Haem: Lymphoma 2, CLL and Lymphoproliferative disorder

Question 1

Describe the typical presentation of lymphoma.

Answer 1

Painless progressive lymphadenopathy

• Can cause compression symptoms e.g. dysphagia if compressing oesophagus

Inflitration symptoms - skin rash, visual changes, neurological deficits

Recurrent infection (BM supression)

Constitutional symptoms (B symptoms)

Question 2

How is lymphoma diagnosed?

Answer 2

Biopsy with histological WHO classification of lymphoma subtype

Question 3

Which investigations may be used to stage lymphoma?

Answer 3

• Imaging - PET, CT, MRI
• Bone marrow biopsy
• Lumbar puncture (if CNS involvement)

Question 4

What are some important tests to perform in lymphoma
and why are they important?

Answer 4

• LDH - marker of cell turnover
• HIV serology - HIV can predispose to NHL (HTLV1 serology may also be important)
• Hepatitis B serology - NHL treatment may deplete B cells resulting in fulminant liver failure due to reactivation of hepatitis B in chronic carriers

Question 5

What are the 2 main types of Hodgkin’s lymphoma

Answer 5

Classical (95%)

Nodular lymphocyte predominant (5%) - causes recurrent disease in elderly

Question 6

What is the main type of classical HL and which type has a poor prognosis?

Answer 6

Nodular sclerosing is the main type of classical HL (predominantly affects young women aged 20-30)

Lymphocyte depleted HL is the type that has a poor prognosis

Question 7

What is the chemotherapy regime used in cHL

Answer 7

ABVD

• Adriamycin
• Bleomycin
• Vinblastine
• Dacarbazine (DTIC)

Given at 4 weekly intervals for 2-6 cycles (dependant on stage and response)

Question 8

How is HL relapse treated

Answer 8

High dose chemotherapy with PB autologous stem cell transplant

Question 9

Broadly speaking, what are the treatment approaches to non-Hodgkin lymphoma?

Answer 9

• Monitor only (in indolent lymphoma)
• Urgent chemotherapy
• Non-chemotherapy treatment (e.g. antibiotics to eradicate H. pylori in gastric marginal zone lymphoma)

Question 10

What are the two most common types of non-Hodgkin lymphoma?

Answer 10

Diffuse large B cell lymphoma (DLBCL) - 30%

Follicular lymphoma - 22%

Question 11

List some types of non-Hodgkin lymphoma that are:

1. Very agressive
2. Aggresive
3. Indolent

Answer 11

1. Very agressive
   
   • Burkitt’s lymphoma
   • T or B cell lymphoblastic lymphoma/leukaemia
2. Aggressive
   
   • Diffuse large B cell lymphoma
   • Mantle cell lymphoma
3. Indolent
   
   • Follicular lymphoma
   • Small lymphocytic lymphoma (CLL)
   • MALToma (marginal zone lymphoma)

Question 12

What is the correlation between how aggressive a lymphoma is and how curable it is?

Answer 12

The more aggressive it is, the more curable

Indolent lymphoma is more likely to recur

Question 13

Which factors are taken into account by the international prognostic index (IPI) for lymphoma?

Answer 13

• Age
• Ann Arbor stage
• LDH
• Presence of extra-nodal disease
• ECOG performance status

Question 14

Which chemotherapy treatment is usually used for diffuse large B cell lymphoma?

Answer 14

• R-CHOP
  
  • Rituximab
  • Cyclophosphamide
  • Doxorubucin
  • Vincristine
  • Prednisolone

NOTE: usually 6-8 cycles

NOTE: achieves a 50% cure rate

Question 15

What treatment option may be considered for patients with diffuse large B cell lymphoma who relapse?

Answer 15

Autologous stem cell transplantation

Question 16

Which genetic abnormality is associated with follicular lymphoma?

Answer 16

t(14;18) - over-expression of Bcl-2 (anti-apoptosis gene)

NOTE: follicular lymphoma is incurable but is indolent - median survival 12-15 years

Question 17

What is the usual first-line treatment approach to follicular lymphoma?

Answer 17

Watch and wait

Only treat it clinically indicated (e.g. compression symptoms, massive nodes, recurrent infection)

Question 18

Which chemotherapy regimen may be used in the treatment of follicular lymphoma?

Answer 18

R-CVP (rituximab, cyclophosphamide, vincristine, prednisolone)

Question 19

Which lymphoid tissue tends to be affected by marginal zone lymphoma?

Answer 19

Extranodal lymphoid tissue (e.g. MALT)

Question 20

What is the cause of marginal zone lymphoma?

Answer 20

• H. pylori infection - gastric MALToma
• Sjogren’s syndrome - parotid lymphoma
• Hashimoto’s thyroiditis - thyroid lymphoma

Question 21

Where is marginal zone lymphoma most commonly seen and how does it tend to present?

Answer 21

• Usually in the stomach
• Presenting with dyspepsia or epigastric pain
• Usually Stage 1{E} (E=extranodal)
• B symptoms are uncommon

Question 22

Outline the process of MALToma pathogenesis.

