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{{Chronic lymphocytic leukemia}}
{{Chronic lymphocytic leukemia}}
{{CMG}} {{AE}}{{HL}}
==Overview==
According to the Rai Staging System, there are five stages of chronic lymphocytic leukemia based on the degree of [[lymphocytosis]], [[hemoglobin]] level, [[platelet]] level, presence of [[splenomegaly]], and presence of [[lymphadenopathy]]. According to the Binet Staging System, there are three stages of chronic lymphocytic leukemia based on the degree of [[lymphocytosis]], the presence of [[anemia]] or [[thrombocytopenia]], and the involvement of three or more lymphoid regions. The tumor stage is considered one of the important factors that determine the optimal management protocol of chronic lymphocytic leukemia patients.


{{CMG}}
==Staging System==
===Rai Staging System:===
According to the Rai Staging System, there are five stages of chronic lymphocytic leukemia based on the degree of [[lymphocytosis]], [[hemoglobin]] level, [[platelet]]s level, presence of [[splenomegaly]], and presence of [[lymphadenopathy]].<ref name="pmid11390392">{{cite journal |vauthors=Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS |title=Clinical staging of chronic lymphocytic leukemia |journal=Blood |volume=46 |issue=2 |pages=219–34 |date=August 1975 |pmid=1139039 |doi= |url=}}</ref><ref name="pmid3357070">{{cite journal |vauthors=MacDougall BK, Weinerman BH |title=Staging and prognosis of chronic lymphocytic leukemia: the Manitoba experience |journal=J Gen Intern Med |volume=3 |issue=2 |pages=139–43 |date=1988 |pmid=3357070 |doi= |url=}}</ref><ref name="pmid9482526">{{cite journal |vauthors=Zwiebel JA, Cheson BD |title=Chronic lymphocytic leukemia: staging and prognostic factors |journal=Semin. Oncol. |volume=25 |issue=1 |pages=42–59 |date=February 1998 |pmid=9482526 |doi= |url=}}</ref><ref name="pmid28782884">{{cite journal |vauthors=Hallek M |title=Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment |journal=Am. J. Hematol. |volume=92 |issue=9 |pages=946–965 |date=September 2017 |pmid=28782884 |doi=10.1002/ajh.24826 |url=}}</ref>


==Overview==
{| style="border: 0px; font-size: 90%; margin: 3px; width: 1050px"
| valign="top" |
|+
! style="background: #4479BA; width: 300px;" | {{fontcolor|#FFF|'''Stage'''}}
! style="background: #4479BA; width: 300px;" | {{fontcolor|#FFF|'''Hemoglobin Level'''}}
! style="background: #4479BA; width: 300px;" | {{fontcolor|#FFF|'''Platelets Level'''}}
! style="background: #4479BA; width: 300px;" | {{fontcolor|#FFF|'''Lymphocytosis'''}}
! style="background: #4479BA; width: 300px;" | {{fontcolor|#FFF|'''Splenomegaly'''}}
! style="background: #4479BA; width: 300px;" | {{fontcolor|#FFF|'''Lymphadenopathy'''}}
! style="background: #4479BA; width: 300px;" | {{fontcolor|#FFF|'''Median Survival'''}}


==Classification==
|-
===Clinical staging===
Staging is done with the Rai staging system and the Binet classification (see details<ref name="NCI-CLL-page2">{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page2 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: Stage Information |author=National Cancer Institute |accessdate=2007-09-04 |format= |work=}}</ref>).


# '''Rai staging system''':
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" align="center" |
'''Stage 0'''
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
>11 g/dL
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
>100,000/L
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
'''Present'''
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
Absent
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
Absent
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
>150 months


{|style="width:80%; height:100px" border="1"
|style="height:100px"; style="width:25%" border="1" bgcolor="LightSteelBlue" | '''Stage 0'''
|style="height:100px"; style="width:75%" border="1" bgcolor="Beige" | Absolute lymphocytosis (>15,000/mm3) without adenopathy, hepatosplenomegaly, anemia, or thrombocytopenia.
|-
|-
|-bgcolor="LightSteelBlue"
 
| '''Stage 1'''
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" align="center" |
|bgcolor="Beige"| Absolute lymphocytosis with lymphadenopathy without hepatosplenomegaly, anemia, or thrombocytopenia.
'''Stage 1'''
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
>11 g/dL
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
>100,000/L
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
'''Present'''
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
Absent
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
'''Present'''
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
101 months
 
|-
|-
|-bgcolor="LightSteelBlue"
 
| '''Stage 2'''
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" align="center" |
|bgcolor="Beige"| Absolute lymphocytosis with either hepatomegaly or splenomegaly with or without lymphadenopathy.
'''Stage 2'''
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
>11 g/dL
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
>100,000/L
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
'''Present'''
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
'''Present'''
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
Present or absent
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
71 months
 
