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Chronic Lymphocytic Leukemia/lymphoma - CLL/SLL

Last update: 04/02/2014

TOPICS
Overview | In the News | Natural History | Statistics | Risk Factors | Signs and SymptomsDiagnosis | Workup | Essential resources
Treatment | Clinical Trials | Prognostic Factors | Staging | TargetsRichter's Syndrome
| Research News
 

TOPIC SEARCHES of 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.

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

bullet 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 causes (etiology) 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.

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

bullet

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. 
 

bullet

Enlarged lymph nodes are the most common presenting symptom,
seen in 87% of patients symptomatic at time of diagnosis.

bullet

Systemic symptoms:

Fevers, chills, and night sweats and weight loss constitute B symptoms 

bullet

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.

bullet

Frequent bleeding from low platelets

bullet

Enlarged lymph nodes, 
which may be felt if near the surface of the skin, or detected by CT imaging.

bullet

Pain

bullet

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.

bullet

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

bullet Hematopoietic insufficiency (inability to produce  normal blood cell counts)
 
bullet B-symptoms,
 
bullet Rapidly progressive disease, or
 
bullet 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

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

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

Useful in select circumstances:

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

Imaging:

bullet CT prior to therapy particularly if bulky disease
bullet 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.

bullet At diagnosis treatment OR observation may be indicated.
bullet 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.
 
bullet

Absolute lymphocyte count (doubling time)

bullet

Albumin and Creatinine levels 

bullet

Beta2-microglobulin  

bullet

CD38+, Zap70+,  and p53 defect (FISH)

bullet

Deletion 17p or 6q with or without 
other cytogenetic abnormalities (FISH)

bullet

Disease-related symptoms

bullet

Mutated versus non-mutated cells. 

bullet

Response to prior therapies 

bullet

Stage of disease* (most important)
 

bullet
What type of CLL do you have?   CLLTopics.org 
bullet
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.
bullet
Prognostic and Monitoring Tests  CLLtopics.org 
bullet
What are the criteria for starting treatment?  ACOR.org 
bullet
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

Staging helps to determine the risk of the CLL based on clinical factors (how it has behaved and advnaced so far).  Staging can be more reliable than cytogenetic findings (which are investigational in many cases) for guiding clinical decisions.

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

bullet
Overview  LLSPDQ® | CLLTopics.org | Wikipedia.org
bullet
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."
bullet
Biology and Treatment of CLL  asheducationbook.org 
bullet
Novel Insights into the Biology of CLL
Lanasa, Asheducation Book 2010 http://bit.ly/eJHpEM
bullet
Chronic Lymphocytic Leukemia  asheducationbook.org  
 
"Current information on the diagnosis, biology, and intervention required to more fully develop algorithms for management of this disease. 
bullet
CLL Question & Answers  acor.org
bullet
Genetics  Cancer Genetics Web 
bullet
Management Strategies for Chronic Lymphocytic Leukemia CME Author: Michael J. Keating, MB, BS  Medscape (free login req.) 
bullet
Richter’s transformation (DLBCL) can arise from CLL
Aggressive NHL: Oncology Board Review Manual  yr 2000 PDF 
bullet
Signs and Symptoms of CLL  ACS
bullet
Treatment: A New World of Possibilities, Levine  Medscape free login req.
bullet
 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

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


In the News

bullet

Obinutuzumab Gains Role in CLL NCCN Guidelines http://bit.ly/Qn5K6G
based on age and other factors summarized also below. 

In recent outcome reports, Obinutuzumab (first-in-class glycoengineered type-2 anti-cd20 antibody) has shown superior outcomes in combination with chlorambucil to both Rituxan plus chlorambucil and to chlorambucil alone.  

