Lymphoid Malignancies

Question 1

What is lymphoma?

Answer 1

Cancer of lymphoid origin which can present with

• Lympadeonpathy OR
• Extranodal involvement OR
• Bone marrow involvement
• Systemic B symptoms including weight loss (>10 % in 6 months), fever, night sweats, pruritus, fatigue

Question 2

How is are differnt types of lymphoma defined?

Answer 2

By the malignant cell characteristics

Question 3

What investigation tells us what type of lymphoma it is?

Answer 3

Biopsy

Question 4

What investigations tells us where the lymphoma is?

Answer 4

Clinical examination and imaging

Question 5

What is a high grade non-Hodgkin lymphoma?

Answer 5

A diffuse large B cell lymphoma

Question 6

Give examples of lymphoproliferative disorders in order from most common.

Answer 6

• Most common
• Non-Hodgkin lymphoma (NHL)
  
  • High-grade (diffuse large B-cell lymphoma)
  • Low-grade (follicular, marginal zone)
• Chronic lymphocytic leukaemia (CLL)
• Hodgkin lymphoma
• Acute lymphoblastic leukaemia (ALL) (common in children)

Question 7

What is acute lymphoblastic leukaemia?

Answer 7

Cancerous disorder of lymphoid progenitor cells

Question 8

How is acute lymphoblastic leukaemia diagnosed?

Answer 8

By >20% lymphoblasts present in bone marrow

Question 9

What is the epidemiology of acute lymphoblastic leukaemia?

Answer 9

• Incidence 1-2/100,000 population/year
• -75% cases occur in children < 6 years
• 75-90% cases are of B-cell lineage

Question 10

What is the standard treatment for acute lymphoblastic leukaemia?

Answer 10

• Induction chemotherapy to obtain remission
• Consolidation therapy
• CNS directed treatment
• Maintenance treatment for 18 months

Question 11

What other treatment is there for acute lymphoblastic leukaemia?

Answer 11

• Stem cell transplantation (if high risk)
• Bispecifc T-cell engagers (BiTe molecules): e.g. Blinatumumab
• CAR (chimeric antigen receptor T-cells)

Question 12

How is CAR treatment carried out?

Answer 12

• Patient/ healthy 3rd party T-cells harvested
• T-cells are genetically modified so that they target CD19 expressed on leukaemia cells
• Expanded in vitro
• Re-infused into patient

Question 13

How does T-cell immunotherapy associated neurotoxicity present?

Answer 13

• Confusion with normal conscious level
• Seizure, headache, focal neurology, coma

Question 14

How does T-cell immunotherapy associated cytokine release syndrome present?

Answer 14

• Fever, hypotension, dyspnoea
• CAR T-cell effect correlated to presence of CRS (significant number require ITU support)

Question 15

What are poor prognostic factors associated with acute lymphoblastic leukaemia?

Answer 15

• Increasing age
• Increased white cell count
• Immunophenotype (more primitive forms)
• Cytogenetics/molecular genetics: t(9;22); t(4;11)
• Slow/poor response to treatment

Question 16

What are the outcomes of acute lymphoblastic leukaemia?

Answer 16

Adults with ALL

• Complete remission rate 78–91%
• Leukaemia-free survival at 5y 30–35%

Children with ALL

• 5y overall survival ~90%
• Poor risk patients (slow response to induction or Philadelphia positive) 5y OS 45%

Question 17

What is the typical presentation of acute lymphoblastic leukaemia?

Answer 17

• Bone marrow failure +/- raised white cell count
• Bone pain, infection, sweats

Question 18

How is chronic lymphocytic leukaemia diagnosed?

Answer 18

• Blood > 5 x 109/L lymphocytes (normal is <4)
• Bone marrow > 30% lymphocytes
• Characteristic immunophenotyping (B-cell markers (CD 19, 20, 23) & CD5 positive)

Question 19

What is the incidence of CLL?

Answer 19

• > 1700 new cases CLL per year in the UK
• Commonest leukaemia worldwide
• M:F 2:1
• Occasionally familial
• Rare in far East

Question 20

How does CLL present?

