**3. Prognostication**

CLL is commonly thought of as an indolent disease associated with a prolonged clinical course and that patients with CLL will die from unrelated cause rather than the disease itself. It is important to know that this only happens in one third of the patients. More commonly, patients will have two phases of the disease: an initial asymptomatic phase (5–10 years) where the course will be benign, followed by the terminal phase (1–2 years) where performance status will decline due to recurring need for hospitalization. Some patients die quickly within 1–2 years of the diagnosis. Because of this variable natural clinical course of CLL, there have been always efforts to come up with reliable and clinically applicable criteria that would allow recognizing those patients with poor prognosis to start treatment as soon as possible and improve their survival and differentiate them from the other group where the prognosis is good and treatment can be delayed to avoid treatment toxicity [6–8].

#### **3.1 Rai and Binet staging systems**

Rai and Binet staging systems are the most commonly used systems in practice and the international workshop Group on CLL (iwCLL) recommends using an integrated system using both methods [9]. Both systems depend on findings of CBC and physical exam findings only, addition of CT scan of the chest, abdomen, and pelvis is not routinely recommended to stratify patients.

Rai staging system divides patients into 5 groups (**Table 1**). It was published initially in 1975, with initial reports showing one quarter of patients fall in stage 0 on presentation, half of patients fall in stages 1 and 2, and a quarter of them fall in stages 3 and 4. Later reports showed that more patients fall in earlier stages because of earlier diagnosis due to the more routine testing being done in recent years including CBC [10]. Median survival decreases from almost 12 years in stage 0 to a year and a half in stages 3 and 4 [11]. In 1980s, this staging system was modified to include three stages based on actuarial survival pattern: Low risk (Rai stage 0), intermediate risk (Rai stages 1 and 2), and high risk (Rai stage 3 and 4). Of note,

**101**

*Chronic Lymphocytic Leukemia: Rapidly Changing Treatment Landscape*

hepatosplenomegaly (II)

B Three or more areas of lymphadenopathy; no anemia or

C Hemoglobin <100 g/L or platelets <100 x 109

thrombocytopenia

if complete or partial remission is achieved with successful therapy, and a patient's stage shifts from a higher risk to a lower risk category, the outlook for survival

**Stage Clinical features Median survival (in years)**

**Stage Clinical features Median survival (in years)** A <3 areas of lymphadenopathy; no anemia or thrombocytopenia Comparable to age-matched

5–8

controls

7

g/L 2

0 (low risk) Lymphocytosis only >10

III and IV (high risk) Anemia (III), thrombocytopenia (IV) 1.5

One important practical concept is to reliably differentiate between autoimmune cytopenias and cytopenias related to CLL because patients with autoimmune cytopenias have better outcome than Binet stage C patients although still worse than stage A and they can normalize their counts with treatments directed at the

Both systems are not very effective for predicting early disease progression. Although routine imaging is not recommended for staging of patients with CLL, visceral adenopathy may occur in early-stage disease and might predict an early disease progression. It is not known if the presence of visceral adenopathy warrants

Historically, the presence of CD38 by flow cytometry appeared to be independently associated with an adverse prognosis as well as Increased levels of ZAP-70 detected by flow cytometry [17]. It is a tyrosine kinase normally expressed by NK and T cells, and required for normal T cell receptor signaling. ZAP-70 is not normally expressed in B lymphocytes, but has been found in a subset of patients with CLL. The clinical significance of CD38 and ZAP-70 have declined overtime with

Currently, we use cytogenetics, molecular studies, lymphocyte doubling time, and beta-2 microglobulin [18]. Patients with del(13q) have favorable outcome, patients with trisomy 12 have intermediate outcome while patients with del(11q) and del(17p)/P53 have poor outcome. The prognosis of patients with del(11q) has

autoimmune cytopenia thus delay CLL treatment [14, 15].

