Chronic Lymphocytic Leukaemia Flashcards
What is the typical presentation of lymphoma?
Painless progressive lymphadenopathy
- Palpable node
- Extrinsic compression of any “tube”: e.g. Ureter, bile duct, large blood vessel, bowel, trachea, oesophagus
Infiltrate/impair an organ system
- e.g. Skin rash, ocular and CNS, liver failure
Recurrent infections
Constitutional symptoms
Coincidental e.g. FBC, Imaging
What are the two broad classifications of B cell Non-Hodgkin’s Lymphoma?
Precursor B lymphoblastic leukaemia
Mature B lymphoblastic leukaemia
What are common types of B cell lymphoma?
Diffuse Large B-Cell Lymphoma (DLBCL)
Follicular NHL
CLL
What are the two broad classification of T cell lymphoma?
Precursor T lymphoblastic leukaemia or lymphoma (T-ALL)
Mature T and NK neoplasm
What are common types of T cell lymphoma?
PTCL
Anaplastic
Cutaneous
Summarise the epidemiology of Hodgkin’s Lymphoma.
- 1% of all cancer, 3:100,000 population
- HL is more common in males than females.
Bimodal age incidence:
- Most common age 20-29, young women NS subtype
- Second smaller peak affecting elderly >60 years old
What are signs and symptoms associated with lymphoma?
Painless enlargement of lymph node/nodes.
May cause obstructive symptoms/signs
Constitutional symptoms:
- Fever
- Night sweats
- Weight loss
- Pruritis and rarely alcohol induced pain
What are the four types of classical Hodgkin’s Lymphoma?
Nodular sclerosing
Mixed cellularity
Lymphocyte rich
Lymphocyte depleted
What is the most common type of Hodgkin’s Lymphoma?
Nodular sclerosing
80%
Good prognosis
Causes the peak incidence in young women
Which Hodgkin’s Lymphoma are rare?
Lymphocyte rich: Rare - Good prognosis
Lymphocyte depleted: Rare - Poor Prognosis
How common is mixed cellularity Hodgkin’s Lymphoma?
17% - uncommon
Good prognosis
How is Hodgkin’s Lymphoma staged and why is this important?
Following pathological diagnosis of a lymph node biopsy patients are ‘staged’ this has prognostic significance and also may determine the best approach for therapy.
FDG-PET/CT scan
Consider biopsy of other site if possibly infiltrated e.g. liver
What is the staging for Hodgkin’s Lymphoma?
Stage:
- I: One group of nodes
- II: >1 group of nodes same side of the diaphragm
- III: Nodes above and below the diaphragm
- IV: Extra nodal spread
Suffix A if none of below, B if any of below
- Fever
- Unexplained Weight loss >10% in 6 months
- Night sweats
What is the management for classical Hodgkin’s Lymphoma?
Combination chemotherapy - ABVD:
- Adriamycin
- Bleomycin
- Vinblastine
- DTIC
ABVD is given at 4-weekly intervals and is effective treatment. Preserves fertility (unlike MOPP the original chemo).
Can cause (long term):
- Pulmonary fibrosis
- Cardiomyopathy
How is chemotherapy administered in classical Hodgkin’s Lymphoma? What other management options are available?
Chemotherapy (essential for cure)
- ABVD 2-6 cycles (depends: stage and interim response)
- PET CT
- Interim: After x2 cycles, response assessment
- End of Treatment: Guides need for additional radiotherapy
n+/- Radiotherapy
Relapse (salvage chemotherapy)
High dose chemotherapy + Autologous PB stem cell transplant as support
Explain radiotherapy for classical Hodgkin’s Lymphoma.
Low/negligible risk of relapse
Risk of damage to normal tissue (collateral damage)
- Ca breast (risk 1:4 after 25 years)
- Leukaemia/mds (3%@10years)
- Lung or skin cancer
Combined modality (chemo + radio) is the greatest risk of 2o malignancy
What is the prognosis of classical Hodgkin’s Lymphoma?
Older patients generally do less well as do those with lymphocyte-depleted histology.
Prognosis:
Cure rate ranges from 50-90%.
Over 80% of patients with stage I or II disease are cured
Only 50% of stage IV patients are cured
What is Non-Hodgkin’s Lymphoma?
Neoplastic proliferation of lymphoid cells.
Incidence rising 200/million population/year
Clinical course highly variable :
- Fastest proliferating malignancy (Burkitt Lymphoma)
- Indolent diseases (eg Follicular NHL with a possible 25 year survival)
- Antibiotic responsive disease such as Gastric MALT
How is Non-Hodgkin’s Disease staged?
CT scan
PET scan (indicated in aggressive lymphomas)
BM biopsy
Lumbar puncture (if risk of CNS involvement)
What are prognostic markers of Non-Hodgkin’s Lymphoma?
LDH
Performance status
HIV serology (if appropriate HTLV1 serology)
Hepatitis B serology (risk of reactivation if B cell depleting therapy given)
What is the most common type of Non-Hodgkin’s Lymphoma?
Diffuse Large B Cell Lymphoma
(Followed by Follicular Lymphoma)
Which types of Non-Hodgkin’s Lymphoma are classified by the WHO as being high grade and very aggressive?
Burkitt’s Lymphoma
T or B cell Lymphoblastic leukaemia/lymphoma
Which types of Non-Hodgkin’s Lymphoma are classified by the WHO as being high grade and aggressive?
Diffuse Large B cell
Mantle cell
Which types of Non-Hodgkin’s Lymphoma are classified by the WHO as being low grade and indolent?
