20.06.17 Mature B cell neoplasms/CLL

Question 1

Main Mature B cell neoplasms

Answer 1

• CLL (chronic lymphocytic leukemia)

- plasma cell myeloma

Question 2

What is involved in the maturation of B and T lymphocytes

Answer 2

• Intrachromosomal rearrangements of genes encoding immunoglobulins (iG) in B-lymphocytes and t-cell receptors (TCR) in T lymphocytes.
• Produces diversity

Question 3

What is CLL

Answer 3

• Chronic lymphocytic leukemia.
• Chronic mature B-cell neoplasm caused by proliferation and accumulation of monomorphic small round B lymphocytes in peripheral blood. Mature but dysfunctional cells, accumulate in bone marrow and prevent haematopoiesis of normal blood cells.
• Most common leukemia in Western countries.
• 2-6/100,000, up to 12.8/100,000 by 65yrs

Question 4

Does CLL have a high genetic predisposition

Answer 4

• Yes, highest of all haematologic neoplasias.

- Risk is 2-7x higher in first degree relatives of CLL patients.

Question 5

How does CLL present

Answer 5

• Often asymptomatic and diagnosed incidentally. Can be highly variable.
• Fatigue, autoimmune haemolytic anemia, splenomegaly, infections.

Question 6

CLL clinical course

Answer 6

• Pre-malignant condition+ Monoclonal B-cell lymphocytosis (MBL)
• Overt CLL
• Transforms to an aggressive lymphoma in 5-15% cases.

Question 7

Is CLL easy to test by karyotype

Answer 7

No as cells divide very slowly in vitro, even with the use of mitogens like TPA.

Question 8

Main cytogenetic findings in CLL

Answer 8

• del(13q14.3) mono or bi-allelic. Good prognosis
• del11q23 (ATM). Poor prognosis
• Trisomy 12. Intermediate prognosis
• del(17p13) (TP53). Poor prognosis. Commonly acquired after treatment.

Question 9

What abnormalities are usually first step in CLL

Answer 9

• del(13q14.3) and Trisomy 12.
• Often seen through various stages of disease
• Considered to be clonal driver mutations

Question 10

What proportion of CLL cases have translocations involving immunoglobulin gene IGH

Answer 10

• 20%

- 14q32

Question 11

Common translocations in CLL

Answer 11

• t(11;14)(q13;q32) (IGH-CCND1) seen in MCL- Mantle cell lymphoma
• t(8;14)(q24;q32) (IGH-MYC) poor prognostic features.
• t(14;18)(q32;q21) (IGH-BCL2)

Question 12

Recurrent somatic mutations in CLL commonly affect which gene

Answer 12

NOTCH1 (4-15% cases)

Question 13

How is CLL diagnosed

Answer 13

• Blood count
• Blood smear
• Immunophenotype of circulating lymphoid cells.
• FISH , to indicate clinical course/prognosis
• SNP arrays. Doen’t need dividing cells, can detect LOH, higher resolution than karyotype. Limitations: can’t detect low level mosaicism or low copy clones.

Question 14

CLL treatment

Answer 14

• Incurable
• Treated with chemo/immuno-therapies lead to remissions but often patients relapse
• Should have TP53 testing prior to treatment. These patients will relapse early and may benefit from allogeneic stem cell transplantation

Question 15

What is a plasma cell myeloma

Answer 15

• 10-15% of haemopoietic neoplasms
• 60-70 per million.
• Median age= 70 years
• Plasma cells are terminally differentiated B lymphocytes, secrete antibodies

Question 16

Clinical course of plasma cell myeloma

Answer 16

• Monoclonal gammopathy of undetermined significance. Plasma cell content <10%
• Smouldering myeloma. PC content 10-30%
• Plasma cell myeloma. PC content >10%

Question 17

Clinical symptoms of plasma cell myeloma

Answer 17

Hypercalcemia
Renal failure
Anaemia
Bone disease

Question 18

What percentage of chromosomal abnormalities will be detected by FISH and karyotyping

Answer 18

• FISH= >90%

- Karyotyping= 30-40%

Question 19

What main two groups of plasma cell myeloma based on cytogenetic abnormality

Answer 19

• Hyperdiploid: 48-75 chromosomes (more favourable prognosis). Often gains of the odd chromosomes (3, 5, 7, 9, 11, 15, 19, 21)
• Non-Hyperdiploid: Often involve structural rearrangements of IGH (14q32)

Question 20

Common IGH translocations in plasma cell myeloma

Answer 20

• t(4;14)(p16.3;q32) (FGFR3-IGH). 15%. Poor prognosis

- t(11;14)(q13;q32) (CCND1-IGH). 15%. Good prognosis.

Question 21

What genetic changes are commonly associated with disease progression in plasma cell myeloma

Answer 21

• Monosomy/del chr 13. 50%

- del 17p (TP53). 10%

Question 22

Diagnostic strategies in plasma cell myeloma

Answer 22

• Metaphase chromosomes a problem due to low proliferative activity of cells in vitro. Not routinely done.
• FISH on interphase nuclei preferred. Need cell selection before testing otherwise high risk of false negatives
• Cell selection via magnetic activated cell sorting (MACS)
• ImmunoFISH using CD138+ so plasma cells can be identified during FISH

Question 23

Treatment of plasma cell myeloma

Answer 23

• Incurable

- treatment includes standard chemotherapy, steroids, thalidomide, stem cell transplants.