Types of Lymphoma >
Chronic Lymphocytic Leukemia/lymphoma - CLL/SLL
Last update: 06/27/2017
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TOPICS Overview | Natural History | Statistics | Risk Factors | Signs and Symptoms | Diagnosis | Workup | Essential resources
Treatment | Clinical Trials | Prognostic Factors | Staging | Targets | Richter's Syndrome | Research News
TOPIC SEARCHES of PubMed: Diagnosis | Review | Therapies | Prognosis | Richter's | Refractory
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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
CLL Society http://bit.ly/1AU0gRo
Regarding CLL and SLL,
by Dr. Furman as of 1/2015:
CLL and SLL are the identical disease. The confusion relates back to the classification system we started using in 1982. Back then, a lymph node read by a pathologist was SLL, but a bone marrow biopsy (or peripheral blood) would be read as CLL. In 1994, SLL and CLL were combined into one diagnosis, CLL/SLL.
Some trials require the CLL diagnosis so that cells can be collected from the peripheral blood. Some trials just call it CLL at this time. It is important to remember that a bone marrow biopsy of >30% CLL cells qualifies someone as CLL. A pathologist would call a lymph node in 2015 from an SLL patient, CLL/SLL.
Also, in 1982 (NCI Working Formulation) and still in 1994 (REAL Classification), there was a B-CLL/SLL and a T-CLL/SLL, where as in 1997 with the WHO Classification there was only a B cell type, as the T cell variety was reclassified as other diseases. Therefore, there is just CLL/SLL (dropped the "B" because they are all B-cells).
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
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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
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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.
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Etiologic (risk factors) heterogeneity (variations) among NHL subtypes,
Blood. 2008 http://bit.ly/bUDXZw
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Occupation and malignant lymphoma: a population based case control study in Germany, Occup Environ Med 2006 http://bit.ly/btSkWn
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Environmental and Occupational Causes of Cancer New Evidence, 2005–2007, Rev Environ Health 2009 http://bit.ly/afBT4S
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Patterns of autoimmunity and subsequent CLL in Nordic countries,
Blood. 2006 http://bit.ly/d95BDm
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Inherited predisposition to CLL, http://bit.ly/a7dfp8
Expert Rev Hematol. 2008
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Signs and symptoms associated with CLL/SLL
Non-specific symptoms and signs of CLL may include:
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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.
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Enlarged lymph nodes are the most common presenting symptom,
seen in 87% of patients symptomatic at time of diagnosis.
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Systemic symptoms:
Fevers, chills, and night sweats and weight loss constitute B symptoms
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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.
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Frequent bleeding from low platelets
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Enlarged lymph nodes,
which may be felt if near the surface of the skin, or detected by CT imaging.
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Pain
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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.
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unexplained weight loss
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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
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Hematopoietic insufficiency (inability to produce normal blood cell counts)
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B-symptoms,
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Rapidly progressive disease, or
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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.
- Bone marrow aspirate
to take a sample of cells for further testing.
- Immunophenotyping test
to determine the type and maturation stage of the abnormal cells obtained from the bone marrow or blood
- F.I.S.H. (Fluorescence In-situ Hybridization) test (now essential)
to detect cytogenetic abnormalities of the cells.
- Staging: Rai and Binet staging systems to quantify disease, and determine risk group and appropriate treatment approach.
Resources on diagnosis
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See Diagnosis, Staging, and Risk Groups for CLL Cancer.net | ACS
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Pan B-Cell Markers Are Not Redundant in Analysis of CLL
karpuslab.northwestern.edu .pdf
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SLL/CLL Advanced - Stanford Differential Diagnosis
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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
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Physical exam |
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Performance status |
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B symptoms |
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CBC, differential, platelets |
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LDH |
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Comprehensive metabolic panel |
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Hep B testing if anti-cd20 antibody considered |
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MUGA scan / echo if anthracycline therapy planned |
Useful in select circumstances:
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Quantitative Immunoglobulins (IgG, IgA, and IgM) in blood |
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Beta-2-microglobulin in blood |
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Uric acid |
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Bone marrow biopsy prior to therapy |
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Pregnancy testing/ fertility counseling in women of child-bearing age. |
Imaging:
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CT prior to therapy particularly if bulky disease |
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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.
