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Dr. Ajay YadavMedical OncologistAIIMS, New Delhi

Lancet Oncol 2016; 17: 779–90

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CLL - Epidemiology

• Most common lymphoproliferative disorder in the West (30)

• Incidence in India 2–4% • Median age: 59 years

• Chlorambucil based : ORR 69%, CR 3%• Fludarabine-based : ORR 89%, CR 44%

• Median overall survival:5.1yr• Event-free survival 4.6 years

Gogia A. et al.Leuk Lymphoma. 2012 Oct;53(10):1961-5. doi: 10.3109/10428194.2012.672734. Epub 2012 May 21

50%required

treatment at presentation

010%

116%

233%3

20%

421%

Rai Stage

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Rai Stage Characteristics Median survival(months)

0 Lymphocytosis 150

I Lymphadenopathy 101

II Organomegaly 71

III Anemia 19

IV Thrombocytopenia 19

Prognosis of CLL

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Binet Stagging

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Newer prognostic markers

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Newer Prognostic Markers

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Aim of study:

• To create an international prognostic index for CLL patients that integrates the major prognostic parameters

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Study Design

• Meta-analysis individual patient data from eight phase III trials

• Study Place : France, Germany, Poland, the United Kingdom, and the United States

• N=3472

• Treatment naïve patients with CLL, both early and advanced stage

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End Point

• Primary End Point: Overall survival

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Methods• Prospective, Clinical phase 3 trials of CLL, published between Jan 1, 1950

and Dec 31, 2010

• Chemo naïve patients with all stages

• Phase II or III trials

• At least one of the following new prognostic factors: del(17p), del(13q), del(6q), del(11q), trisomy 12, TP53 and IGHV mutational status, and ZAP-70 and CD38 expression

• Eligible clinical trials : 13 (phase III trials)

• Eight investigators - agreed to provide individual patient data

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Overview of study datasets

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Patient Segregation

• Total 3,472 patients after univariate analysis of randomized into – Training dataset N=2308 (66%)– Internal-validation data set N=1164 (34%)

• Two additional dataset (838 and 416) used as external validation sets (population-based case-control study)

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Statistical analysis

• Kaplan-Meier method, including the log-rank test used for estimations and comparisons of overall survival

• Hazard ratios (HR) was calculated using Cox proportional hazard regression analyses

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• Univariate analyses :

• Univariate analysis was done with 27 baseline variables

• Categorized laboratory variables by published thresholds and quartiles

• Categorized variables used for further analyses if significantly associated with overall survival

• Out of 27, 17 had significant association with survival

• Random allocation of participant data to Training dataset (66%) and Internal-validation data set (34%)

• Multivariate analysis:• All factors that were significantly associated with overall survival in univariate analyses were included

for the multivariate analysis

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Results

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Baseline Characteristics

• Median age: 61 years (range 27–86)

• 1542 (44%) died from any cause

• Median observation time of 79·9 months (IQR 79·9–101·4)

• Median overall survival: 95·3 months [95% CI 89·7–98·5]

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Univariate Analysis for OS

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Multivariate Analysis

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CLL- IPI Prognostic Model

Risk Group CLL-IPI riskscore

Low-risk 0-1

Intermediate-risk 2-3

High-risk 4-6

Very High-risk 7-10

1) TP53 status (no abnormalities v/s del[17p] or TP53 mutation or both)

2) IGHV mutational status (mutated v/s unmutated)

3) Serum β2-microglobulin concentration (≤3.5 mg/L v/s >3.5 mg/L)

4) Clinical stage (Binet A or Rai 0 v/s Binet B–C or Rai I–IV)

5) Age (≤65 years v/s >65 years)

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Analysis at Training dataset (N: 1214 )

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OS: Training dataset of 1214 patients

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Internal-validation cohort (N:585 )

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Internal-validation cohort (N:585 )

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External Validation :Mayo Clinic (N: 838)

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External Validation:Mayo Clinic (N:838)

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External Validation: SCAN cohort (N=416)

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OS: External validation in SCAN cohort of 416 patients

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Risk Group CLL-IPI riskscore

Management

Low-risk 0-1 Do not touch : watch-and-wait approach

CLL –IPI : How to implement

Intermediate-risk 2-3 Do not treat (except when the patient is symptomatic)

Very High-risk 7-10 Treat in experimental protocol or with non-cytotoxic drugs if possible (no chemotherapy or chemo -immunotherapy)

High-risk 4-6 Treat (except when the patient is asymptomatic)

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Discussion

Rai and Binet clinical staging systems developed :No biological or genetic variable available

CLL-IPI working group collected data from 8 international, phase III clinical trials from 5 countries

Evaluated the data of Individual patients

CLL-IPI combines genetic, biochemical, and clinical parameters into a prognostic model

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Discussion

Easily reproducible prognostic model

Identified four distinct groups of patients, on the basis of five parameters

Both Internally and externally validated

More realistically classify CLL patients

More targeted management of patients with CLL in clinical practice and in trials testing novel drugs

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Limitations of the Study

At the time of analysis, phase 3 trials of novel oral inhibitors (idelalisib, ibrutinib, or venetoclax) did not have sufficiently long follow-up to be included

Median age was lower than the general median age of patients at diagnosis (61 years vs 72 years)

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Further Study

CLL-IPI recently validated externally in two independent, prospective cohorts of newly diagnosed patients from the USA and Europe

Caspar et al The International prognostic Index for patients with chronic lymphocytic leukemia (CLL-IPI) applied in a population-based cohort Blood 2016 :blood-2016-07-724740

Molica et al Is the International Prognostic INDEX for CLL (CLL-IPI) Useful to Predict Time to First Treatment of Patients with early Disease? Results of a Prospective Multicenter Analysis:ASH 57th ASH Annual Meeting & Exposition 2015

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Take Home

• CLL-IPI combines the most important genetic risk factors with clinical stage, age, and β2-microglobulin

• An easily applicable prognostic score for CLL patients

• Cost effective, detection of number of markers can be avoided

•  Provides an important framework for treatment recommendations

• Identifies very poor risk groups, who may be benefited with novel therapies

Thank You

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Dr. Kanti Roop Rai