1. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)
Curs an IV – limba engleza

2. CLL - Definition
CLL is a neoplastic disease characterized by proliferation and accumulation (blood, marrow and lymphoid organs) of morphologically mature but immunologically dysfunctional lymphocytes
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3. CLL - Definition Clonal B cell malignancy.
Progressive accumulation of long lived mature lymphocytes.
Increase in anti-apoptotic protein bcl-2.
In most cases, the cells are monoclonal B lymphocytes that are CD5+
Intermediate stage between pre-B and mature B-cell.
T cell CLL can occur rarely
Results in prolonged cell survival despite of low proliferate index.
Generally marked hypogammaglobulinemia, with increased incidence of infections.

4. Cancer statastics 2000; CA J Clin 2000; 50:7-33
CLL - Epidemiology
Most common leukemia of Western world.
Less frequent in Asia and Latin America.
Male to female ratio is 2:1.
Median age at diagnosis is years.
Uncommon (10%) in patients under 50 years
In US population incidence is similar in different races.
Accounting for 25% of all the cases.
For unknown reasons.
Rarely seen before age 35 years.
Cancer statastics 2000; CA J Clin 2000; 50:7-33

5. CLL - Etiology (1) The cause of CLL is unknown
There is increased incidence in farmers, rubber manufacturing workers, asbestos workers, and tire repair workers
Genetic factors have been postulated to play a role in high incidence of CLL in some families
Like radiation exposure, alkylating agents.
No link with HTLV nor EBV.

6. CLL - Etiology (2) Cytogenetics Oncogenes
clonal chromosomal abnormalities are detected in approximately 50% of CLL patients
the most common clonal abnormalities are:
trisomy 12
structural abnormalities of chromosomes 13, 14 and 11
patients with abnormal karyotypes have a worse prognosis
Oncogenes
in most cases of CLL is overexpressed the proto-oncogene c-fgr 9a member of the src gene family of tyrosine kinases

7. CLL – Initial symptoms
Approximately 40% are asymptomatic at diagnosis – discovered by a CBC
In symptomatic cases the most common complaint is fatigue
Well’s syndrome – increase sensitivity to insects bites
B symptoms – fever, sweats, weight loss
Less often the initial complaint are enlarged nodes or the development of an infection (bacterial)

8. CLL - Clinical findings
Most symptomatic patients have enlarged lymph nodes (more commonly cervical and supraclavicular) and splenomegaly
The lymph nodes are usually discrete, freely movable, and nontender
Hepatomegaly may occure
Less common manifestation are infiltration of tonsils, mesenteric or retroperitoneal lymphadenopathy, and skin infiltration
Patients rarely present with features of anemia, and bruising or bleeding

9. CLL – Lab findings a) Blood test lymphocytosis ≥ 5G/l (4 weeks)
b) Morphology monoconal population of small mature lymphocyte
c) B-cell CLL phenotype clonal CD5+/CD19+ population
of lymphocyte
d) Markers of clonality κ/λ light chain restriction; cytogenetical abnormalities
e) Bone marrow infiltrate > 30% of nuceated cells on aspirate
f) Lymph node diffuse infiltrate of small lymphocye

10. CLL - Laboratory findings (1)
The blood lymphocyte count above 5.000/mmc
Leukemic cells have the morphologic appearance of normal small lymphocytes
In the blood smears are commonly seen ruptured lymphocytes (“basket” or “smudge” cells)
Careful examination of the blood smear can usually differentiate CLL, and the diagnosis can be confirmed by immunophenotyping

11. CLL - Peripheral Blood Absolute lymphocytosis Lymphs = B cells
Thin cytoplasm
Dense nucleus
Partially aggregated
chromatin
No recognizable
nucleoli
Smudge cells
Patients with CLL have absolute lymphocytosis and pretty much all of the lymphs look like this. The cytoplasm is thin, the nucleus is dense and clumped, and no nucleoli can be seen. These are commonly called soccer ball lymphs. Also there are a lot of broken cells which we call smudge cells.
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12. CLL - Laboratory findings (2)
Clonal expansion of B (99%) or T(1%) lymphocyte
In B-cell CLL clonality is confirmed by
the expression of either  or  light chains on the cell surface membrane
the presence of unique idiotypic specificities on the immunoglobulins produced by CLL cells
by immunoglobulin gene rearrangements
typical B-cell CLL are unique in being CD19+ and CD5+

