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= monoclonal disorder characterized by progressive accumulation of functionally incompetent

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.

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
• 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)
• 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,

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.

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