Relative Risk (Sokal & Hasford): Relationship with Treatment Results. Michele Baccarani

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1 Relative Risk (Sokal & Hasford): Relationship with Treatment Results Michele Baccarani

2 European LeukemiaNet EVOLVING CONCEPTS IN THE MANAGEMENT OF CHRONIC MYELOID LEUKEMIA VENICE 8 9 MAY 2006 Disease risk (Sokal and Hasford) Michele Baccarani

3 1975 JACQUILLAT et al NOUV REV FR D HEMAT: 15; TURA et al BR J HAEMATOL: 47; GOMEZ et al CANCER: 47; OGUMA et al CANCER: 50; CERVANTES et al BLOOD: 60; KANTARJIAN et al BLOOD: 66; KANTARJIAN et al AM J MED: 88; 1-8

et al CANCER: 50; 2928-2934 1982 CERVANTES et al BLOOD: 60; 1298-1304 1985

4 1984 PROGNOSTIC DISCRIMINATION IN GOOD RISK CHRONIC GRANULOCYTIC LEUKEMIA. - J.E. SOKAL, E.B. COX, M. BACCARANI, S. TURA, G.A. GOMEZ et al, BLOOD 1984; 63: A NEW PROGNOSTIC SCORE FOR SURVIVAL OF PATIENTS WITH CHRONIC MYELOID LEUKEMIA TREATED WTH INTERFERON ALFA. J. HASFORD, M. PFIRRMANN, R. HEHLMANN, N.C. - ALLAN, M. BACCARANI et al, J NATL CANCER INST 1998; 90:

CARANI, S. TURA, G.A. GOMEZ et al, BLOOD 1984; 63: 789-799 1998 A NEW PROGNOSTIC SCORE FOR

5 SOKAL (1) EUROPEAN (2) AGE (YEARS) (AGE-43.4) WHEN AGE >50 *SPLEEN (Cm) (SPLEEN 7.51) x SPLEEN PLATELET COUNT (x19 9 /L) [(PLT:700) ] WHEN PLT>1500 BLOOD MYELOBLASTS (%) (MB-2.10) x MB BLOOD BASOPHILS (%) / WHEN BASO >3% BLOOD EOSINOPHILS (%) / Xeos RELATIVE RISK EXPONENTIAL OF THE TOTAL TOTAL X 1000 LOW RISK < 0.8 < 780 INTERMEDIATE RISK HIGH RISK > 1.2 > 1480 * MAXIMUM DISTANCE FROM COSTAL MARGIN (1) SOKAL et al. BLOOD 1984; 63: (2) HASFORD et al. JNCI 1998; 90:

0584 x MB BLOOD BASOPHILS (%) / 0.20399 WHEN BASO >3% BLOOD EOSINOPHILS (%) / 0.

7 New Prognostic Score Low risk Intermed. risk High risk median survival 100 Mon. median survival 69 Mon. median survival 45 Mon. Probability of survival Score: Age Spleen size Blasts Eosinophils Basophils Platelets 10 y. survival 40% p<0,0001 EI-CML, Hasford et al. JNCI 1998 Years after diagnosis

8 SOKAL 1984 (INTERNATIONAL) HASFORD 1998 (EUROPEAN) No. OF SERIES 6 14 No. OF PATIENTS EUROPE USA YEARS OF DIAGNOSIS MEDIAN AGE TREATMENT CONVENTIONAL IFNα-BASED CHEMOTHERAPY REGIMES

OF PATIENTS 813 1303 EUROPE 435 1228 USA 378 0 YEARS OF

9 SOKAL HASFORD (1984) (1998) PTS. DISTRIBUTION - LOW RISK 48% 59% - INT RISK 29% 32% - HIGH RISK 23% 9% MEDIAN SURVIVAL (mo) - LOW RISK INT RISK HIGH RISK YEAR SURVIVAL - LOW RISK 34% 37% - INT RISK 28% 16% - HIGH RISK 8% 0 ICSG ON CML, 272 IFNα - TREATED PTS BJH 2000: 111;

SURVIVAL (mo) - LOW RISK 105 105 - INT RISK 76 65 - HIGH RISK 45 45 10-YEAR

10 SOKAL FORMULATION WAS DERIVED FROM PATIENTS TREATED WITH CONVENTIONAL CHEMOTHERAPY ( ) HASFORD FORMULATION WAS DERIVED FROM PATIENTS TREATED WITH IFNα - BASED REGIMES ( ) NEITHER FORMULATIONS APPLY TO PATIENTS SUBMITTED TO ALLOGENEIC STEM CELL TRANSPLANTATION DO THEY APPLY TO PATIENTS TREATED WITH IMATINIB?

