Chronic Leukaemias

Question 1

What are the different types of leukaemia?

Answer 1

Acute

Chronic

Question 2

Give examples of acute leukaemias

Answer 2

Acute Myeloblastic Leukaemia (AML)

Acute Lymphoblastic Leukaemia (ALL)

Question 3

Give examples of chronic leukaemias

Answer 3

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

Question 4

What is Chronic Lymphocytic Leukaemia (CLL)?

Answer 4

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.

Question 5

Describe the epidemiology of CLL

Answer 5

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

Question 6

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

Answer 6

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

Question 7

How is Chronic Lymphocytic Leukaemia (CLL) diagnosed?

Answer 7

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!)

Question 8

What other laboratory results may occur with CLL?

Answer 8

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

Question 9

How many CLLs have detectable chromosomal anomalies?

Answer 9

50%

Question 10

What chromosomal anomalies occur in CLL?

Answer 10

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

Question 11

How is CLL staged?

Answer 11

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

Question 12

When is CLL treated?

Answer 12

When patient has:

• Massive hepatosplenomegaly or bulky lymph nodes
• Significant disease related systemic symptoms
• BM infiltration with cytopenias

Question 13

What are the standard treatments for CLL?

Answer 13

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

Question 14

What newer treatments can be used to treat CLL?

Answer 14

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

Question 15

How does CLL contribute to Cause of Death?

Answer 15

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

Question 16

What is Hairy cell leukaemia?

Answer 16

A chronic B-cell leukaemia

Question 17

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

Answer 17

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

Question 18

When is treatment indicated for Hairy Cell Leukaemia?

Answer 18

Onset of recurrent or serious infection

Neutrophil count

Question 19

What treatments can be given for Hairy Cell Leukaemia?

Answer 19

Splenectomy
Interferon-α
Purine analogues - Current standard therapy

Question 20

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

Answer 20

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

Question 21

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

Answer 21

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

Question 22

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

Answer 22

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

Question 23

What is the standard treatment for Hairy Cell Leukaemia?

Answer 23

Purine Analogues - Cladribine and Pentostatin

Question 24

What is Chronic Myeloid Leukaemia?

Answer 24

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

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

Question 25

What is the pathogenesis of Chronic Myeloid Leukaemia?

Answer 25

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

Question 26

What are the clinical features of Chronic Myeloid Leukaemia?

Answer 26

Non-specific: - Weight loss, sweating, malaise Signs: - Splenomegaly, sternal tenderness Rare: - Hyperleucostasis: priapism, urticaria, gout, splenic infarction

Question 27

What are laboratory features of Chronic Myeloid Leukaemia?

Answer 27

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

Question 28

What are the treatment options for Chronic Myeloid Leukaemia?

Answer 28

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.

Question 29

What is the prognosis of Chronic Myeloid Leukaemia?

Answer 29

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