Chronic myeloid leukemia (CML): prognostic factors and survival analysis

(1)

G is e le W a lly B ra g a , M a ria d e L o u rd e s L o p e s F e rra ri C h a u ffa ille , J o s e E d u a rd o C a ja d o M o n c a u , E liz a b e th X is to S o u to , M a ria R e g in a R e g is S ilv a , J o s e K e rb a u y

C h ro n ic m y e lo id le u k e m ia (C M L ): p ro g n o stic

factors and survival analysis

Disciplina de Hematologia

e Hemoterapia,

Escola Paulista de Medicina,

Universidade Federal de sao Paulo - sao Paulo, Brazil

T h e p ro g n o s tic v a lu e o f d iffe re n t fa c to rs u p o n d ia g n o s is o f C M L w a s a n a ly s e d in 4 5 P h ila d e lp h ia (P h 1 )-p o s itiv e p a tie n ts . T h e m e d ia n s u rv iv a l w a s 4 8 m o n th s . U n iv a ria te a n a ly s is s h o w e d 5 p o o r p ro g n o s tic fa c to rs (m a le s e x , u n d e r 4 5 y e a rs -o ld , b o n e m a rro w b la s ts g re a te r th a n o r e q u a l to 1 0 p e rc e n t, b lo o d b a s o p h ils g re a te r th a n o r e q u a l to 6 p e rc e n t a n d b lo o d e o s in o p h ils g re a te r th a n o r e q u a l to 6 p e rc e n t) w h ic h p ro v id e d fo r th e d e v e lo p m e n t o f a c lin ic a l s ta g in g s y s te m : S ta g e I w ith n o n e o r o n e fa c to r a n d a tw o -y e a r s u rv iv a l ra te o f 1 0 0 p e rc e n t; S ta g e II w ith tw o o r th re e fa c to rs a n d tw o y e a r s u rv iv a l o f 7 2 .2 p e rc e n t; a n d S ta g e III w ith fo u r o r fiv e fa c to rs a n d tw o -y e a r s u rv iv a l o f 0 p e rc e n t (p = 0 .0 0 0 1 6 ). M u ltiv a ria te s u rv iv a l a n a l-y s is s h o w e d th a t c o m b in a tio n o f b lo o d b a s o p h ilia a n d b o n e m a rro w b la s ts h a d th e s tro n g e s t p re d ic tiv e re la tio n s h ip to s u rv iv a l tim e . W e c o n c lu d e th a t a c o m b in a tio n o f p re tre a tm e n t fa c to rs id e n tifie s d iffe re n t ris k s u b c a te g o rie s in C M L p a tie n ts a n d is h e lp fu l in a s s e s s in g th e o v e ra ll p ro g n o s is a n d th e tre a tm e n t a p p ro a c h .

U N IT E R M S : C h ro n ic M y e lo id L e u k e m ia . P h ila d e lp h ia C h ro m o s o m e . P ro g n o s is .

IN T R O D U C T IO N

O B J E C T IV E

T

h eth e e la b o r a tio na n a ly s is o f p r o g n o s tico f s ta g in g s y s te m sf a c to r s h a s a llo w e din o r d e r to p la nf o r f o r th e tr e a tm e n t2

.1 7 o f s e v e r a l h e m a to lo g ic d is e a s e s .

I n C M L , th e s e s tu d ie s h a v e b e e n u s e d to g u id e th e b e s t

th e r a p e u tic a p p r o a c h in e a c h c a s e , s u c h a s b o n e m a r r o w

tr a n s p la n ta tio n , w h ic h s h o u ld b e im p le m e n te d a s s o o n a s

p o s s ib le d u r in g th e c h r o n ic p h a s e in y o u n g p a tie n ts w ith a

c o m p a tib le d o n o r .

T h is s tu d y s e e k s to a n a ly z e th e p r o g n o s tic

s ig n if ic a n c e o f d if f e r e n t f e a tu r e s d e te c te d a t d ia g n o s is in

a s e r ie s o f C M L p a tie n ts f r o m a p u b lic B r a z ilia n h o s p ita l,

in o r d e r to d e te r m in e if th e p r o g n o s tic f a c to r s o f th is

p o p u la tio n w e r e d if f e r e n t f r o m w e ll- e s ta b lis h e d f a c to r s

d e te c te d in s tu d ie s p e r f o r m e d in o th e r c o u n tr ie s .

M A T E R IA L A N D M E T H O D S

A d d re s s fo r c o rre s p o n d e n c e : G is e le W a lly B ra g a

E s c o la P a u lis ta d e M e d ic in a - U n iv e rs id a d e F e d e ra l d e S P

R u a B o tu c a tu , 7 4 0 -39_{a n d a r}

S a o P a u lo /S P - B ra s il - C E P 0 4 0 2 3 -0 6 2

W e a r e r e p o r tin g o n th e a n a ly s is o f 4 5 a d u lt P h 1

-p o s itiv e C M L p a tie n ts in th e c h r o n ic p h a s e w h o w e r e

a d m itte d to o u r h o s p ita l b e tw e e n S e p te m b e r 1 9 7 7 a n d

B R A G A , G .w .; C H A U F F A IL L E , M .D .D .F .; M O N C A U , J .E .C . e t a l. - C h ro n ic m y e lo id le u k e m ia (C M L ): p ro g n o s tic fa c to rs a n d s u rv iv a l a n a ly s is

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•

192

M O N T H S

160

1 2 8

9 6

64 There were 25 (55.6 percent)

m ales and 20 (44.4

percent) fem ales. The m edian age was 42 (ranging

from

15-77). There were 25 (55.6 percent)

white patients,

18 (40.0 percent) were black, and 2 (4.4 percent) were Asian.