Answer 20

Often asymptomatic

Frequent findings

• Bone marrow failure (anaemia, thrombocytopenia)
• Lymphadenopathy
• Splenomegaly (30%)
• Fever and sweats (< 25%)

Less common findings

• Hepatomegaly
• Infections
• Weight loss

Question 21

What conditions/states are associated with CLL?

Answer 21

• Immune paresis (loss of normal immunoglobulin production)
• Haemolytic anaemia (20% have positive direct antiglobulin test, 8% clinical evidence of haemolytic anaemia)

Question 22

What system is used to stage CLL?

Answer 22

Binet

Question 23

What are the stages of CLL according to the Binet system?

Answer 23

• Stage A -<3 lymph nodes
  
  • Same survival as age matched controls
• Stage B -3 or more lymph node areas
  
  • -~8 year survival
• Stage C -Stage B + anaemia or thrombocytopenia
  
  • ~6 years survival

Question 24

What are the indications for treatment in CLL?

Answer 24

• Progressive bone marrow failure
• Massive lymphadenopathy
• Progressive splenomegaly
• Lymphocyte doubling time <6 months or >50% increase over 2 months
• Systemic symptoms
• Autoimmune cytopenias

Question 25

What is the treatment for CLL?

Answer 25

* Often nothing: “watch and wait” * Cytotoxic chemotherapy e.g. fludarabine, bendamustine * Monoclonal antibodies e.g. Rituximab, obinutuzamab * Novel agents: (Bruton tyrosine kinase inhibitor eg ibrutinib) (PI3K inhibitor eg idelalisib) (BCL-2 inhibitor eg venetoclax)

Question 26

What are poor prognostic factors in CLL?

Answer 26

* Advanced disease (Binet stage B or C) * Atypical lymphocyte morphology * Rapid lymphocyte doubling time (\<12 mth) * CD 38+ expression * Loss/mutation p53; del 11q23 (ATM gene) * Unmutated IgVH gene status

Question 27

How is chronic lymphocytic leukaemia different from acute lymphoblastic leukaemia?

Answer 27

* Unlike ALL, the abnormal cells are mature - they usually resemble normal, well-behaved lymphocytes * Grow slowly (or not at all) * Classic example of a low-grade condition * Carry many of the normal markers that B lymphocytes have

Question 28

How does lymphoma present?

Answer 28

* Lymphadenopathy/ hepatosplenomegaly * Extranodal disease * “B symptoms” * Bone marrow involvement

Question 29

How is lymphoma assessed and staged?

Answer 29

* Lymph node biopsy * CT scan * Bone marrow aspirate and trephine

Question 30

What are the stages of lymphoma?

Answer 30

* Can be classified by presence of B symptoms * Stage 1 = 1 node involved * Stage 2 = 2 nodes * Stage 3 = multiple nodes * Stage 4 = node and hepatosplenomegaly

Question 31

How is non-Hodgkin lymphoma classified?

Answer 31

* Lineage (B-cell or T-cell) (Majority are B-cell in origin) * Grade of disease (high grade or low grade) * Histological features of disease

Question 32

What are the features of low grade NH lymphoma?

Answer 32

* Indolent, often asymptomatic * Responds to chemotherapy but incurable * Median survival varies by subtype

Question 33

What are the features of high grade NH lymphoma?

Answer 33

* Aggressive, fast-growing * Require combination chemotherapy * Can be cured, but again varies widely

Question 34

Give examples of specific NH lymphoma disease entitie.

Answer 34

* Diffuse large B-cell lymphoma * Commonest subtype of lymphoma (of any kind) * High-grade lymphoma * Follicular lymphoma * 2nd commonest subtype of lymphoma * Low-grade lymphoma

Question 35

How is NH lymphoma treated?

Answer 35

Combination chemotherapy, typically anti-CD20 monoclonal antibody and chemo

Question 36

What is the epidemiology of Hodgkin lymphoma?

Answer 36

* 30% of all lymphomas * Bimodal age curve with 1st peak at 15-35y and 2nd peak later in life * M:F 1.9:1 * association with Epstein Barr virus; familial and geographical clustering

Question 37

What is the treatment for Hodgkin lymphoma?

Answer 37

* Combination chemotherapy (ABVD) * +/- radiotherapy * Monoclonal antibodies (anti-CD30) * Immunotherapy (checkpoint inhibitors) * Use of PET scan to assess response to treatment and to limit use of radiotherapy