CLL and Lymphoproliferative Disorders Flashcards by Katerina Fernandez

Reed Sternberg Cells

Classical Hodgkin Lymphoma

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NHL

Neoplastic proliferation of lymphoid cells.
Originates in lymphoid tissue (lymph nodes, bone marrow, spleen)
Incidence rising 200/million population/year

Fastest growing human cancer (Burkitt Lymphoma)
Indolent diseases with a 25 year survival

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Presentation of NHL

Painless lymphadenopathy
Compression symptoms
B symptoms

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Why is a biopsy taken in NHL

WHO classification of lymphoma subtype

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Management NHL

Stage the disease: CT scan, PET scan (indicated in aggressive lymphomas), BM biopsy, LP (if risk of CNS involvement)
Prognostic markers and important tests: LDH, performance status, HIV serology (if appropriate HTLV1 serology), Hepatitis B serology (risk of reactivation if B cell depleting therapy given)
Plan therapy: urgent chemotherapy, monitor only, antibiotic eradication (H.pylori gastric MALT lymphoma)

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NHL subtypes

Follicular lymphoma 
Small lymphocyte lymphoma 
Marginal zone lymphoma 
Diffuse large B cell lymphoma 
Burkitt's lymphoma
B cell lymphoblastic lymphoma 
Mantle cell lymphoma 
Lymphoblastic lymphoma 
NK cell/T cell lymphoma

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Very aggressive NHL

Burkitt lymphoma

T or B cell lymphoblastic leukaemia/lymphoma

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Aggressive NHL

Diffuse large B cell

Mantle cell

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Indolent NHL

Follicular
Small lymphocytic/CLL
Mucosa associated (MALT)

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Incurable NHL

Indolent forms

Prognosis 10-15 years

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Curable NHL

Very aggressive forms

Prognosis 2-5 weeks (without treatment)

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How are very aggressive NHL treated

The same as for acute leukaemia

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Features of DLBCL

Aggressive B cell NHL
30-40% of all NHL

Prognosis and treatment determined by:
Precise histological diagnosis
Anatomical stage
IPI (International Prognostic Index)

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What is the IPI for DLBCL

Age > 60y
serum LDH > normal
performance status 2-4
stage III or IV
more than one extranodal site

5 year predicted survival is by number of risk factors: 
0-1 = 73%
2 = 51%
3 = 43%
4-5 = 26%

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Treatment of DLBCL

Treated by x 6-8 cycles of R-CHOP (Rituximab-CHOP)

combination chemotherapy using a mixture of drugs usually including an anthracycline (e.g. doxorubicin).

Combination drug regimens e.g. CHOP
Cyclophosphamide 750mg/m2 IV
Adriamycin 50mg/m2 IV
Vincristine 1.4mg/m2 IV
Prednisolone 40mg/m2 PO

R is Immunotherapy using the anti CD20 monoclonal antibody Rituximab

Aim of therapy is curative (overall approx 50%)

Relapse: Autologous Stem Cell transplant salvage 25% of patients

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Features of follicular NHL

Indolent lymphoma
35% of NHL
Associated with t(14;18) which results in over-expression of bcl2 an anti-apoptosis protein
FLIPI score (modified IPI)
Incurable, median survival 12-15 years
May require 2-3 different chemotherapy schedules over the 12-15 year period

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Treatment of follicular NHL

Indolent slow progressing B cell NHL
Incurable
variable/long natural history

At presentation Watch and wait only treat “if clinically indicated”
Nodes compressing;eg bowel, ureter, vena cava
Massive painful nodes, recurrent infections

Treatment:
combination Immuno-chemotherapy R-CVP
Maintenance rituximab delays Time to next progression
Conventional treatment is not curative

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Features of MALT lymphomas

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Is a Marginal zone NHL involving extranodal lymphoid tissue (ie mucosa-associated lymphoid tissue MALT)
Comprise ~ 8% of all NHL
Chronic antigen stimulation
Sjogrens syndrome ; parotid lymphoma (MZL)
H.Pylori ; Gastric MALT lymphoma (MZL)
Hashimoto’s Thyroid; Thyroid (MZL)
Lachrymal gland (?Psittaci infection)
Median age at presentation 55-60y
Most commonly arise in stomach, usually present with dyspepsia or epigastric pain
Usual presentation is Stage I[E]
‘B’-symptoms uncommon

Pathogenesis of MALT lymphomas

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Proliferation polyclonal antigen specific B cells (due to chronic gastritis caused by h.pylori infection)
Antigen dependent transformed B cell clone (at this point is an antibiotic sensitive MALT)
Antigen independent transformed B cells (antibiotic insensitive MALT)

Treatment of gastric MALT (MZL) stage 1-2 disease

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Omep 20mg/Clarith 500mg/amox 1gm bd
Repeat breath test at 2 months
Repeat endoscopy every 6 months for 1st 2years then annually