The m edian survival was 48 m onths (Fig.

I ) .

At the tim e

the analysis was conducted in M ay 1993, 15 (33.4 percent)

patients had died, 23 (51.1 percent) were alive and 7 (15.5

percent)

had discontinued

follow-up

som e

tim e

after

diagnosis. Of the 23 living patients,

18 (78.3 percent) were

in the chronic phase, 3 (13.0 percent)

in the accelerated

phase, and 2 (8.7 percent) were alive after blastic phase.

R E S U L T S

Kaplan

and M eyer's

m ethod

'2.

Different

curves

were

statistically

com pared

using the Cox-M antel

(log rank)

or the generalized

W ,ilcoxon Test

1 3

•

The staging

system

was derived from univariate

analysis

using the variables

associated

with bad prognosis.

Thus,

the low-risk

or

Stage

I group

consisted

of patients

with

zero or one

factor; the interm ediate-risk

group or Stage II consisted

of 2 or 3 factors and the high-risk

group, 4 or 5 factors.

Using

the Cox m odel

4

,

we perform ed

a m ultivariate

analysis

of all

variables

previously

selected

by

univariate

analysis,

which

were then put into a single

equation

to determ ine

the

variable~

which

were

prim arily

im portant

to prognosis

and those which were

only secondary

factors.

F ig u r e 1 - G e n e r a l s u r v iv a l o f 4 5 C M L P h 1 - p o s it iv e p a t ie n t s .

32 o

o

60

4 0

20

80

100 January

1993. The follow-up

period

varied

from

1 to

184 m onths.

There were 7 (15.5 percent)

patients

with

a follow-up

of less than 1 year, and 3 (6.7 percent)

with

less than 6 m onths.

The diagnosis

of CM L was based

on conventional

criteria.

The karyot~pe

was evaluated

by usual

m ethods

with

G banding

and

classified

according

to ISCN

(1985,

1991). The characterization

of blast

crisis

was

m ade

from

the analysis

of bone

m arrow

aspiration

(m ore than 30 percent of blasts), and

the type of crisis was determ ined

by cytochem istry

and

im m unophenotyping

m ethods.

Patients

in the chronic

or accelerated

phase

were

treated

with

busulfan

or

hydroxyurea.

Lym phoid

blast crisis

was treated

with

vincristine,

daunorubicin

and prednisone,

and m yeloid

blast crisis with daunorubicin

and cytosine

arabinoside,

until

patients

returned

to the

chronic

phase

when

busulfan

or hydroxyurea

was restarted.

At diagnosis,

the following

clinical

and

hem atological

data

were

recorded

and evaluated

for prognosis:

1) age, sex, race,

spleen

and

liver

size;

2) peripheral

blood

features:

hem oglobin

concentration

(Hb), platelet

counts,

white

blood cell counts

(W BC)

with differential

counts;

and

blood

erythroblast

percentage;

3) bone

m arrow

aspiration

features:

blast cells percentage

and m yeloid/

erythroid

(M /E) ratio; 4) bone m arrow

biopsy features:

granulocytic

proliferation

(Gran)

or granulocytic

plus

m egakaryocytic

proliferation

(Gran/M eg),

eosinophilia,

presence

of blast

cells,

fibrosis

and m egakaryocyte

m orphology

10.

For patients

who discontinued

follow-up som etim e

during

this study, the survival

period was

defined

as the date when the patient

was last seen; for

patients

who died,

the survival

period

was defined

as the date

of death;

for patients

who were

alive in M ay

1993, the survival

period was considered

to be until

that date.

For univariate

analysis,

the

cut-off level of each quantitative

variable

was established

based

on those com m only

found in the

literature

data.

In som e

cases,

this was established

by chance,

until "p" values

near 5 percent

were

found.

The

different

of

qualitative

~

variables,

such as sex, race and

0

bone

m arrow

histology,

were

com pared

to

each

other.

Actuarial

survival

probability

curves were plotted

according

to

S a o P a u lo M e d ic a l J o u r n a l/ R P M 1 1 4 ( 1 ) : 1 0 8 3 - 1 0 9 0 , 1 9 9 6 B R A G A , G . w . ; C H A U F F A I L L E , M . D . D . F . ; M O N C A U , J . E . C . e t a l. - C h r o n ic m y e lo id

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O BS: N = num ber of patients; * = pO .O S; H b = hem oglobin; BM = bone m arrow ; M /E = m yeloid/erythroid

Table 1

R esults of the univariate analysis

BM BLASTS

Factor N

SEX m ale

fem ale

AG E <45 yr

>=45yr

<60 yr

>=60yr

R AC E w hite

black

SPLEEN O -10 cm

> 10 cm

LIVER norm al

enlarged

H b(FEM ALE) < 12g%

>=12g%

H b(M ALE) < 13g%

>=13g%

W BC < 1O O X 109/1

>=100X109/1

PLATELET < 400X1 09_/1

>=400X109_/1

150<x<500X109 /1

<150 or >500

ER YTH R O BLASTS 0%

>0%

PER IPH ER AL BLASTS 0 - 1

> 1 <5% >=5% <10% >=10% < 10% >=10%

BLO O D BASO PH ILS < 6%

>=6%

BLO O D EO SIN O PH ILS < 6%

>=6%

M /E R ATIO <20

>=20

<30

>=30

BM G R AN

G R AN /M EG

FIBR O SIS 0/+

++/+++ P 2 5

20

2 4 2 1 3 3 1 2 2 5 18 1 9

23

1 7

26

1 5 0 4 2 3

00

1 6

26

2 7 14 1 1 3 0 34 1 1 2 2 2 0 3 5 07 4 0 02 3 8 0 2

32

1 2

32

1 0 1 7 1 5 2 2 1 0 12 1 6

09

19 0.04664* 0.00783* 0.26745 0.73522 0.07330 0.52875 0.63783 0.39870 0.15681 0.88121 0.39574 0.56602 0.77335 0.27416 0.00121' 0.00010' 0.02938' 0.70445 0.64397 0.74759 0.42116