Follicular
Small lymphocytic/CLL
Mucosa associated (MALT)
What is the predicted survival and curability of high grade, very aggressive forms of Non-Hodgkin’s Lymphoma?
Weeks 2-5 (Without Rx)
Curable
What is the predicted survival and curability of high grade, aggressive forms of Non-Hodgkin’s Lymphoma?
Months 3-12 (Without Rx)
Moderately curable
What is the predicted survival and curability of low grade, indolent forms of Non-Hodgkin’s Lymphoma?
Years 10-15
Incurable (long remission)
How are very aggressive Non-Hodgkin’s Lymphoma managed?
These are treated like acute leukaemia
What are the prognostic characteristics of DLBCL?
IPI (International Prognostic Index):
- Age
- Stage (Ann Arbor)
- LDH
- Extra-nodal disease sites
- ECOG performance status
What is the treatment of DLBCL?
R-CHOP
Rituximab - Anti-CD20 monoclonal antibody
Combination therapy e.g.
- Cyclophosphamide
- Adriamycin
- Vincristine
- Prednisolone
Aim of therapy is curative (overall approx 50%)
Relapse: Autologous Stem Cell transplant salvage 25% of patients
What is Follicular NHL?
Associated with t(14;18) which results in over-expression of bcl2 an anti-apoptosis protein.
FLIPI score (modified IPI) to stage.
Incurable, median survival 12-15 years
What are extranodal marginal zone lymphomas?
Marginal zone NHL involving extra-nodal lymphoid tissue (e.g. Gastric mucosa-associated lymphoid tissue MALT/H.Pylori, Parotid MZL/Sjogren syndrome).
- Comprise ~ 8% of all NHL
- Chronic antigen stimulation; H.Pylori infection
- Median age at presentation 55-60y
Most commonly arise in stomach, usually present with epigastric pain, ulceration or bleeding. Usual presentation is Stage I[E].
Constitutional symptoms uncommon.
H.Pylori eradication may cure 75% of patients.
What is Enteropathy Associated T-cell Lymphoma?
T cell NHL seen in patients with Coeliac disease
Mature T cells (not precursor). Involving small intestine, jejunum and ileum. Has an aggressive (not indolent clinical course).
Chronic antigen stimulation, triggered by gluten in a gluten sensitive individual.
Presentation & Clinical course:
- Abdominal pain, obstruction perforation, GI bleeding
- Malabsorption
- Systemic symptoms
- Responds poorly to chemo generally fatal
- Aim to prevent (strict adherence to Gluten free diet)
What is chronic lymphocytic leukaemia?
Proliferation of mature B-lymphocytes.
Commonest leukaemia in the western world. Caucasian. UK incidence 4.2/100,000/year.
Age at presentation median 72 (10% aged <55yrs)
Relatives x7 increased incidence
What are common laboratory features of CLL?
Lymphocytosis between 5 and 300 x 109/l
Smear cells
Normocytic normochromic anaemia
Thrombocytopenia
Bone marrow Lymphocytic replacement of normal marrow elements
What is the timecourse of CLL?
Highly variable natural history:
- 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
What are prognostic features of CLL and how is it staged?
Cell based prognostic factors:
- IgHV mutation status
- CLL FISH cytogenetic panel
- TP53 mutation status (Chromosome 17p del and/or TP53 point mutation)
Clinical staging systems:
- Binet or Rai (clinical staging)
- CLL IPI score
What is the median survival of CLL?
- Mutated: 25 years
- Unmutated: 8 years
What are clinical complications with CLL?
Population of malignant (non functional) mature B cells+ hypogammaglobulinaemia: Increased risk of infection
Proliferate within Bone marrow (efface): Bone marrow failure
Circulate to nodes, spleen and blood: Lymphadenopathy+/splenomegaly, lymphocytosis
Acquire further mutations: Transform to high grade lymphoma; Richter Transformation (1% per year)
Disease of immune cells: Auto-immune complications e.g. Immune haemolytic anaemia
How can sino-pulmonary infections in CLL be treated?
Early Rx with antibiotics
Pneumocystis prophylaxis (may also require zoster ppx)
Recurrent infection + IgG < 5g/l > IVIG replacement therapy
Which vaccinations should be offered to patients with CLL?
Pneumococcal
Covid19
Seasonal flu
Avoid live vaccines
Watch and wait is the preferred approach to CLL.
When should treatment be given?
Progressive lymphocytosis:
- >50% Increase over 2 months
- Lymphocyte doubling time <6 months
Progressive marrow failure:
- Hb < 100, platelets <100, neutrophils <1
Massive or progressive lymphadenopathy/splenomegaly
Systemic symptoms
Autoimmune cytopenias (treat with immunosuppression not chemotherapy)
What therapy can be offered for CLL patients?
Combination Immuno-chemotherapy (being superseded by targeted Rx)
Targeted Therapy:
- BTK inhibitor
- BCL2 inhibitor
Cellular therapy only for relapsed high risk cases:
- Allogeneic SCT
- CAR-T therapy
Which BCR kinase can be used to treat CLL?
Ibrutinib (BTK)
Idelalisib (PI3K)
Which BCL2 inhibitors can be used to treat CLL?
Venetoclax
Which experimental cell based therapies can be used to treat CLL?
Chimaeric Antigen Receptor T cells (CAR-T)
How does venetoclax work in CLL?
Orally active Bcl 2 inhibitor, permits apoptosis of CLL cells.
In high risk CLL p53 mutated 85% response and maintained at greater than 1 year.
Main risk is tumour lysis syndrome when initiating therapy (potentially fatal).