13. CLL - Immunophenotype Detect antigens on surface of cells
Specific antibodies
Use flow cytometry or immunohistochemistry
CLL = mature B cells
CD5
CD19
CD20 - low
CD22 - low
CD23
Light chains (κ, λ)
Determining the immunophenotyping of the cells can help diagnose CLL. Just to review, immunophenotyping means detecting antigens on cell surfaces using specific monoclonal antibodies. For fluid samples we use a flow cytometer to detect the antibodies bound to the cells and for tissue we use immunohistochemistry. As I had said, the leukemic cells in CLL are mature B cells. So they express some of the appropriate B cell markers like CD19, CD20 and CD23. CD20 expression is usually decreased compared to normal. CD5 is usually on T cells but it is also present on CLL cells. Normal B cells only express one type of light chain, either Kappa or Lambda but a few studies have shown that CLL cells can have a mixed expression of both.
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14. CLL - Immunophenotype scoring system
Scoring system for B-CLL
Membrane marker
Points 1
Smlg
Weak
Moderate/strong
CD5
Positive
Negative
CD23
FMC7
CD79b (SN8)
Until recently, B-CLL cells were differentiated from other B-cell lymphoproliferative diseases by immunophenotyping with 5 cell membrane protein markers: SmIg (Surface Membrane-bound Immunoglobulin), CD5 (T1 antigen), CD23 (The Fc Receptor for IgE), FMC7 (a specific conformation of CD20, possibly multimeric and possibly associated with membrane cholesterol), and CD22 (gp135; a B-cell adhesion molecule).
CD79b (a signal transduction molecule that associates with SmIg) is now preferred to CD22, a change that has significantly increased the ability to discriminate between B-CLL and other B-cell disorders.
An immunophenotyping scoring system was developed that gives a value of 1 or 0 according to whether it is typical or atypical for CLL. Total scores range from 5 (typical of CLL) to 0 (atypical of CLL).
1. Matutes E, et al. Leukemia. 1994;8: Moreau EJ, et al. Am J Clin Pathol. 1997;108:
1. Matutes E, et al. Leukemia. 1994;8:
2. Moreau EJ, et al. Am J Clin Pathol. 1997;108:

15. CLL – Other lab tests
Hypogammaglobulinemia or agamma-globulinemia are often observed
% of patients with CLL develop autoimmune hemolytic anemia, with a positive direct Coombs’ test
The marrow aspirates shows greater than 30% of the nucleated cells as being lymphoid
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16. CLL - Bone Marrow Infiltrates of small lymphocytes
Causes neutropenia, anemia, thrombocytopenia
Extramedullary expansion
Splenomegaly
Hepatomegaly
Lymphadenopathy
If a bone marrow collection is done, you would see that the soccer ball lymphs have infiltrated the bone marrow, which leaves little room for normal hematopoiesis to occur. So the patient also can experience low neutrophils, red cells, and platelets. These cells can also infiltrate other lymphoid tissues like the spleen, liver, and lymph nodes and cause enlargement.
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17. CLL – Lymph node Loss of nodal architecture
Diffuse infiltration of small lymphocytes
Lymphadenopathy
A lymph node biopsy would show that the small lymphs have taken over the tissue. This causes lymphadenopathy or enlarged lymph nodes, and node loss. This is a picture of a normal lymph node and you can see the different nodes and germinal centres. This is a picture of a lymph node in CLL and all of these purple dots are the infiltrating lymphs. You can’t see any nodes or germinal centres anymore.
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18. CLL - diagnostic criteria
A peripheral blood lymphocyte count of greater than 5 G/L, with less than 55% of the cells being atypical
2) The cell should have the presence of Bcell-specific differentiation antigens (CD19, CD20, and CD24) and be CD5(+)
3) A bone marrow aspirates showing greater than 30% lymphocytes

19. CLL - Differential diagnosis
Infectious causes
bacterial (tuberculosis)
viral (mononucleosis)
Malignant causes
B-cell
T-cell
leukemic phase of non-Hodgkin lymphomas
Hairy-cell leukemia
Waldenstrom macroglobulinemia
large granular lymphocytic leukemia

20. Investigations
Pretreatment studies of patients with CLL should include examination of:
complete blood count
peripheral blood smear
reticulocyte count
Coomb’s test
renal and liver function tests
serum protein electrophoresis
immunoglobulin levels
plasma 2 microglobulin level
If available immunophenotyping should be carried out to confirm the diagnosis
Bone marrow biopsy and cytogenetic analysis is not routinely performed in CLL

