About Lymphoma > Types of Lymphoma > CLL/SLL

Last update: 04/22/2008

Overview | Signs and Symptoms | Treatment | Clinical Trials   
Prognostic factors | Targets | Richter's syndrome | Research News

TOPIC SEARCHES: PubMed: Diagnosis | Review | Therapies | Prognosis | Richter's | Refractory
 
Treatment: ASCO | Medscape | FDA | Web

Overview of CLL & SLL

How does CLL compare to SLL? 
 Are they the same disease?  ACOR.org

"CLL shows up primarily in the bone marrow and peripheral blood." 

"SLL presents itself primarily in the lymph nodes or lymphoid tissues" 

ACOR.org

Do you need to locate 
CLL experts?

See: The Research Consortium  cll.ucsd.edu
 
it lists member institutions, contains  links to the clinicians and researchers who make up the membership.  

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Staging elements

adenopathy / 
lymphadenopathy - abnormal swelling or enlargement of lymph nodes

anemia - a shortage of healthy red blood cells. Treatment depends on cause.

hepatosplenomegaly - liver and spleen enlargement

hepatomegaly- an enlarged liver

splenomegaly - an enlarged spleen

lymphocytosis - an abnormal increase in the number of lymphocytes — a type of white blood cell — in your blood. The most common cause is viral infection.

thrombocytopenia - low platelet counts

Chronic Lymphocytic Leukemia/lymphoma

Chronic lymphocytic leukemia (CLL) is the second most common type of leukemia. It's caused by the overproduction of abnormal b-cells (a type of lymphocyte). 

Lymphocytes are specialized immune cells, of which there are two types: B and T-cells. B lymphocytes are produced in the bone marrow. 

Most CLL cases involve mature B-lymphocytes that tend to live much longer than normal, accumulating in the blood, bone marrow, lymph nodes and spleen. 

Background on CLL:  "The cells accumulate mainly in the bone marrow and blood. CLL is closely related to (and most consider it the same as) a disease called small lymphocytic lymphoma (SLL), a type of non-Hodgkin's lymphoma which presents primarily in the lymph nodes. In the past, cases with similar microscopic appearance in the blood but with a T cell phenotype were referred to as T-cell CLL. However, it is now recognized that these so-called T-cell CLLs are in fact a separate disease group and are currently classified as T cell prolymphocytic leukemias." - Wikipedia.org 

Note: Splenic Lymphoma is very difficult to diagnose and often misdiagnosed for CLL

Natural history

"Chronic lymphocytic leukaemia (CLL) is a B-cell disorder, which has a median survival of over 10 years from diagnosis for stage A disease. The natural history of stage A disease is generally indolent or only slowly progressive. 

It is less well known that CLL may undergo spontaneous regression. We report a series of 10 such cases (eight stage A and two stage B) followed at our institutions."   - Spontaneous clinical regression in chronic lymphocytic leukaemia.
Br J Haematol. 2002 Feb;116(2):341-5. PMID: 11841436

B-cell stage:  mature, before antigen exposure

Also see  NHL- A Detailed Description for a discussion of b-cells and stages of b-cell maturation.

Signs and symptoms associated with CLL

¹ Anemia and other blood cell deficiencies may result when abnormal lymphocytes overwhelm the bone marrow's normal blood-making cells in advanced stage CLL.

Note: These signs and symptoms may also be caused by other conditions.

Also see: Signs and Symptoms of CLL:   ACS

Diagnosis

1. Bone marrow aspirate
   to take a sample of cells for further testing.
    
2. Immunophenotyping test
   to measure the chemical or physical properties of cells
    
3. F.I.S.H. test  
   to detect chromosomal abnormalities of cells.
    
4. Staging: Rai and Binet staging systems to quantify disease, and determine risk group and appropriate treatment approach.
   

What are blast cells?