|-
|-
|-bgcolor="LightSteelBlue"
 
| '''Stage 3'''
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" align="center" |
|bgcolor="Beige"| Absolute lymphocytosis and anemia (hemoglobin <11 g/dL) with or without lymphadenopathy, hepatomegaly, or splenomegaly.
'''Stage 3'''
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
'''<11''' g/dL
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
>100,000/L
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
'''Present'''
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
Present or absent
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
Present or absent
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
19 months
 
|-
|-
|-bgcolor="LightSteelBlue"
 
| '''Stage 4'''
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" align="center" |
|bgcolor="Beige"| Absolute lymphocytosis and thrombocytopenia (<100,000/mm3) with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemia.
'''Stage 4'''
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
<11 g/dL '''or''' >11g/dL
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
'''<100,000'''/L
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
'''Present'''
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
Present or absent
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
Present or absent
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
19 months
|}
 
The staging is further modified into 3 groups:<ref name="pmid18216293">{{cite journal |vauthors=Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ |title=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 |journal=Blood |volume=111 |issue=12 |pages=5446–56 |date=June 2008 |pmid=18216293 |pmc=2972576 |doi=10.1182/blood-2007-06-093906 |url=}}</ref>
* '''Low Risk''': Stage 0
* '''Intermediate Risk''': Stages 1 and 2 combined
* '''High Risk''': Stage 3 and 4 combined
 
===Binet Staging System===
According to the Binet Staging System, there are three stages of chronic lymphocytic leukemia based on the degree of [[lymphocytosis]], the presence of [[anemia]] or [[thrombocytopenia]], and the involvement of three or more lymphoid regions: cervical, axillary and inguinal lymph nodes, and spleen and liver.<ref name="pmid7237385">{{cite journal |vauthors=Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, Vaugier G, Potron G, Colona P, Oberling F, Thomas M, Tchernia G, Jacquillat C, Boivin P, Lesty C, Duault MT, Monconduit M, Belabbes S, Gremy F |title=A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis |journal=Cancer |volume=48 |issue=1 |pages=198–206 |date=July 1981 |pmid=7237385 |doi= |url=}}</ref><ref name="pmid33570702">{{cite journal |vauthors=MacDougall BK, Weinerman BH |title=Staging and prognosis of chronic lymphocytic leukemia: the Manitoba experience |journal=J Gen Intern Med |volume=3 |issue=2 |pages=139–43 |date=1988 |pmid=3357070 |doi= |url=}}</ref><ref name="pmid94825262">{{cite journal |vauthors=Zwiebel JA, Cheson BD |title=Chronic lymphocytic leukemia: staging and prognostic factors |journal=Semin. Oncol. |volume=25 |issue=1 |pages=42–59 |date=February 1998 |pmid=9482526 |doi= |url=}}</ref><ref name="pmid287828842">{{cite journal |vauthors=Hallek M |title=Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment |journal=Am. J. Hematol. |volume=92 |issue=9 |pages=946–965 |date=September 2017 |pmid=28782884 |doi=10.1002/ajh.24826 |url=}}</ref>
 
{| style="border: 0px; font-size: 90%; margin: 3px; width: 1050px"
| valign="top" |
|+
! style="background: #4479BA; width: 250px;" | {{fontcolor|#FFF|'''Stage'''}}
! style="background: #4479BA; width: 250px;" | {{fontcolor|#FFF|'''Lymphocytosis'''}}
! style="background: #4479BA; width: 500px;" | {{fontcolor|#FFF|'''Anemia or Thrombocytopenia'''}}
! style="background: #4479BA; width: 250px;" | {{fontcolor|#FFF|'''Lymphadenopathy'''}}
! style="background: #4479BA; width: 700px;" | {{fontcolor|#FFF|'''Median Survival'''}}
 
