1. Chronic
Lymphocytic
Leukemia
(CLL)

2. CLINICAL PRESENTATION:
CLL has a wide range of symptoms and physical and laboratory abnormalities at the time of its initial discovery in an individual patient.
     
Lymphadenopathy — 87 percent      Splenomegaly — 54 percent      Hepatomegaly — 14 percent      Total white blood cell count >100,000/µL 30%      Hemoglobin concentration <11.0 g/dL 31% .      Platelet count <100,000/µL — 16 percent

3. - Unintentional weight loss -Fevers of >38؛C for 2 weeks
Symptoms :
Approximately 25 percent with no symptoms lymphocytosis, leading to a diagnosis of CLL.
Approximately 5 to 10 percent of patients present with typical "B" symptoms of lymphoma, formally defined one or more of the following .
  - Unintentional weight loss  
-Fevers of >38؛C for  2 weeks
-Night sweats
-Extreme fatigue

4. Symptoms : Approximately 25 percent with no symptoms lymphocytosis, leading to a diagnosis of CLL.
Approximately 5 to 10 percent of patients present with typical "B" symptoms of lymphoma, formally defined one or more of the following .
  - Unintentional weight loss  
-Fevers of >38؛C for  2 weeks
-Night sweats
-Extreme fatigue
Most patients have painless swelling of lymph nodes
Most often in the cervical area, which spontaneously wax and wane, but do not altogether disappear.
Infections, autoimmune complications such as hemolytic anemia, thrombocytopenia, or pure red cell aplasia, or exaggerated reactions to insect bites.

5. Most patients have painless swelling of lymph nodes.
Symptoms :
Most patients have painless swelling of lymph nodes.
Most often in the cervical area,
which spontaneously wax and wane , but do not altogether disappear.

6. Symptoms : Approximately 25 percent with no symptoms lymphocytosis, leading to a diagnosis of CLL.
Approximately 5 to 10 percent of patients present with typical "B" symptoms of lymphoma, formally defined one or more of the following .
  - Unintentional weight loss  
-Fevers of >38؛C for  2 weeks
-Night sweats
-Extreme fatigue
Most patients have painless swelling of lymph nodes
Most often in the cervical area, which spontaneously wax and wane, but do not altogether disappear.
Infections, autoimmune complications such as hemolytic anemia, thrombocytopenia, or pure red cell aplasia, or exaggerated reactions to insect bites.

8. Physical findings:
  Lymphadenopathy : present in 50 to 90 percent of patients among various series. Lymph node enlargement may be generalized or localized
 - Splenomegaly :The spleen is the second most frequently enlarged lymphoid organ. It may be palpably enlarged in 25 to 55 percent of cases.
  -Hepatomegaly : Enlargement of the liver may be noted at the time of initial diagnosis of CLL in 15 to 25 percent of cases.
  -Other organ involvement: other lymphoid tissue in the body may be enlarged at diagnosis, such as Waldeyer's ring or the tonsils.Skin Infiltration lesions are the most commonly involved non-lymphoid organ, and are seen in fewer than 5 percent of cases., gastrointestinal mucosal involvement and meningeal leukemia is rarely seen in CLL.
Membranoproliferative glomerulonephritis:appears to be a paraneoplastic phenomenon mediated by deposition and possibly processing of cryoprecipitating : Mechanisms:
1-mixed cryoglobulinemia,
2- classic type 1 MPGN,
3-immunotactoid glomerulopathy.

9. Physical findings:
  Lymphadenopathy : present in 50 to 90 percent of patients among various series. Lymph node enlargement may be generalized or localized
 Splenomegaly :The spleen is the second most frequently enlarged lymphoid organ. It may be palpably enlarged in 25 to 55 percent of cases.

10. Physical findings:
 Hepatomegaly : Enlargement of the liver may be noted at the time of initial diagnosis of CLL in 15 to 25 percent of cases.
Other organ involvement: other lymphoid tissue in the body may be enlarged at diagnosis, such as Waldeyer's ring or the tonsils.
Skin Infiltration lesions are the most commonly involved non-lymphoid organ, and are seen in fewer than 5 percent of cases., gastrointestinal mucosal involvement and meningeal leukemia is rarely seen in CLL.