A m o n g s t a ll th e p a tie n ts , th e n u m b e r o f b la s t c ris e s w a s

1 6 , w ith 2 (1 2 .5 p e rc e n t) p a tie n ts s till a liv e a n d 1 4 (8 7 .5

p e rc e n t) d e a d . T h e re w e re 6 (3 7 .5 p e rc e n t) ly m p h o id b la s t

c ris e s , 9 (5 6 .3 p e rc e n t) m y e lo id b la s t c ris e s a n d I (6 .2

p e rc e n t) u n c la s s ifie d . T h e m e a n s u rv iv a l o f a ll b la s t c ris e s

w a s 4 .5 m o n th s , w ith 6 .2 m o n th s fo r ly m p h o id a n d 4 .1

m o n th s fo r m y e lo id , b u t th is d iffe re n c e w a s n o t s ig n ific a n t

(p

=

0 .2 2 2 8 5 ). D e a th w a s d u e to b la s tic tra n s fo rm a tio n in

1 4 (9 3 .3 p e rc e n t) c a s e s , a n d in 1 p a tie n t (6 .7 p e rc e n t), to

o th e r c o m p lic a tio n s . T h e u n iv a ria te a n a ly s is d e m o n s tra te d

5 v a ria b le s th a t s e e m e d to b e a s s o c ia te d w ith p o o r

p ro g n o s is (p

<

0 .0 5 ): m a le s e x (p = 0 .0 4 6 6 4 ), a g e d

<

4 5 (p

=

0 .0 0 7 8 3 ); b o n e m a rro w b la s ts g re a te r th a n o r e q u a l

to 1 0 p e rc e n t (p

=

0 .0 0 1 2 l); b lo o d b a s o p h ils g re a te r th a n

o r e q u a l to 6 p e rc e n t (p

=

0 .0 0 0 1 0 ); a n d b lo o d e o s in o p h i Is

g re a te r th a n o r e q u a l to 6 p e rc e n t (p

=

0 .0 2 9 3 8 ). T h e o th e r

v a ria b le s , s u c h a s s p le e n s iz e , liv e r s iz e , h e m o g lo b in le v e l,

w h ite b lo o d c e ll c o u n ts , p la te le t c o u n ts , p e rip h e ra l b la s ts ,

c irc u la tin g e ry th ro b la s ts , M /E ra tio a n d b o n e m a rro w

fe a tu re s (G ra n o r G ra n /M e g a n d fib ro s is ), w e re n o t

s ta tis tic a lly s ig n ific a n t a t th e d iffe re n t c u t-o ff le v e ls te s te d

(T a b le 1 ).

T h e s ta g in g s y s te m , d e riv e d fro m th e u n iv a ria te

a n a ly s is , p e rm itte d th e p o p u la tio n to b e d iv id e d in to 3

g ro u p s : S ta g e I w ith 1 9 (4 2 .2 p e rc e n t) p a tie n ts , S ta g e II

w ith 1 6 (3 5 .5 p e rc e n t) a n d S ta g e IIIw ith 4 (8 .8 p e rc e n t). S ix (1 3 .3 p e rc e n t) p a tie n ts w e re e x c lu d e d d u e to la c k o f

d a ta o n o n e o r m o re s e le c te d v a ria b le s . T h e d e a th ra te

w a s 0 .0 p e rc e n t (0 /l9 ) fo r S ta g e 1 ,3 7 .5 p e rc e n t (6 /1 6 ) fo r

S ta g e II,a n d 7 5 .5 p e rc e n t (3 /4 ) fo r S ta g e III,a n d th is d iffe re n c e w a s s ig n ific a n t (p

=

0 .0 0 0 1 6 ) (F ig . 2 ).

M u ltiv a ria te a n a ly s is w a s p e rfo rm e d o n 3 8 p a tie n ts w h o

h a d d a ta fo r 5 v a ria b le s s e le c te d b y u n iv a ria te a n a ly s is

a n d 4 v a ria b le s o f p ro g n o s tic im p o rta n c e (h e m o g lo b in ,

s p le e n , p la te le t c o u n ts a n d p e rip h e ra l b la s t c e lls ). O n ly

tw o v a ria b le s w e re id e n tifie d a s p rim a rily im p o rta n t fo r

p ro g n o s is : b lo o d b a s o p h ils (p

=

0 .0 0 4 ) a n d b o n e m a rro w

b la s ts (p

=

0 .0 4 2 ). T h e e q u a tio n d e riv e d fro m m u ltiv a ria te

a n a ly s is w a s :

R R = E X P { 0 .2 9 3 6 (B M B L - 2 .5 8 )

+

0 .2 6 4 7

(P B B A S O - 4 .2 1 )}

R R = relative risk; BM BL = % bone m arrow blasts; PB BASO =

% peripheral blood basophils; 2.58 = m ean of bone m arrow blasts

(% ); 4.21 = m ean of blood basophils (% ).

