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A. Epidemiology navigator

  1. Most Common Leukemia in USA
    1. Incidence: 10,000-15,000 new cases per year in USA
    2. Incidence 3.9 / 100,000 per year in whites, versus 2.8 / 100,000 per year in blacks
    3. Prevalence ~40,000 in USA
  2. Affects primarily older (>55 years) patients; rare in age <50 years
  3. Median age 70 years for men, 74 for women
  4. ~75% of patients are asymptomatic at diagnosis
  5. Both B lymphocyte (B-CLL) and T lymphocyte (T-CLL) forms occur
  6. B-CLL represents >90% of CLL cases
    1. In ~35% of patients, B-CLL is indolent and lifespan >10 years (mainly Ig H chain mutated)
    2. In ~35% of patients, indolent B-CLL progresses to serious disease requiring treatment
    3. In ~30% of patients, B-CLL is aggressive from the onset; immediate treatment required
    4. These outcomes correspond to the different subtypes of B-CLL (see also below)
    5. Unmutated subtype survival 8-9 years
    6. Patients with mutated Ig H chains have survival >25 years
  7. T-CLL is discussed separately below

B. Characteristics of B-CLL [6] navigator

  1. Origins
    1. Derived from malignant B lymphocyte clone
    2. Express CD5, CD19, CD23; CD22, CD79b week (CD5 normally expressed only on T cells)
    3. Surface Ig levels low or nill
    4. Derives from B cells that are antigen experienced; V chain mutations to varying degrees
    5. Most B-CLL express high levels of (normal) Bcl-2 protein
    6. Nearly 50% of B-CLL have abnormal expression of ataxia-telangiectasia gene (ATM)
    7. Two subtypes with distinct prognoses have been defined
    8. These subtypes are based on various molecular markers that predict outcomes
    9. About 55% of cases with chromosome 13q deletion, 18% with trisomy 12
  2. Two Subtypes of CLL defined by [1,2,3,4]:
    1. Chromosomal (chr) abnormalities
    2. CD38 expression
    3. ZAP70 expression / Immunoglobulin mutation status
    4. Global gene expression comparisons [9]
  3. Type I (~40% of B-CLL)
    1. >30% CD38+
    2. More males
    3. Advanced stage
    4. Chr 17p- (average lifespan <4 years) or 11q- (average lifespan <9 years)
    5. Unmutated Ig heavy chain (IgH) variable (V) region (usually with high ZAP-70 [16])
    6. ZAP-70 tyrosine kinase high or overexpression in >20% of leukemic cells [19]
    7. ZAP-70 is elevated in ~70% with unmutated IgH V chains [10]
    8. High ZAP-70 is a stronger predictor of aggressive disease than lack of IgH V chain mutations [10]
    9. Poor prognosis with average lifepsan 2-10 years depending on specific markers
  4. Type II (~60% of B-CLL)
    1. <30% CD38+
    2. More females
    3. Chr 13q- (55% of cases; micro RNAs found in this region) [11] or normal karytype (~18%)
    4. <20% of leukemic cells express ZAP-70 tyrosine kinase [19]
    5. Mutated IgH V region - correlates with lack of ZAP-70 expression [16]
    6. Lack of or low ZAP-70 expression is a better predictor of indolent disease than IgH V chain mutations [10]
    7. Unique combination of 13 microRNAs correlate with V region mutations and ZAP-70 [11]
    8. Good prognosis with average lifepsan >10-15 years for 13q- or normal karyotype
    9. IgVH mutations found / ZAP70 negative carry median survival >20 years
  5. Abnormalities of p53 (15%)
    1. p53 on chromsome (chr) 17p deletion is found in 7% of cases
    2. Particularly in drug resistant disease (after fludarabine)
    3. Generally poor prognosis
  6. Chr +12 (trisomy 12) in 16% of cases (poor prognosis)
  7. Chr 11q23 deletion (likely involves ATM or ataxia telangiectasia gene) in 18%
  8. Other Uncommon Findings
    1. Bcl-3 fusion with Ig Genes (<10%)
    2. Chr 6q deletion (6%)
    3. Chr 8q Trisomy (5%)
    4. Trisomy 3q (3%)
    5. ~30% of patients with CLL have >1 chromsomal abnormality [4]
    6. Bcl-1 and bcl-2 abnormalities are very uncommon
    7. Loss of function polymorphism of Purinergic P2X7 receptor associated with reduced levels of apoptosis in CLL cells [15]
  9. CLL cell interactions with microenvironment critically important for abnormally long survival

