1. What to test. 2. When to test

Transcription

1 Biomarkers: the triad of questions 1. What to test 2. When to test 3. Who to test

2 Biomarkers: the triad of questions 1. What to test 2. When to test 3. Who to test

3 Impact of CLL biological features on FCR performance N CR 3-year PFS 3-year OS del17p 22 5% 18% 38% del11q 80 51% 64% 94% % 83% 96% del13q % 76% 95% Normal 80 35% 58% 83% IGHV M % 80% 91% IGHV UM % 55% 86% CD38 na na na na ZAP-70 na na na na Hallek M, Lancet 2010;376:

4 NCI-IWCLL considerations on biomarkers Hallek et al, Blood 2008 Detection of cytogenetic abnormalities (17p) has apparent prognostic value and may influence therapeutic decisions It is uncertain whether expression of IGHV unmutated genes, ZAP-70 or CD38 predict the response to treatment or overall survival Need to standardize the assessment of IGHV mutations and ZAP-70 and CD38 expression

5 Biomarkers: the triad of questions 1. What to test 2. When to test 3. Who to test

6 NCI-IWCLL recommendations for IGHV mutation status, ZAP-70 and CD38 assessment outside clinical trials Hallek et al, Blood 2008 Diagnosis IGHV mutation status, ZAP-70 and CD38 assessment will not influence watch and wait strategy Not recommended Treatment requirement IGHV mutation status, ZAP-70 and CD38 assessment will not influence therapeutic decisions Not recommended

7 NCI-IWCLL recommendations for del17p, del11q, del13q, and +12 assessment outside clinical trials Hallek et al, Blood 2008 Diagnosis FISH results will not influence watch and wait strategy Not recommended Treatment requirement FISH results may influence therapeutic decisions Desirable

8 Biomarkers: the triad of questions 1. What to test 2. When to test 3. Who to test

9 PFS is poor independent of the induction regimen in previously untreated CLL harboring 17p deletion Regimen N ORR CR PFS (mo) Hillmen P Cam 11 64% na 10.7 Pettitt AR CamHDMP 17 88% 65% 18.3 Stilgenbauer S CamDexa 30 97% 20% 16.9 Hallek M FCR 22 68% 5% 11.3 Fischer K BR 8 37% 0% 7.9 Hillmen P, J ClinOncol 2007;25: Hallek M, Lancet 2010;376: Stilgenbauer S, ASH 2011 #2854 Pettitt AR, J ClinOncol 2012;30: Fischer K, J ClinOncol 2012, doi: /JCO

10 Allogeneic SCT is the sole treatment that may prolong PFS in 17p deleted CLL CLL8 trial (GCLLSG)= FCR CLL2H trial (GCLLSG)= Alemtuzumab s.c. PFS PFS Biomarkers may provide a benefit only to patients who are fit and may receive aggressive treatment CLL206 trial (NCRI)= HDM+A Remissionattainment CLL3X trial (GCLLSG)= allo SCT PFS PFS Schetelig, JCO 2008 Stilgenbauer, JCO 2009 Hallek, Lancet 2010 Zenz, JCO 2010 Gonzalez, JCO 2011

11 ERIC recommendations on TP53 analysis outside clinicaltrials When: immediately before treatment decision Who: patients requiring therapy who would be eligible to an allogeneic stem cell transplantation or other intensive therapies Previously treated patients with wild-type TP53 at the time of treatment, should be retested when further therapy is needed and results can be expected to influence choice of therapy Pospisilova et al, Leukemia 2012

12 No more than 50% CLL patients (<65 y) are eligible to intensive treatment < >90 Age (years) Cumulative prevalence of patients harboring TP53 abnormalities

13 Novel recurrent genetic lesions individually showing impact on CLL survival NOTCH1 SF3B1 BIRC3 NOTCH1wt NOTCH1 M p<.001 SF3B1 wt SF3B1 M p=.011 p<.001 BIRC3wt BIRC3 dis N=309 N=301 N=306