WITH IFNα - BASED REGIMES (1985 1996) NEITHER FORMULATIONS APPLY TO PATIENTS

11 COMPLETE CYTOGENETIC RESPONSE SOKAL RISK LOW INTERM. HIGH ITALIAN MULTICENTER STUDY, 77 PTS, 400 MG, 6 MONTHS (1) 70% 41% 8% IRIS STUDY, 383 PTS, 400 MG - 12 MONTHS (2) 76% 67% 49% - 42 MONTHS (3) 91% 84% 69% HOUSTON STUDY, 187 PTS, MG, OVERALL RESPONSE 84% 85% 69% (1) ROSTI et al, HAEMATOLOGICA 2003, 88: (2) HUGHES et al, NEJM 2003; 349: (3) GUILHOT et al, BLOOD 2004; 104: 10a (ASH 2004) (4) SIMONSSON et al, BLOOD 2005; 106: 52a (ASH 2005)

76% 67% 49% - 42 MONTHS (3) 91% 84% 69% HOUSTON STUDY, 187 PTS, 400-800 MG, OVERALL RESPONSE 84% 85% 69% (1) ROSTI et

12 % responding Estimated CCyR to First-line Imatinib by Sokal Group Low risk Intermediate risk High risk Months since randomization 93% (89-97) 87% (80-94) 73% (62-83) p< n=201 n=111 n=71 95% CI

1 8 2 1 2 4 2 7 3 0 3 3 6 3 9 4 2 4 5 4 8 5 1 5 4 5 7 6 0 Months since

13 Progression-free Survival by Sokal Group % without progression Low risk Intermediate risk High risk (Unknown n= 170) Estimated rate at 54 months n= % n= % n= 71 71% } p< Months since randomization } p=0.05

n= 170) Estimated rate at 54 months n= 201 90% n= 111 83% n= 71 71% }

14 Survival without AP/BC by Sokal Group % without PD to AP/BC Low risk Intermediate risk High risk (Unknown n= 170) Estimated rate at 54 months n= % n= % n= 71 85% } p<0.001 } p= Months since randomization

n= 170) Estimated rate at 54 months n= 201 96% n= 111 92% n= 71 85% }

15 Overall Survival by Sokal Group % alive Low risk Intermediate risk High risk (Unknown n= 170) Estimated rate at 54 months n= % n= % n= 71 81% p< Months since randomization } } p=0.14

Estimated rate at 54 months n= 201 94% n= 111 89% n= 71 81% p<0.

16 % months Survival by Sokal Score given by CCyR Firstline Imatinib Low risk 97% Intermediate risk 92% High risk 90% Months since randomization

Intermediate risk 92% High risk 90% 0 3 6 9 1 1 1 2 2 2 3 3 3

17 CANDIDATE (PUTATIVE) BIOLOGIC PROGNOSTIC FACTORS GENOMIC PROFILE GENETIC POLYMORPHISMS WILM S TUMOR GENE EXPRESSION TOTAL PHOSPHOTYROSINE LEVEL IN CD34+ CELLS CrKl PHOSPHORILATION DURING TREATMENT BCR-ABL TRANSCRIPT LEVEL ADDITIONAL CHROMOSOME ABNORMALITIES (Ph AMPLIFICATION, DEL 9q+, etc) PRE-EXISTING ABL KD MUTATIONS IN CD34+ CELLS

CELLS CrKl PHOSPHORILATION DURING TREATMENT BCR-ABL TRANSCRIPT LEVEL ADDITIONAL

18 CELLULAR AND MOLECULAR BIOLOGY STUDIES WILL HELP IMPROVE PROGNOSIS AND TREATMENT BUT DON T FORGET THAT TODAY SOKAL / HASFORD RISK DEFINITION IS REQUIRED TO PLAN THE TREATMENT OF A CML PATIENT. ALL WHAT YOU NEED IS SPLEEN SIZE, BLOOD COUNTS AND BLOOD DIFFERENTIAL PRIOR TO ANY TREATMENTS

IS REQUIRED TO PLAN THE TREATMENT OF A CML PATIENT.

Response Definition, Evaluation and Monitoring. Michele Baccarani

Response Definition, Evaluation and Monitoring Michele Baccarani European LeukemiaNet EVOLVING CONCEPTS IN THE MANAGEMENT OF CHRONIC MYELOID LEUKEMIA VENICE 8 9 MAY 2006 Response definition, evaluation