|-
|-
|}


===Gene mutation status===
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" align="center" |
Recent publications suggest that two<ref name="pmid11733578">{{cite journal |author=Rosenwald A, Alizadeh AA, Widhopf G, ''et al'' |title=Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia |journal=J. Exp. Med. |volume=194 |issue=11 |pages=1639-47 |year=2001 |pmid=11733578 |doi=}}</ref> or three<ref name="pmid12406914">{{cite journal |author=Ghia P, Guida G, Stella S, ''et al'' |title=The pattern of CD38 expression defines a distinct subset of chronic lymphocytic leukemia (CLL) patients at risk of disease progression |journal=Blood |volume=101 |issue=4 |pages=1262-9 |year=2003 |pmid=12406914 |doi=10.1182/blood-2002-06-1801}}</ref> prognostic groups of CLL exist based on the maturational state of the cell. This distinction is based on the maturity of the lymphocytes as discerned by the immunoglobulin variable-region [[heavy chain]] (IgV<sub>H</sub>) gene mutation status.<ref name="pmid16983131">{{cite journal |author=Shanafelt TD, Byrd JC, Call TG, Zent CS, Kay NE |title=Narrative review: initial management of newly diagnosed, early-stage chronic lymphocytic leukemia |journal=Ann. Intern. Med. |volume=145 |issue=6 |pages=435-47 |year=2006 |pmid=16983131 |doi=|url=http://www.annals.org/cgi/content/full/145/6/435}}</ref>  High risk patients have an immature cell pattern with few mutations in the DNA in the IgV<sub>H</sub> antibody gene region whereas low risk patients show considerable mutations of the DNA in the antibody gene region indicating mature lymphocytes.
'''Stage A'''
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
Present
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
Absent
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
2 or less lymphoid regions
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
Almost normal age and sex adjusted survival rate
|-


Since assessment of the IgV<sub>H</sub> antibody DNA changes is difficult to perform, the presence of either [[cluster of differentiation]] [[CD38|38]] ([[CD38]]) or Z-chain–associated protein kinase-70 ([[ZAP-70]]) may be surrogate markers of high risk subtype of CLL.<ref name="pmid16983131"/> Their expression correlates with a more immature cellular state and a more rapid disease course.  Unmutated IGVH survive worse than mutated and are associated with aggressive CLL.  The ZAP70 (AKA Zeta-Associated Protein) presence on the CLL cell correlates with unmutated immunoglobulin genes and a poor prognosis.  Conversely, its absence indicates the presence of mutated genes and a good clinical outcome.  Patients positive for ZAP70 have a CLL more aggressive in nature and more refractory to treatment.  They are more likely to evolve to more unfavorable cytogenetic abnormalitites. 
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" align="center" |
'''Stage B'''
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
Present
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
Absent
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
>3 lymphoid regions
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
7 years


===Fluorescence in situ hybridization (FISH)===
|-
In addition to the maturational state, the prognosis of patients with CLL is dependent on the genetic changes within the neoplastic cell population. These genetic changes can be identified by fluorescent probes to chromosomal parts using a technique referred to as [[fluorescent in situ hybridization]] (FISH).<ref name="pmid16983131"/> Compared with fluorescence in-situ hybridization (FISH), conventional metaphase cytogenetics play ONLY a MINOR prognostic role in CLL, so far, due to technical problems resulting from a limited proliferation of CLL cells in-vitro.  Therefore conventional cytogenetics  may define subgroups with a high risk of progression.  FISH can be done (in CLL) on dividing and non-dividing cells.  FISH doesn't tell about IgVH mutations nor does it define the presence of trisomy either.  FISH is useful as long as there are CLL cells to test; you can't do it in a complete response (CR).The application of FISH to study interphase nuclei gives important prognostic information with B-cell CLL, especially for patients with 11q-, trisomy 12, 13q- and 17q-.   
The procedure of FISH involves cell cultures which are prepared after metaphase and prometaphase chromosomes are fixed to a glass slide.  A DNA probe is then hybridized onto the chromosome; the probe is labeled with fluorochrome which can be detected with fluorescent microscopy.  FISH can be done on dividing and non-dividing cells.  Inversions will be missed as probes detect sequences not precise locations.  Small mutations, such as small deletions and insertions, will also be missed.  FISH is a cytogenetic technology that looks at 200-500 blood cells (obtained with a bone marrow biopsy).  Because of the small size it is not as sensitive as PCR.  (PCR has extreme sensitivity as well as being quite specific). 
PCR amplifies a fragment of DNA.  It is at least 2-3 logs more sensitive than cytogenetic technology like FISH.  PCR measurement requires a sample blood draw which is less invasive and intense than a bone marrow biopsy (with FISH). 
Four main genetic aberrations are recognized in CLL cells that have a major impact on disease behavior.
# Deletions of part of the short arm of chromosome 17 (del 17p13) which target the cell cycle regulating protein p53 (a tumore suppressor gene) are particularly deleterious. Patients with this abnormality have significantly short interval before they require therapy and a shorter survival. This abnormality is found in 5-10% of patients with CLL.
# Deletions of the long arm on chromosome 11 (del 11q22-q23) are also unfavorable although not to the degree seen with del 17p. The abnormality targets the ATM gene and occurs infrequently in CLL (5-10%).
# Trisomy 12, an additional chromosome 12, is a relatively frequent finding occurring in 20-25% of patients and imparts an intermediate prognosis.  It has a higher frequency of DNA aneuploidy. 
# Deletion of the long arm of chromosome 13 (del 13q14) is the most common abnormality in CLL with roughly 50% of patients with cells containing this defect. These patients (along with those of normal karyotype) have the best prognosis and most will live many years, even decades, without the need for therapy. The gene targeted by this deletion is a segment that likely produces small inhibitory RNA molecules that affect expression of important death inhibiting genes.


