CHRONIC LYMPHOCYTIC LEUKEMIA

DEFFINITION AND EPIDEMIOLOGY

- Chronic Lymphocytic Leukemia (CLL) is a low-grade Non-Hodgkin lymphoma . It is main characteristic is proliferation of malignant clone of mature- appearing Ly in the bone marrow with leukemic component- absolute lymphocytosis in the peripheral blood. In 90% it is B-CLL

-B-cell chronic lymphocytic leukemia(CLL) -the most common lymphoproliferative disorder in Western countries- incidence- 5/100,000-for males and 2,5/100,000 for females

- Disease of older adults – median age-65-68 years

Clinical features

- has a long course, could be asymptomatic, often is diagnosed accidentally , on a routine blood count

In symptomatic patients- widespread lymphadenopathy, splenomegaly-the lymph nodes are nontender, non matted or fixed to surrounding tissue. Even bulky lymph node enlargement does not usually result in compressive symptoms

Rarely- malaise, easy fatigability, weight loss, night sweats- these symptoms usually correlate with the overall tumor load

CLINICAL FEATURES

Anemia, thrombocytopenia, neutropenia- due to disease progression within the bone marrow; autoimmune complication; hypersplenism or treatment side effects

Symptoms of immune defficiency-hypogammaglobulinemia – pulmonary bacterial infections; T-cell deficiency-more often result of treatment- high risk of viral and opportinistic infections

Autoimmune manifestations such as autoimmune thrombocytopenia, Coombs positive hemolytic anemia or pure red cell aplasia

LABORATORY STUDIES

Increase in the number of mature-appearing lymphocytes in circulation to more than 5000/microL

In the advance stages – anemia, thrombocytopenia In patients with very large tumor burden-elevated serum

lactic dehydrogenase (LDH), beta2 –microglobulin and uric acid levels

In 5%- serum protein electrophoresis detects M-components(paraprotein)

Often- hyppogammaglobulinemia Often- Coombs test is positive

LABORATORY STUDIES

Bone marrow generally shows a diffuse infiltration of small, mature-appearing lymphocytes

Flow cytometric immunophenotyping of the B cells-in typical CLL CD 19 B-cells express CD5, CD20 and CD23 together with abnormally low surface amounts of monotypic s Ig ( usually IgM or IgD) and always only a single Ig light chain , either kappa or lambda

DIAGNOSIS

- Absolute lymphocytosis- > 5000/ microL mature-appearing lymphocytes in circulation

- Diffuse infiltration of bone marrow of small , mature –appearing lymphocytes

- Typical immunophenotyping of B-cells-CD19+; CD5+; CD23+; CD20+; low amounts of sIg

CYTOGENETIC ANALYSIS AND FISH

The most common chromosomal abnormalities:

-Del on 11q; 13p; 13q; 17p;17q; del17p has very poor prognostic value- involves loss of p53 gene, which is important in the tumor response to purine nucleoside analogues.

-trisomy12

- balanced and unbalanced translocations

DIFFERENTIAL DIAGNOSIS

Other Non-Hodgkin Lymphoma ( NHL) with leukemic component ( circulating lymphoma cells) – immunophenotyping of circulating Ly helps to differentiate CLL from NHLwith leukemization; when adenopathy is the prominent aspect of the clinical presentation , a node biopsy with immunohistochemistry may be required to rule out more aggressive form of lymphoma ;

Hairy cell leukemia- usually affects men; splenomegaly without adenopathy, pancytopenia, Ly with specific morphology in peripheral blood and bone marrow-Hairy cells with large nucleus and filamentous projections of cytoplasm, with specific phenotype- CD11c+CD103+; CD5,CD23-neg . Bone marrow biopsy with immunohistochemistry is often required for the diagnosis .

