Types of Lymphoma >

Chronic Lymphocytic Leukemia/lymphoma - CLL/SLL

Last update: 04/20/2013

TOPICS
Overview | Natural History | Statistics | Risk Factors | Signs and Symptoms | Diagnosis | Workup
Treatment | Clinical Trials | Prognostic Factors | Staging | Targets | Richter's Syndrome | Research News
 
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PubMed: Diagnosis | Review | Therapies | Prognosis | Richter's | Refractory
 

Overview of
CLL & SLL

CLL Blogs

Brian Kaufman

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

Centers and Oncologists
that Specialize in CLL

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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 -
enlarged liver

splenomegaly -
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 (CLL/SLL)

Chronic lymphocytic leukemia (CLL) is caused by the overproduction of abnormal b lymphocytes (a type of white blood cell).  It is sometimes considered or classified as a lymphoma. 

"Small lymphocytic lymphoma (SLL) is almost identical to CLL both morphologically (in appearance under the microscope) and clinically (how it behaves and is treated).

Normal 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.   "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.

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

In the News

	April 2013: Pharmacyclics Completes Enrollment of Phase III Ibrutinib CLL Study and Phase II Ibrutinib MCL Study  ascopost.com
	CLL Abstracts - ASH 2012 - grouped by PAL
	Dr. Sharman's CLL & Lymphoma Blog: Choosing first therapy in CLL http://bit.ly/13vDKTa  Per usual, very interesting and readable commentary by Dr. Sharman.
	Dr. Sharman's CLL & Lymphoma Blog: What is FCR? http://bit.ly/PBQkI6  An excellent explanation. A good read- even if your battle is not with CLL.
	CLL - ASCO 2012 abstracts
	OncLive: Dr. Wierda Discusses Watchful Waiting in CLL
	Two reports on same study: Chronic Lymphocytic Leukemia - Aggressive Drug Combo Restores Quality Of Life  and  http://bit.ly/xJitXk
	Medscape (login required): New Class of Drug May Vanquish CLL Also see Navitoclax - Lancet, Wilson et al a Targeted High Affinity Inhibitor of BCL-2 (ABT-263), in Lymphoid Malignancies - full text
	ASH Education Book Dec 2011: Alemtuzumab Use In Relapsed and Refractory CLL/SLL
	ASH Education Book Dec 201: Nurture versus Nature: The Microenvironment in Chronic Lymphocytic Leukemia
	ASH Education Book Dec 2011: Using the Biology of CLL to Choose Treatment
	ASH Education Book Dec 2011: The Treatment of Relapsed Refractory CLL/SLL
	Medscape, Dr. Cheson - ASH review: A Dickensian CLL Story
	Medical News Today: Chronic Lymphocytic Leukemia Patients' Lives Extended By New Combination Treatment
	NCCN: Advances in CLL Therapy Offer Prolonged Survival; Toxicities Continue to Plague Elderly Patients

Natural history

TOPIC SEARCH: SearchMedica

"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

Statistics

SEER fast facts  seer.cancer.gov It is estimated that 15,490 individuals (9,200 men and 6,290 women) will be diagnosed with and 4,390 men and women will die of CLL in 2009

Risk factors for developing CLL/SLL

The etiology or causes of CLL and lymphomas are not yet known. There could be many contributing factors that lead to it development over time, such as advancing age, inherited disposition, exposures to chemicals or radiation, and chance. 

Regarding suspected environmental factors, scientists often study groups that are exposed in the workplace (because these exposures can be estimated with greater assurance), to see if the incidence rates of disease are significantly higher compared to the general population.

