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CHRONIC LYMPHOCYTIC LEUKEMIA

= monoclonal disorder characterized by progressive accumulation of functionally incompetent


lymphocytes.
It is the most common form of leukemia found in adults in Western countries
The prognosis varies widely at diagnosis
—> Some patients die rapidly, within 2-3 years of diagnosis
—> Most patients live 5-10 years

1) Etiology
 As in the case of most malignancies, the exact cause of CLL is uncertain.
 The protooncogene bcl2 is known to be overexpressed, which leads to suppression of apoptosis

2) Epidemiology
 incidence of CLL is higher among whites than blacks.
 The incidence of CLL is higher in males than in females,1.7:1.
 primarily affects the elderly, with the median age of presentation being 72 years.

3)Pathophysiology
The cells of origin are clonal B cells arrested in the B-cell differentiation pathway, intermediate
between pre-B cells and mature B cells( resemble mature lymphocytes)
—> B-cell surface antigen: CD19, CD20dim, CD21, CD23, CD5 (more in T cells)
—> CLL express: very low levels of IgM, IgD and kappa/ lambda Ig chain
karyotype:
• deletion of 13q: is the most common abnormality
• trisomy 12
• 17p13 deletions: loss of function of the tumor suppressor gene p53.
• deletions of bands 11q22-q23
!!! High risk:
 Germline immunoglobulin variable heavy chain (IgVH): IgVHV3-21 gene
 High Zap70+ beta2-microglobulin +thymidine kinase activity
 Short lymphocyte doubling time (< 6 mo)
 Increased serum levels of soluble CD23+ CD38

4) Clinical
a) History
⇨ Onset is insidious, at presentation, patients are often asymptomatic
⇨ Enlarged lymph nodes are the most common presenting symptom,
⇨ A predisposition to repeated infections: pneumonia, herpes simplex, herpes zoster
⇨ Early satiety and/or abdominal discomfort may be related to an enlarged spleen.
⇨ Mucocutaneous bleeding and/or petechiae may be due to thrombocytopenia.
⇨ Tiredness and fatigue may be present secondary to anemia
⇨ Richter syndrome or Richter transformation refers to the transformation of CLL into an
aggressive large B-cell lymphoma: weight loss, fevers, night sweats, muscle wasting,
increasing hepatosplenomegaly and lymphadenopathy
b) Physical examination
In addition to localized or generalized lymphadenopathy, patients may manifest the following:
 Splenomegaly (30-54% of cases)
 Hepatomegaly (10-20% of cases)
 Petechiae
 Pallor

5) Paraclinical
a) Lab Studies:
➢ CBC count: absolute lymphocytosis(smudge cells) with more than 5.000 lymphocytes/mmc.
➢ Peripheral blood flow cytometry: clonal B-lymphocytes
• positive: CD5, CD19, CD20(dim), CD 23,
• negative: FMC-7
➢ check quantitative Ig levels: monthly intravenous immunoglobulin administration in patients with
low levels of immunoglobulin G (<500 mg) may be beneficial in reducing the frequency of
infectious episodes.
➢ Biopsy
b) Imaging Studies:
➢ Ultrasonography
➢ CT
c) Cytology
!!! Diagnostic Criteria
❖ lymphocyte count >5000 (with less than 55% of the cells being atypical)
❖ B cell antigens : CD19, CD20, CD24, CD5
❖ A bone marrow aspirates > 30% lymphocytes
6) Differential Diagnoses
 Acute Lymphoblastic Leukemia
 Large granular lymphocytic leukemia: NK phenotype( CD2,CD16,CD56) or T cell
phenotype ( CD2,CD3,CD8)
 Hairy Cell Leukemia: positive (IgM/IgD) and negative (CD5,CD21)
 Lymphoma: Diffuse large cell/small lymphocytic/ Follicular/ Lymphoblastic/ non-hodgkin
 Lymphoma, Mantle Cell: positive( CD19, high CD20,CD5,FMC-7) and negative (CD23)
=> more aggressive than CLL
 T-Prolymphocytic leukemia: positive( CD19,CD20,IgM/IgD) and negative(CD5)

7) Staging
a) Rai staging (USA)

 Low risk (formerly stage 0) – Lymphocytosis in the blood and marrow only (25% of
presenting population}
 Intermediate risk (formerly stages I and II) – Lymphocytosis with enlarged nodes in any site
or splenomegaly or hepatomegaly (50% of presentation)
 High risk (formerly stages III and IV) – Lymphocytosis with disease-related anemia
(hemoglobin < 11 g/dL) or thrombocytopenia (platelets < 100 x 109/L) (25% of all patients)

b) Binet staging (Europe)


