Additional Investigations

In early chronic lymphocytic leukaemia (CLL), time to first treatment (TTFT) and overall survival (OS) prediction can be improved by the addition of other clinical and laboratory parameters to the clinical staging information. These include lymphocyte count, lymphocyte doubling time (LDT), levels of serum β2-microglobulin (B2M), lactate dehydrogenase (LDH), thymidine kinase and IGHV status as well as genomic aberrations (Furman, 2010; Oscier et al., 2012; Stilgenbauer et al., 2015; Sun & Weistner 2015).

A prognostic index incorporating six clinical and laboratory parameters (age, B2M, lymphocyte count, gender, Rai stage and number of involved lymph node groups) predictive of OS has been devised and validated in previously untreated CLL patients using Mayo Clinic data (Table 3) (Shanafelt et al., 2009; Wierda et al., 2007).​

Table 3. Prognostic index based on presence of risk factors (Wierda et al., 2007).
  Point Contribution
Characteristic 0 1 2 3

Age, years

<50

50–65

>65

B2M, mg/L

<ULN

1–2 x ULN

>2 x ULN

ALC, x 109

<20

20–50

>50

Sex

Female

Male

Rai stage

0-II

III-IV

No. involved nodal groups

≤2

3

Index score is the sum total of the point contribution for each of the six characteristics. An index score of 1–3 indicates low risk; 4–7, intermediate risk; and ≥8, high risk. To convert B2M from milligrams per litre to nanomoles per litre, multiply milligrams per litre by 85. B2M, β-2 microglobulin; LDH, lactate dehydrogenase; ALC, absolute lymphocyte count; —, not applicable; ULN, upper limit of normal.

The survival probability can then be estimated based on the point score (Table 4).

Table 4. Overall survival probability and relative risk of death according to risk group (Wierda et al., 2007)
Risk Group Index score No. patients 5-year OS (SE) 10-year OS (SE) RR (95% CI)

Low

1–3

194

0.97 (0.01)

0.8 (0.05)

1.00 (Ref)

Intermediate

4–7

1236

0.8

0.52 (0.03)

3.89 (2.42–6.26)

High

≥8

187

0.55 (0.04)

0.26 (0.06)

10.48 (6.27–17.53)

OS, overall survival; SE, standard error; RR, relative risk; CI, confidence interval.

A novel prognostic index for categorisation of patients with CLL has more recently been devised that also incorporates genetic factors, using data from patients participating in Phase III trials by the German CLL Study Group (GCLLSG). Eight independent factors were found to be predictive of OS which included age, sex, Eastern Cooperative Oncology Group (ECOG) status, the deletions del 17p and del 11q, immunoglobulin heavy chain variable region (IGHV)gene mutational status, serum BM2 and serum thymidine kinase (Table 5) (Pflug et al., 2014).​

Table 5. Risk scores of independent factors for CLL prognosis (adapted from Pflug et al., 2014)
Independent factor   HR (95% CI) Risk score

Del 17p

Del 17p

6.0 (4.2–8.6)

6

Thymidine kinase

>10 U/L

2.1 (1.5–2.9)

2

B2M

>3.5 mg/L

2.3 (1.4–3.6)

2

B2M

>1.7 and ≤3.5 mg/L

1.7 (1.1–2.7)

1

IGHV mutational status

Unmutated

1.9 (1.5–2.5)

1

Del 11q

Del 11q

1.4 (1.03–2.0)

1

Sex

Male

1.3 (1.01–1.6)

1

Age

>60 years

1.3 (1.04–1.7)

1

HR, hazard ratio; CI, confidence interval; B2M, serum β2-microglobulin; IGHV, immunoglobulin heavy chain variable region gene.

Four different risk categories for OS were determined using a grading system based on the 8 prognostic factors (Table 6) (Pflug et al., 2014).

Table 6. Rates of 5- year OS according to the single risk scores and the risk groups of the prognostic index (adapted from Pflug et al., 2014).
Risk Group Risk score 5-year OS HR (95% CI)

Low

0–2

95.2%

Intermediate

3–5

86.9%

4.8 (2.9–8.0)

High

6–10

67.6%

12.5 (7.7–20.5)

Very High

11–14

18.7%

57.7 (33.0–101.2)

HR, hazard ratio; CI, confidence interval.

In 2016, an international prognostic index for chronic lymphocytic leukaemia (CLL-IPI) was created that integrates the major prognostic parameters. Five independent prognostic factors were identified: TP53 status (no abnormalities vs. del[17p] and/or TP53 mutation), IGHV (immunoglobulin heavy chain variable region gene) mutational status (mutated vs. unmutated), serum β2-microglobulin concentration (≤3·5 mg/L vs. >3·5 mg/L), clinical stage (Binet A or Rai 0 vs. Binet B-C or Rai I-IV), and age (≤65 years vs. >65 years). The CLL-IPI combines genetic, biochemical, and clinical parameters into a prognostic model, discriminating four prognostic subgroups: low risk (OS at 5 years 93.2% [95% CI 90.5-96.0]), intermediate risk (79.3% [75.5-83.2]), high risk (63.3% [57.9-68.8]), and very high risk (23.3% [12.5-34.1]). It is envisaged that the CLL-IPI will allow a more targeted management of patients with CLL in clinical practice and in clinical trials of novel drugs (International CLL-IPI working group et al., 2016).