The presence of 17p- typifies cells that are resistant to fludarabine, alkylators and rituxumab. 
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" align="center" |
11q- portends a decreased RR to fludrabine as well as an early relapse after bone marrow transplant (BMT). 
'''Stage C'''
Both the 17p- and the 11q- have a decreased progression-free survival (PFS) and overall survival (OS).
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
Present
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
Present
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
>3 lymphoid regions
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
2 years
|}


==References==
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Latest revision as of 15:54, 28 February 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]

Overview

According to the Rai Staging System, there are five stages of chronic lymphocytic leukemia based on the degree of lymphocytosis, hemoglobin level, platelet level, presence of splenomegaly, and presence of lymphadenopathy. According to the Binet Staging System, there are three stages of chronic lymphocytic leukemia based on the degree of lymphocytosis, the presence of anemia or thrombocytopenia, and the involvement of three or more lymphoid regions. The tumor stage is considered one of the important factors that determine the optimal management protocol of chronic lymphocytic leukemia patients.

Staging System

Rai Staging System:

According to the Rai Staging System, there are five stages of chronic lymphocytic leukemia based on the degree of lymphocytosis, hemoglobin level, platelets level, presence of splenomegaly, and presence of lymphadenopathy.[1][2][3][4]

Stage Hemoglobin Level Platelets Level Lymphocytosis Splenomegaly Lymphadenopathy Median Survival

Stage 0

>11 g/dL

>100,000/L

Present

Absent

Absent

>150 months

Stage 1

>11 g/dL

>100,000/L

Present

Absent

Present

101 months

Stage 2

>11 g/dL

>100,000/L

Present

Present

Present or absent

71 months

Stage 3

<11 g/dL

>100,000/L

Present

Present or absent

Present or absent

19 months

Stage 4

<11 g/dL or >11g/dL

<100,000/L

Present

Present or absent

Present or absent

19 months

The staging is further modified into 3 groups:[5]

  • Low Risk: Stage 0
  • Intermediate Risk: Stages 1 and 2 combined
  • High Risk: Stage 3 and 4 combined

Binet Staging System

According to the Binet Staging System, there are three stages of chronic lymphocytic leukemia based on the degree of lymphocytosis, the presence of anemia or thrombocytopenia, and the involvement of three or more lymphoid regions: cervical, axillary and inguinal lymph nodes, and spleen and liver.[6][7][8][9]

Stage Lymphocytosis Anemia or Thrombocytopenia Lymphadenopathy Median Survival

Stage A

Present

Absent

2 or less lymphoid regions

Almost normal age and sex adjusted survival rate

Stage B

Present

Absent

>3 lymphoid regions

7 years

Stage C

Present

Present

>3 lymphoid regions

2 years

References

  1. ↑ Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS (August 1975). "Clinical staging of chronic lymphocytic leukemia". Blood. 46 (2): 219–34. PMID 1139039.
  2. ↑ MacDougall BK, Weinerman BH (1988). "Staging and prognosis of chronic lymphocytic leukemia: the Manitoba experience". J Gen Intern Med. 3 (2): 139–43. PMID 3357070.
  3. ↑ Zwiebel JA, Cheson BD (February 1998). "Chronic lymphocytic leukemia: staging and prognostic factors". Semin. Oncol. 25 (1): 42–59. PMID 9482526.
  4. ↑ Hallek M (September 2017). "Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment". Am. J. Hematol. 92 (9): 946–965. doi:10.1002/ajh.24826. PMID 28782884.
  5. ↑ Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ (June 2008). "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. 111 (12): 5446–56. doi:10.1182/blood-2007-06-093906. PMC 2972576. PMID 18216293.
  6. ↑ Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, Vaugier G, Potron G, Colona P, Oberling F, Thomas M, Tchernia G, Jacquillat C, Boivin P, Lesty C, Duault MT, Monconduit M, Belabbes S, Gremy F (July 1981). "A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis". Cancer. 48 (1): 198–206. PMID 7237385.
  7. ↑ MacDougall BK, Weinerman BH (1988). "Staging and prognosis of chronic lymphocytic leukemia: the Manitoba experience". J Gen Intern Med. 3 (2): 139–43. PMID 3357070.
  8. ↑ Zwiebel JA, Cheson BD (February 1998). "Chronic lymphocytic leukemia: staging and prognostic factors". Semin. Oncol. 25 (1): 42–59. PMID 9482526.
  9. ↑ Hallek M (September 2017). "Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment". Am. J. Hematol. 92 (9): 946–965. doi:10.1002/ajh.24826. PMID 28782884.

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