U s in g th is a n a ly s is , p a tie n ts w e re d iv id e d in to 3

g ro u p s : lo w re la tiv e ris k (R R )

«

1 .0 ); in te rm e d ia te R R

(1 .0 to 1 0 .0 ); a n d h ig h R R (> 1 0 .0 . T h e W ilc o x o n te s t

s h o w e d th a t th e re w a s a s ig n ific a n t d iffe re n c e o f s u rv iv a l

BR AG A, G .w .; C H AU FFAILLE, M .D .D .F.; M O N C AU , J.E.C . et al. - C hronic m yeloid

leukem ia (C M L): prognostic factors and survival analysis

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1 9 2

lo w

M O N T H S

1 6 0 1 2 8

9 6

I in te rm e d ia te

6 4

32

h ig h

1 9 2

im p o rta n t, b e c a u s e p a tie n ts u n d e r 4 5 y e a rs -o ld a re th o s e re fe rre d fo r b o n e m a rro w tra n s p la n ta tio n . U n fo rtu n a te ly , th e m u ltiv a ria te a n a ly s is d id n o t c o n firm a g e a s a n im p o rta n t p ro g n o s tic fa c to r, p e rh a p s d u e to th e s m a ll n u m b e r o f p a tie n ts in th is s tu d y . A s d e s c rib e d b y o th e rs 2 .1 0 .1 1 , b o n e m a rro w b la s ts o f 1 0 p e rc e n t o r m o re w a s a n o th e r fin d in g n e g a tiv e ly re la te d to s u rv iv a l in o u r p o p u la tio n (p

=

0 .0 0 1 2 1 ) , w h ic h m ig h t b e a s s o c ia te d w ith a n e a rly a c c e le ra te d p h a s e . M a rk e d p e rip h e ra l b a s o p h ilia a t d ia g n o s is w a s d e s c rib e d a s a p o o r p ro g n o s tic fa c to rs .,o .'1 .'9 , a n d w a s a n o th e r s ig n ific a n t

n e g a tiv e fa c to r in o u r s tu d y ( 6 p e rc e n t o r m o re ) (p

=

0 .0 0 0 I 0 ) . A lo n g th e s a m e lin e , e o s in o p h ilia w h ic h is o r is n o t a s s o c ia te d w ith b a s o p h ilia h a s b e e n re la te d to a b a d p ro g n o s is s .'7 .'s , a s s h o w n in th is re p o rt (p = 0 .0 2 9 3 8 ) . O th e r fa c to rs te s te d in th is s tu d y s u c h a s s p le e n a n d liv e r s iz e , w h ite b lo o d c e ll c o u n ts , p la te le t c o u n ts , p e rip h e ra l b la s t c e lls , b lo o d e ry th ro b la s ts , M /E ra tio a n d b o n e m a rro w a s p e c ts (G ra n o r G ra n /M e g a n d fib ro s is ) d id n o t s ig n ific a n tly a ffe c t th e p ro g n o s is in o u r p o p u la tio n . S o m e a u th o rs h a v e d e s c rib e d e n la rg e d s p le e n 2 .,o .'I.'lU O o r liv e r2 .

'1 .2 0 , lo w h e m o g lo b in 1 0 .1 1 ,in c re a s e d le u k o c y te c o u n ts S .1 9 , lo w o r h ig h p la te le t c o u n ts IO .II.2 0 , h ig h p e rc e n ta g e s o f b la s ts in p e rip h e ra l b lo o d s .

'l

I.2 O , p re s e n c e o f e ry th ro b la s ts in p e rip h e ra l b lo o d 2 .'7 , h ig h la c tic d e h id ro g e n a s e le v e ls .1 7 , h ig h u ric a c id a n d a n in c re a s e d M /E ra tio S a s u n fa v o ra b le fa c to rs a t d ia g n o s is . S a K A L e t a l.ls re p o rte d a n a c tu a ria l d e a th ra te o f 5 -1 0 p e rc e n t in

M O N T H S s ta g e I

o o

100

160

Figure 3 -S u rv iv a l o f p a tie n ts w ith lo w , in te rm e d ia te a n d h ig h re la tiv e

ris k (R R ), a c c o rd in g to th e e q u a tio n d e riv e d fro m m u ltiv a ria te a n a ly s is (p =0 .0 0 0 0 0 ) .

128

9 6

s ta g e II

6 4

32

100

...J

~

80

~ ::>

(J)

60

W

>

~

40

::> ~ ::>

20

0

~0

0

0 D IS C U S S IO N

in th e 3 g ro u p s (p

=

0 .0 0 0 0 0 ) (F ig . 3 ) . T h e a c tu a ria l d e a th ra te ; 5 .1 p e rc e n t d u rin g th e firs t y e a r a fte r d ig n o s is , 1 8 .1 p e rc e n t d u rin g th e s e c o n d , 2 3 .1 p e rc e n t d u rin g th e th ird , a n d 1 8 .2 p e rc e n t d u rin g th e fo u rth , a c h ie v e d a " p la te a u " a fte r th e fifth y e a r.

Figure 2 -A c tu a ria l s u rv iv a l p ro b a b ility c u rv e s o f S ta g e s 1 ,'1 1a n d III, a c c o rd in g to th e p ro p o s e d s ta g in g s y s te m (p =0 .0 0 0 1 6 ) .