"Leukemia is either acute or chronic. In acute leukemia, the abnormal blood cells (blasts) remain very immature and cannot carry out their normal functions. The number of blasts increases rapidly, and the disease gets worse quickly. In chronic leukemia, some blast cells are present, but in general, these cells are more mature and can carry out some of their normal functions. Also, the number of blasts increases less rapidly than in acute leukemia. As a result, chronic leukemia gets worse gradually." -  http://training.seer.cancer.gov

Factors that determine treatment timing and approach:  

The characteristics of the lymphoma at diagnosis as determined by pathology tests, and it's actual clinical behavior, and other factors determine the type of treatment and the timing of treatment you and your doctor will consider. 

Favorable prognosis is indicated for somatically mutated versus non-mutated cells. (Expensive test; not perfect; 
not widely available ~ 2006)

Unfavorable prognosis is associated with CD38+, Zap70+, 
and p53 defect.

Staging

"Staging is useful in chronic lymphocytic leukemia (CLL) to predict prognosis and also to stratify patients to achieve comparisons for interpreting specific treatment results. Anemia and thrombocytopenia are the major adverse prognostic variables.

CLL has no standard staging system. The Rai staging system and the Binet classification are presented below.[1,2] A National Cancer Institute (NCI)-sponsored working group has formulated standardized guidelines for eligibility, response, and toxic effects criteria to be used in future clinical trials in CLL."

Staging systems allows comparison of clinical results and establishment of therapeutic guidelines:

Stage I - absolute lymphocytosis with lymphadenopathy without hepatosplenomegaly, anemia, or thrombocytopenia.

Stage II - absolute lymphocytosis with either hepatomegaly or splenomegaly, with or without lymphadenopathy.

Stage III - absolute lymphocytosis and anemia (hemoglobin <11 g/dL) with or without lymphadenopathy, hepatomegaly, or splenomegaly.

Stage IV - absolute lymphocytosis and thrombocytopenia (<100,000/mm3) with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemia.

Clinical stage A* - no anemia or thrombocytopenia and fewer than 3 areas of lymphoid involvement (Rai stages 0, I, and II).

Clinical stage B* - no anemia or thrombocytopenia with 3 or more areas of lymphoid involvement (Rai stages I and II).

Clinical stage C - anemia and/or thrombocytopenia regardless of the number of areas of lymphoid enlargement (Rai stages III and IV).

* [Note: Lymphoid areas include cervical, axillary, inguinal, and spleen.]

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Essential Resources

1. PDQ cancer.gov 

2. Cancer.gov: General Information about CLL
   For patients | For professionals

3. CLL primer CLLTopics.org

4. CLL Research Consortium  cll.ucsd.edu
    
   Lists member institutions, contains  links to the clinicians and 
   researchers who make up the membership.  

5. Current Approach to Diagnosis and Management of CLL mayoclinic 

6. About CLL  leukemia-lymphoma.org   pdf 

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Resources

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Small Lymphocytic Lymphoma

"Small lymphocytic lymphoma (SLL), which accounts for approximately 5% of non-Hodgkin's lymphomas in adults, is almost identical to chronic lymphocytic leukemia (CLL) both morphologically and clinically. A somewhat arbitrary distinction is drawn between them based on the relative degree of marrow and nodal involvement and the numbers of circulating lymphoma cells." LymphomaInfo.Net

Prognostic Factors

Cytogenetic factors that may

predict survival 

or clinical behavior

or response to specific therapies

Telomere "is an enzyme that adds telomere repeat sequences to the 3' end of DNA strands.

Most cancers arise from somatic cells (from the body; not germline - from parents). 

But one of the crucial features that distinguishes a cancer cell from a normal somatic cell is its ability to divide indefinitely. 

It turns out that most (85–90%) cancer cells have regained the ability to synthesize high levels of telomerase throughout the cell cycle, and thus are able to prevent further shortening of their telomeres."  

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Prognostic Factors versus Response Predictors

"Oncology does not need more prognostic factors, it needs 
predictive factors that are treatment-regimen specific.  Prognostic factors 
are unlikely to be used unless they are therapeutically relevant ... "
 ~ Richard Simon, DSc

Prognostic factors are features of the disease that are associated with the clinical behavior, response to treatment and survival.  

Prognostic Factors

The many interrelated factors that influence survival have not been defined definitively at this time.   

