6. Lymphoma 2 - Chronic lymphocytic leukaemia and lymphoproliferative disorders Flashcards
(98 cards)
1
Q
What percentage of lymphoma/leukaemia become Reed Sternberg cells vs. Non Hodgkin lymphoma?
A
15% - Reed Sternberg -> classical Hodgkin lymphoma. 85% - Non Hodgkin lymphoma
2
Q
Give examples of precursor B cell NHL?
A
Precursor B lymphoblastic leukaemia or lymphoma
3
Q
Give examples of mature B cell NHL?
A
Mature B cell neoplasm DLBCL, follicular NHL, CLL etc.
4
Q
Give examples of precursor T cell NHL?
A
Precursor T lymphoblastic leukaemia or lymphoma
5
Q
Give examples of mature T cell NHL?
A
Mature T and NK neoplasm PTCL, anaplastic, cutaneous
6
Q
What is non-Hodgkin lymphoma?
A
Neoplastic proliferation of lymphoid cells
7
Q
Where does NHL originate?
A
Originates in lymphoid tissue (lymph nodes, bone marrow, spleen)
8
Q
How common is NHL?
A
Incidence is rising, 200 per 1 million per year
9
Q
What is the fastest growing human cancer?
A
Burkitt’s lymphoma
10
Q
How does disease severity vary in NHL?
A
Burkitt’s lymphoma - fastest growing human cancer. Indolent diseases with a possible 25 year survival
11
Q
What mutation causes NHL to occur and why?
A
lymphocytes in the germinal centres are capable of massive expansion, however, 90% of the lymphocytes produced in germinal centres will die via apoptosis. Mutations that prevent apoptosis will produce a very aggressive tumour.
12
Q
What is the presentation of NHL?
A
Painless lymphadenopathy, compression symptoms, B symptoms
13
Q
How do you stage NHL?
A
CT scan, PET scan, bone marrow biopsy, lumbar puncture
14
Q
What are prognostic markers and important tests for NHL?
A
LDH, performance status, HIV serology, if appropriate HTLV1 serology, hepatitis B serology
15
Q
Why measure LDH for NHL?
A
marker of cell turnover
16
Q
Why measure HIV serology for NHL?
A
HIV may have predisposed to NHL
17
Q
Why measure hepatitis B serology?
A
Many patients are asymptomatic carriers of hepatitis B. NHL patients may be given treatments that deplete B cells. This may cure the lymphoma but the patient might then present with fulminant liver failure because you have reactivated hepatitis B.
18
Q
What will be in your plan for therapy for NHL?
A
Urgent chemotherapy, monitor only, ABx eradication (H pylori gastric MALToma)
19
Q
Common types of lymphomas (see notes)
A
Diffuse large B cell lymphoma and follicular lymphoma
20
Q
According to the WHO classification, what is the clinical behaviour as predicted by histological type of Burkitt lymphoma?
A
Very aggressive (high grade)
21
Q
According to the WHO classification, what is the clinical behaviour as predicted by histological type of T or B cell lymphoblastic leukaemia/lymphoma?
A
Very aggressive (high grade)
22
Q
According to the WHO classification, what is the clinical behaviour as predicted by histological type of diffuse large B cell?
A
Aggressive (high grade)
23
Q
According to the WHO classification, what is the clinical behaviour as predicted by histological type of mantle cell?
A
Aggressive
24
Q
According to the WHO classification, what is the clinical behaviour as predicted by histological type of follicular lymphoma?
A
Indolent (low grade)
25
According to the WHO classification, what is the clinical behaviour as predicted by histological type of small lymphocytic lymphoma/CLL?
Indolent (low grade)
26
According to the WHO classification, what is the clinical behaviour as predicted by histological type of mucosa associated (MALT)?
Indolent (low grade)
27
The very aggressive lymphomas do not need to be treated with very intensive chemotherapy
False, the very aggressive lymphomas need to be treated with very intensive chemotherapy
28
The more aggressive the type of lymphoma, the more curable it is - true or false?
True
29
What is the median survival and response to treatment of very aggressive lymphomas?
Median survival: weeks 2-5 (without Rx). Response to Rx: curable.
30
What is the median survival of aggressive lymphomas?
Months 3-12 (without Rx)
31
What is the median survival and response to treatment of indolent lymphomas?
Years 10-15, incurable
32
Why can indolent lymphomas have poor outcomes?
Indolent lymphomas may go into remission following treatment, however, they tend to recur. When they recur, the next line of therapy doesn't tend to be as effective.