C. Presentation, Diagnosis, Stagingnavigator

  1. Presenation
    1. Usually found on routine blood smear
    2. Symptoms include fever, night sweats, weight loss (>10%), fatigue, splenomegaly
    3. May present initially with recurrent infections and/or lymphadenopathy (LAD)
    4. Suppression of other marrow components and monoclonal gammopathy
    5. Skin infiltration may be seen with T cell CLL
  2. Diagnosis requires demonstration of clonotypic expansion of mature lymphocytes >5K/µL
  3. Two Different Staging Systems in Use [5]
    1. Rai Staging
    2. Binet Staging
    3. Correlation between staging systems for low-risk disease is weak
    4. Staging systems do not predict well which patients will go on to develop aggressive disease
    5. Various molecular markers with good prognostic characteristics have evolved (see above)
  4. Rai Staging
    1. Stage 0: absolute lymphocytosis of >10K/µL, >40% lymphocytes in bone marrow
    2. Stage I: Lymphocytosis with enlarged Lymph nodes
    3. Stage II: Lymphocytosis, hepatic and/or splenic enlargement
    4. Stage III: Anemia with hemoglobin (Hb) levels <11gm/dL
    5. Stage IV: Thrombocytopenia with platelets <100K/µL
  5. Binet Staging
    1. Low A: Lymphocytosis with enlargement of <3 lymphoid areas
    2. Low A': Stage A with lymphocyte count <30,000/µL and hemoglobin >12gm/dL c Low A'': Stage A with lymphocyte count >30,000/µL or hemoglobin <12gm/dL
    3. Intermediate (B): Lymphocytosis with enlargement of >2 lymphoid areas
    4. High (C): Lymphocytosis and either anemia or thrombocytopenia or both
  6. Poor Prognostic Markers
    1. Elevated serum levels of ß2-microglobulin
    2. Elevated levels of CD23 in serum predict higher disease burden
    3. Chromosome 11q deletion (>16% of cases)
    4. Lack of mutations in IgH V chains and low expression of ZAP70 [16,19]
    5. Intracellular ZAP70 can be measured by flow cytometry [16]
    6. Rai or Binet staging are not sufficient prognostic markers; molecular markers here are used
  7. Clinical Progression
    1. Slow progression with increasing marrow suppression
    2. Hypogammaglobulinemia followed by increased infection risk
    3. Aggressive disease with pancytopenia
    4. Rare transformation to acute, blastic leukemia (ALL) or to Richter's Syndrome
    5. Richter's Syndrome is a large cell, non-Hodgkin's lymphoma with poor prognosis

D. Differential Diagnosis of Malignant B Cell Disorders [1,2] navigator

  1. CLL: sIg-dim, CD5+, 19+, 20dim, 23+ 43+, 10-, 11c/22± ,23+, 25±, 103-
  2. Lymphoplasmacytoid lymphoma (immunocytoma): sIg++, CD5±, 19+, 20+, 23±, 10-, 103-
  3. Prolymphocytic leukemia: sIg++, CD5±43
  4. Hairy-Cell Leukemia: sIg++, CD5-, 43+, 22+,23-, 25+, 103+
  5. Marginal Zone B Lymphoma: sIg++, CD5-, 19+, 20++, 43±, 11c/22±, 23±,10-, 103-, 25-
  6. Mantle-Cell Lymphoma: sIg++, CD5+, 43+, 22-, 23dim/-, 25-, 19+, 20++, 10-, 103-
  7. Follicular Lymphoma: sIg++, CD5-, 19+, 20+, 23±, 10±, 43- ,11c/22-, 103-, 25-
  8. Splenic Lymphoma / Villous lymphocytes

E. Complications of CLLnavigator

  1. Autoimmune
    1. Hemolytic Anemia 10-25%
    2. Thrombocytopenia 2%
    3. Neutropenia 0.5%
  2. Hypogammaglobulinemia
    1. Increased risk of infection
    2. Reduced infection risk by use of intravenous immunoglobulin (IVIg) [4]
  3. Infections
    1. Bacterial: S. pneumoniae, H. influenzae, staphylococci
    2. Fungal: candida, aspirgillus
    3. Herpes Zoster (varicella zoster virus), cytomegalovirus
  4. Disease Transformation [13]
    1. Prolymphocytic leukemia 10%
    2. Large-cell lymphoma (Richter's Syndrome)
    3. Acute Leukemia <1%
    4. Multiple Myeloma <1%
  5. Richter's Syndrome (Large Cell Lymphoma) [13]
    1. These patients usually patients have CLL for many years
    2. Then develop rapidly progressive adenopathy ±systemic symptoms
    3. Elevated lactate dehydrogenase (LDH) levels associated with progression
    4. No specific chromosomal abnormalities observed
    5. Likely clonally derived from CLL cells
  6. Second Cancers (~10%): skin, lung, gastrointestinal