T h e fa ta l o u tc o m e o f C M L h a s s tim u la te d th e a n a ly s is o f p ro g n o s tic fa c to rs . H o w e v e r, b e s id e s th e a b s e n c e o f th e P h 1 c h ro m o s o m e , w h ic h le a d s to a ra p id e v o lu tio n to th e b la s tic p h a s e 2 .6 .S .IO .1 7 .IS ,th e re is n o a g re e m e n t a s to th e

p ro g n o s tic im p o rta n c e o f th e m a n y d iffe re n t fe a tu re s a t d ia g n o s is .

T h e m e d ia n a g e o f 4 2 in th is s tu d y w a s lo w e r th a n e x p e c te d 's . T h e m e d ia n s u rv iv a l o f ~ 4 8 m o n th s w a s in a c c o rd a n c e w ith o th e r 8 0

a u th o rs 2 .S .IO .1 6 .T h e re w a s n o d iffe re n c e b e tw e e n ~

s u rv iv a l a n d d e a th ra te s a fte r th e o n s e t o f b la s t ~ 6 0

c ris e s , a lth o u g h ly m p h o id b la s t c ris e s s e e m e d ~ to b e m o re re s p o n s i v e to c o n v e n tio n a l ~ 4 0

c h e m o th e ra p y 9 . M a le s e x , a s d e s c rib e d b y o th e r .J

a u th o rs Ill.1 7 , a n d a g e u n d e r 4 5 w e re a s s o c ia te d ~

w ith a n u n fa v o ra b le p ro g n o s is (p = ,0 .0 4 6 6 4 a n d ~ 2 0

0 .0 0 7 8 3 , re s p e c tiv e ly ) in o u r s tu d y . In a ~ o w o rld w id e m u ltic e n tric s tu d y , S a K A L e t a l.ls d e s c rib e d a g e a s a fa c to r w ith a p ro g re s s iv e ly u n fa v o ra b le p ro g n o s is a t h ig h e r v a lu e s :

T h e re fo re , th is is th e firs t s ig n ific a n t d iffe re n c e b e tw e e n o u r p o p u la tio n a n d o th e rs p re v io u s ly s tu d ie d . T h is a s p e c t s e e m s h ig h ly

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T a b le 2

N u m b e r, in itia ls , s e x , a g e (in y e a rs ), ra c e , s p le e n s iz e (le ft rib e d g e , in c e n tim e te rs ), liv e r s iz e (rig h t rib e d g e , in

c e n tim e te rs ), %o f h e m o g lo b in (H b ), n u m b e r o f w h ite b lo o d c e lls (W B C ) p e r c u b ic m illim e te r, p la te le ts (p e r c u b ic

m illim e te r) a n d e ry th ro b la s ts (E ry th ro ) in th e p e rip h e ra l b lo o d o f th e 4 5 p a tie n ts .

0

24

L A S M

36

W

20

4

IG N IG N IG N

0

25

L C N F M

31

B

10

2

13 122000

260000

1

26

L R P M

25

W

16

4

11 80000

470000

1

27

M S A M

27

W

23

4

7 280000

200000

0

28

M R C M

21

W

18

4

9 192000

500000

0

29

M A C A F

46

B

5

4

11 13500

1000000

2

30

M L N H F

58

W

10

0

11 180900

350000

0

31

M H S F

51

W

3

77

A

4

11 58300

110000

0

40

M S S F

65

B

20

0

10 142000

160000

6

41

M C C F

42

B

0

12 80000

240000

0

42

L G N S M

27

B

10

0

10 348000

190000

0

43

J F S F

64

B IG N

12

16 100000

450000

0

44

E G F R F

34

B IG N IG N IG N IG N IG N

0

45

J F C M

47

B

30

8

7 700000

550000

0

L e g e n d : M = M a le ; F = F e m a le ; W = W h ite ; B = B la c k ; A = A s ia n ; IG N = ig n o re d

~~::;$;:::;;m:m:tm*;w:m.;;m:m::x«~m::::.~::::::~:::.-:::::.:&:~..mm::;:m:;;:~::::::::~.:»'t:t.::-::::::;'1-:'$;w..;,::.««::..:m::»x:»»::,~~m:*~:~--::~:::..-::::mx::z:-::~:::~;~:~..m:::::w~~:~*;::t ..~x:;:~;~:X.W....:.:WN:-'.«:»:•••~:::;::'::z:r.~:r::~~~~~;~:;:-:$X$w«::**:m.;:-x:;:xw:::.~~::::~:m-.:::m

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T a b le 3

P a tie n t n u m b e r ( N ) , % o f b la s ts ( B L A S T ) , p r o m y e lo c y te ( P M ) a n d m y e lo c y te ( M ) in th e p e r ip h e r a l b lo o d , % o f b la s ts in

th e b o n e m a r r o w ( B M B ) , % o f e o s in o p h ils ( E O S I) a n d b a s o p h ils ( B A S O ) in th e p e r ip h e r a l b lo o d , b o n e m a r r o w M /E

r a tio ( M lE ) , o v e r a ll s u r v iv a l ( O S ) in m o n th s , p o s t b la s t c r is is s u r v iv a l ( P B C S ) in m o n th s , b o n e m a r r o w b io p s y

c la s s ific a tio n ( B M C ) , d e g r e e o f fib r o s is in b o n e m a r r o w ( F IB R O ) , s c o r e ( S C O R E ) a n d r e la tiv e r is k ( R R )