33
What is the clinical behaviour of diffuse large B cell lymphomas?
Aggressive
34
What percentage of all NHL are DLBCL?
30-40%
35
What age does DLBCL tend to occur in?
Middle-aged and elderly patients
36
What is the prognosis and Tx of DLBCL determined by?
Histological diagnosis, anatomical stage, IPI (international prognostic index)
37
What factors are included in the international prognostic index (IPI)?
Age > 60 years, serum LDH > normal, performance status 2-4, stage III or IV, more than one extranodal site
38
What is the 5 year predicted survival by number of risk factors according to the international prognostic index (IPI)?
0-1 RF = 73%; 2 RF = 51%; 3 RF = 43%; 4-5 RF = 26%
39
What is the treatment for DLBCL?
Treated with 6-8 cycles of R-CHOP: Rituximab (anti-CD20) - this is a form of immunotherapy; cyclophosphamide; doxorubicin (hydroxydaunorubicin); vincristine (Oncovin); prednisolone.
40
What is the aim of treatment for DLBCL?
The aim of treatment is to CURE (50% cure rate)
41
What treatment for patients who relapse with DLBCL and what is the cure rate?
Patients who relapse are considered for autologous stem cell transplantation (25% cure rate)
42
What is the clinical behaviour of follicular NHL?
Indolent lymphoma
43
What percentage of NHL is follicular NHL?
35%
44
What chromosomes and gene is associated with follicular NHL?
•Associated with t(14;18) which results in over-expression of bcl2. Bcl2 is an anti-apoptosis protein. NOTE: the normal B cell germinal centre is bcl2-negative
45
What is used to score follicular NHL?
FLIPI score (modified IPI)
46
What is the prognosis for follicular NHL?
Incurable (median survival 12-15 years)
47
What is the chemotherapy schedule like for follicular lymphoma?
May require 2-3 chemotherapy schedules over 12-15 years
48
What are the INITIAL treatment options for follicular NHL?
Indolent slow-progressing B cell NHL. Incurable and variable/long natural history. At presentation - watch and wait (only treat if clinically indicated). E.g. compression due to nodes (e.g. bowel, ureter, vena cava). E.g. massive painful nodes, recurrent infections.
49
What is the treatment for follicular NHL?
Combination immuno-chemotherapy (R-CVP): rituximab, cyclophosphamide, vincristine, prednisolone.
Maintenance with rituximab will delay time until next progression. Conventional treatment is NOT curative.
50
What is marginal zone lymphoma?
A marginal zone NHL involving extranodal lymphoid tissue (e.g. MALT)
51
What percentage of all NHL is marginal zone lymphomas?
8% of all NHL
52
What is marginal zone lymphomas associated with?
Chronic antigen stimulation
53
What are 4 examples of MZL or chronic antigenic stimulation?
Sjogren's syndrome - parotid lymphoma (MZL); Helicobacter pylori - gastric MALToma (MZL); Hashimoto's thyroiditis - thyroid (MZL); Psittaci infection - lacrimal gland
54
What is the median age at presentation of marginal zone lymphomas?
55-60 years
55
Where do MZL commonly arise? At what stage do they present?
Usually present with dyspepsia or epigastric pain. Usual presentation is stage I [E]. NOTE: the [E] means extranodal. B symptoms are UNCOMMON
56
Describe the MALT lymphagenesis
- Lymphocytes will respond to the H. pylori infection
- At some point, they will overproliferate
- They may develop cancer-associated changes in phenotype, however, they will still be reliant on the antigenic stimulation from H. pylori to keep proliferating
- So, treating the H. pylori and removing this stimulus may cure the lymphoma
57
What is the treatment for gastric MALToma?
For gastric MALT stage I-II disease: omep 20mg/ clarith 500mg / amox 1gm bd; repeat breath test at 2 months; repeat endoscopy every 6 months for 1st 2 years then annualy.
Results: durable remission in 75% of patients. Response may be delayed until 1 year. If fails then may require chemotherapy.
58
Patients with which condition is Enteropathy-Associated T Cell Lymphoma (EATL) seen in?
T cell NHL seen in patients with Coeliac disease
59
Mature or precursor T cells in enteropathy-associated T cell lymphoma?
Mature T cells
60
Which organs does EATL involve?
Small intestines (jejunum and ileum)
61
What is the clinical behaviour of EATL?
AGGRESSIVE
62
What is the cause of EATL?
Caused by chronic antigenic stimulation (gluten/gliadin)
63
What is the presentation of EATL?