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At diagnosis treatment OR observation may be indicated.
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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
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PDQ Cancer.gov
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Cancer.gov: General Information about CLL
For patients | For professionals
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CLL primer CLLTopics.org
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CLL Research Consortium cll.ucsd.edu
Lists member institutions, contains links to the clinicians and
researchers who make up the membership.
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Current Approach to Diagnosis and Management of CLL Mayo clinic
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Tumor Lysis Syndrome in Patients with CLL http://bit.ly/aHpGYF
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About CLL leukemia-lymphoma.org pdf
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CLL Perspectives cllperspectives.com
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Preventing infectious complications in patients with CLL http://bit.ly/cpSReT
- 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
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Overview LLS | PDQ® | CLLTopics.org | Wikipedia.org
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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."
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Biology and Treatment of CLL asheducationbook.org
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Novel Insights into the Biology of CLL
Lanasa, Asheducation Book 2010 http://bit.ly/eJHpEM
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Chronic Lymphocytic Leukemia asheducationbook.org
"Current information on the diagnosis, biology, and intervention required to more fully develop algorithms for management of this disease.
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CLL Question & Answers acor.org
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Genetics Cancer Genetics Web
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Management Strategies for Chronic Lymphocytic Leukemia CME Author: Michael J. Keating, MB, BS Medscape (free login req.)
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Richter’s transformation (DLBCL) can arise from CLL
Aggressive NHL: Oncology Board Review Manual yr 2000 PDF
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Signs and Symptoms of CLL ACS
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Treatment: A New World of Possibilities, Levine Medscape free login req.
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Flow Cytometry and Polymerase Chain Reaction-Based Analyses of Minimal Residual Disease in Chronic Lymphocytic Leukemia hindawi.com
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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
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About Small Lymphocytic Lymphoma (SLL) LymphomaInfo.Net
(B-cell stage: mature, before antigen exposure)
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SLL - Low number of DNA copy number changes in small lymphocytic lymphoma Haematologica 1998 Aug;83(8):690-2
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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
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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
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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
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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
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Stage (see Rai staging system (Most reliable according to some experts)
and Binet classification above)
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Mutated (more favorable) versus non-mutated (less favorable)
(Immunoglobulin variable region heavy chain gene (IgVH) mutation). *
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ZAP-70 (less favorable)
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CD38+ immunophenotype (has cd38 protein on cell surface).
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Lymphocyte doubling time (unfavorable)
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High Beta-2-microglobulin (unfavorable)
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* 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
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Clinical stage, Bone marrow infiltration,
Doubling time, Morphology (appearance)
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Strong Predictors
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Genetics
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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:
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CD38+, Zap 70+, Un-mutated (either alone or combined)
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Stronger predictors
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High Beta-2-microglobulin -
poor response to chemo-immunotherapy
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CLLU1 gene -
poor response to chemo-immunotherapy
See also http://bloodjournal.hematologylibrary.org
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Patients achieving response have longer survival
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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)
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Question: Does treatment timing correlate with MRD negativity?
Source: Dr. Emillio Montserrat, MD presentation L&M conference 2007
Related Resources
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CLL PDQ Cancer.gov
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Chronic lymphocytic leukemia: A review of some new aspects of the biology, factors influencing prognosis and therapeutic options ~ Yair Herishanu a,*, Aaron Polliack PDF
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DISC assay to predict response to treatment? acor.org
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Skin infiltration with chronic lymphocytic leukemia is consistent with a good prognosis. Hematology. 2002 Jun;7(3):187-8. PMID: 12243983 PubMed
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Richter syndrome: biology, incidence, and therapeutic strategies. Cancer 103 (2): 216-28, 2005. PUBMED Abstract
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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
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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).” …
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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
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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
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Presenting Features and Prognosis in CLL http://bloodjournal.hematologylibrary.org/cgi/reprint/79/11/3093.pdf
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CLLU1 expression analysis adds prognostic information to risk prediction in chronic lymphocytic leukemia http://bloodjournal.hematologylibrary.org
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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:
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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
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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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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.
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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)
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See also Pipeline and Clinical Trials
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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
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Primary digestive Richter's syndrome.