	Etiologic (risk factors) heterogeneity (variations) among NHL subtypes, Blood. 2008 http://bit.ly/bUDXZw
	Occupation and malignant lymphoma: a population based case control study in Germany, Occup Environ Med 2006 http://bit.ly/btSkWn
	Environmental and Occupational Causes of Cancer New Evidence, 2005–2007, Rev Environ Health 2009 http://bit.ly/afBT4S
	Patterns of autoimmunity and subsequent CLL in Nordic countries, Blood. 2006  http://bit.ly/d95BDm
	Inherited predisposition to CLL, http://bit.ly/a7dfp8 Expert Rev Hematol. 2008

Signs and symptoms associated with CLL/SLL

Non-specific symptoms and signs of CLL may include:

	A predisposition to repeated infections frequent infections (such as pneumonia, herpes simplex labialis, and herpes zoster) NOTE: Although CLL can lead to very high white blood cell counts due to excess numbers of lymphocytes (lymphocytosis), the abnormal lymphocytes do not protect against infection.
	Enlarged lymph nodes are the most common presenting symptom, seen in 87% of patients symptomatic at time of diagnosis.
	Systemic symptoms: Fevers, chills, and night sweats and weight loss constitute B symptoms
	Fatigue and weakness, secondary to anemia anemia (ten percent will present with an autoimmune hemolytic anemia)   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.
	Frequent bleeding from low platelets
	Enlarged lymph nodes,  which may be felt if near the surface of the skin, or detected by CT imaging.
	Pain
	Fullness in the belly. Early satiety and/or abdominal discomfort may be related to an enlarged spleen. Mucocutaneous bleeding and/or petechiae may be due to thrombocytopenia.
	unexplained weight loss

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

Also see: Signs and Symptoms of CLL:  ACS

Commonly Used Need-to-treat Criteria for CLL

	Hematopoietic insufficiency (inability to produce  normal blood cell counts)
	B-symptoms,
	Rapidly progressive disease, or
	Risk of complications from bulky lymphadenopathy. Based on criteria from Bendamustine vs. Chlorambucil clinical trials

Diagnosis

The diagnosis of CLL/SLL requires the evaluation of cells by appearance, cell type, and specific abnormalities. 

1. Bone marrow aspirate
   to take a sample of cells for further testing.
    
2. Immunophenotyping test
    
   to determine the type and maturation stage of the abnormal cells obtained from the bone marrow or blood
    
3. F.I.S.H. (Fluorescence In-situ Hybridization) test  (now essential)
   to detect cytogenetic abnormalities of the cells.
    
4. Staging: Rai and Binet staging systems to quantify disease, and determine risk group and appropriate treatment approach.
   

Resources on diagnosis

	See Diagnosis, Staging, and Risk Groups for  CLL Cancer.net | ACS
	Pan B-Cell Markers Are Not Redundant in Analysis of CLL  karpuslab.northwestern.edu .pdf

SLL/CLL Advanced - Stanford Differential Diagnosis

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
 

Workup (adapted from NCCN)

Essential

	Physical exam
	Performance status
	B symptoms
	CBC, differential, platelets
	LDH
	Comprehensive metabolic panel
	Hep B testing if anti-cd20 antibody considered
	MUGA scan / echo if anthracycline therapy planned

Useful in select circumstances:

	Quantitative Immunoglobulins (IgG, IgA, and IgM) in blood
	Beta-2-microglobulin in blood
	Uric acid
	Bone marrow biopsy prior to therapy
	Pregnancy testing/ fertility counseling in women of child-bearing age.

Imaging:

	CT prior to therapy particularly if bulky disease
	PET generally not useful, unless directing biopsy for suspected Richter's transformation

Factors that may 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. 

According to NCCN guidelines, the most appropriate treatment can depend on age and clinical trials are recommended.

Clinical Trials for the treatment of CLL/SLL
Untreated: http://bit.ly/hqtnd7 | previously treated: http://bit.ly/e10yeN

Tip: Click the Result on Map tab to locate
studies in your region of the USA or the World.

At diagnosis treatment OR observation may be indicated.