11. 1-mixed cryoglobulinemia, 2- classic type 1 MPGN,
Physical findings:
 Membranoproliferative glomerulonephritis:
appears to be a paraneoplastic phenomenon mediated by deposition and possibly processing of cryoprecipitating :
Mechanisms:
1-mixed cryoglobulinemia,
2- classic type 1 MPGN,
3-immunotactoid glomerulopathy.

13. Lymph node biopsy :
B-cell CLL and small lymphocytic lymphoma (SLL) are considered to be the same disease at different stages .
-The diagnosis of SLL was made via a lymph node biopsy in a patient presenting with lymphadenopathy but without peripheral lymphocytosis.

14. Lymph node biopsy :
The histopathologic lymph node findings in SLL and CLL are identical , and consist of a diffusely effaced nodal architecture with occasional residual naked germinal centers.
The infiltrate is mostly mature-appearing, small lymphocytes, with an admixture of prolymphocytes and para - immunoblasts. Mitotic activity is usually very low.

15. CLL was diagnosed through examination of the peripheral blood and bone marrow in patients with lymphocytosis.

16. *The direct antiglobulin (Coombs') test positive
  Other abnormalities :
*Anemia
*Thrombocytopenia :
*The direct antiglobulin (Coombs') test positive

17.   Other abnormalities :
Anemia and thrombocytopenia hemoglobin (<11 g/dL) and platelet levels (<100,000/µL), are observed at the time of diagnosis in about 20 percent of patients.

18.  The direct antiglobulin (Coombs') test may be positive at some time during the course of the disease in up to 35 percent of cases; overt autoimmune hemolytic anemia (AIHA) occurs in 11 percent whose antibody was an IgM had significantly shorter survival following diagnosis of the AIHA than those with an IgG antibody.

19. Autoimmune thrombocytopenia is most often diagnosed on the basis of the presence of adequate numbers of megakaryocytes in the bone marrow with an abnormally low platelet count in the peripheral blood.

20. Agranulocytosis:
may be encountered in CLL, but is rare (approximately 0.5 percent).

21. Hypogammaglobulinemia may be present at the time of initial diagnosis.

22. Pure red cell aplasia (PRCA) is rare, AIHA, PRCA may occur early in the course of CLL.

23. Elevated levels of serum lactate dehydrogenase (LDH) and beta-2 microglobulin
were found in 60 percent of patients. Elevations of uric acid, hepatic enzymes (ALT or AST) and, rarely, calcium may also be observed.

26. Chromosomal changes in CLL :
There is no one chromosomal change that is specific for CLL, although certain patterns are frequently seen. These include:
     
Trisomy of chromosomes 12, 3, or 16      del(13q14)      del(11q)      del(17p)      t(11;14)(q13;q32).

27. Absolute lymphocytosis in the peripheral blood occurs in an adult.
DIAGNOSTIC CRITERIA :
Absolute lymphocytosis in the peripheral blood occurs in an adult.
Blood lymphocytosis may also occur with viral or other infections

28. DIAGNOSTIC CRITERIA :
Infection:
(eg, infectious mononucleosis, pertussis, toxoplasmosis ) as well as in neoplastic conditions other than CLL:
(eg, the leukemic phase of lymphomas, hairy cell leukemia, prolymphocytic leukemia, and large granular cell lymphocyte leukemia).

29. DIAGNOSTIC CRITERIA :
The task is therefore to distinguish between reactive causes of lymphocytosis and clonal (malignant) causes, and, for the latter, to distinguish CLL from the other malignant lymphoproliferative disorders.

31. DIFFERENTIAL DIAGNOSISin CLL :
-Small lymphocytic lymphoma :
-Mantle cell lymphoma :The small lymphocytes with irregular or cleaved nuclei seen in mantle cell lymphoma (MCL) share with B-CLL positivity for CD5 and CD20.
-Lymphoplasmacytic lymphoma :Lymphoplasmacytic lymphoma, which is indistinguishable from Waldenstrom's macroglobulinemia.
-Hairy cell leukemia : (HCL) is associated with an elevated lymphocyte, cytochemically, a moderately strong TRAP+
-Large granular lymphocyte leukemia :(LGL) leukemia, lymphocytes are T-cells and express a mature post-thymic phenotype, CD3+, CD4-, CD8+, CD57.
-Mycosis fungoides :cutaneous T-cell lymphoma (CTCL), the lymphocytes have a cerebriform nucleus (Sezary cells, which are usually CD4+, CD8-.
-Adult T cell lymphoma/leukemia
-Prolymphocytic leukemia :
-T cell CLL :A series of twenty-five cases of T-cell CLL (T-CLL) has been reported;