Mod Pathol. 2001 May;14(5):452-7. PMID: 11353056 | More
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Richter syndrome: biology, incidence, and therapeutic strategies. Cancer 103 (2): 216-28, 2005. PUBMED
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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
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Source: thedoctorsdoctor
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About Prolymphocytic transformation Terry Hamblin
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CLL / SLL Treatments
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Treatments
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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.
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Related treatment resources
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ACOR.org | Cancer.gov | LLS | 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.
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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
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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 articles | ClinicalTrials.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
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ClinicalTrials.gov searches
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Research News and Perspectives
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Venetoclax Achieves Durable and Deep "treatment free" Remissions in CLL - The ASCO Post http://bit.ly/2tuyRcD
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Background and video on Selective BCL-2 Inhibitor (venetoclax) | BioOncology http://bit.ly/1O122KO
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Farrukh T. Awan, MD
How I Manage Relapsed Chronic Lymphocytic Leukemia #CLL http://bit.ly/1QvkY2I
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CLL - Weill Cornell 2015: FDA Grants Breakthrough Therapy Designation to Venetoclax (ABT-199)
for Patients with Relapsed/Refractory CLL with 17P Deletion http://bit.ly/1cmRGoX
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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 : )
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
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* 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."
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Imedex 2014:
Autoimmunity in CLL http://bit.ly/1aohU22
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Ibrutinib in the News!
approved by FDA under accelerated pathway for MCL (a Btk-inhibitor) PAL
Studies recruiting patients PAL query - Find trials
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April 2013: Pharmacyclics Completes Enrollment of Phase III Ibrutinib CLL Study
and Phase II Ibrutinib MCL Study ascopost.com
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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.
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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.
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OncLive: Dr. Wierda Discusses Watchful Waiting in CLL
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Two reports on same study: Chronic Lymphocytic Leukemia - Aggressive Drug Combo Restores Quality Of Life and http://bit.ly/xJitXk
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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
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ASH Education Book Dec 2011: Alemtuzumab Use In Relapsed and Refractory CLL/SLL
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ASH Education Book Dec 201: Nurture versus Nature: The Microenvironment in Chronic Lymphocytic Leukemia
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ASH Education Book Dec 2011: Using the Biology of CLL to Choose Treatment
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ASH Education Book Dec 2011: The Treatment of Relapsed Refractory CLL/SLL
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Medscape, Dr. Cheson - ASH review: A Dickensian CLL Story
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Medical News Today: Chronic Lymphocytic Leukemia Patients' Lives Extended By New Combination Treatment
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NCCN: Advances in CLL Therapy Offer Prolonged Survival; Toxicities Continue to Plague Elderly Patients
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Jennifer R. Brown, MD, PhD
How I Manage Deletion 17p Chronic Lymphocytic Leukemia http://bit.ly/1MLTnZE
An important article (often technical) on a validated risk factor for high risk CLL . It includes her recommendations for treatment and how this has changed for this high risk group.
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2015: Experts discuss Initiation and Discontinuation of Ibrutinib From http://bit.ly/1uYT1EH
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Ofatumumab in Refractory Chronic Lymphocytic Leukemia: Experience ... - PubMed - NCBI http://1.usa.gov/1Dx2IxZ
results confirm the efficacy and acceptable tolerability profile of ofatumumab as a single agent in severely ill patients with CLL
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Dr Sharman 2014:
Can CLL be cured? http://bit.ly/ZeEITc
The point I wish to make is this. The new drugs are very "sexy." It is very appealing to think of taking a non-chemo pill rather than chemotherapy, but if I am ever a patient with CLL and IgVH mutated BCR lacking 17P/11Q/TP53/NOTCH1/SF3B1 abnormality, I will absolutely take chemoimmunotherapy because there is a VERY GOOD chance I will not have to think about my CLL for many years, and based upon these two studies, I think he plateau in the survival curve is very provocative.
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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
Thomas S. Lin, MD, PhD
"The choice of initial therapy for an individual patient should depend upon the patient's age and medical condition, cytogenetic and other prognostic factors, and whether the goal of therapy is maximization of CR and PFS or palliation of symptoms with minimal toxicity."
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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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