Abdominal pain, obstruction, perforation, GI bleeding, malabsorption, systemic symptoms
64
What is the clinical course of EATL? How to prevent?
Responds poorly to chemotherapy, generally FATAL. Aim to prevent by strict adherence to Gluten-free diet.
65
What is CLL?
Proliferation of mature B cells
66
What is the most common leukaemia in the Western world?
CLL
67
Who does CLL tend to affect?
Caucasians
68
What is the UK incidence of CLL?
4.2/100,000 per year
69
What is the median age at presentation of CLL?
72 years (10% aged < 55 yrs)
70
What is the risk of CLL in relatives?
7 x increased risk
71
What are the laboratory findings of CLL?
Lymphocytosis (5-300 x 109/L), smear cells, normocytic normochromic anaemia, thrombocytopaenia, bone marrow lymphocytic replacement of normal marrow elements
72
What is the clinical behaviour of CLL?
Indolent leukaemia. NOTE: as this is an indolent leukaemia, it is often only picked up during routine blood tests for other reasons.
73
What antigens do normal mature B cells express?
CD19 POSITIVE and CD5 NEGATIVE
74
What antigens do normal mature T cells express?
CD3 positive; CD4 or CD8 positive depending on whether it is a T-helper or cytotoxic T lymphocyte. CD19 NEGATIVE, CD5 POSITIVE.
75
How does immunophenotyping by flow cytometry indicate CLL?
In CLL, the B cells continue to express CD5 (the intermediate B cell expresses CD5 but this is normally not expressed as a mature B cell). The presence of CD5 on B cells should make you think of CLL. (In an example immunophenotyping assay, it shows a separate population of lymphocytes that are co-expressing CD19 AND CD5 - see notes for picture).
76
What is the diagnostic algorithm for CLL?
1. lymphocytosis and morphology -> if immature lymphoblasts (TdT positive) think ALL,
2. Small mature lymphocytes and smear cells (need immunophenotype)
3. Mature B cells CD5 +ve (undergraduate small print - could be a mantle cell lymphoma)*
4. Immunophenotype CLL score 4-5/5
5. Diagnose CLL
77
What are clinical prognostic factors in CLL?
Quantify the burden of malignant cells. Use Rai staging or Binet staging.
Binet stage A: <3 lymphoid areas, 60% of patients and median survival of 12 years
Binet stage B: >3 lymphoid areas, 30% of patients and median survival of 5 years
Binet stage C: Above plus Hb <100g/L and platelets <100x10^9/L, 10% of patients, median survival of 2 years
78
What are the laboratory tests can be used to determine prognosis in CLL?
CD38 expression - associated with POOR prognosis. Cytogenetics (FISH). Immunoglobulin gene mutation status: IgH mutated, IgH unmutated.
79
What is VH?
variable heavy chain (the part that undergoes somatic hypermutation by VDJ recombination)
80
What do mutated and unmutated VH genes tell us about CLL prognosis?
Prognosis is MUCH WORSE in patients with UNMUTATED VH i.e. arising from pre-germinal centre cells
81
Why do half of CLL patients have mutated VH and half have unmutated VH?**
- Pre-germinal centre B cells will have immunoglobulin genes (VH genes) that have NOT undergone somatic hypermutation
- So, if you look at the VDJ section in these cells, you will find that they are UNMUTATED and conform precisely to the germline sequence
- Once an individual B cell has undergone antigen selection through the germinal centre, the reason it gets selected as being the best antibody-producing cell for that particular antigens is due to the introduction of somatic mutations around the VDJ section
- These antibodies will come out as a post-germinal centre B cell, where the heavy chain varies from the germline
- Half of CLL patients have MUTATED VH (i.e. arising from post-germinal centre cells) and half have UNMUTATED VH (i.e. arising from pre-germinal centre cells)
* **
82
What are biological prognostic factors of CLL? And which gene is associated with a poor prognosis?
There are a collection of common genetic abnormalities that are screened using FISH. The most important is DELETION of 17p (TP53). The part of the chromosome that goes missing contains the p53 tumour suppressor gene. This is associated with a POOR prognosis (they don't tend to respond to chemotherapy)
83
CLL clinical issue 1: why is there an increased risk of infection?
Although there is a high lymphocyte count, these lymphocytes are monoclonal so they are NOT useful for antibody production. So, there is an abundance of non-functioning B cells and you will have a hypogammaglobulinaemia because the normal B cells are being suppressed. This leads to increased risk of infection (e.g. pneumonia, sinusitis).