 COMMENT: This is big news for CLL.   It’s not yet clear to me that the superiority of this cd20 antibody in CLL will translate to other types of b-cell lymphomas.  As always, the study reports from well designed trials will tell us that (requiring our participation)  … not opinions and theories : ) 

NCCN Guidelines for

Obinutuzumab in CLL1 Frail patient with significant comorbidity
(not able to tolerate purine analogues / fludarabine)

Obinutuzumab + chlorambucil as 1st preference First-line therapy for patients without del 11q or 17p

Obinutuzumab + chlorambucil as 1st preference for patients aged ≥70 y, or younger with comorbidities

Obinutuzumab + chlorambucil among chemo-immunotherapy options for patients aged <70 y, or older without significant comorbidities

First-line therapy for patients with del 17p Obinutuzumab + chlorambucil among combination therapy options

First-line therapy for patients with del 11q Obinutuzumab + chlorambucil as 1st preference for patients aged ≥70 y, or younger with comorbidities

Obinutuzumab + chlorambucil among chemoimmunotherapy options for patients aged <70 y, or older without significant comorbidities

 
bullet
* ASCO Post:
“Encouraging Early Results With Novel Agents in CLL” http://bit.ly/1g8gFL1

If preliminary results are validated in phase III studies, ABT-199 and IPI-145 will be poised to join an explosion of new therapies—obinutuzumab (Gazyva), ibrutinib (Imbruvica), and idelalisib among them—that promise to improve outcomes for all CLL patients.

ASCO Post:
“Ibrutinib for Previously Treated Chronic Lymphocytic Leukemia”
http://bit.ly/1l9YyaR

The ASCO Post, Furman:
Rituxan with Idelalisib in heavily treated relapsed CLL
http://bit.ly/1mkJZ4r

* NEJM:
Obinutuzumab (GA101) plus Chlorambucil in Patients with CLL and Coexisting Conditions
  http://bit.ly/1r573F1

COMMENT:  A definitive study in respect to its design ... showing that this type II antibody is much more than a me-too drug in CLL

NEJM: Editorial
Movement toward Optimization of CLL Therapy
Kanti R. Rai, M.B., B.S., and Jacqueline C. Barrientos, M.D.

http://www.nejm.org/doi/full/10.1056/NEJMe1400599  (requires subscription)

"exciting new discoveries will indisputably shape the clinical landscape of CLL in the next decade." ...

"One important aspect of recent advances in CLL therapy, which has been regularly neglected by past investigators, is that the disease primarily affects the elderly population, with a median age at diagnosis of 72 years and with multiple clinically significant coexisting conditions. This neglect is unfortunate, but it is understandable because it stems from safety concerns that an elderly patient with a coexisting condition (e.g., compromised renal function) is considered ineligible to be entered into a therapeutic research study. The result of this long-standing neglect is that whatever progress in CLL has been achieved, it has excluded the most representative and perhaps the largest population with the disease." 
 

bullet
Imedex 2014:
Autoimmunity in CLL http://bit.ly/1aohU22
bullet
Ibrutinib in the News!
 approved by FDA under accelerated pathway for MCL (a Btk-inhibitor)  PAL 

Studies recruiting patients PAL query - Find trials
bullet
April 2013: Pharmacyclics Completes Enrollment of Phase III Ibrutinib CLL Study
and Phase II Ibrutinib MCL Study  ascopost.com
bullet
CLL Abstracts - ASH 2012 - grouped by PAL
bullet
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.
bullet
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.
bullet
CLL - ASCO 2012 abstracts
bullet
OncLive: Dr. Wierda Discusses Watchful Waiting in CLL
bullet
Two reports on same study: Chronic Lymphocytic Leukemia - Aggressive Drug Combo Restores Quality Of Life  and  http://bit.ly/xJitXk
bullet
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
bullet
ASH Education Book Dec 2011: Alemtuzumab Use In Relapsed and Refractory CLL/SLL
bullet
ASH Education Book Dec 201: Nurture versus Nature: The Microenvironment in Chronic Lymphocytic Leukemia
bullet
ASH Education Book Dec 2011: Using the Biology of CLL to Choose Treatment
bullet
ASH Education Book Dec 2011: The Treatment of Relapsed Refractory CLL/SLL
bullet
Medscape, Dr. Cheson - ASH review: A Dickensian CLL Story
bullet
Medical News Today: Chronic Lymphocytic Leukemia Patients' Lives Extended By New Combination Treatment
bullet
NCCN: Advances in CLL Therapy Offer Prolonged Survival; Toxicities Continue to Plague Elderly Patients