	Factors that may influence timing and type of treatment (alphabetical): Blood markers for risk are imperfect.  They "inform about which curve you are on, but not what point on the curve."  Most important, perhaps, is the clinical stage* and behavior of the CLL as determined by staging, below.   Absolute lymphocyte count (doubling time) Albumin and Creatinine levels  Beta2-microglobulin   CD38+, Zap70+,  and p53 defect (FISH) Deletion 17p or 6q with or without  other cytogenetic abnormalities (FISH) Disease-related symptoms Mutated versus non-mutated cells.  Response to prior therapies  Stage of disease* (most important)
	What type of CLL do you have?   CLLTopics.org
	State-of-the-art treatment of chronic lymphocytic leukemia  ehaweb.org  pdf  Jun 2007 This review attempts to summarize the best developments today in the initial management of CLL.
	Prognostic and Monitoring Tests  CLLtopics.org
	What are the criteria for starting treatment?  ACOR.org
	High White counts?  ACOR.org

Staging (Rai | Binet) of CLL/SLL

Today, (2011) SLL and CLL are managed as the same diagnosis. Patients diagnosed as SLL should should be staged using the CLL staging methods (Rai or Binet below), not as a lymphoma according to at least some experts.

Regarding liver involvement, Dr. Furman writes: "it is important to remember that Rai stage II is hepatomegaly and/or splenomegaly, not just splenomegaly. Any liver biopsy will show some CLL, just like any spleen or bone marrow biopsy would. Having CLL in the liver is expected. We are often confronted with CLL patients who have a liver problem and the liver biopsy demonstrates CLL. It is almost always that the CLL is just there and not causing problems."

"Staging is useful in 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.

Rai staging (risk factors)¹

Stage 0 (LOW RISK)

Lymphocytosis >15,000/mm3) and >40% lymphocytes in bone marrow
without adenopathy (enlarged lymph nodes), hepatosplenomegaly (enlarged spleen), anemia (low red blood cells), or thrombocytopenia (low platelets). 

Stage I  (INTERMEDIATE RISK)

Stage 0 with lymphadenopathy (enlarged nodes)

Stage II  (INTERMEDIATE RISK)

Stage 0 - I with hepatomegaly (enlarged liver) or
splenomegaly (enlarged spleen), with or without lymphadenopathy (enlarged lymph nodes).

Stage III (HIGH RISK)

Stage 0 - II with hemoglobin (protein molecule in red blood cells that carries oxygen from the lungs) < 11.0 g/dL, or hematocrit (proportion of the blood that consists of red blood cells) < 33%.

Stage IV (HIGH RISK)

Stage 0 - III with low platelets < 100,00/mcL

See also Staging Elements

Binet staging ¹

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.]

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 Mayo clinic 

6. Tumor Lysis Syndrome in Patients with CLL http://bit.ly/aHpGYF

7. About CLL  leukemia-lymphoma.org   pdf 

8. CLL Perspectives cllperspectives.com

9. Preventing infectious complications in patients with CLL http://bit.ly/cpSReT 

10. Chronic lymphocytic leukemia and autoimmunity: a systematic review
    
    haematologica.org  pdf
    
    "Chronic lymphocytic leukemia is frequently associated with immune disturbances. Whereas the association of CLL with autoimmune cytopenias, particularly autoimmune hemolytic anemia and immune thrombocytopenia, is well established, there is no proof of an increased risk of non-hemic autoimmune disorders in CLL.
    
    The predilection in CLL for autoimmune disease attacking the formed elements of the blood is only partially understood and may be related to the ability of CLL cells to process and present antigens derived from blood cells, in contrast to their poor general performance as antigen presenting cells.
    
    The mechanisms leading to autoimmune cytopenia in CLL are complex and involve interactions between the malignant B- CLL cells, abnormally functioning T-cells, microenvironment, and the immune system."

Other Resources

	Overview  LLS |  PDQ® | CLLTopics.org | Wikipedia.org
	CLL diagnosis and prognosis: implications of the IWCLL guidelines  2009 lymphomaforum.org.uk  "It is important to recognize that the value of the cellular prognostic markers detailed above is very much determined by the clinical context in which they are demonstrated."
	Biology and Treatment of CLL  asheducationbook.org
	NEW Novel Insights into the Biology of CLL Lanasa, Asheducation Book 2010 http://bit.ly/eJHpEM
	Chronic Lymphocytic Leukemia  asheducationbook.org     "Current information on the diagnosis, biology, and intervention required to more fully develop algorithms for management of this disease.
	CLL Question & Answers  acor.org
	Genetics  Cancer Genetics Web
	Management Strategies for Chronic Lymphocytic Leukemia CME Author: Michael J. Keating, MB, BS  Medscape (free login req.)
	Richter’s transformation (DLBCL) can arise from CLL Aggressive NHL: Oncology Board Review Manual  yr 2000 PDF
	Signs and Symptoms of CLL  ACS
	Treatment: A New World of Possibilities, Levine  Medscape free login req.
	NEW Flow Cytometry and Polymerase Chain Reaction-Based Analyses of Minimal Residual Disease in Chronic Lymphocytic Leukemia hindawi.com