N Q B L A S T P M M B M B E O S I B A S O M /E O S P B C S B M C F IB R O S C O R E R R

1 0 0 0 7 2 0 IG N 1 0 N C IG N IG N II 1 ,2 0

2 0 3 0 5 2 7 4 1 0 2 7 N C G + II 1 ,9 3

3 2 1 3 5 6 7 1 3 3 6 4 G + M + + II 4 ,2 7

4 4 5 1 5 3 1 8 7 5 3 1 1 0 G + M + + + II 3 ,0 9

5 2 0 2 9 0 0 0 8 1 3 N C G + M + + II 0 ,1 5

6 4 0 9 0 2 2 1 2 1 3 N C G + I 0 ,2 6

7 4 8 4 0 5 0 IG N 3 0 N C IG N IG N I 0 ,1 5

8 2 5 1 6 0 5 3 IG N 1 2 N C G + M + + I 0 ,3 4

9 2 2 2 0 0 3 4 5 1 6 N C G + M + I 0 ,4 4

1 0 5 3 4 0 1 1 3 IG N 4 8 N C G 0 I 0 ,4 6

1 1 3 5 5 1 4 0 1 9 3 9 N C G + + I 0 ,2 1

1 2 5 1 4 1 5 1 4 4 1 3 9 7 N C G + M + I 0 ,6 0

1 3 1 4 2 9 3 0 5 7 0 1 1 5 9 3 G 0 II 0 ,6 7

1 4 5 6 3 0 IG N 4 2 IG N 1 N C IG N IG N IG N IG N

1 5 0 0 0 2 4 0 1 0 3 3 8 IG N IG N II 0 ,2 8

1 6 1 8 1 2 0 3 7 9 2 4 N C IG N IG N II 0 ,9 8

1 7 0 6 6 IG N 0 0 IG N 4 8 N C IG N IG N IG N IG N

1 8 2 8 2 5 3 1 2 1 0 0 3 5 N C G + M + + + I 0 ,6 3

1 9 8 1 2 1 2 7 3 1 1 2 4 4 G + + III IG N

2 0 0 5 1 3 1 0 3 1 0 9 1 0 1 IG N IG N III 4 1 ,0 0

2 1 2 1 3 0 2 1 0 6 3 4 3 G + M + + + II 2 ,1 0

2 2 5 2 4 5 5 1 2 3 0 1 0 5 G + + II 1 6 ,0 0

2 3 0 0 0 1 2 2 4 5 0 1 3 N C G + M + + II 0 ,6 0

2 4 IG N IG N IG N IG N IG N IG N IG N 1 8 7 IG N IG N IG N IG N

2 5 0 0 0 1 0 1 IG N 1 1 N C G + II 0 ,2 0

2 6 0 0 6 0 8 1 0 3 2 1 6 4 G + M + III 2 ,1 0

2 7 0 2 5 3 0 2 1 2 6 5 5 1 4 N C G + III 1 5 0 ,3 0

2 8 0 0 2 1 7 0 2 3 1 5 N C G + M + + II 0 ,2 0

2 9 0 0 1 1 1 5 IG N 6 6 N C G + M + + + I 0 ,7 0

3 0 0 4 6 1 0 0 3 9 3 5 N C G + M + + I 0 ,2 0

3 1 0 0 7 0 1 1 1 8 1 8 N C IG N IG N

,

0 ,2 0

3 2 2 0 5 IG N 1 8 IG N 3 3 1 IG N IG N IG N IG N

3 3 0 1 1 0 2 2 IG N 7 3 N C IG N IG N I 0 ,2 0

3 4 0 1 2 0 4 4 6 1 8 4 N C IG N IG N I 0 ,4 4

3 5 1 1 8 8 4 0 2 1 7 8 N C G + M + + I 1 ,6 2

3 6 4 2 3 2 8 6 2 0 1 9 1 G + + + II 1 ,3 6

3 7 IG N IG N IG N IG N IG N IG N IG N 4 2 1 IG N IG N IG N IG N

3 8 4 1 0 9 5 1 1 1 1 3 1 1 7 6 IG N IG N II 1 2 ,3 8

3 9 2 0 3 3 0 2 4 8 6 8 N C G + + I 0 ,6 3

. 4 0 ₀ ₀ ₁ ₂ ₄ ₀ _{2 4} ₇ _{N C} _G

+ + I 0 ,2 8

4 1 0 0 2 1 3 1 2 2 5 N C IG N IG N I 0 ,2 7

4 2 0 5 1 4 6 4 1 IG N 5 N C G + M + + + II 1 ,1 7

4 3 0 0 0 0 2 0 1 7 7 N C G + M + + + I 0 ,1 5

4 4 IG N 0 0 7 IG N IG N 3 6 6 4 1 0 IG N IG N IG N IG N

4 5 0 0 0 4 4 1 4 1 0 9 N C IG N IG N II 2 0 ,3 1

L e g e n d : N C = N o b la s tic c r is is ; IG N = Ig n o r e d

m '«=»:~*«-:«-'h::",)"<::,,,),~W -:«-:H :::::::::m ~;:::m *t"":-::r:::~~~~~~~:;::-,~-=:::~~::: •••*=*:::~~$::.:~% ;-r& .:::::::t::~m ::::::m .::::::r.:::::~*,-::,~.m ::::::~~:m ».~~w ;::::.sr::::::;:::~':::::;*:::;;:$m =*::t.~*m m m :::::.:::.;::W .::::::;"~~~~~:~s:-'~~:m ;:.~:::$;W -::=% ':«:~~W .:::t::::m ::::::m