DIFFERENTIAL DIAGNOSIS

Prolymphocytic leukemia-splenomegaly, bulky adenopathy, very high Leu count; aggressive course; >55% of Ly are proLy-larger than typical small Ly with prominent nucleolus; IFT- CD23-neg;CD 5+-; FCM7 + and strong expression of sIg

Mantle cell lymphoma-CD5+, CD23-neg;70%- t(11,14) wich results in overexpression of cyclin D1; aggressive course

Small-cell lymphocytic lymphoma- Ly has the same IFT, in SCLL the adenopathy is prominent and Leu count is not so eleveted , the difference is largely semantic since the treatment is identical. Both disorders should be considered varying manifestation of the same disease.

DIFFERENTIAL DIAGNOSIS

Other non-hematologic disease- viral infections with reactive lymphocytosis-

- infectious mononucleosis- affects younger patients- < 35 years; sore throat, fever, lymphadenopathy, hepatosplenomegaly, hepatitis, absolute lymphocytosis with polimorphism of Ly, usually without anemia and thrombocytopenia; the diagnosis is confirmed serologically

- CMV

Staging

. Rai staging system: Stage 0- lymphocytosis whithout clinical symptoms Stage 1- lymphocytosis with lymphadenopathy Stage 2 – lymphocytosis with splenomegaly Stage 3- anemia with Hb< 100g/l whatever the oter signs Stage 4- thrombocytopenia< 100 000/ microL whatever

the other signs

Staging

Binet staging system: A- with Hb> 100g/L , Plt> 100, 000/ microL and limited

lymphadenopathy and/or splenomegaly B - Hb>100g/L, Plt>100, 000/microL, extensive

lymphadenopathy and splenomegaly C- Hb< 100g/l or Plt< 100,000/ microL

TREATMENT AND PROGNOSIS

Prognostic factors: -advanced stage- stage 3-4 according to Rai or 3

according to Binet -lymphocyte doubling time < 6 months -cytogenetic abnormalities , esp. del 17 -expression of CD38 and ZAP-70 - elevated LDH and beta 2 -microglobulin

Treatment and Prognosis

The treatment of CLL with chemotherapy with or without transplantation is never curative.When patients are asymptotic, without large tumor burden and unfavorable prognostic factors it is better option to delay treatment till progression of the disease happens.

1. Chlorambucil – oral alkylating agent- response is obtained in 60-70% but is usually partial and last less 20 months.

2. Fludarabine- purine analog . The overall response rate is 75% with a mean duration 25 months. It could be administated alone( complete response-20%) or in combination with Cyclophosphamide ( complete response- 40%)

Treatment and Prognosis

3.Alemtuzumab- recombinant CD 52 –antibody which is shared by CLL-B cells and normal T cells. It is the first-line option for CLL with del 17. Side effects- “ first dose effect”- rigors, fever, hypotension and respiratory distress; severe immunosupression, reactivation of CMV

4. Combination Fludarabine with Cyclophosphamide, Mitoxantrone and/or Rituximab- results in higher response rate including complete ( 60%) and sometimes molecular remissions and longer event-free survival. Side effects and toxity are more severe

Treatment and prognosis

5. Intensive therapy-in younger patient with adverse prognostic factors- intensification with autologous stem cell rescue. However this procedure is not curative. Allogenic stem cell transplantation could be potentially curative, but its application is limited because of patient’s age and tolerance. It is currantly considered the therapy of choice for younger patients with refractory disease esp. 17p mutation

Complications

1. Autoimmune disease: - Hemolytic anemia and thrombocytopenia. The

treatment include corticosteroids. - Pure red cell aplasia- usually responds to cyclosporin 2.Severe infections-viral or bacterial due to severe

hypogammaglobulinemia and suppressed T-Ly function ( therapy-related)- antibiotics, antiviral agents, sometimes administration of i.v.gamma globulin

3.Richter syndrome- transformation to diffuse large cell lymphoma or prolymphocytic leukemia- it is suspectet when the disease’s coure changes abruptly.