21. CLL – Rai staging system
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22. CLL – Rai stages

23. CLL – Binet staging system
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24. CLL – Binet stages

25. Staging: Rai and Binet staging systems for CLL
Clinical staging systems for CLL
Stage
Value
Rai
Binet
Median survival
Lymphocytosis (>15,000/mm3) -
150 months (12.5 years)
Lymphocytosis plus nodal involvement I A
<3 node groups
months (8.5-9 years)
Lymphocytosis plus organomegaly II B
>3 node groups
60-71 months (5-6 years)
Anemia (RBCs)
III Hgb <11 g/dL C
Hgb <10 g/dL
19-24 months (1.5-2 years)
Lymphocytosis plus thrombocytopenia (platelets)
IV PLT <100,000/mm3
PLT <100,000/mm3
The clinical staging of CLL is usually done according to the staging of Rai or Binet. The Rai system is more common in the US, whereas the Binet system is prevalent in Europe.
Both systems classify the disease stages according to platelet count, hemoglobin count, and the size of lymph nodes, spleen, and liver.
The original Rai staging system included 5 stages of disease progression. However, it was modified by Rai into 3 categories: Low risk (Rai stage 0), Intermediate risk (Rai stages I and II), and High risk (Rai stages III and IV). This revision is the preferred version according to the modified NCI guidelines.
The predictive nature of both systems is limited by the wide-ranging nature of the clinical course of CLL, which can be unpredictable at the early stage of the disease.
1. Rai KR, et al. Blood. 1975;46:
2. Binet JL, et al. Cancer. 1981;48:
3. Binet JL, et al. Cancer. 1977;40:

26. CLL - Markers of poor prognosis
Advanced Rai or Binet stage
Peripheral lymphocyte doubling time <12 months
Diffuse marrow histology
Increased number of prolymphocytes or cleaved cells
Poor response to chemotherapy
High 2- microglobulin level
Abnormal karyotyping

27. Prognosis: histologic bone marrow patterns
Nodular (low risk)
Interstitial (low risk)
Diffuse (high risk)
The different bone marrow patterns probably reflect variations in amount of lymphoid accumulation during the natural course of the disease
Histologic patterns of trephine biopsies from bone marrow reveal patterns that can be useful in assessing patient risk.
Nodular patterns are made up of mature lymphocytes. The nodules are larger-than-normal lymphoid follicles and lack clear centers. There is no interstitial infiltration. Fat cells are preserved. Nodular patterns are associated with low-risk disease.
Interstitial patterns show some degree of replacement of normal hematopoietic tissue by mature lymphocytes, but fat cells and bone marrow structure are preserved. Interstitial patterns are also associated with low-risk disease.
Diffuse patterns show diffuse lymphoid infiltration with massive replacement of normal hematopoietic tissue as well as replacement of fat cells. Diffuse patterns are associated with high-risk disease.
Biopsy patterns may reflect variations in the amount of lymphoid accumulation during the course of the disease.
Randy Gascoyne, MD., Montserrat E, et al. Cancer. 1984;54:
1. Montserrat E, et al. Cancer. 1984;54:

29. Prognosis: lymphocyte doubling time
Survival time according to LDT (all stages)
1.0
0.9
0.8
Doubling time ≤12 months
0.7
Doubling time >12 months
0.6
Probability of survival
0.5
0.4
0.3
Lymphocyte doubling time (LDT) is clearly related to prognosis in patients with CLL.
In a study of 100 untreated patients, LDT correlated partially with clinical stage and with bone marrow patterns, but it also had a clear prognostic significance by itself.
Patients with an LDT 12 months were likely to have a poor prognosis, whereas those with an LDT >12 months had a good prognosis, with a long treatment-free period and survival.
0.2
0.1
0.0 20 40 60 80
100
120
140
160
Months
1. Montserrat E, et al. Br J Haematol. 1986;62:
1. Montserrat E, et al. Br J Haematol. 1986;62:

30. CLL - Genetic abnormalities
Genetic abnormality
Incidence (%)
Median survival (months)
Clinical correlation
13q14
55-62
Typical morphology Mutated VH genes Stable disease
+ 12
16-30
Atypical morphology Progressive disease
del 11q23 18
79-117
Bulky lymphadenopathy Unmutated VH genes Progressive disease Early relapse post autograft
p53 loss/mutation 7
32-47
Atypical morphology Unmutated VH genes Advanced disease Drug resistance
Because of the limitations of the Rai and Binet systems in predicting the progression of CLL, other prognostic criteria are being considered; for instance, advanced disease stage, male gender, CD38 expression >30%, and atypical morphology predict relatively poor outcomes in CLL. Additionally, karyotyping and molecular biology techniques reveal that the behavior of certain genetic markers in CLL may offer insights into the molecular mechanism of the disease and predict treatment outcome.
In a study of 205 patients with CLL, 69% were found to have an abnormal karyotype. Genetic abnormalities included:
structural abnormality of chromosome 13q14
trisomy 12
11q23 deletion
17p13 abnormalities; loss or mutation of the p53 gene
13q14 deletion carries a better prognosis than deletion of 11q13 or 17p13.
Deletion of 11q23 is associated with bulky lymphadenopathy and a high incidence of residual disease following autologous transplantation.
17p13 abnormalities that result in mutation or loss of the p53 gene correlate with resistance to purine analogs.
1. DÖhner H, et al. N Engl J Med. 2000;343: Oscier DG, et al. Blood. 2002;100:
1. Döhner H, et al. N Engl J Med. 2000;343:
2. Oscier DG, et al. Blood. 2002;100:

31. Effect of genetic abnormalities on survival
Döhner et al evaluated 325 cases of CLL to assess the frequency and clinical relevance of genomic aberrations.1 Of the 325 patients, 248 had received no prior treatment, 39 had received 1 chemotherapeutic agent, and 38 had received 2 or more chemotherapeutic regimens before the cytogenetic analysis was conducted.1
Of the 325 patients, 268, or 82%, exhibited abnormalities. The primary endpoint for this study was survival from time of diagnosis. All cases were evaluated by interphase cytogenetics. On the basis of regression analysis, the investigators constructed a hierarchical model of 5 genetic categories for evaluation as prognostic factors: 17p deletion; 11q deletion but not a 17p deletion; 12q trisomy but not a 17p or 11q deletion; normal genome; and 13q deletion as the sole aberration. Of the 325 patients, 300 could be assigned to one of these 5 subgroups; 25 with various chromosomal abnormalities could not.
This slide illustrates the percentage of surviving patients by genetic aberration over 168 months. Median survival times for the groups were: 17p deletion, 32 months; 11q deletion, 79 months; 12q trisomy, 114 months; normal genome, 111 months; and 13q deletion as the only abnormality, 133 months. As the slide shows, patients with 17p deletions had by far the worst prognosis.1
1. Döhner H, et al. N Engl J Med. 2000;343:
1. Döhner H, et al. N Engl J Med. 2000;343:

32. CLL - VH Status “Variable” region of immunoglobulin gene H=heavy chain
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33. CLL - VH Mutation Naïve B cells have unmutated V regions
Make initial IgM and IgG that bind Ag poorly
Somatic hypermutation of V region creates memory B cells
Make Ab with higher affinity for Ag
CLL progression is dependent on mutation status of B cells
Unmutated VH = rapid progression, short survival
Mutated VH = slow progression, long survival
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34. CLL - VH Mutation Naïve B cells Unmutated VH Memory B cells Mutated VH
Fast progression
Short survival
CLL
Slow Progression
Long Survival

35. Prognosis: effect of VH gene mutations on survival
100
Unmutated VH gene Median = 117 months
Mutated VH gene Median = 293 months 90 80 70 60
Percent surviving (%) 50 40 30
In this patient population, median survival times were significantly worse for patients with unmutated VH genes than for those with mutated VH genes (117 months vs 293 months, respectively; P=.001). However, this comparison may be skewed because in this population a greater number of patients with unmutated VH genes had advanced stage disease. 20 10 25 50 75
100
125
150
175
200
225
250
275
300
325
Months
1. Hamblin TJ, et al. Blood. 1999;94:
1. Hamblin TJ, et al. Blood. 1999;94:

