Haem 6 - Lymphoma 2 – CLL and lymphoproliferative disorders

Question 1

Hodgkin’s lymphoma epidemiology

Answer 1

• M > F
o Bimodal age incidence – 20-29yo (women, NS subtype, most common), >60yo (smaller peak)
o Women get a sclerosing sub-type more often

Question 2

Hodgkin’s lymphoma symptoms

Answer 2

o Asymmetrical painless progressive lymphadenopathy
 Becomes painful after alcohol consumption
 Obstructive symptoms  Extrinsic compression of any tube (ureter, bile duct, large blood vessel, bowel, trachea, oesophagus)

o Infiltrate/impair an organ system
 Skin rash
 Ocular+ CNS
 Liver failure

o Recurrent infections

o B symptoms
 Drenching night sweats
 Weight loss >10% in 6 months unintentional

o Pruritis
o Coincidental e.g. FBC, Imaging

Question 3

Hodgkin’s lymphoma histology

Answer 3

 Cells stain with CD15 + CD30

 Reed-Sternberg cell – bi-nucleate/multinucleate (owl eyed) cell on a background of lymphocytes + reactive cells

Question 4

HL classification Hodgkin’s lymphoma

Answer 4

Classical HL
 Nodular sclerosing 80% - Good prognosis
 Mixed cellularity 17% - Good prognosis
 Lymphocyte rich (rare) – Good prognosis
 Lymphocyte depleted (rare) – Poor Prognosis

o Nodular Lymphocyte predominant HL 5% - disorder of the elderly, multiple recurrences

Question 5

How do you stage HL? Hodgkin’s lymphoma

Answer 5

FDG-PET
CT scan
BM biopsy
+/-Lumbar puncture

Question 6

Describe the Ann Arbor staging system

Answer 6

 Stage 1 – one LN region (LN region can include the spleen)
 Stage 2 - >2 LN regions on the same side of the diaphragm
 Stage 3 - >2 LN regions on the opposite sides of the diaphragm
 Stage 4 – extranodal sites (liver, BM)

 A – no constitutional symptoms
 B – constitutional symptoms

Constitutional symptoms
Fever
Unexplained Weight loss >10% in 6 months
Night sweats

https://www.lls.org/sites/default/files/National/USA/Image/get_support/HL_Staging_Diagram.JPG

Question 7

classical HL

Nodular sclerosing subtype sx, epidemiology

Answer 7

Most common (80%) 
F > M (20-29yo)

Neck nodes + mediastinal mass (may be massive and compress SVC or trachea)
May have B symptoms

Spreads contiguously
Needs tissue diagnosis

Question 8

Treatment of classical HL

Answer 8

CHEMO
All patients get chemotherapy - ABVD
Adriamycin 
Bleomycin
Vinblastine
Dacarbazine 

2-6 cycles
4 weekly intervals

interim PET CT after 2 cycles to assess response to treatment
End of treatment PET CT to assess need for any radiotherapy

Preserves fertility

RADIO
Often given after chemo

Question 9

Risks of consolidation radiotherapy in the treatment of HL

Answer 9

• Risk of damage to normal tissues (collateral damage)
• Associated with increased risk of breast/lung/skin cancer, leukaemia/myelodysplasia
• Very high risk of breast cancer in women
• Damage to normal tissue

 Combined modality (chemo + radio) – greatest risk of 2o malignancy

Question 10

Which chemotherapy agents are used to treat classical HL?

Side effects?

Answer 10

ABVD

Adriamycin
Bleomycin
Vinblastine
DTIC Dacarbazine

Adriamycin - cardiomyopathy
Bleomycin - pulmonary fibrosis

Question 11

Relapse of HL mx

Answer 11

Salvage chemo

Autologous HSCT

Question 12

Autologous vs allogenic SCT where is it used

Answer 12

Autologous - stem cells from peripheral blood, BM, umbilical cord blood
MM, lymphoma
Not in leukaemias

Allogenic
Leukaemias

Question 13

Deaths in cHL (classical hodgkin’s lymphoma)are due to

Answer 13

highly curable disease, excellent prognosis
80% will be long-term survivors

10% die from relapse of HL (first 10 years)
10% die from treatment complications (after 10 years)

~5 years, patients are more likely to die of a secondary malignancy or cardiovascular complications (complications of curative treatment)

Question 14

Why is it important to test for Hep B in HL and NHL?

Answer 14

o Many patients are asymptomatic carriers of hepatitis B
o NHL patients may be given treatments that deplete B cells
o This may cure the lymphoma, but the patient might then present with fulminant liver failure because you have reactivated any asymptomatic hepatitis B

Question 15

The two commonest types of NHL

Answer 15

Diffuse large B cell lymphoma

Follicular lymphoma

Question 16

Which lymphomas respond better to chemotherapy; indolent or very aggressive?

Answer 16

Very aggressive (curable)

indolent lymphomas are less treatable - incurable but long remissions

exception - enteropathy associated T cell lymphoma
quick clinical course but not responsive to treatment

Question 17

How are very aggressive lymphomas treated?