S a o P a u lo M e d ic a l J o u r n a l/R P M 1 1 4 ( 1 ) : 1 0 8 3 - 1 0 9 0 , 1 9 9 6 B R A G A , G .w .; C H A U F F A IL L E , M .D .D .F .; M O N C A U , J .E .C . e t a l. - C h r o n ic m y e lo id

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a Ph I-positive population during the first year after diagnosis, and 23-28 percent per year during the third to . the fifth year. In another study20, the rates w ere 5 percent

during the first year after diagnosis, 12 percent during the second and 22,5 percent per year during the next eight years. O ur data is com patible: 5.1 percent in the first year, 18.1 percent in the second, 23.1 percent in the third, 18.2 percent in the fourth, and a "plateau" after the fifth year. T he staging system proposed here perm its our population to be divided into three distinct groups: low , interm ediate and high risk, w ith significant differences betw een m ean survi vals and death rates. A long the sam e line, the m ultivariate analysis perm itted the population to be divided into 3 groups (low , interm ediate and high risk groups) w ith significant difference in survival (p

=

0.00000) w hich w e believe is m ore accurate than the

proposed staging system , w hich provides an equation that only includes prognostic factors w ith prim ary im portance.

C O N C L U S IO N S

W e conclude that there is the possibility of identifying som e high-risk factors in a C M L population w ith the aim of recognizing patients at a high risk of acceleration so as to schedule bone m arrow transplantation as soon as possible. Further studies should be carried out in order to identify other poor prognostic factors in the C M L B razilian population, and to investigate the reason for high death rates am ong younger patients.

RESUMO

A v a lia m o s 0 v a lo r p r o g n 6 s tic o d e d ife r e n te s fa to r e s , a o d ia g n 6 s tic o , e m 4 5 p a c ie n te s c o m L M C P h 1 - p o s itiv o s . A s o b r e v id a m e d ia n a fo i d e 4 8 m e s e s . A a n a lis e u n iv a r ia d a id e n tific o u 5 fa to r e s a s s o c i a d o s a p io r p r o g n 6 s tic o ( s e x o m a s c u lin o , id a d e in fe r io r a 4 5 a n o s , b la s to s n a m e d u la 6 s s e a m a io r o u ig u a l a 1 0 p e r c e n t, b a s 6 filo s n o s a n g u e p e r ife r ic o m a io r o u ig u a l a 6 p e r c e n t e e o s in 6 filo s n o s a n g u e p e r ife r ic o m a io r o u ig u a l a 6 p e r c e n t) , o r ig in a n d o u m s is te m a d e e s ta d ia m e n to : e s ta g io I c o m

z e r o o u u m fa to r e s o b r e v id a d e 1 0 0 p e r c e n t e m d o is a n o s ; e s ta g io II c o m d o is o u tr e s fa to r e s e s o b r e v id a d e 7 2 ,2 p e r c e n t e m d o is a n o s ; e s ta g io I I I c o m 4 o u 5 fa to r e s e s o b r e v id a d e 0 p e r c e n t e m d o is a n o s ( p = 0 .0 0 0 1 6 ) . A a n a lis e m u ltiv a r ia d a d e m o n s tr o u

q u e a b a s o filia n o s a n g u e p e r ife r ic o e o s b la s to s n a m e d u la 6 s s e a fo r a m o s fa to r e s q u e m e lh o r s e c o r r e la c io n a r a m c o m 0 te m p o d e s o b r e v id a . C o n c lu fm o s q u e a c o m b in a y 6 0 d e fa to r e s p r e s e n te s n o d ia g n 6 s tic o p e r m ite a id e n tific a y a o d e d ife r e n te s g r u p o s d e r is c o n a L M C , p o d e n d o s e r u til n a d e te r m in a y 6 0 d o p r o g n 6 s tic o e n a a b o r d a g e m te r a p e u tic a .

. R E F E R E N C E S

I. A lim e n a G , M o r r a E , L a z z a r in o M , e t a l. In te r fe r o n a lfa

-2 b a s th e r a p y fo r p a tie n ts w ith P h I- p o s itiv e c h r o n ic

m y e lo g e n o u s le u k e m ia . E u r J H a e m a to l 1 9 9 0 ;

4 5 ( 5 2 ) :2 5 - 8 .

2 . C e r v a n te s F , R o z m a n C . A m u ltiv a r ia te a n a ly s is o f

p r o g n o s tic fa c to r s in c h r o n ic m y e lo id le u k e m ia . B lo o d

1 9 8 2 ;6 0 : 1 2 9 8 - 1 3 0 4 .

3 . C h a m p lin R E , G o ld e D W . C h r o n ic m y e lo id le u k e m ia :

r e c e n t a d v a n c e s . B lo o d 1 9 8 5 ;6 5 ( 5 ) :1 0 3 9 - 1 0 4 7 .

4 . C o x R D . R e g r e s s io n m o d e ls a n d life - ta b le s . J R S ta t S o c B

1 9 8 2 ;3 4 : 1 8 7 - 2 0 2 .

5 . E z d in li E Z , S o k a l J E , C r o s s w h ite B S , S a n d b e r g A A .

P h ila d e lp h ia - c h r o m o s o m e - p o s itiv e a n d - n e g a tiv e

c h r o n ic m y e lo c y tic le u k e m ia . A n n In t M e d 1 9 7 0 ;

7 ( 2 ) : 1 7 5 - 1 8 2 .