 

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

bullet
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
bullet
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

bullet

Stage (see Rai staging system  (Most reliable according to some experts)
and Binet classification above)

bullet

Mutated (more favorable) versus non-mutated (less favorable)
(Immunoglobulin variable region heavy chain gene (IgVH) mutation). *

bullet

ZAP-70 (less favorable)

bullet

CD38+ immunophenotype (has cd38 protein on cell surface).

bullet

Lymphocyte doubling time (unfavorable)

bullet

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 
bullet

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

Strong Predictors 
bullet

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:
bullet

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

Stronger predictors
bullet

High Beta-2-microglobulin - 
poor response to chemo-immunotherapy

bullet

CLLU1 gene - 
poor response to chemo-immunotherapy
 
See also http://bloodjournal.hematologylibrary.org  

bullet

Patients achieving response have longer survival

bullet

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

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

See also Pipeline and Clinical Trials

Richter's syndrome Transformation
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Richter's syndrome Transformation

"The clinical and morphologic transformation is very low -- 3 to 5% of chronic lymphocytic leukemia (CLL) to diffuse large-cell lymphoma (DLCL) is commonly referred to as Richter's syndrome.

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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About Prolymphocytoid Transformation

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Follows CLL from 1.3 to 5 years

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Increasing splenomegaly (enlarged spleen)

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Lymphadenopathy (enlarged lymph nodes) 

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Increased prolymphocytes (abnormal lymphocytes) in the blood 

Source: thedoctorsdoctor 

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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. 

Quality of response (minimal residual disease status) might be key to improving outcomes. Age and fitness are important clinical factors that guide clinical practice as is the stage and behavior of the disease.

Newly approved and investigational targeted agents (such as ibrutinib) with better toxicity profiles are expected to change practice rapidly.   See for example, Jain, Rai: Overview of recent developments in chronic lymphocytic leukemia http://1.usa.gov/1fsLkSw and related farticles:  ncbi.nlm.nih.gov
 

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Obinutuzumab Gains Role in CLL NCCN Guidelines http://bit.ly/Qn5K6G
based on age and other factors summarized also below. 

In recent outcome reports, Obinutuzumab (first-in-class glycoengineered type-2 anti-cd20 antibody) has shown superior outcomes in combination with chlorambucil to both Rituxan plus chlorambucil and to chlorambucil alone.  

 COMMENT: This is big news for CLL.   It’s not yet clear to me that the superiority of this cd20 antibody in CLL will translate to other types of b-cell lymphomas.  As always, the study reports from well designed trials will tell us that (requiring our participation)  … not opinions and theories. 
 

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What Is the Optimal Initial Treatment for CLL?  cancernetwork.com 
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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

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ACOR.org | Cancer.govLLS | Research Reports_LLS
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CLL Treatment: A New World of Possibilities, Levine 
Medscape free login req.
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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
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Improving the Complete Remission Rate in CLL
Hematology.org, Keating  PDF 
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Setting the Stage for Stem Cell Transplantation for CLL 
Medscape free login req.
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Protocols for Refractory Disease  PAL
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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