32. -Small lymphocytic lymphoma : -Mantle cell lymphoma :
DIFFERENTIAL DIAGNOSISin CLL :
-Small lymphocytic lymphoma :
-Mantle cell lymphoma :
The small lymphocytes with irregular or cleaved nuclei seen in mantle cell lymphoma (MCL) share with B-CLL positivity for CD5 and CD20.
-Lymphoplasmacytic lymphoma: Lymphoplasmacytic lymphoma, which is indistinguishable from Waldenstrom's macroglobulinemia.

33. DIFFERENTIAL DIAGNOSISin CLL :
-Hairy cell leukemia : (HCL) is associated with an elevated lymphocyte, cytochemically, a moderately strong TRAP+
-Large granular lymphocyte leukemia :(LGL) leukemia, lymphocytes are T-cells and express a mature post-thymic phenotype, CD3+, CD4-, CD8+, CD57.

34. -Adult T cell lymphoma/leukemia
DIFFERENTIAL DIAGNOSISin CLL :
-Mycosis fungoides :cutaneous T-cell lymphoma (CTCL), the lymphocytes have a cerebriform nucleus (Sezary cells, which are usually CD4+, CD8-.
-Adult T cell lymphoma/leukemia

35. DIFFERENTIAL DIAGNOSISin CLL :
-Prolymphocytic leukemia :
-T cell CLL :A series of twenty-five cases of T-cell CLL (T-CLL) has been reported;

37.   Partial response :
A partial response (PR) is defined (NCI criteria) as presence of all of the following for two or more months:
    
- A reduction in previously enlarged nodes, spleen, and liver by at least 50 percent and
 -Absolute neutrophil count   1,500/µL or  -Platelet count   100,000/µL or  -Hemoglobin concentration   11 g/dL or      50 percent improvement over pretherapy reductions in hemoglobin concentration and/or platelet count

38. Complete remission :
A complete remission in CLL requires all of the following to be present for two or more months
     
-Absence of symptoms attributable to CLL.   -Normal findings on physical examination.   -Absolute lymphocyte count <4,000/µL.   
-Absolute neutrophil count >1,500/µL.   -Platelet count >100,000/µL.   -Hemoglobin concentration >11 g/dL (untransfused).   -Bone marrow lymphocytosis <30 percent.   -No nodules (lymphoid aggregates) on BM biopsy.

39. CHEMOTHERAPY: Cyclophosphamide Chlorambucil Corticosteroids  
Cyclophosphamide
Corticosteroids
Nucleoside (purine) analogs
Fludarabine &  Cladribine
Pentostatin —
Chlorambucil
  High dose steroid salvage therapy
Total body irradiation
LEUKAPHERESIS
SPLENECTOMY
BONE MARROW TRANSPLANTATION
IMMUNOTHERAPY
MONOCLONAL ANTIBODIES
Anti-CD20 (rituximab)
Anti-CD52 (alemtuzumab, Campath-1H) — Alemtuzumab,
Other antibodies — Infusions of a T101 antibody

40. Cyclophosphamide Chlorambucil Corticosteroids
CHEMOTHERAPY:   
Cyclophosphamide
Corticosteroids
Nucleoside (purine) analogs
Fludarabine &  Cladribine
Pentostatin —
Chlorambucil

41. Total body irradiation
CHEMOTHERAPY:   
 High dose steroid salvage therapy
Total body irradiation
LEUKAPHERESIS
SPLENECTOMY
BONE MARROW TRANSPLANTATION

42. Anti-CD52 (alemtuzumab, Campath-1H) — Alemtuzumab,
Chemotherapy:
IMMUNOTHERAPY
MONOCLONAL ANTIBODIES
Anti-CD20 (rituximab)
Anti-CD52 (alemtuzumab, Campath-1H) — Alemtuzumab,
Other antibodies — Infusions of a T101 antibody

43. Infection in CLL :
      
Mycobacteria      Listeria monocytogenes      Pneumocystis carinii      Cytomegalovirus      Herpes simplex virus

52.                                                   Survival of untreated patients with chronic
lymphocytic leukemia by time period.

53.                                                   Survival of untreated patients with chronic lymphocytic
leukemia by Rai stage.