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

	About Small Lymphocytic Lymphoma (SLL)  LymphomaInfo.Net  (B-cell stage: mature, before antigen exposure)
	SLL - Low number of DNA copy number changes in small lymphocytic lymphoma  Haematologica 1998 Aug;83(8):690-2

Prognostic Factors

Cytogenetic
factors that may
predict survival or the 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

NOTABLE QUOTE ON LIMITATIONS OF PROGNOSTIC MARKERS: "What is really the most important for people to remember is that prognostic markers only tell you which curve you are on, they do not tell you where you are on the curve. [For CLL] nothing is more helpful than the pace of your disease. If your WBC is rising slowly, hemoglobin and platelets stable, lymphadenopathy and spleen size stable, then you are behaving in a very indolent manner. This means that the CLL is progressing very slowly and, by and large, will continue to do so for future." ~ Rick Furman, MD

How I treat CLL up front http://bit.ly/favAVV  (2010) Includes comments on limitations of prognostic markers John G. Gribben, Institute of Cancer, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, United Kingdom

Prognostic Factors in CLL/SLL - a work in progress

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

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

	Stage (see Rai staging system  (Most reliable according to some experts) and Binet classification above)
	Mutated (more favorable) versus non-mutated (less favorable) (Immunoglobulin variable region heavy chain gene (IgVH) mutation). *
	ZAP-70 (less favorable)
	CD38+ immunophenotype (has cd38 protein on cell surface).

	Lymphocyte doubling time (unfavorable)
	High Beta-2-microglobulin (unfavorable)

* Telomere and mutation status:

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

Factors that May Help to Predict Treatment Response
(notes from presentation)

Response predictors may help to
 
  (1) spare patients from ineffective treatments 
 
  (2) select patients most likely to respond to a given therapy 

       (Example: alemtuzumab in p53 cases* ), 
 
  (3) investigate new treatments targeting specific biologic abnormalities.   

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

Weak Predictors 

Clinical stage, Bone marrow infiltration,  Doubling time,  Morphology (appearance)

Strong Predictors 

Genetics

chromosomal translocations

17p-  resistance to Fludarabine, alkylators, Rituxan

11q-  lower response rate to fludarabine (vs. FC)
        early relapse from autologous Stem Cell Transplant

p53 mutations and deletions 
      predicts response to Alemtuzumab
 
See  BloodJournal.hematologyli  pdf 

Response to Therapy

Questionable predictor:

CD38+, Zap 70+, Un-mutated (either alone or combined)

Stronger predictors

	High Beta-2-microglobulin -  poor response to chemo-immunotherapy
	CLLU1 gene -  poor response to chemo-immunotherapy   See also http://bloodjournal.hematologylibrary.org
	Patients achieving response have longer survival
	Minimal Residual Disease (MRD) after treatment correlates  with better outcome (Progression Free Survival and Overall Survival) MRD-positivity - particularly increasing MRD levels, anticipates  clinical relapse (exception: after allotransplantation)

Question:  Does treatment timing correlate with MRD negativity?

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

Related 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   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. Autoimmune Cytopenias in Chronic Lymphocytic Leukemia: Prevalence, Clinical Associations, and Prognostic Significance
   
   http://bit.ly/boX70s
   
   "TAKE-HOME MESSAGE - Results of this retrospective analysis of 960 patients with CLL indicated that the cause of cytopenia is an important prognostic factor, particularly in advanced disease, and should be used to guide therapeutic decision-making.”
   