Answer 22

• Lymphocytes will respond chronic antigen stimulation from H. pylori infection and proliferate
• At some point, they will over-proliferate and develop cancer-like features but they will still be dependent on antigenic stimulation by H. pylori
• At this point, treating H. pylori will treat the lymphoma

Question 23

What are the symptoms of early stage gastric MALToma

Answer 23

Epigastric pain, ulceration, bleed

B-symptoms uncommon

Question 24

How might gastric MALToma stage I-II disease be treated?

Answer 24

• Tripy therapy to eradicate H. pylori (2 antibiotics + 1 PPI)
• Repeat breath test at 2 months
• Repeat endoscopy every 6 months for 1-2 years then annually

NOTE: failure may require chemotherapy

Question 25

What are the main features of enteropathy-associated T cell lymphoma?

Answer 25

* Mature T cells * Involves small intestines * Aggressive * Caused by chronic antigenic stimulation by gliadin/gluten

Question 26

Describe the typical presenting features of enteropathy-associated T cell lymphoma.

Answer 26

* Abdominal pain/ obstruction/ bleeding/ perforation * Systemic symptoms

Question 27

Why is it important to prevent EATL by following a strict gluten-free diet?

Answer 27

EATL responds poorly to chemotherapy and is usually fatal

Question 28

What is the most common leukaemia in the Western world and what is its median age of presentation

Answer 28

Chronic lymphocytic leukaemia - proliferation of mature B-cells Median age of presentation is 72

Question 29

What are the typical laboratory findings in a patient with CLL?

Answer 29

1. Lymphocytosis 2. **Smear cells** 3. Normocytic normochromic anaemia 4. Thrombocytopaenia 5. Bone marrow lymphocytic replacement of normal marrow elements NOTE: it is indolent so is often only picked up on routine blood tests

Question 30

What distinctive antigen phenotype (presence and absence) is suggestive of: * Mature B cells * Mature T cells

Answer 30

1. Mature B cells: * CD19 positive * CD5 negative 2. Mature T cells: * CD19 negative * CD5 positive * CD3 positive * CD4 or CD8 positive

Question 31

Which antigen phenotype is suggestive of CLL?

Answer 31

CD19+ and CD5+ NOTE: this could potentially also be mantle cell lymphoma

Question 32

Which staging system is used for CLL?

Answer 32

**Rai and Binet** Binet: stages A-C depending on number of lymphoid areas (\< or \> 3, Hb and platelets)

Question 33

Which specific tests are used in CLL to help gauge prognosis?

Answer 33

FISH cytogenetic panel * **TP53** mutation status **IgH V gene** mutation status CD38 expression (associated with poor prognosis)

Question 34

How do TP53 and IgH V gene mutations affect prognosis

Answer 34

TP53 - mutation/deletion associated with worse prognosis IgH V gene - mutation associated with better prognosis

Question 35

What is the difference between the VH genes of pre- and post-germinal centre B cells?

Answer 35

Pre-germinal centre: variable region is unmutated and looks identical to germline Post-germinal centre: undergone somatic hypermutation so variable region is mutated and looks different to germline

Question 36

Describe the immunoglobulin levels you would expect to see in CLL.

Answer 36

**Hypogammaglobulinaemia** - because the malignant B cells are suppressing antibody production by other B cells Leads to increased risk of infection

Question 37

What is the term used to describe CLL changing into a high grade lymphoma?

Answer 37

Richter transformation - 1% risk per year

Question 38

What are some supportive measures used in the treatment of CLL?

Answer 38

* Vaccination (covid, flu, pneumococcus) * Infection prophylaxis and treatment (e.g. PCP prophylaxis)

Question 39

How would autoimmune cytopaenias caused by CLL be treated?

Answer 39

Steroids NOTE: 2nd line is rituximab

Question 40

How would a Richter transformation be treated?

Answer 40

R-CHOP

Question 41

What is leukaemia-directed therapy?

Answer 41

* Tailored to the patient * Usually involves watching and waiting because it is incurable by chemotherapy * Aim to establish remission NOTE: young people may be cured with allogeneic stem cell transplantation

Question 42

What are some indications to stop watch and wait and initate treatment of CLL?

Answer 42

* Progressive lymphocytosis (doubling in <6 months or **>50% increase in 2 months**) * Progressive bone **marrow failure** * **Massive** or progressive lymphadenopathy/splenomegaly * Systemic symptoms (**B symptoms**) * **Autoimmune cytopaenias**

Question 43

What is the first line treatment for TP53 intact CLL?

Answer 43

**FCR - Fludarabine, Cyclophosphamide, Rituximab** NOTE: less intensive options may include, rituximab and bendamustine or obinutuzumab (anti-CD20) and chlorambucil (alkylating agent)

Question 44

What are some newer treatment options for high risk CLL?

Answer 44

B cell receptor kinase inhibitors * Bruton tyrosine kinase inhibitors - **ibrutinib** = (p53 mutation) * PI3K inhibitor - idelalisib Bcl2 Inhibitors - **venetoclax** (effective but risk of tumour lysis syndrome) CAR-T therapy

Question 45

Describe how CAR-T therapy for CLL works.

Answer 45

* CAR-T are autologous T cells that are modified to contain chimeric antigen receptors * The internal part of the receptor is responsible for cell signalling * The external part is designed to target CD19 (on B cells) thereby enabling B cell depletion