Durable remission in 75% of patients
response may be delayed until 1yr
If fails eradication therapy then may require chemotherapy

Features of CLL

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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

Laboratory findings in CLL

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Lymphocytosis between 5 and 300 x 109/l 
Smear cells
Normocytic normochromic anaemia
Thrombocytopenia
Bone marrow	Lymphocytic replacement of normal marrow elements

Important targets in CLL treatment

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sIg
CD19
CD5

Diagnostic algorithm in CLL

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Lymphocytes + morphology –> immature lymphoblastic (TdT positive) think acute lymphoblastic leukaemia (ALL)

Lymphocytes + morphology –> small mature lymphocytes + smear cells (need immunopheotype) –> mature B cells CD5 +ve (COULD BE A MANTLE CELL LYMPHOMA) –> immunophenotype CLL score 4-5/5 –> CLL

What is the CLL score

``` CD5 CD23 FMC7 CD79b SmIg ```

Prognostic factors in CLL

Clinical (quantify the burden of malignant cells) : Rai staging Binet staging Laboratory/malignant cell based: CD38 expression bad prognosis Cytogenetics (FISH panel) Immunglobulin gene mutation status: IgH mutated, IgH unmutated

How is clinical stage determined in CLL

Stage A: <3 lymphoid areas B: >3 lymphoid areas C: >3 lymphoid areas, Hb<100, platelets <100

What are the steps of normal B cell development

Stem cells produce primary repertoire, undergo VDJ joining to produce low affinity antigen specific B cells, which then undergo class switching to produce high affinity antigen-specific B cells Class switching can lead to IgH mutations. Unmutated VH accounts for 56% of CLL, whilst mutated VH accounts for 44% of CLL.

What IgH is associated with better long-term prognosis in CLL

Mutated median survival 25 years | Unmutated median survival is 8 years

What chromosomal abnormality is associated with a worse prognosis in CLL

Deletion of 17p - median survival is 32 months

Malignant (non functional) mature B cells+ hypogammaglobulinaemia Clinical issue?

Increased risk of infection

Proliferate within Bone marrow (efface) | Clinical issue?

Bone marrow failure

Circulating to nodes, spleen and blood | Clinical issue?

Lymphadenopathy +/- splenomegaly, lymphocytosis

Acquired further mutations | Clinical issue?

Transform to high grade lymphoma

Disease of immune cells | Clinical issue?

Auto-immune complications e.g. haemolytic anaemia

Treatment principles in CLL

Suportive treatment: Vaccination Anti-infective prophylaxis and treatment Specific scenarios: Auto-immune cytopaenias High grade (Richter) transformation Leukaemia directed treatment: Tailored to patient

Principles of supportive treatment in CLL

Prophylaxis and treatment of infections: Account for 50% of all CLL related deaths Most are bacterial, but fungal and viral are becoming increasingly prevalent Prophylaxis: Aciclovir, PCP prophylaxis for those receiving fludarabine or alemtuzumab (Campath) IVIG is recommended for those with hypogammaglobulinemia and recurrent bacterial infections, Immunisation against pneumococcus, and seasonal flu

Management of auto-immune phenomena in CLL

Auto-immune phenomena: 1st Line Steroids 2nd Line Rituximab Irradiated Blood products if risk of TA GVHD

Richter's syndrome

CLL transformation to high grade lymphoma

Principles of leukaemia directed treatment in CLL

Incurable by chemotherapy: Watch and wait versus active treatment Conventional not to treat Stage A: What are the indications for treatment? If required tailor treatment (age/co-morbidities) Aim of therapy obtain response/remission: disease will relapse, 2nd line therapy Young patients may be cured by allogeneic stem cell transplants

Indications for CLL treatment

``` Watch and wait unless: Progressive lymphocytosis lymphocyte doubling time <6 months Progressive marrow failure Hb < 100, platelets <100, neutrophils <1 Massive or progressive lymphadenopathy/splenomegaly Systemic symptoms (B symptoms) Autoimmune cytopenias (treat with steroids) ```

Chemo-immunotherapy for CLL

``` 1st line Given if TP53 intact FCR: fludarabine cyclophosphamide, rituximab (anti CD20) Rituximab-Bendamustine Obinutuzumab (anti CD20) + chlorambucil Supportive care only ```

How are high risk CLL cases managed

Patients with TP53/17p deleted CLL 1st Line Refractory disease or early relapse (<24 months) Patients failed 2 lines of chemotherapy New agents: ibrutinib (bruton tyrosine kinase inhibitor), venetoclax 9anti Bcl2 oral agent)

Emerging treatment options for CLL

BCR kinase inhibitors: ibrutinib, idelalisib BCL2 inhibitors: venetoclax Experimental cell based therapies: chimaeric antigen receptor T cells (CAR-T)

CLL and Lymphoproliferative Disorders Flashcards

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