   “Importantly, patients with advanced (Binet C stage) disease due to an autoimmune mechanism had a significantly better survival than those in advanced stage related to a massive bone marrow infiltration (median survivals: 7.4 years vs. 3.7 years; p=0.02).” …
    

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. 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

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

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

12. Changing the Way We Think About Chronic Lymphocytic Leukemia http://jco.ascopubs.org/cgi/content/full/23/18/4009  
    Journal of Clinical Oncology, Vol 23, No 18 (June 20), 2005:

13. Treatment options for high-risk CLL http://bit.ly/kTWK01 
    
    "The only group that can be clearly identified pretreatment for whom conventional fludarabine-based therapies produce significantly inferior response rates, PFS and overall survival are the patients who harbour a genetic fault; deletion or mutation or a combination of deletion and mutation of tumour protein p53 (TP53). TP53 inactivation is a less common finding at first treatment but becomes much more common in fludarabine-refractory patients. Alemtuzumab and high-dose corticosteroids have been shown to be effective in this group of CLL patients. Trials combining these two agents have shown improved responses, particularly for those patients with bulky nodal disease for whom alemtuzumab alone may be insufficient. Since the duration of responses remains relatively short, suitable patients should be considered for allogeneic stem cell transplantation according to the European Group for Blood and Marrow Transplantation guidelines.

14. How I treat CLL up front http://bit.ly/favAVV  (2010)
    
    John G. Gribben, Institute of Cancer, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, United Kingdom

15. Positive Phase I/IIa Results With Acadra (Acadesine) in CLL prnewswire.com 

16. Relapsed CLL: Does adding lumiliximab (anti-cd23) improve on FCR?  ncbi.nlm.nih.gov 
    
    "Thirty-one patients gave consent and were treated at 5 clinical sites.

Investigational 
therapeutic targets

New topic placeholder

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Clinical Trials for the treatment of CLL/SLL:

Untreated |  Previously treated | Ritcher's

Tip: Click the Result on Map tab to locate
studies in your region of the USA or the World.

	inhibitors of apoptosis
	micro-RNAs
	microenvironment (e.g., Lenalidomide)
	telomeres inhibitor (GRN163L)

See also Pipeline and Clinical Trials

Richter's syndrome Transformation

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Richter's syndrome occurs mostly in lymph nodes and may represent a second neoplasm or a transformation from the same clonal population." ¹
 

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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	Follows CLL from 1.3 to 5 years
	Increasing splenomegaly (enlarged spleen)
	Lymphadenopathy (enlarged lymph nodes)
	Increased prolymphocytes (abnormal lymphocytes) in the blood

Source: thedoctorsdoctor 

About Prolymphocytic transformation Terry Hamblin

 
CLL / SLL Treatments

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

	What Is the Optimal Initial Treatment for CLL?  cancernetwork.com
	NCCN recommends Clinical Trials for the treatment of CLL/SLL: Lookup for previously untreated: http://bit.ly/hqtnd7 Previously treated: http://bit.ly/e10yeN Tip: Click the Result on Map tab to locate studies in your region of the USA or the World.

Related treatment resources

	ACOR.org | Cancer.gov |  LLS | Research Reports_LLS
	CLL Treatment: A New World of Possibilities, Levine  Medscape free login req.
	Eradication of Minimal Residual Disease in B-Cell Chronic Lymphocytic Leukemia After Alemtuzumab Therapy Is Associated With Prolonged Survival. J Clin Oncol. 2005 Feb 28; PMID: 15738539
	Improving the Complete Remission Rate in CLL Hematology.org, Keating  PDF
	Setting the Stage for Stem Cell Transplantation for CLL  Medscape free login req.
	Protocols for Refractory Disease  PAL
	How I treat CLL up front,  2010 John G. Gribben Full text: http://bloodjournal.hematologylibrary.org  But it may open on page 2.

