrs = 5/100,000
- 80-90yrs = 31/100,000
Male:Female ratio- 2:1
Cause unclear – occasionally familial with anticipation

6

What are the clinical features of Chronic Lymphocytic Leukaemia (CLL)?

Enlarged lymph nodes
Hepatosplenomegaly
Night sweats
Weight loss
Anaemia - lethargy/breathless
Repeated infections (especially chest)
Bruising/haemorrhages
Often asymptomatic (perhaps majority at
presentation)

7

How is Chronic Lymphocytic Leukaemia (CLL) diagnosed?

Often detected on “routine” blood tests
Persistent lymphocytosis >5x10^9 (small, apparently
normal, lymphocytes)
Bone marrow >30% lymphocytes
Typical cell marker results:
- CD5 positive, CD23 positive
- CD19, CD 20 positive
- weak surface immunoglobulin (IgM/IgD) and FMC7
- light chains kappa or lambda restricted
- CD38 + or zap70 expression (bad!)

8

What other laboratory results may occur with CLL?

Auto-immune haemolytic anaemia (8%) and thrombocytopenia. (auto-antibodies not produced by malignant clone! – product of T cells disregulation)

Occasional monoclonal gammopathy (5%)
Frequent hypogammaglobulinemia (often severe)
Defects of T-cell function

9

How many CLLs have detectable chromosomal anomalies?

50%

10

What chromosomal anomalies occur in CLL?

13q abnormalities (15%) retinoblastoma gene
Trisomy 12 (17%)
Del 11q, del 17p (p53 - bad)
Unmutated VH genes – (bad)
Complex abnormalities – (always bad)

11

How is CLL staged?

Stage A - Blood and marrow lymphocytosis, 3 lymph areas involved - Median survival 5 years

Stage C - Blood and marrow lymphocytosis, > 3 lymph areas involved, Hb

12

When is CLL treated?

When patient has:
- Massive hepatosplenomegaly or bulky lymph nodes
- Significant disease related systemic symptoms
- BM infiltration with cytopenias

13

What are the standard treatments for CLL?

Alkylating agents –
- Chlorambucil (still useful agent in the elderly)
- Cyclophosphamide
Purine Analogues:
- Fludarabine, 2-CDA deoxycoformycin
- Fludarabine most used
- Toxic: Marrow suppression, Autoimmune problems,
Profound immunosuppression
Steroids
- Often used as a gentle ‘pre-treatment’
Combination therapy:
- FC, CVP, CHOP, POACH, etc. etc.
Mab Campath – anti-CD52
Rituximab – anti-CD20
- NICE approved with FC
Autografting/allografting
Radiotherapy

14

What newer treatments can be used to treat CLL?

Small molecules – target specific
- Brutons Kinase Inhibitors
- Idelalisib
- BCL2 Inhibitors
Newer anti-CD20’s
- More potent

15

How does CLL contribute to Cause of Death?

30% it doesn’t contribute!
46% infection
16% complications of therapy!
4% Thrombocytopenia
2% Haemolytic anaemia
2% other disease related causes
In

16

What is Hairy cell leukaemia?

A chronic B-cell leukaemia

17

What unusual or distinctive biological features does hairy cell leukaemia posses?

The pathognomonic hairy cell
Monocytopenia
Distinctive tissue distribution
Excellent response to treatment

18

When is treatment indicated for Hairy Cell Leukaemia?

Onset of recurrent or serious infection
Neutrophil count

19

What treatments can be given for Hairy Cell Leukaemia?

Splenectomy
Interferon-α
Purine analogues - Current standard therapy

20

What are the features of splenectomy given for treatment of Hairy Cell Leukaemia?

Treatment of choice pre-1984
Prolonged complete haematological response in 20%.
Useful response in 98%
Median duration of response 8 months
Poor response if:
- Small spleen
- >80% BM infiltration

21

What are the features of Interferon-α treatment of Hairy Cell Leukaemia?

First used 1984
3x/week s/c injections for 1 year
Proved superior to splenectomy 1992
Normalisation of blood counts in 90%
Normalisation of BM in 25-30%
- upto 50% if continued for 2 yrs
Median duration of response 2 years
Side effects often unacceptable

22

What are the features of Purine analogue treatment of Hairy Cell Leukaemia?

Cladribine and Pentostatin

Immunosuppressive - Can cause cytopenias but otherwise relatively non toxic.
Less toxic if given subcut (Cladribine)
Durable Complete Remission in majority of patients (80%)
Survival up to 87% at 12 years

23

What is the standard treatment for Hairy Cell Leukaemia?

Purine Analogues - Cladribine and Pentostatin

24

What is Chronic Myeloid Leukaemia?

A clonal haemopoetic disorder characterised by granulocytic leukocytosis, basophilia, anaemia, thrombocytosis and splenomegaly.

It is associated with a specific chromosomal abnormality t(9:22)

25

What is the pathogenesis of Chronic Myeloid Leukaemia?

Malignant transformation of a single stem cell. Cause not clear

Gene abnormality (Philadelphia Chromosome) leads to fusion of BCR (22) and ABL (9) genes

Chimeric gene leads to a novel 210kd tyrosine kinase

Increased granulocyte production
- (and sometimes platele)ts

26

What are the clinical features of Chronic Myeloid Leukaemia?

Non-specific:
- Weight loss, sweating, malaise

Signs:
- Splenomegaly, sternal tenderness

Rare:
- Hyperleucostasis: priapism, urticaria, gout, splenic infarction

27

What are laboratory features of Chronic Myeloid Leukaemia?

Neutrophilia (often>100x10^9/l)
Basophilia, eosinophilia, thrombocytosis
Hyperuricemia, high LDH and B12, pseudohyperkalaemia
Low LAP score
Hypercellular marrow
Philadelphia chromosome or molecular translocation

28

What are the treatment options for Chronic Myeloid Leukaemia?

Allopurinol
Leukopheresis: for leukostasis
Busulphan: not used much now
Hydroxyurea: standard for years – no longer…
α-interferon improves survival – 15% wrt above.
α-interferon + cytarabine (10% CCR, 25%MCR)
Allogenic BMT: previously treatment of choice for young patients – potentially curative in 65-70% . High TRM
Tyrosine kinase inhibitors – the first targeted therapy. Imatinib – current standard - also dasatinib, nilotinib and others on the way.

29

What is the prognosis of Chronic Myeloid Leukaemia?

Mean survival was around 42 months pre-imatinib
Natural history – disease terminates in “blast crisis” (N.B. accelerated phase)
- Random event
- ALL or AML
- very difficult to treat – esp if myeloid
- Prognosis poor
Allogenic BMT – best performed in chronic phase

Overall survival without progression to accelerated phase or blast crisis was 99 percent in patients who achieved complete cytogenetic response by 19 months after treatment, versus 83 percent in those who did not achieve at least a major cytogenetic response.

Response at 9 years remains similar