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Chlorambucil Is Still an Appropriate First-Line Therapy for Chronic Lymphocytic
 Medscape (free login req.) 2001
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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®.
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Alone or combined with Rituxan for refractory CLL  mdanderson.org
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Campath + Rituxan in high risk CLL  PubMed articles
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Campath data for CLL  PubMed articles
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Flavopiridol (investigational)  PubMed articles | ClinicalTrials.gov
New dosing being explored in clinical trials
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Oblimersen Sodium/Genasense (investigational)  PubMed articles
Improves durability of response in responders to combination therapy.
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Lenalidomide ( Revlimid) investigational  PubMed articles | ClinicalTrials.gov
A potent immune modulating agent
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Monoclonal antibodies other than Rituxan/Campath (investigational)
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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 
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Ofatumumab / Humax cd20  Related articles | ClinicalTrials.gov
Unique cd20 epitope, induces fast and sustained drop in CLL b-cells
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Purine analogs (fludarabine, cladribine, pentostatin)  PubMed articles
Pentostatin might provide an improved therapeutic index (safety)
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Fludarabine as frontline? - Cheson  HealthTalk
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Rituxan  
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Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol. 2001 Apr 15;19(8):2165-70. PMID: 11304768  PubMed | Related Abstracts
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Preliminary Positive Data from Rituxan Multi-Center Trial in First-Line and Maintenance Therapy in Patients With Chronic Lymphocytic Leukemia  Buswire
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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
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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.
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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.
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Treanda (Bendamustine) approved for chronic lymphocytic leukemia - http://health.usnews.com 
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Stem cell Rescue/Transplants  ClinicalTrials.gov
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Mini Allogeneic Stem Cell Transplants Effective in Advanced Chronic Lymphocytic Leukemia  cancerconsultants.com

Treatment combinations

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F+R - fludarabine + Rituxan  PubMed articles
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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
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P+C+R - pentostatin + Cytoxan + Rituxan
PCR therapy for CLL - comparing it to FCR:  medscape.com/ 
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Thalidomide + Fludarabine  PubMed articlesClinicalTrials.gov
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Rituxan Combo For CLL: Rituximab and methylprednisolone for therapy of CLL www.haematologica.org
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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
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For Untreated CLL/SLL

For relapsed CLL/SLL

Excluding Stem Cell Rescue therapy
 
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State or Country
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Other criteria such as age, stage, phase, refractory
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Research News

Research News
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Autologous stem cell transplantation as a first-line treatment strategy for CLL: a multicenter, randomized, controlled trial http://bit.ly/je7iRh

snip: " This is the first published randomized clinical trial of ASCT as part of the first-line treatment for patients with stage B or C CLL. We found that ASCT doubled the EFS (effect free survival) probability in patients who entered CR after up-front chemotherapy. This is consistent with the results of previous phase 2 trials of ASCT for first-line treatment consolidation, in which the median EFS ranged from 5-6.3 years.19-21 In contrast, ASCT was not more beneficial than FC in our non-CR patients rescued with DHAP."
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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.
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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
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Positive Phase I/IIa Results With Acadra (Acadesine) in CLL prnewswire.com 

“The study was closely followed by a Data Monitoring Board formed by four independent CLL international experts which concluded that, "Although the study was not designed to analyze peripheral blood response and lymph node response, clear evidence of efficacy has been obtained to move forward. The good safety profile of Acadra observed makes it an attractive combination partner with other CLL therapies."

As always, we should be cautious about reports that come only from the media and await expert review… but it does seem encouraging so far.
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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.
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Tumor Flare Reaction Associated With Lenalidomide Treatment in Patients With CLL Predicts Clinical Response

http://onlinelibrary.wiley.com/doi/10.1002/cncr.25748/pdf 
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Fludarabine Provides OS Advantage vs Chlorambucil in Previously Untreated CLL http://bit.ly/5LgDhj
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CLL Aggressiveness May Be Predicted By New Biomarker medicalnewstoday.com 

They found that high levels of a particular enzyme PDE7B) in the blood are an indicator that chronic lymphocytic leukemia (CLL) - the most common form of adult leukemia - will be aggressive and in need of immediate treatment.
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Comprehensive review: Treating CLL  ncbi.nlm.nih.gov/books