F. Treatment [7] navigator

  1. Decision to Treat
    1. Stage O or A is not treated (no mortality benefit; possible increased morbidity)
    2. Stage I treatment is recommended only for Binet Stage B or C disease [7]
    3. Poor prognosis forms (unmutated Ig chains, others) are usually offered treatment
    4. Symptomatic disease is always treated
    5. Richter transformation is always treated
    6. High risk, asymptomatic early stage disease patients should enter specific clinical trials
  2. Primary Treatment
    1. Fludarabine and combinations including monoclonal antibodies (mAb)
    2. Alkylating Agents - most patients
    3. Alemtuzumab (subcutaneous)
  3. Fludarabine (Fludara®)
    1. Fludarabine is an adenosine analog with best single agent antitumor activity
    2. Fludarabine response rates >50%, and useful in patients who have failed chlorambucil [5]
    3. Fludarabine first line has higher response rates than chlorambucil, but with more side effects and no overall mortality benefit [8]
    4. No benefit to combination fludarabine+chlorambucil over fludarabine alone [8]
    5. Cyclophosphamide (CYC) added to fludarabine increases complete response rate to 38% versus 15% with fludarabine alone as initial therapy [17]
    6. CYC + fludarabine had lower hemolytic anemia than fludarabine or chlorambucil alone [17]
  4. Alkylating Agents
    1. CYC is more active than chlorambucil and is preferred
    2. Chlorambucil dose (0.1mg/kg po qd or 0.4-0.8mg/kg po q2 weeks)
    3. Chlorambucil often combined with glucocorticoids but no proven benefit to combination
    4. Responses usually last 8-12 months, usually incomplete, ~60% of patients
    5. Main side effects are cyopenias, nausea, hair loss, infection 5, Combinations
    6. Addition of rituximab (Rituxan®), anti-CD20 monoclonal Ab, to fludarabine or CYC improves response rates and probably survival with minimal side effects [2,7]
    7. Fludarabine (± rituximab) is recommended instead of chlorambucil first line when survival >5 years for age >70 years, or for very poor performance status with age <70 years [2]
    8. CYC can also be combined with rituximab with good effect
    9. Fludarabine + CYC + rituximab in first line has 70% complete remissions and 95% response rates and should be considered strongly for first line therapy; clinical trials ongoing [7,17]
  5. Alemtuzumab (Anti-CD52 mAb, Campath®) [18]
    1. FDA approved after failure of alkylating agents and fludarabine
    2. Usually given intravenously (IV) and causes marked cytokine release effects
    3. Responses in ~35-40% of patients refractory to other agents
    4. Effective in chromosome 17 deletion (mutatied TP53) CLL; superior to chlorambucil
    5. Leads to prolonged lymphopenia and increased pneumocystis and CMV risk
    6. Prophylaxis for pneumocystis and CMV strongly recommended
    7. Can also be given subcutaneously (SC) with improved tolerance [18]
    8. Alemtuzumab SC has minimal cytokine release symptoms and reduced infection risk
  6. Other Agents [2]
    1. 2-chlorodeoxyadenosine - some efficacy fludarabine resistant disease [7]
    2. Main side effects are increased opportunistic infections, tumor lysis, hemolytic anemia
    3. Interferon alpha shows some activity
    4. CYC + vincristine + predisone (CVP) is often used as well
  7. Immune Specific Therapy
    1. Trial using idiotype (surface Ig) purified from tumor cells
    2. Tumor cells were fused with myelomas and secreted Ig was purified
    3. Tumor Ig was then conjugated to carrier protein (KLH) and injected subcutaneously into patients along with aluminum type adjuvant
    4. In 7 of 9 injected patients, idiotype specific T and/or B cell immunity was detected
    5. In the 2 patients with measurable disease, regression was complete (duration not given)
    6. Toxicity of formulation was very minimal
    7. Note that these patients had received chemotherapy but maintained a good respons
  8. Bone Marrow Transplantation
    1. Applicable only to a minority of CLL patients, usually <60 years old
    2. HLA-identical BMT in patients <60 years old with CLL appears to be effective
    3. Unclear how BMT compares with conventional therapy in these patients
  9. Intravenous immunoglobulin (IVIg) in hypoglobulinemic patients is beneficial [12]