Answer 17

Like leukaemia

Question 18

Enteropathy associated T cell lymphoma mx

Answer 18

Responds poorly to chemo, generally fatal

aim is to prevent - strict adherence to gluten free diet

Question 19

Most likely subtype of cHL in

young women
eldelry

Answer 19

young women - nodular sclerosing

elderly - lymphocyte rich

both have a good prognosis

Question 20

NHL Monitoring only appropriate for asymptomatic small volume disease in this lymphoma sub type

Answer 20

Follicular lymphoma

Question 21

Gastric MALT mx -

Answer 21

indolent lymphoma but needs abx to prevent complications

Question 22

Which cells are proliferating in CLL?

Answer 22

Mature B cells

lots of monoclonal lymphocytes

Question 23

CLL clinical features

Answer 23

Asymptomatic
Painless lymphadenopathy
BM failure
B symptoms
Hepatosplenomegaly
Associated with autoimmunity (Evan's syndrome) - AIHA, ITP

Question 24

CLL laboratory features

Bloods
Blood film
flow cytometry

Answer 24

FBC
Massive lymphocytosis (>200x10^9/L)
Normocytic anaemia
thrombocytopenia
neutropenia
low serum immunoglobulin

Blood film
Smear cells (smear CLLs)
Normocytic normochromic anaemia
B cells - CD19 +, CD5+

flow cytometry to confirm monoclonal population

Question 25

What risk is there with CLL/SLL?

Answer 25

Can transform to the aggressive diffuse large B cell lymphoma via Richter transformation

Question 26

How can CLL be staged clinically?

Answer 26

 Rai or Binet staging ```  CLL IPI score • Age >60y • Serum LDH > normal • Performance status 2-4 • Stage III or IV • >1 extra-nodal site ```

Question 27

Cell based prognostic factors in CLL

Answer 27

``` • IgH mutation status unmutated = bad • CLL FISH cytogenetic panel • tp53 mutation status • chr 17p deletion (tp53) [loss of tp53 tumour suppressor gene] ```

Question 28

Worst case scenario in CLL

Answer 28

* Binet stage C * IgH unmutated * 17p del * p53 mutated

Question 29

CLL prognosis

Answer 29

Initially 5-10 years good health until progression to a 2-3 year terminal phase Rapid progression to death within 2-3 years In a disorder of elderly 1/3 never progress 1/3 Progress, respond to CLL Rx (death from unrelated disorder) 1/3 Progress, require multiple lines of Rx, refractory disease, death from CLL

Question 30

Binet staging

Answer 30

``` Binet stage • A <3 groups of enlarged lymph nodes High WBC Usually no treatment required ``` • B >3 groups of enlarged lymph nodes • C Anaemia (<100g/l) or thrombocytopenia (<100x10^9/l)

Question 31

Rai staging

Answer 31

0 - lymphocytosis only I - lymphadenopathy II - hepatosplenomegaly +/- lymphadenopathy III - Hb <110 g/l IV - plt <100x10^9/l

Question 32

Indication for Ig replacement therapy in CLL

Answer 32

Recurrent infections + IgG <5 g/l

Question 33

Vaccination in CLL

Answer 33

annual influenza pneumococcal covid19 avoid live vaccines

Question 34

Indications to treat CLL

Answer 34

Watch and wait unless  Progressive lymphocytosis • >50% increase over 2 months • Count doubling < 6 months  Progressive bone marrow failure (Hb < 100; Platelets < 100; Neutrophils < 1)  Massive or progressive lymphadenopathy/splenomegaly  Systemic symptoms (B symptoms)  Autoimmune cytopenias • Treat with immunosuppression not chemotherapy

Question 35

How to treat CLL in young people vs eldelry

Answer 35

Elderly Watch and wait Chemo to establish remission Young patients Allogenic SCT

Question 36

CLL targeted therapy

Answer 36

BCR kinase inhibitors Ibrutinib (BTK) - irreversibly binds to BTK - for refractory CLL P53 mutation - initially high lymphocyte count which then falls - associated with Bruton's x-linked hypogammaglobulinemia (=Abnormal BTK (B cell tyrosine kinase) gene – mutation in B cell tyrosine kinase • Pre-B cells cannot develop into mature B cell  Absence of mature B cells  no antibody production) Idelasibe (PI3K) BCL-2 inhibitors Venetoclax - for refractory CLL P53 mutation (bcl-2 is an anti-apoptotic protein therefore ventoclax permits apoptosis of CLL cells)

Question 37

CLL therapy if it transforms to high grade B cell NHL through Richter transformation (diffuse large B cell NHL)

Answer 37

treat as high grade lymphoma R-CHOP (6-8 cycles) ``` Rituximab (anti-CD10 monoclonal antibody) Cyclophosphamide Adriamycin Vincristine Prednisolone ```

Question 38

Which is the biggest risk when initiating Venetoclax

Answer 38

 Risk of tumour lysis syndrome at start of therapy (potentially fatal) – rapid cell death over a 24h period, release of intracellular electrolytes, mediators