In most malignant diseases, early treatment of the malignant process is optimal. The first decision to be made in CLL is whether the patient requires therapy at the time of initial diagnosis. This approach is based on the extreme heterogeneity of the disease and lack of evidence that early treatment affects long-term survival. An increasing number of "early stage" patients diagnosed while asymptomatic have "smoldering" CLL ... (full text)
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FCR Versus FC Improves Response Rates and Progression-Free Survival of Previously Untreated [and fit] Patients with Advanced CLL

n = 817 pts with good physical fitness - median CIRS score was 1 (range 0-8), median age was 61 years (range 30 to 81), The overall incidences of trisomy 12 and abnormalities of 13q, 11q23, and 17p13 detected by FISH were 12%, 57%, 25%, and 8%, respectively, with no statistically significant differences between treatment arms.

http://ash.confex.com/ash/2008/webprogram/Paper9237.html
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Flavopiridol (Alvocidib) Induces Durable Responses in Relapsed Chronic Lymphocytic Leukemia (CLL) Patients with High-Risk Cytogenetic Abnormalities

http://ash.confex.com/ash/2008/webprogram/Paper11242.html

n = 117 pts with relapsed CLL (n=107) or small lymphocytic lymphoma (n=10) , median age 60 years, 116 pts had received prior purine analog therapy, and 85 pts (73%) were refractory to (n=82) or intolerant of purine analog (n=3).  Ninety-three pts were Rai stage III/IV (79%), and 85 pts had bulky lymph nodes ³ 5 cm (73%).
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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.
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Fludara (Fludarabine) Not Superior to Cytoxan (Chlorambucil) for Elderly with CLL cancerconsultants.com

involved 206 patients with CKK older than 64 years of age. Eighty-five percent of patients in this study were Binet stage B-C. The median age was 70 years.
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What Is the Optimal Initial Treatment for Chronic Lymphocytic Leukemia?  cancernetwork.com
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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
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First line Campath for CLL:  FDA Approves Expanded Labeling For Campath® To Include First Line Treatment For CLL  medicalnewstoday.com  

"The data that supported this label expansion add to a growing body of evidence about the effectiveness of Campath across the entire CLL treatment pathway," stated Mark Enyedy, president of Genzyme's oncology business unit. "A broader range of patients is now eligible for Campath treatment, regardless of whether they have received prior therapy. The approval also marks an important step in a long-term development plan that is exploring the full potential of Campath in high-risk CLL, combination and consolidation therapy."
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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
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New agents in chronic lymphocytic leukemia.
Curr Treat Options Oncol. 2006 May;7(3):200-12. Review. PMID: 16615876
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Gene expression signatures separate B-cell chronic lymphocytic leukaemia prognostic subgroups defined by ZAP-70 and CD38 expression status
A Hüttmann1, L Klein-Hitpass2, J Thomale2, R Deenen2, A Carpinteiro1,3, H Nückel1, P Ebeling4, A Führer1, J Edelmann1, L Sellmann1,2, U Dührsen1 and J Dürig1
"Remarkably, the microarray experiments described herein revealed relative overexpression of additional BCR pathway components such as CD5, IGHD, IGL, IGLJ3 and IGLC2. These findings are in accordance with a recent flow cytometry study showing higher IgM surface levels on IgVH unmutated as compared to mutated B-CLL cells.36 Furthermore, the present microarray analysis showed that FcRH2/IRTA4 was significantly downmodulated in ZAP-70+CD38+ B-CLL, results which were subsequently confirmed at the protein level using flow cytometry in a series of 26 B-CLL patients."
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Potential protein markers in diagnosis and treatment of B-CLL  cancerprev.org
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Therapy-related myeloid leukemias are observed in patients with chronic lymphocytic leukemia after treatment with fludarabine and chlorambucil: results of an intergroup study, cancer and leukemia group B 9011. J Clin Oncol. 2002 Sep 15;20(18):3878-84. PMID: 12228208  PubMed
 
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For all medical concerns,  you should always consult your doctor. 
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