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

Michele BaccaraniMichele Baccarani

Michele Baccarani Michele Baccarani

European LeukemiaNet European LeukemiaNet

EVOLVING CONCEPTS IN THE MANAGEMENT OF CHRONIC

MYELOID LEUKEMIA

EVOLVING CONCEPTS IN THE MANAGEMENT OF CHRONIC

MYELOID LEUKEMIA

VENICE 8 – 9 MAY 2006 VENICE 8 – 9 MAY 2006

Disease risk (Sokal and Hasford) Disease risk (Sokal and Hasford)

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

-

-

* MAXIMUM DISTANCE FROM COSTAL MARGIN (1) SOKAL et al. BLOOD 1984; 63: 789-799 (2) HASFORD et al. JNCI 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 (x199/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

10 y. survival 40%

Years after diagnosis

Low risk median survival 100 Mon. Intermed. risk median survival 69 Mon. High risk median survival 45 Mon.

Prob

abili

ty o

f sur

viva

l

p<0,0001

Score: • Age • Spleen size • Blasts • Eosinophils • Basophils • Platelets

EI-CML, Hasford et al. JNCI 1998

New Prognostic Score New Prognostic Score

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

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 1984

(INTERNATIONAL)

SOKAL 1984

(INTERNATIONAL)

HASFORD 1998

(EUROPEAN)

HASFORD 1998

(EUROPEAN)

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

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 ICSG ON CML, 272 IFNα - TREATED PTS BJH 2000: 111; 587 - 595

SOKAL HASFORD (1984) (1998) SOKAL HASFORD (1984) (1998)

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)

EstimatedEstimated CCyRCCyR toto FirstFirst--lineline Imatinib by Imatinib by SokalSokal GroupGroup

p< 0.001

93% (89-97) 87% (80-94)

73% (62-83)

95% CI

n=201 n=111 n=71

Low riskIntermediate riskHigh risk

% re

spon

ding

0102030405060708090

100

Months since randomization

0 3 6 9 12

15

18

21

24

27

30

33

36

39

42

45

48

51

54

57

60

Progression-free Survival by Sokal Group

n= 201 90% n= 111 83% n= 71 71%

Estimated rate at 54 months

p<0.001 } (Unknown n= 170)

} p=0.05 Low risk Intermediate risk High risk

% w

ithou

t pro

gres

sion

0 10 20 30 40 50 60 70 80 90

100

Months since randomization 0 6 12 18 24 30 36 42 48 54 60

Survival without AP/BC by Sokal Group

n= 201 96% n= 111 92% n= 71 85%

Estimated rate at 54 months

p<0.001 } (Unknown n= 170)

} p=0.12 Low risk Intermediate risk High risk

% w

ithou

t PD

to A

P/B

C

0 10 20 30 40 50 60 70 80 90

100

Months since randomization 0 6 12 18 24 30 36 42 48 54 60

Low risk Intermediate risk High risk

% a

live

0 10 20 30 40 50 60 70 80 90

100

Months since randomization 0 6 12 18 24 30 36 42 48 54 60

Overall Survival by Sokal Group

n= 201 94% n= 111 89% n= 71 81%

Estimated rate at 54 months

p<0.001 } (Unknown n= 170)

} p=0.14

SurvivalSurvival by by SokalSokal ScoreScore givengiven by by CCyRCCyR FirstlineFirstline Imatinib Imatinib

Low risk 97%Intermediate risk 92%High risk 90%

% m

onth

s

0102030405060708090

100

Months since randomization

0 3 6 9 12

15

18

21

24

27

30

33

36

39

42

45

48

51

54

57

60

CANDIDATE (PUTATIVE) BIOLOGIC PROGNOSTIC FACTORS

CANDIDATE (PUTATIVE) BIOLOGIC PROGNOSTIC FACTORS

• GENOMIC PROFILE • GENETIC

POLYMORPHISMS • WILM’S TUMOR GENE

EXPRESSION • TOTAL

PHOSPHOTYROSINE LEVEL IN CD34+ CELLS

• CrKl PHOSPHORILATION DURING TREATMENT

• 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

• 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

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