Diagnosis and Prognosis

Diagnosing CLL

  • ŸWhile some CLL patients are asymptomatic at diagnosis, others present with symptoms that may include1:
    • Fever
    • Night sweats
    • Weight loss
    • Weakness
    • Fatigue
    • Abdominal pain or “fullness”
    • Lymphadenopathy
  • The diagnosis of CLL requires the presence of at least 5000 clonal B cells per microliter in the peripheral blood2
  • As CLL progresses, abnormal lymphocyte proliferation can cause anemia, neutropenia, and thrombocytopenia1
  • Immunophenotyping and blood tests are useful for distinguishing CLL from other lymphoproliferative diseases (Table 1)2

Table 1. Diagnostic features of CLL

Morphology2

  • Cells appear as small, mature lymphocytes
  • May be admixed with larger atypical cells, cleaved cells, or prolymphocytes

Clinical features3

  • 70% to 80% of patients diagnosed through routine complete blood count with early-stage disease

Immunophenotype4

  • Typically CD5+, CD23+, CD43+/–, CD10–, CD19+, CD20 dim, sig dim+, and cyclin D1–

Staging CLL

Staging systems provide standardized parameters to help assess the prognosis of patients at the time of diagnosis and during the course of illness

  • Rai and Binet are the most commonly used staging systems for patients with CLL (Table 2)2

Table 2. Rai and Binet staging systems5,6

 

Stage

Definition

Rai5
Low Risk 0 Lymphocytosis only
Intermediate risk I Lymphocytosis and lymphadenopathy
II Lymphocytotis in blood and marrow with spenomegaly and/or hepatomegaly, with or without lymphadenopathy
High risk III Lymphocytosis and anemia (hemoglobin <11g/dL or hematocrit <33%)
IV Lymphocytosis and thrombocytopenia (platelet count <100,000/mm3)
Binet6
  A Enlargement of <3 lymphoid areas (cervical, axillary, inguinal, spleen/liver); no anemia or thrombocytopenia
  B Enlargement of ≥3 lymphoid areas
  C Anemia (hemoglobin <10g/dL) or thrombocytopenia (platelet count <100,000/mm3), or both

Prognostic Indicators

  • Categorizing a patient based on a set of prognostic factors provides complementary information on predictors of disease outcome and survival2,7-13 (Table 3 and Figure 1). A patient may present with one or multiple prognostic markers

Table 3. Prognostic indicators in CLL. A patient may present with multiple markers

Prognostic indicators for poor outcomes (<10 years median survival)

Β2 microglobulin (B2M) >2 x ULN14
Unmutated IgVH 7
High expression of ZAP-70 (>20%)11
High expression of CD38 (≥30%)13
Chromosomal aberrations by FISH2

Figure 1. Schematic of selected biological differences between lgVH unmutated and mutated CLL B-cell clones8

Blood, journal of the American Society of Hematology. Copyright 2004 by AMERICAN SOCIETY OF HEMATOLOGY (ASH). Reproduced with permission of AMERICAN SOCIETY OF HEMATOLOGY (ASH) in the format Internet posting via Copyright Clearance center.

  • Additionally, CLL is characterized by a variety of chromosomal abnormalities.15 These genetic aberrations include chromosomal deletions del 17p, del 11q, del 13q, del 6q, and trisomy 1216
    • Current National Comprehensive Cancer Network® (NCCN®) recommendations are generally based on the presence or absence of a chromosome 17p deletion4
      • Patients with chromosomal deletion 17p have a poor prognosis15 (Figure 2)

Figure 2. Prognostic implication of chromosomal abnormalities.15
Adapted from Döhner H et al. N Engl J Med. 2000;343:1910-1916.

  • Additional unfavorable prognostic factors include but are not limited to:
    • Advanced stage (Rai Stage II/IV or Binet Stage C)17
    • Short lymphocyte doubling time (<1 year)17
    • Diffuse bone marrow involvement17

References

  1. Leukemia—Chronic Lymphocytic. American Cancer Society website. http://www.cancer.org/acs/groups/cid/documents/webcontent/003111-pdf.pdf. Updated February 26, 2015. Accessed September 21, 2015.
  2. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines. Blood. 2008;111:5446-5456.
  3. Palmer S, Hanson CA, Zent CS, et al. Prognostic importance of T and NK-cells in a consecutive series of newly diagnosed patients with chronic lymphocytic leukaemia. Br J Haematol. 2008;141:607-614.
  4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Hodgkin’s Lymphomas. V.1.2016. © National Comprehensive Cancer Network, Inc. 2016. All rights reserved. Accessed December 4, 2015. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.
  5. Rai KR. A critical analysis of staging in CLL. In: Gale PR, Rai KR, eds. Chronic Lymphocytic Leukemia: Recent Progress and Future Direction. New York, NY: Alan R. Liss, Inc.; 1987:253-264. UCLA Symposium and Cellular Biology New Series; vol 59.
  6. Binet JL, Auquier A, Dighiero G, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981;48:198-206.
  7. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94:1848-1854.
  8. Shanafelt TD, Geyer SM, Kay NE. Prognosis at diagnosis: integrating molecular biologic insights into clinical practice for patients with CLL. Blood. 2004;103:1202-1210.
  9. Damle RN, Wasil T, Fais F, et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999;94:1840-1847.
  10. Wiestner A, Rosenwald A, Barry TS, et al. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood. 2003;101:4944-4951.
  11. Rassenti LZ, Huynh L, Toy TL, et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med. 2004;351:893-901.
  12. Delgado J, Pratt G, Phillips N, et al. Beta2-microglobulin is a better predictor of treatment-free survival in patients with chronic lymphocytic leukaemia if adjusted according to glomerular filtration rate. Br J Haematol. 2009;145:801-805.
  13. Del Principe MI, Del Poeta G, Buccisano F, et al. Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia. Blood. 2006;108:853-861.
  14. Wierda WG, O'Brien S, Wang X, et al. Prognostic nomogram and index for overall survival in previously untreated patients with chronic lymphocytic leukemia. Blood. 2007;109:4679-4685.
  15. Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910-1916.
  16. Gribben JG. Molecular profiling in CLL. Hematology Am Soc Hematol Educ Program. 2008:444-449.
  17. Sagatys EM, Zhang L. Clinical and laboratory prognostic indicators in chronic lymphocytic leukemia. Cancer Control. 2012;19:18-25.