36. 4/19/2017 6:49 PM
Clinical Course of CLL
Clinical Course of CLL
Disease has a variable course; however, it often progresses from an indolent lymphocytosis without other evident disease to one of generalized lymphatic enlargement with concomitant pancytopenia
Progression: bone marrow impairment,  susceptibility to infection
Complications of pancytopenia, including hemorrhage and infection, represent a major cause of death in these patients
Although CLL is predominantly an indolent disorder of late middle-aged or elderly individuals, the disease may cause significant morbidity. In its least aggressive pattern, patients die of causes unrelated to CLL at a rate that closely follows actual norms for their age. In its most aggressive form, patients may die within 1 to 2 years after diagnosis.
At presentation, patients are often asymptomatic. Initial symptoms are generally secondary to lymphocytosis or anemia. As the disease advances, the following may appear: increasingly elevated lymphocyte counts; progressive lymphadenopathy and hepatosplenomegaly; and more severe anemia, granulocytopenia, or thrombocytopenia. Late in the course of the disease, hypogammaglobulinemia and progressive splenomegaly are prevalent. Infections are common with disease progression and are the leading cause of death in patients with CLL.
Most CLL patients die of infection or illness unrelated to the leukemia.
Long-term consequences of CLL include the development of autoimmune phenomena and/or transformation.
Faguet. J Clin Oncol. 1994;12:
ART General SLIDES\NCI Slides\CP Slides\CP CLLSlideKit G22

37. CLL - Immunologic Complications
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CLL - Immunologic Complications
Immunologic Complications of CLL
Autoimmune hemolytic anemia
Coombs’ positive
Clinical hemolysis
Pure red cell aplasia
Immune-mediated thrombocytopenia
Depressed immunoglobin levels
Granulocytopenia
Hypogammaglobulinemia  with advanced disease
Long-term complications: autoimmune phenomena, Richter’s transformation
The development of autoantibodies is a cardinal feature of the natural history of CLL.1 In general, autoantibodies are generated against formed elements of the hematopoietic system.
Autoimmune hemolytic anemia develops in between 10% and 15% of patients with CLL.2 Usually, these patients are Coombs’ positive, and clinical hemolysis is evident.
Pure red cell aplasia occurs less often.2 Patients with this autoimmune manifestation are often Coombs’ negative, despite clinical hemolysis. Examination of the bone marrow reveals a deficiency of red blood cell precursors.
Immune-mediated thrombocytopenia is less common, occurring in 2% to 5% of patients with CLL.2
Most patients with CLL do not have other autoimmune disorders, such as rheumatoid arthritis, although some investigators find these diseases more prevalent in relatives of patients with CLL.2
Recall that CLL cells express CD5. Normal CD5+ B cells are usually found at the edge of germinal centers in the mantle zone of lymphoid follicles. These cells generally produce polyreactive, low-affinity autoantibodies.1
1. Caligaris-Cappio et al. J Clin Oncol. 1999;17:
2. Keating. Semin Oncol. 1999;26(suppl 14):
ART General SLIDES\NCI Slides\CP Slides\CP CLLSlideKit G22

38. CLL - Complications Severe systemic infections Bleeding
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CLL - Complications
Complications of CLL
Severe systemic infections
Bleeding
Richter’s transformation
Prolymphocytoid transformation
Secondary malignancies
Acute myeloid leukemia
Severe systemic infections represent the leading cause of death for patients with CLL. Increased susceptibility to infections is due both to intrinsic features of the pathogenesis of CLL as well as to therapy.
CLL evolves into a more aggressive lymphoid malignancy in about 10% to 15% of cases. Richter’s transformation is the most common of these, in which patients develop a diffuse large cell immunoblastic lymphoma. Survival is poor.
Prolymphocytoid transformation occurs when the morphologic appearance of the CLL cells alters to somewhat larger cells with distinct nucleoli and less dense chromatin. This condition is refractory to typical chemotherapeutic agents.
Secondary malignancies may develop in patients with CLL, particularly carcinomas of the lung.
CLL may evolve into acute leukemia as a terminal event. When this occurs, the leukemia is myeloid in origin.
Kalil et al. Drugs & Aging. 2000;16:9-27.
ART General SLIDES\NCI Slides\CP Slides\CP CLLSlideKit G22

39. Transforming the way we approach CLL therapy
Traditional treatment goal: Palliation
Age is a factor
Treat to relieve symptoms
Continuous/intermittent treatment
No survival advantage for any tested treatment to date
New advances may allow treatment for remission and survival
Treat to complete remission (CR)
Eliminate minimal residual disease
Response predicts for survival: More CRs