14 Mutational complementation groups in newly diagnosed CLL Newly diagnosed CLL (N=637) N=286 (44.8%) TP53 M Frequency N=105 (16.4%) N=46 (7.2%) N=62 (9.7%) del13q del11q22-q23 del17p13 N=637 N=54 (8.4%) N=71 (11.1%) N=43 (6.7%) N=17 (2.6%) TP53 M NOTCH1 M SF3B1 M BIRC3 M N=22 (3.4%) N=26 (4.0%) BIRC3 del MYD88 M del13q14 del11q22-q23 N=26 (4.0%) * * * del17p13 * +12 NOTCH1 M SF3B1 M BIRC3 M MYD88 M BIRC3 del

15 Integrated mutational and cytogenetic model for CLL prognostication OS TFS del13q14 Normal/+12 NOTCH1 M/SF3B1 M/del11q22-q23 TP53 DIS/BIRC3 DIS del13q14 Normal/+12 NOTCH1 M/SF3B1 M/del11q22-q23 TP53 DIS/BIRC3 DIS del13q14 vs Normal/+12 Normal/+12 vs NOTCH1M/SF3B1 M/del11q22-q23 NOTCH1 M/SF3B1 M/del11q22-q23 vs TP53DIS/BIRC3 DIS p= p= p= del13q14 vs Normal/+12 Normal/+12 vs NOTCH1M/SF3B1 M/del11q22-q23 NOTCH1 M/SF3B1 M/del11q22-q23 vs TP53DIS/BIRC3 DIS p= p< p=0.0150

16 The integrated mutational and cytogenetic model predicts CLL survival independent of confounders Multivariate analysis in the training series External validation HR LCI UCI p Age (in year units) < Female Male Rai stage 0-I II < III-IV IGHV homology <98% IGHV homology >98% Integrated mutational and cytogenetic model Very-low risk Low-risk Intermediate-risk High-risk N=370

17 Inclusion of mutations in addition to FISH abnormalities significantly improves the accuracy of CLL prognostication Matched general population del13q14 Normal +12 del11q22-q23 del17p13 Matched general population del13q14 Normal/+12 NOTCH1 M/SF3B1 M/del11q22-q23 TP53 DIS/BIRC3 DIS Cumulative probability of OS (%) c-index=0.617 Cumulative probability of OS (%) c-index= Years from diagnosis N Observed Expected 5-year OS 10-year OS 10-year events events* (%) (%) relative OS* p* % < % < % < % < % < Years from diagnosis N Observed Expected 5-year OS 10-year OS 10-year events events* (%) (%) relative OS* p* % % < % < % <0.0001

18 The integrated mutational and cytogenetic model maintains its prognostic relevance at any time from diagnosis del13q14 Normal/+12 NOTCH1 M/SF3B1 M/del11q22-q23 TP53 DIS/BIRC3 DIS N=257 N=224 Diagnosis p< year landmark p< N=190 N=130 2-year landmark p< year landmark p=0.0018

19 Biomarkers in CLL outside of clinical trials New biomarkers (TP53, IGHV, ZAP70, CD38, ) Stick to the NCI-IWCLL and ERIC guidelines! Only TP53 deletion/mutation has the potential to affect choice of therapy NO to a generalized use in the clinical practice New New biomarkers (NOTCH1, SF3B1, BIRC3) Abstain from testing and wait for future guidelines

20 Hierarchical order of relevance of the genetic lesions in predicting survival in newly diagnosed CLL TP53 DIS p<0.001 BIRC3 DIS p<0.001 No Yes SF3B1 M p=0.017 No Yes NOTCH1 M p=0.042 No Yes del11q22-q23 p=0.030 No Yes No Yes Cumulative probabilityof OS Node 6 (n = 383) 1 Node 7 (n = 20) 1 Node 8 (n = 50) 1 Node 9 (n = 29) 1 Node 10 (n = 27) 1 Node 11 (n = 74) Years Years Years Years Years Years SF3B1 M and/or NOTCH1 M and/or del11q22-q23 TP53 DIS and/or BIRC3 DIS