Binet staging system takes into consideration five potential sites of involvement: cervical, axillary, and inguinal lymphadenopathy (each area counts as one either unilateral or bilateral), spleen, and liver, in addition to the presence of anemia and/ or thrombocytopenia. Based on these factors, Binet staging system divide patients

*DOI: http://dx.doi.org/10.5772/intechopen.88070*

I and II (intermediate risk) Lymphadenopathy (I) and

improves accordingly [12].

**Table 1.** *Rai staging system.*

**Table 2.**

*Binet staging system.*

into three groups (**Table 2**) [13].

any specific change in therapy [16].

better understanding of CLL cytogenetics.

**3.2 Other prognostic factors**

*Chronic Lymphocytic Leukemia: Rapidly Changing Treatment Landscape DOI: http://dx.doi.org/10.5772/intechopen.88070*


#### **Table 1.**

*Advances in Hematologic Malignancies*

CLL in 2008 eliminated this overlap [4, 5].

**3.1 Rai and Binet staging systems**

pelvis is not routinely recommended to stratify patients.

**3. Prognostication**

small lymphocytes, and flow cytometry showing the typical immunophenotype of CLL cells: extremely low levels of surface membrane immunoglobulin (SmIg) and either Kappa or Lambda (but not both), CD19, CD20, CD23 and CD5 positive cells. Evaluation of the bone marrow is not usually necessary, but is included in the evaluation of patients with unexplained cytopenias. Patients presenting with lymphadenopathy without lymphocytosis will need ideally an excisional lymph node biopsy or alternatively a needle biopsy showing mature lymphocytes with the previously mentioned phenotype to diagnose small lymphocytic lymphoma (SLL) which is considered by WHO the same disease as CLL with different manifestations [3]. Monoclonal B cell lymphocytosis is diagnosed when B-ALC is <5000/micrL persistently with no other manifestations of disease activity such as lymphadenopathy, hepatosplenomegaly, disease related cytopenias, or disease related symptoms. Patients with disease related cytopenias are diagnosed with CLL regardless of B-ALC and patients with any of the other manifestations are considered to have SLL [2]. Before 2008, the diagnosis of CLL was based on ALC equal or more than 5000/microL in the setting of appropriate immunophenotype. Patients with an absolute B lymphocyte count (B-ALC) less than 5000/microL and an ALC more than 5000/microL represented an overlap between CLL and monoclonal B cell lymphocytosis. The switch to using B-ALC for the diagnosis of

CLL is commonly thought of as an indolent disease associated with a prolonged clinical course and that patients with CLL will die from unrelated cause rather than the disease itself. It is important to know that this only happens in one third of the patients. More commonly, patients will have two phases of the disease: an initial asymptomatic phase (5–10 years) where the course will be benign, followed by the terminal phase (1–2 years) where performance status will decline due to recurring need for hospitalization. Some patients die quickly within 1–2 years of the diagnosis. Because of this variable natural clinical course of CLL, there have been always efforts to come up with reliable and clinically applicable criteria that would allow recognizing those patients with poor prognosis to start treatment as soon as possible and improve their survival and differentiate them from the other group where the prognosis is good and treatment can be delayed to avoid treatment toxicity [6–8].

Rai and Binet staging systems are the most commonly used systems in practice and the international workshop Group on CLL (iwCLL) recommends using an integrated system using both methods [9]. Both systems depend on findings of CBC and physical exam findings only, addition of CT scan of the chest, abdomen, and

Rai staging system divides patients into 5 groups (**Table 1**). It was published initially in 1975, with initial reports showing one quarter of patients fall in stage 0 on presentation, half of patients fall in stages 1 and 2, and a quarter of them fall in stages 3 and 4. Later reports showed that more patients fall in earlier stages because of earlier diagnosis due to the more routine testing being done in recent years including CBC [10]. Median survival decreases from almost 12 years in stage 0 to a year and a half in stages 3 and 4 [11]. In 1980s, this staging system was modified to include three stages based on actuarial survival pattern: Low risk (Rai stage 0), intermediate risk (Rai stages 1 and 2), and high risk (Rai stage 3 and 4). Of note,

**100**

*Rai staging system.*


#### **Table 2.**

*Binet staging system.*

if complete or partial remission is achieved with successful therapy, and a patient's stage shifts from a higher risk to a lower risk category, the outlook for survival improves accordingly [12].

