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

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

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

1975 JACQUILLAT et al NOUV REV FR D HEMAT: 15; 229-240 1981 TURA et al BR J HAEMATOL: 47; 105-119 1981 GOMEZ et al CANCER: 47; 2470-2477 1981 OGUMA et al CANCER: 50; 2928-2934 1982 CERVANTES et al BLOOD: 60; 1298-1304 1985 KANTARJIAN et al BLOOD: 66; 1326-1335 1990 KANTARJIAN et al AM J MED: 88; 1-8

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: 789-799 1998 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: 850-858

SOKAL (1) EUROPEAN (2) AGE (YEARS) 0.116 (AGE-43.4) 0.666 WHEN AGE >50 *SPLEEN (Cm) 0.0345 (SPLEEN 7.51) 0.042 x SPLEEN PLATELET COUNT (x19 9 /L) 0.188 [(PLT:700) 2-0.563] 1.0956 WHEN PLT>1500 BLOOD MYELOBLASTS (%) 0.0887 (MB-2.10) 0.0584 x MB BLOOD BASOPHILS (%) / 0.20399 WHEN BASO >3% BLOOD EOSINOPHILS (%) / 0.0413Xeos RELATIVE RISK EXPONENTIAL OF THE TOTAL TOTAL X 1000 LOW RISK < 0.8 < 780 INTERMEDIATE RISK 0.8 1.2 781 1480 HIGH RISK > 1.2 > 1480 * MAXIMUM DISTANCE FROM COSTAL MARGIN (1) SOKAL et al. BLOOD 1984; 63: 789-799 (2) HASFORD et al. JNCI 1998; 90: 850-858

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

SOKAL 1984 (INTERNATIONAL) HASFORD 1998 (EUROPEAN) No. OF SERIES 6 14 No. OF PATIENTS 813 1303 EUROPE 435 1228 USA 378 0 YEARS OF DIAGNOSIS 1962-1981 1985-1996 MEDIAN AGE 43 49 TREATMENT CONVENTIONAL IFNα-BASED CHEMOTHERAPY REGIMES

SOKAL HASFORD (1984) (1998) PTS. DISTRIBUTION - LOW RISK 48% 59% - INT RISK 29% 32% - HIGH RISK 23% 9% MEDIAN SURVIVAL (mo) - LOW RISK 105 105 - INT RISK 76 65 - HIGH RISK 45 45 10-YEAR SURVIVAL - LOW RISK 34% 37% - INT RISK 28% 16% - HIGH RISK 8% 0 ICSG ON CML, 272 IFNα - TREATED PTS BJH 2000: 111; 587-595

SOKAL FORMULATION WAS DERIVED FROM PATIENTS TREATED WITH CONVENTIONAL CHEMOTHERAPY (1962 1981) HASFORD FORMULATION WAS DERIVED FROM PATIENTS TREATED WITH IFNα - BASED REGIMES (1985 1996) NEITHER FORMULATIONS APPLY TO PATIENTS SUBMITTED TO ALLOGENEIC STEM CELL TRANSPLANTATION DO THEY APPLY TO PATIENTS TREATED WITH IMATINIB?

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, 400-800 MG, OVERALL RESPONSE 84% 85% 69% (1) ROSTI et al, HAEMATOLOGICA 2003, 88: 256-259 (2) HUGHES et al, NEJM 2003; 349: 1421-1432 (3) GUILHOT et al, BLOOD 2004; 104: 10a (ASH 2004) (4) SIMONSSON et al, BLOOD 2005; 106: 52a (ASH 2005)

% responding Estimated CCyR to First-line Imatinib by Sokal Group 100 90 80 70 60 50 40 30 20 10 Low risk Intermediate risk High risk 0 0 3 6 9 1 2 1 5 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 randomization 93% (89-97) 87% (80-94) 73% (62-83) p< 0.001 n=201 n=111 n=71 95% CI

Progression-free Survival by Sokal Group % without progression 100 90 80 70 60 50 40 30 20 10 0 Low risk Intermediate risk High risk (Unknown n= 170) Estimated rate at 54 months n= 201 90% n= 111 83% n= 71 71% } p<0.001 0 6 12 18 24 30 36 42 48 54 60 Months since randomization } p=0.05

Survival without AP/BC by Sokal Group % without PD to AP/BC 100 90 80 70 60 50 40 30 20 10 0 Low risk Intermediate risk High risk (Unknown n= 170) Estimated rate at 54 months n= 201 96% n= 111 92% n= 71 85% } p<0.001 } p=0.12 0 6 12 18 24 30 36 42 48 54 60 Months since randomization

Overall Survival by Sokal Group % alive 100 90 80 70 60 50 40 30 20 10 0 Low risk Intermediate risk High risk (Unknown n= 170) Estimated rate at 54 months n= 201 94% n= 111 89% n= 71 81% p<0.001 0 6 12 18 24 30 36 42 48 54 60 Months since randomization } } p=0.14

% months 100 90 80 70 60 50 40 30 20 10 0 Survival by Sokal Score given by CCyR Firstline Imatinib Low risk 97% Intermediate risk 92% High risk 90% 0 3 6 9 1 1 1 2 2 2 3 3 3 3 4 4 4 5 5 5 6 2 5 8 1 4 7 0 6 9 2 5 8 1 4 7 0 Months since randomization

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

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