G. Prognosis [5,7]navigator

  1. Chromosomal Abnormalities and Prognosis [2,4]
    1. Chr 17p Deletion (p53 abnormality) - poorest prognosis, 50% surival 36 months (7% of CLL)
    2. Chr 11q deletion - poor prognosis, 50% surival 72 months (6-9 year survival)
    3. Normal chromsomes or 12q trisomy - 50% surival 120 months
    4. Chr 13q deletion as only abnormality - 50% surival 132 months
    5. ZAP-70 positive: 8-10 year survival; ZAP70 negative: >20 year survival
    6. IgVH region mutations: >20 year survival; non-mutated IgVH: 7-10 year survival
  2. Stage 0
    1. Blood lymphocytes >15K/µL with BM 40% lymphocytes
    2. Completely asymptomatic; discovered fortuitously
    3. ~14 year 50% survival
    4. 59% alive at 10 years
    5. Stage A has similar prognosis
  3. Stage I
    1. Lymphocytosis with lymphadenopathy
    2. Symptoms from lymph node swelling
    3. 8-9 year 50% (median) survival
    4. Stage A'' has 7 year median survival; 38% alive at 10 years
    5. IgH mutated stage A 75% survival at 144 months; unmutated median survival 97 months
  4. Stage II
    1. Lymphocytosis with enlarged spleen or liver
    2. Lymphadenopathy may not be present
    3. ~6 year 50% survival
    4. Stage B has 5 year median survival
  5. Stage III
    1. Lymphocytosis with anemia
    2. Anemia may be due to reduced production or to hemolysis (immune mediated)
    3. LAD, splenic or liver enlargement need not be present
    4. ~2-3 year 50% survival (similar prognosis for Stage C)
    5. Median survival for stages B+C: mutated 120 months; unmutated 78 months
  6. Stage IV
    1. Lymphocytosis with thrombocytopenia
    2. Hypoglobulinemia nearly always present
    3. <2 year 50% survival (similar prognosis for Stage C)
  7. Staging by Binet or Rai systems is best prognostic indicator
  8. Richter's Syndrome has median ~5 month survival
  9. Good Prognostic Genetic Alterations [7,10,11,16]
    1. Ig H V chain mutations
    2. ZAP-70 expression
    3. MicroRNA signature
    4. CD38 strongly positive: 8-10 year survival; negative: >20 year survival

H. T Cell CLL (T-CLL) [14] navigator

  1. Represents 5-10% of CLL cases
  2. T-CLL (mature T cells) and T-cell prolymphocytic leukemia (T-PLL) described
  3. Disease Characteristics
    1. Cells have T cell receptor (TCR) rearrangements
    2. Usually express CD5 marker (similar to B-CLL)
    3. Highly elevated peripheral cell counts typical (>200K/µL in many cases)
    4. Splenomegaly and/or hepatomegaly very common
    5. Anemia and thrombocytopenia <50% of patients
    6. Mucosal and cutaneous manifestations common
    7. Pleural effusions and ascites often occur
  4. Molecular Genetics
    1. Nearly all cases involve activation of the TCL1 locus on chromosome 14q32.1
    2. TCL1 activation usually due to translocations or inversions involving locus
    3. Four genes in the TCL1 locus are overexpressed in T-CLL
    4. These include TCL1, TCL1b, TNG1, TNG2
    5. Tcl1 protein involved in Akt (protein kinase B) survival pathway
    6. Tcl1 is an oncogene
  5. Median survival time 7 months
  6. Poor response to therapy

References navigator

  1. Chiorazzi N, Rai KR, Ferrarini M. 2005. NEJM. 352(8):804 abstract
  2. Shanafelt TD, Byrd JC, Gall TG, et al. 2006. Ann Intern Med. 145(6):435 abstract
  3. Stewart AK and Schuh AC. 2000. Lancet. 355(9213):1447 abstract
  4. Dohner H, Stilgenbauer S, Benner A, et al. 2000. NEJM. 343(26):1910 abstract
  5. Dighiero G and Binet JL. 2000. NEJM. 343(24):1799 abstract
  6. Fegan C. 2002. Lancet. 360(9328):184 abstract
  7. Dighiero G and Hamblin TJ. 2008. Lancet. 371(9617):1017 abstract
  8. Rai KR, Peterson BL, Appelbaum FR, et al. 2000. NEJM. 343(24):1750 abstract
  9. Staudt LM. 2003. NEJM. 348(18):1777 abstract
  10. Rassenti LZ, Huynh L, Toy TL, et al. 2004. NEJM. 351(9):893 abstract
  11. Calin GA, Ferracin M, Cimmino A, et al. 2005. NEJM. 353(17):1793 abstract
  12. Cooperative Group Study of Intravenous Immunoglobulin. 1988. NEJM. 319:902
  13. Mintzer D and Bagg A. 2001. Am J Med. 2001. 111(6):480 abstract
  14. Pekarsky Y, Hallas C, Croce CM. 2001. JAMA. 286(18):2308 abstract
  15. Wiley JS, Dao-Ung LP, Gu BJ, et al. 2002. Lancet. 359(9312):1114 abstract
  16. Orchard JA, Ibbotson RE, Davis Z, et al. 2004. Lancet. 363(9403):105 abstract
  17. Catovsky D, Richards S, Matutes E, et al. 2007. Lancet. 370(9583):230 abstract
  18. Lundin J, Kimby E, Bjorkholm M, et al. 2002. Blood. 100(3):768 abstract
  19. Crespo M, Bosch F, Villamor N, et al. 2003. NEJM. 348(18):1764 abstract