Binet staging system takes into consideration five potential sites of involvement: cervical, axillary, and inguinal lymphadenopathy (each area counts as one either unilateral or bilateral), spleen, and liver, in addition to the presence of anemia and/ or thrombocytopenia. Based on these factors, Binet staging system divide patients into three groups (**Table 2**) [13].

One important practical concept is to reliably differentiate between autoimmune cytopenias and cytopenias related to CLL because patients with autoimmune cytopenias have better outcome than Binet stage C patients although still worse than stage A and they can normalize their counts with treatments directed at the autoimmune cytopenia thus delay CLL treatment [14, 15].

Both systems are not very effective for predicting early disease progression. Although routine imaging is not recommended for staging of patients with CLL, visceral adenopathy may occur in early-stage disease and might predict an early disease progression. It is not known if the presence of visceral adenopathy warrants any specific change in therapy [16].

#### **3.2 Other prognostic factors**

Historically, the presence of CD38 by flow cytometry appeared to be independently associated with an adverse prognosis as well as Increased levels of ZAP-70 detected by flow cytometry [17]. It is a tyrosine kinase normally expressed by NK and T cells, and required for normal T cell receptor signaling. ZAP-70 is not normally expressed in B lymphocytes, but has been found in a subset of patients with CLL. The clinical significance of CD38 and ZAP-70 have declined overtime with better understanding of CLL cytogenetics.

Currently, we use cytogenetics, molecular studies, lymphocyte doubling time, and beta-2 microglobulin [18]. Patients with del(13q) have favorable outcome, patients with trisomy 12 have intermediate outcome while patients with del(11q) and del(17p)/P53 have poor outcome. The prognosis of patients with del(11q) has

improved with the use of certain treatment regimens (e.g., fludarabine, cyclophosphamide, rituximab) while that of del(17p) or TP53 mutations remains poor despite such treatments. Analysis of CLL8 trial showed worse outcome in patients with SF3B1 and RPS15 gene mutations. Also, patients with complex karyotype and NOTCH1 mutations have more aggressive course.

The lymphocyte doubling time is the number of months it takes the absolute lymphocyte count to double. Doubling time <12 months is associated with a progressive course and a longer doubling time is associated with an indolent course. This factor is somewhat limited in usefulness because it takes time to measure. In patients with early stage disease, the presence of a short doubling time may favor more aggressive therapy. Higher levels of Beta-2 microglobulin (B2M) are associated with poorer outcome. B2M should be interpreted with caution in the context of renal disease, or alternatively GFR-adjusted B2M can be used although lacks validation in prospective studies [19]. Moreover, approximately half of CLL clones will demonstrate unmutated immunoglobulin heavy chain variable regions (IGHV), a finding associated with shorter survival overall and a higher risk of relapse following conventional treatment, including chemoimmunotherapy and hematopoietic cell transplantation [20].

#### **3.3 International prognostic index for chronic lymphocytic leukemia (CLL-IPI)**

An international group of investigators did a comprehensive analysis [21] to develop a prognostic index for CLL. Using data from 3472 treatment naive patients participating in prospective, randomized clinical trials, five independent prognostic factors were identified: TP53 deletion or mutation, or both, IGHV mutational status, serum B2M concentration, clinical stage, and age. Using weighted grading of the independent factors, a prognostic index was derived that separated patients into four risk groups with significantly different overall survival at 5 years: low (93%), intermediate (79%), high (63%), and very high risk (23%). This chronic lymphocytic leukemia international prognostic index (CLL-IPI) has now been validated by several other groups and is expected to improve patient counseling and the planning of clinical trials. Other risk scores have been proposed, but none of them has been generally accepted. Of note, none of the scores (including the CLL-IPI) affects the decision of when to initiate therapy.