40. CLL – treatment (1) Watch and wait Monotherapy
glucocorticoids
alkylating agents (Chlorambucil, Cyclophosphamide)
purine analogues (Fludarabine, Cladribine, Pentostatin)
Combination chemotherapy
Chlorambucil/ Cyclophosphamide + Prednisone
Fludarabine + Cyclophosphamide +/- Mitoxantrone
CVP, CHOP
Monoclonal antibodies (monotherapy and in combination)
Alemtuzumab (anti-CD52)
Rituximab (anti-CD20)
Splenectomy
Radiotherapy

41. CLL – treatment (2) Hematopoietic stem cell transplantation
allogeneic with reduced intesity conditioning
autologous
New and novel agents
Oblimersen – bcl2-directed antisense oligonucleotide
Lenalidomide
Flavopiridol
Anti-CD23
Anti-CD40
Vaccine strategies
Supportive therapy (allopurinol, G-CSF, blood and platelet transfusion, immunoglobulins, antibiotics)

42. NCI-WG: Indications to Initiate Treatment for CLL
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NCI-WG: Indications to Initiate Treatment for CLL
NCI-WG: Indications to Initiate Treatment for CLL
Constitutional symptoms referable to CLL (B-symptoms)
Progressive marrow failure
Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroids
Massive or progressive splenomegaly
Massive or progressive lymphadenopathy
Rapid lymphocyte doubling time
When to begin therapy remains one of the most challenging issues confronting physicians who care for patients with CLL. Outside of clinical trials, the therapeutic goal for most patients with CLL who require treatment has been palliation of symptoms. The suggested guidelines for initiation of therapy from the NCI consensus panel on CLL are summarized on this slide.
Initiation of therapy must be individualized according to each patient’s clinical status and comorbid conditions. Although constitutional symptoms alone may be an indicator of when to begin therapy, it is important to search for other causes of weight loss or fever. Cytopenia may be caused by autoantibodies in addition to marrow impairment.
Cheson et al. Blood. 1996;87:
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43. MoAbs citotoxic mechanisms
Once bound to cancer cells, MoAbs can exert tumoricidal effects through a variety of mechanisms.
Antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) may work in synergy with MoAbs to destroy tumor cells.75
Induction of apoptosis (programmed cell death) and inhibition of cell proliferation following antibody binding have been demonstrated in vitro.24,96
Antibodies that lack the ability to interact with the host immune system can be conjugated to radionuclides or toxins to produce a cytotoxic effect.24,60
Effector cells/
Complement
Apoptosis
Radionuclide
Toxin/Antibiotic

44. MoAbs for CLL Antibody Antigen Alemtuzumab (Campath-1H) CD52
Rituximab (Rituxan, Mabthera)
CD20
Epratuzumab (LymphoCide)
CD22
Hu-1D10 (Apolizumab)
HLA-DR
IDEC-152 (Lumiliximab)
CD23
IDEC-114
CD80
Bevacizumab (Avastin)
VEGF
BL-22
CD22( conjugate with Pseudomonas)

45. MabThera®: a chimeric murine/human MoAb
Variable murine regions bounding
CD20 on B cells
Human kappa costant regions
MabThera® binds to the CD20 antigen present on normal and malignant pre-B and B cells.95
MabThera® is an engineered immunoglobulin (Ig) produced from the variable regions (Fab) of a mouse (murine) anti-CD20 MoAb and human IgG1 and kappa constant regions (Fc).
The human Fc domain and kappa constant regions may contribute to the infrequency of host antibody response.
Human domain IgG1 Fc, synergistic
with human effector mechanisms
Chimeric IgG1

46. Rituximab as part of first-line therapy for CLL: Rationale
Rituximab monotherapy is moderately active in CLL1,2
Activity is dose dependent (between 500–2250 mg/m2)1
Rituximab acts synergistically with other cytotoxic agents in vitro
Increases fludarabine activity in NHL cell lines3
Increases activity of bendamustine, mitoxantrone and other chemotherapeutic agents in CLL cells4
Rituximab combination therapies (e.g. R-F, R-FC, R-PC, R-FCM, R-Bendamustine, R-Chlorambucil) are now being assessed

47. Alemtuzumab (anti-CD52) antibody
IgG1 humanised antibody:
Low immunogenicity
CD52 antigen:
Highly expressed on
all lymphocytes
monocytes and macrophages
spermatozoa
eosinophils
Not expressed on haemopoietic stem cells
Does not modulate/shed
Also expressed on the majority of malignant lymphocytes

48. Treatment of CLL

49. CLL – Treatment strategy
How I treat CLL.
Gribben J G Blood 2010;115: