CLL and Lymphoproliferative Disorders Flashcards
Reed Sternberg Cells
Classical Hodgkin Lymphoma
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
Presentation of NHL
Painless lymphadenopathy
Compression symptoms
B symptoms
Why is a biopsy taken in NHL
WHO classification of lymphoma subtype
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)
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
Very aggressive NHL
Burkitt lymphoma
T or B cell lymphoblastic leukaemia/lymphoma
Aggressive NHL
Diffuse large B cell
Mantle cell
Indolent NHL
Follicular
Small lymphocytic/CLL
Mucosa associated (MALT)
Incurable NHL
Indolent forms
Prognosis 10-15 years
Curable NHL
Very aggressive forms
Prognosis 2-5 weeks (without treatment)
How are very aggressive NHL treated
The same as for acute leukaemia
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)
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%
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
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
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
Features of MALT lymphomas
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
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
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
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
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
sIg
CD19
CD5
Diagnostic algorithm in CLL
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)