 Stage A – Hemoglobin >10 g/dL, platelets > 100 × 109/L but < 3 lymph node areas involved
 Stage B – Hemoglobin and platelet levels as in stage A but > 3 lymph node areas involved
 Stage C – Hemoglobin<10 g/dL, platelets < 100 × 109/L

8) Treatment
do not need to be treated with chemotherapy until they become symptomatic
 Weight loss of more than 10% over 6 months
 Extreme fatigue
 Fever related to leukemia for longer than 2 weeks
 Night sweats for longer than 1 month
 Progressive marrow failure (anemia or thrombocytopenia)
 Autoimmune anemia or thrombocytopenia not responding to glucocorticoids
 Progressive or symptomatic splenomegaly
 Massive or symptomatic lymphadenopathy
 Progressive lymphocytosis, as defined by an increase of > 50% in 2 months or a doubling
time of less than 6 months
⇨ Response assessment
Complete response :
 All lymph nodes smaller than 1 cm; normal liver and spleen
 leukocyte counts > 1500/mm3
 normal circulating B lymphocytes
 platelet levels > 100,000/mm3
 hemoglobin level > 11 g/dL
 normocellular bone marrow with < 30% lymphocytes; no B-lymphoid nodules
Partial response :
 Decrease in lymph nodes by 50% or more; liver and spleen sizes decreased by 50% or more
 leukocyte counts > 1500/mm3
 circulating B lymphocytes decreased by 50% or more
 platelet levels > 100,000/mm3 or > 50% increase from baseline
 hemoglobin level > 2 g/dL from baseline
 hypocellular bone marrow or > 30% lymphocytes or B-lymphoid nodules
⇨ Treatment recommendations for symptomatic CLL
Low- intermediate risk (Rai stage 0- 1+2): observation
High risk (Rai stages III and IV):
!!! Allogeneic stem cell transplantation is the only known curative therapy

 Fludarabine-based therapy is preferred for patients with CLL


• Monotherapy
– glucocorticoids
– alkylating agents (Chlorambucil, Cyclophosphamide)
– purine analogues (Fludarabine, Cladribine, Pentostatin)
• Combination chemotherapy
– Pentostatin/ Cyclophosphamide + Rituximab(PCR)
– Fludarabine + Cyclophosphamide +/- Mitoxantrone( FCM)
– CVP, CHOP
• Monoclonal antibodies (monotherapy and in combination)
– Alemtuzumab (anti-CD52): for fludarabine-refractory disease, p53 mutation
– Rituximab (anti-CD20): not effective against p53 mutations
– Ofatumomab (anti-CD20): for refractory to fludarabine and alemtuzumab
– Obinotuzumab (anti-CD20)
– Lumiliximab (anti-CD23)
• Splenectomy
• Radiotherapy
• Hematopoietic stem cell transplantation
• New and novel agents: Oblimersen, Lenalidomide, Flavopiridol
• Vaccine strategies
• Supportive therapy (allopurinol, G-CSF, blood and platelet transfusion, immunoglobulins,
antibiotics)

a) Chemotherapy Regimens
⇨ Nucleoside analogues: fludarabine, cladribine, and pentostatin
⇨ Chlorambucil+ Ibrutinib/rituximab is used as first-line in elderly
⇨ Alemtuzumab
⇨ Idelalisib; for relapsed CLL, relapsed follicular B-cell non-Hodgkin lymphoma, and relapsed
small lymphocytic lymphoma
⇨ Lenalidomide: in multiple myeloma/ myelodysplastic syndrome with 5q deletion

9) Complications
▪ Although CLL is predominantly an indolent disorder of late middle-aged or elderly
individuals, the disease may cause significant morbidity.
▪ In its most aggressive form, patients may die within 1 to 2 years after diagnosis.
=> increasingly elevated lymphocyte counts; progressive lymphadenopathy, hepatosplenomegaly
and more severe anemia, granulocytopenia/thrombocytopenia, hypogammaglobulinemia
!!!! Infections are are the leading cause of death: pneumonia => give IV immunoglobulin

▪ Long-term consequences of CLL include the development of autoimmune phenomena


❖ AIHA - Autoimmune hemolytic anemia: Coombs’ positive => Prednisone 20-60 mg daily

❖ Immune thrombocytopenia => give Thrombopoietin receptor agonists, Rituximab for B


clones inducing autoimmune disease

❖ Pure red cell aplasia : Coombs’ negative, despite clinical hemolysis

❖ Others: Autoimmune neutropenia, Cold agglutinin disease, Paraneoplastic pemphigus,


Neuropathies, Evans syndrome

Virtually all patients requiring therapy should also be given allopurinol to prevent uric
acid nephropathy.

Splenectomy
Refractory splenomegaly and pancytopenia is a common problem in patients with advanced
CLL. All patients with CLL who are to undergo splenectomy should be immunized at least 1
week in advance against the pneumococcus, Haemophilus influenza, and Neisseria meningitidis