6 . F itz g e r a ld P H , B e a r d E J , M o r r is C M , H e a to n D C , R e e v e

A E . P h - n e g a tiv e c h r o n ic m y e lo id le u k e m ia . B r J H a e m a to l

1 9 8 7 ;6 6 :3 1 1 - 4 .

7 . F r is c h B , B a r tl R , B u r k h a r d t R , J a g e r K , M a h l G , K e ttn e r

G . C la s s ific a tio n o f m y e lo p r o life r a tiv e d is o r d e r s b y b o n e

m a r r o w h is to lo g y . B ib lth c a H a e m a t 1 9 8 4 ;5 0 :5 7 - 8 0 .

B R A G A , G .w .; C H A U F F A IL L E , M .D .D .F .; M O N C A U , J .E .C . e t a l. - C h r o n ic m y e lo id le u k e m ia ( C M L ) : p r o g n o s tic fa c to r s a n d s u r v iv a l a n a ly s is

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8 . G o m e z A , S o k a l JE , W a lsh D . P ro g n o stic fe a tu re s a t d ia g n o sis o f c h ro n ic m y e lo c y tic le u k e m ia . C a n c e r

1 9 8 1 ;4 7 :2 4 7 0 -7 .

9 . Ja n o ssy G , W o o d ru ff R K , P ip p a rd M J, e t a l. R e la tio n o f ly m p h o id p h e n o ty p e a n d re sp o n se to c h e m o th e ra p y in c o rp o ra tin g v in c ristin e -p re d n iso lo n e in th e a c u te p h a se o f C M L P h I-p o siti v e le u k e m ia . C a n c e r 1 9 8 9 ;4 3 :4 2 6 -4 3 4 .

1 0 . Jo o ta r S , O n g p h ip h a p h a d h a n a k u l B , C h u n c h a ru n e e S , A tic h a rta k a rn V . M u ltiv a ria te a n a ly sis o f p ro g n o stic fa c to rs in c h ro n ic m y e lo id le u k e m ia . J M e d A sso c T h a i

1 9 9 0 ;7 3 ( 1 2 ):6 6 2 -9 .

1 1 . K a n ta rjia n M H , S m ith T L , M c C re d ie K B , e t a l. C h ro n ic m y e lo g e n o u s le u k e m ia : a m u ltiv a ria te a n a ly sis o f th e a sso c ia tio n s o f p a tie n t c h a ra c te ristic s a n d th e ra p y w ith su rv iv a l. B lo o d 1 9 8 5 ;6 6 (6 ): 1 3 2 6 -1 3 3 5 .

1 2 . K a p la n G L , M e ie r P . N o n p a ra m e tric e stim a tio n fro m in c o m p le te o b se rv a tio n s. J A m S ta t A sso c 1 9 5 8 ; 5 3 :4 5 7 -4 8 1 .

1 3 . L e e E T . S ta tistic a l m e th o d s fo r su rv iv a l d a ta a n a ly sis. L ife tim e L e a rn in g P u b lic a tio n . B e lm o n t:P u b lic a tio n L ife tim e L e a rn in g , 1 9 8 0 :5 5 1 .

1 4 . R o w le y JD . T h e P h ila d e lp h ia c h ro m o so m e tra n slo c a tio n : a p a ra d ig m fo r u n d e rsta n d in g le u k e m ia . C a n c e r 1 9 9 0 ;6 5 ( I 0 ):2 1 7 8 -2 1 8 4 .

1 5 . S ilv e r R T . C h ro n ic m y e lo id le u k e m ia : a p e rsp e c tiv e o f th e c lin ic a l a n d b io lo g ic issu e s o f th e c h ro n ic p h a se . H a e m a to l/ O n c o l. C lin N A m 1 9 9 0 ;4 (2 ):3 1 9 -3 3 5 .

1 6 . S jo g re n U , B ra n d t L , M ie ltm a n F . R e la tio n b e tw e e n life e x p e c ta n c y a n d c o m p o sitio n o f th e b o n e m a rro w a t d ia g n o sis o f c h ro n ic m y e lo id le u k e m ia . S c a n d J H a e m a to l

1 9 7 4 ; 1 2 :3 6 9 -3 7 3 .

1 7 . S o k a l JE , B a c c a ra n i M , T u ra S , e t a l. P ro g n o stic d isc rim in a tio n a m o n g y o u n g e r p a tie n ts w ith c h ro n ic g ra n u lo c y tic le u k e m ia : re le v a n c e o f b o n e m a rro w tra n sp la n ta tio n . B lo o d 1 9 8 5 ;6 6 (6 ): 1 3 5 2 -7 .

1 8 . S o k a l JE , C o x E B , B a c c a ra n i M , e t a l. a n d th e Ita lia n C o o p e ra tiv e C M L S tu d y G ro u p . P ro g n o stic d isc rim in a tio n in " g o o d risk " c h ro n ic g ra n u lo c y tic le u k e m ia . B lo o d 1 9 8 4 ;6 3 (4 ):7 8 9 -7 9 9 .

1 9 . T h e o lo g id e s A . U n fa v o ra b le sig n s in p a tie n ts w ith c h ro n ic m y e lo id le u k e m ia . A n n In t M e d 7 6 :9 5 -9 .

2 0 . T u ra S , B a c c a ra n i M , C o rb e lli, G a n d th e Ita lia n C o o p e ra tiv e S tu d y G ro u p O n C h ro n ic M y e lo id L e u k e m ia . S ta g in g o f c h ro n ic m y e lo id le u k e m ia . B r J H a e m a to l 1 9 8 1 ;4 7 : 1 0 5 -1 1 9 .