See also Chromosomal abnormalities by fluorescent in situ hybridization 
(FISH) - PubMed Topic Search

* Telomere and mutation status:

Mutation status is correlated with Telomere lengths, which 
can vary based on the cellular derivation of B-cells

Antigen-naive would have lengths equal to age-matched controls
Activated pre-GC cells would have heterogeneous (variable) lengths
Chronically -driven B-cells would have shorter than age-matched controls

Telomere length correlates with degree of mutations

Un-mutated CLL have uniformly short telomere lengths
  Have replicated many times in-vivo
  More fragile; associated with genome instability

Mutated CLL have telomeres of very diverse lengths 
   with minimal telomeres activity
   with variable fragility and degree of danger 

Source: Dr. Chiorazzi presentation L&M conference 2007

Response Predictors

Response predictors are gaining increasingly to 
  (1) spare ineffective (but toxic) treatments 
  (2) select patients most likely to respond to a given therapy 
       (e.g. alemtuzumab in p53 cases* ), 
  (3) investigate new treatments targeting specific biologic abnormalities.   

~ Dr. Emillio Montserrat, MD  presentation L&M conference 2007
 

Resources

1. CLL PDQ  cancer.gov

2. Chronic lymphocytic leukemia: A review of some new aspects of the biology, factors influencing prognosis and therapeutic options ~ Yair Herishanu a,*, Aaron Polliack b  PDF

3. DISC assay to predict response to treatment?  acor.org

4. Skin infiltration with chronic lymphocytic leukemia is consistent with a good prognosis. Hematology. 2002 Jun;7(3):187-8. PMID: 12243983   PubMed

5. Richter syndrome: biology, incidence, and therapeutic strategies. Cancer 103 (2): 216-28, 2005.  [PUBMED Abstract]

6. Autoimmune cytopenia (low blood counts) does not predict poor prognosis in chronic lymphocytic leukemia/small lymphocytic lymphoma. Am J Hematol. 2003 Sep;74(1):1-8. PMID: 12949883 | Related

7. Assessment of CLL and SLL by absolute lymphocyte counts in 2,126 patients:  20 years of experience at the University of Texas M.D. Anderson Cancer Center.J Clin Oncol. 2007 Oct 10;25(29):4648-56. PMID: 17925562 
   
   Deletion 17p or 6q with or without other cytogenetic abnormalities, 
   age at least 60 years, 
   beta2-microglobulin at least 2 mg/L, 
   albumin less than 3.5 g/dL, and 
   creatinine at least 1.6 mg/dL 
   
   were each found to independently predict shorter survival

8. Assessment of CLL and SLL by absolute lymphocyte counts in 2,126 patients: 20 years of experience at the University of Texas M.D. Anderson Cancer Center. J Clin Oncol. 2007 Oct 10;25(29):4648-56. PMID: 17925562

9. Presenting Features and Prognosis in CLL http://bloodjournal.hematologylibrary.org/cgi/reprint/79/11/3093.pdf 

10. CLLU1 expression analysis adds prognostic information to risk prediction in chronic lymphocytic leukemia  http://bloodjournal.hematologylibrary.org  

Investigational 
therapeutic targets

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Richter's syndrome Transformation

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1. Primary digestive Richter's syndrome. Mod Pathol. 2001 May;14(5):452-7.
   PMID: 11353056 | More

2. Richter syndrome: biology, incidence, and therapeutic strategies. Cancer 103 (2): 216-28, 2005.  PUBMED

Prolymphocytoid 
Transformation

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Source: thedoctorsdoctor 

Treatments

Also see:

Questions for your doctor
 - Patients Against Lymphoma
General, Treatment & Side Effects, and Tests

Treatment Overview

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Combination therapy, often including purine analogs, are being explored, and are more effective than single agents, often inducing complete responses.  There is more toxicity with this approach, however.  To date (2006) a survival advantage with combination regiments has not been shown to be dependent on the choice of initial therapy.  Randomized studies are needed to determine this.  

Quality of response (duration) might be key, but improvements in overall survival (OS) has not yet been proven.

- Standards therapy for CLL, Dr. Weiss - 2006

Timing and choice of initial therapy

Related treatment resources

Agents:

Treatment combinations

ClinicalTrials.gov  searches

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Research News

Research News

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