84
CLL clinical issue 2: why does CLL lead to bone marrow failure?
CLL proliferates within bone marrow (efface). Healthy bone marrow will become suppressed leading to bone marrow failure (anaemia, infection, bleeding).
85
CLL clinical issue 3: what happens when malignant lymphocytes can spread to lymphoid organs (e.g. lymph nodes, spleen)?
lymphadenopathy+/ splenomegaly, lymphocytosis
86
CLL clinical issue 4: what could happen if more mutations are acquired?
Although this is an indolent disease, there is a 1% chance every year that CLL can acquire more mutations and undergo a RICHTER TRANSFORMATION, and become a high grade lymphoma
87
CLL clinical issue 5: how can CLL result in autoimmune disease?
The presence of a population of malignant B cells can also lead to deregulation of the surviving normal B cell population. This can result in autoimmune disease (e.g. autoimmune haemolytic anaemia).
88
What is supportive treatment for CLL?
1. Vaccination (flu, pneumococcus) - NOTE: VZV vaccine is NOT usually given because it is a live virus and runs the risk of giving the patient VZV.
2. Anti-infective prophylaxis and treatment: Aciclovir may be used; PCP prophylaxis for those that are immunosuppressed; IVIG recommended for those with hypogammaglobulinaemia and recurrent bacterial infections.
89
How to treat autoimmune cytopaenias in CLL?
1st line: Steroids, 2nd line: Rituximab
90
How to treat high-grade Richter transformation?
Follows same treatment as high grade lymphoma (CHOP-R)
91
What is leukaemia-directed treatment for CLL?
- Tailored to the patient. NOTE: they need irradiated blood products if they are at risk of transfusion-associated graft-versus-host disease.
- Incurable by chemotherapy
- Watch and wait is preferred over active treatment (especially because a lot of patients are elderly)
- The decision to treat is often dependent on the age and comorbidities of the patient
- The aim of therapy is to establish remission
- Young patients may be cured by allogenic stem cell transplantation
92
What is indication for treatment (i.e. when to stop watching and waiting) of CLL?
- Progressive lymphocytosis (count doubling < 6 months)
- Progressive bone marrow failure
- Hb < 100
- Platelets < 100
- Neutrophils < 1
- Massive or progressive lymphadenopathy/splenomegaly
- Systemic symptoms (B symptoms)
- Autoimmune cytopaenias (treat with steroids)
93
What is first line treatment for TP53 intact CLL?
Most intense: FCR - fludarabine, cyclophosphamide, rituximab (anti CD20 moab).
Next most intense regimen: Rituximab-bendamustine
Next most intense regimen: obinutuzumab (anti CD20) + chlorambucil
Least intense: supportive care only. This involves blood transfusions and ABx
94
What are examples of high risk CLL cases?
Examples of high risk cases:
| Patients with TP53/17p deletion; refractory disease or early relapse (< 24 months)
95
How to manage high risk CLL cases with new agents?
1. Ibrutinib (bruton tyrosine kinase inhibitor): this enzyme is important in B cell signalling, blocking this enzyme will result in B cell depletion. 2. Venetoclax (anti-Bcl2 oral agent).
96
What are emerging treatment options in CLL? (Note: they are very very expensive)
BCR kinase inhibitors (ibrutinib, idelalisib); BCL2 inhibitors (venetoclax); experimental cell based therapies (chimaeric antigen receptor T cells or CAR-T)
97
What is CAR-T?
Experimental cell based therapy.
- CAR-T are autologous T cells that are modified to contain chimeric antigen receptors.
- The internal portion of these receptors are signalling molecules
- The external portion has been engineered to target CD19 antigens on the surface of B cells
- You reinfuse the patient with these autologous engineered T cells, which then target and kill the B cells
- This leads to complete B cell depletion which shouldn't be a problem provided that you provide immunoglobulin replacement
TLDR: engineered autologous T cells attacking B cells.
98
*** Example case: a 57 y/o woman from Jamaica. Hb 92g/L, WBC 130x10^9/L, platelets 90x10^9/L. Recurrent chest infections. Peripheral blood flow immunophenotype: total lymphocyte count 120x10^9/L, 93% lymphoids express CD19, CD20, CD5, CD23, CD22, CD200; 5% lymphoid cells express CD3 CD4; TdT negative, Cytogenetics FISH study, TP53 17p deletion 33% of cells. Chr 12 centromere no trisomy. Ig heavy chain gene mutation status - unmutated. Serology - HTLV1 Ab +ve.
CLL with poor prognosis??? WATCH LECTURE!