Notes on Agents

	Chlorambucil Is Still an Appropriate First-Line Therapy for Chronic Lymphocytic  Medscape (free login req.) 2001
	Campath / Alemtuzumab / anti-cd52 (humanized IgG1 kappa antibody)   Campath Available For First Line Treatment Of B-Cell Chronic Lymphocytic Leukaemia (CLL) For Whom Fludarabine Chemotherapy Is Not Appropriate  medicalnewstoday.com/articles/97739.php  "In the Phase III trial MabCampath® produced the highest response rate in patients with chronic lymphocytic leukaemia for any single agent seen in previous front-line trials," said Dr Peter Hillmen of the department of clinical haematology and haematological malignancy diagnostic service at Leeds teaching Hospital and principal trial investigator for MabCampath®. Alone or combined with Rituxan for refractory CLL  mdanderson.org Campath + Rituxan in high risk CLL  PubMed articles Campath data for CLL  PubMed articles
	Flavopiridol (investigational)  PubMed articles | ClinicalTrials.gov New dosing being explored in clinical trials
	Oblimersen Sodium/Genasense (investigational)  PubMed articles Improves durability of response in responders to combination therapy.
	Lenalidomide ( Revlimid) investigational  PubMed articles | ClinicalTrials.gov A potent immune modulating agent
	Monoclonal antibodies other than Rituxan/Campath (investigational) Lumiliximab / anti-cd23  Related articles | ClinicalTrials.gov IgG1 chimeric; synergistic with fludarabine and rituxan in preclinical models; Phase I study shows activity in refractory/relapsed CLL  Ofatumumab / Humax cd20  Related articles | ClinicalTrials.gov Unique cd20 epitope, induces fast and sustained drop in CLL b-cells
	Purine analogs (fludarabine, cladribine, pentostatin)  PubMed articles Pentostatin might provide an improved therapeutic index (safety) Fludarabine as frontline? - Cheson  HealthTalk
	Rituxan   Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol. 2001 Apr 15;19(8):2165-70. PMID: 11304768  PubMed | Related Abstracts Preliminary Positive Data from Rituxan Multi-Center Trial in First-Line and Maintenance Therapy in Patients With Chronic Lymphocytic Leukemia  Buswire Standard-dose anti-CD20 antibody rituximab has efficacy in chronic lymphocytic leukaemia: results from a Nordic multicentre study. Eur J Haematol. 2002 Sep;69(3):129-34. PMID: 12406005  PubMed Adding fresh frozen plasma to Rituxan for the treatment of patients with refractory advanced CLL  oxfordjournals.org   A rapid and dramatic clinical and laboratory response was achieved in all patients. Lymphocyte counts dropped markedly followed by shrinkage of lymph nodes and spleen and improvement of the anaemia and thrombocytopenia. This could be maintained over 8 months (median) with additional cycles if necessary. Treatment was well tolerated in all cases. Serum globulins as marker of immune restoration after treatment with high-dose Rituxan for CLL PubMed  An important biological alteration in chronic lymphocytic leukemia (CLL) is the dysregulation of immunoglobulin production, as a consequence of complex and yet incompletely understood interactions between plasma cells and the neoplastic B-cell clone. As a result, most patients develop severe hypogammaglobulinemia during the course of the disease.
	Treanda (Bendamustine) approved for chronic lymphocytic leukemia - http://health.usnews.com
	Stem cell Rescue/Transplants  ClinicalTrials.gov Mini Allogeneic Stem Cell Transplants Effective in Advanced Chronic Lymphocytic Leukemia  cancerconsultants.com

Treatment combinations

	F+R - fludarabine + Rituxan  PubMed articles
	F+C+R - fludarabine + Cytoxan + Rituxan (OR 95%; CR 70%)  Big news for CLL:  70% of complete responders remain in continuous remission: Five-year follow-up of 300 patients treated with FCR as initial therapy of CLL  ASH 2007
	P+C+R - pentostatin + Cytoxan + Rituxan PCR therapy for CLL - comparing it to FCR:  medscape.com/
	Thalidomide + Fludarabine  PubMed articles |  ClinicalTrials.gov
	Rituxan Combo For CLL: Rituximab and methylprednisolone for therapy of CLL www.haematologica.org
	GM-CSF & Rituxan for CLL: Rituximab reduces the number of peripheral blood B-cells in vitro mainly by effector cell-mediated mechanisms. Haematologica. 2002

ClinicalTrials.gov  searches

	For Untreated CLL/SLL For relapsed CLL/SLL Excluding Stem Cell Rescue therapy
	State or Country
	Other criteria such as age, stage, phase, refractory

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Research News

Research News

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