RICHTER'S SYNDROM E IN PATIENTS W ITH CHRONIC LYMPHOCYTIC LEUKEMIA
Ahm et Toprak* / Siret Ratip** / Tülin Budak Alpdoğan**
Ö nder Alpdoğan** / Sevgi Küllü*** / M ahm ut Bayık**
* M .D ., D e p a rtm e n t o f In te rn a l M e d ic in e , S c h o o l o f M e d ic in e , M a rm a ra U n iv e rs ity , Is ta n b u l, Turkey. " M .D ., S u b -d e p a rtm e n t o f H a e m a to lo g y , D e p a rtm e n t o f In te rn a l M e d ic in e , S c h o o l o f M e d ic in e , M a rm a ra U n iv e rs ity , Is ta n b u l, T u rk e y " M .D ., D e p a rtm e n t o f P a th o lo g y, S c h o o l o f M e d ic in e , M a rm a ra U n iv e rs ity , Is ta n b u l, Turkey.
ABSTRACT
Objective:
T h e d e v e lo p m e n t o f a h ig h e r g ra d e ly m p h o m a in p a tie n ts w ith c h ro n ic ly m p h o c y tic le u k e m ia (C LL) is d e fin e d as R ic h te r's s y n d ro m e (R S ). T h e aim o f th is s tu d y w a s to a n a ly z e all C L L p a tie n ts s e e n a t M a rm a ra U n iv e rs ity H o s p ita l d u rin g 7 y e a rs of fo llo w up in o rd e r to d e te rm in e th e in c id e n c e , c lin ic a l fe a tu re s a n d tre a tm e n t o u tc o m e o f p a tie n ts w h o tra n s fo rm e d to RS.Patients and Method:
F ifty fo u r p a tie n ts w ith C LL w e re e v a lu a te d in th is re tro s p e c tiv e s tu d y, w h e re re c o rd s o f all p a tie n ts w ith C LL, w h o a re fo llo w e d up at th e h a e m a to lo g y o u t-p a tie n t c lin ic s d u rin g 7 y e a rs, w e re e x a m in e d in o rd e r to d e te rm in e w h e th e r R ic h te r tra n s fo rm a tio n h ad o c c u rre d at a n y tim e d u rin g th e c o u rs e o f th e d is e a s e .Results:
R ic h te r's s y n d ro m e w a s o b s e rv e d in 3 o u t of 54 p a tie n t, g iv in g an in c id e n c e o f 5 .6% . T h e p re s e n tin g fe a tu re s o f RS h a v e b e e n s y s te m ic s y m p to m s , ra p id ly p ro g re s s iv e ly m p h a d e n o p a th y , a nd e le v a tio n o f la c ta te d e h y d ro g e n a s e LD H . N o n e o f th e p a tie n ts re s p o n d e d to s y s te m ic c h e m o th e ra p y a nd th e m e d ia n s u rviva l w a s o n ly 4 m o n th s fo llo w in g th e d ia g n o s is of RS.Conclusion:
E a rly d ia g n o s is o f RS is p o s s ib le w ith th e re c o g n itio n o f th e w a rn in g s y m p to m s a nd signs, but tre a tm e n t re m a in s u n s a tis fa c to ry . T h e s tu d y h ig h lig h ts th e n e e d to d e v e lo p n e w s tra te g ie s fo r th e s u c c e s s fu l tre a tm e n t o f RS.K e y W o rd s :
R ic h te r's s y n d ro m e , C h ro n ic L y m p h o c y tic L e u k e m iaIN TR O D U CTIO N
D e v e lo p m e n t o f a h ig h e r g ra d e m a lig n a n t ly m p h o m a in a p a tie n t w ith c h ro n ic ly m p h o c y tic le u k e m ia (C LL) w asfirs t d e s c rib e d by R ic h te r in 1928 (1). P revious studies re p o rt th e d e v e lo p m e n t of a h ig h e r g ra d e ly m p h o m a in 3 % to 10% of C LL p a tie n ts (2,3). T ru e in cid e n c e of this tra n s fo rm a tio n m a y be h ig h e r, a s p o s t-m o rte m e x a m in a tio n s are n o t ro u tin e ly p e rfo rm e d in all C LL p a tie n ts in o rd e r to se a rc h fo r o c c u lt or m issed high g ra d e ly m p h o m a . T h e m o rp h o lo g ic tra n s fo rm a tio n of C LL, w h ic h u s u a lly o c c u rs m o n th s to y e a rs a fter the d ia g n o s is o f C L L , is a s s o c ia te d w ith c lin ic a l p ro g re s s io n a nd it has b e e n d e s ig n a te d as R ichter's s y n d ro m e (R S ). S o m e in v e s tig a to rs have included p a tie n ts w ith th e d ia g n o s is o f h is tio c y tic ly m p h o m a (2,4) and H o d g k in 's d is e a s e (5) fo llo w in g C LL in the d e fin itio n o f R S. S y s te m ic s y m p to m s , ra p id ly p ro g re s s iv e ly m p h a d e n o p a th y , e x tra n o d a l dise a se, m o n o c lo n a l g a m m o p a th y , an d e le v a tio n o f lactate d e h y d ro g e n a s e (LD H ) o v e r tw ic e th e no rm a l value h a v e b een d e s c rib e d as th e clin ic a l fe a tu re s w hich c h a ra c te riz e th e d e v e lo p m e n t of RS in a p a tie n t w ith C L L (2,3,6).
T h e aim of th is s tu d y w a s to a n a ly s e all C LL pa tie n ts seen at M a rm a ra U n iv e rs ity H o spital du rin g 7 y e a rs of fo llo w up in o rd e r to d e te rm in e th e in cid e n c e , clin ica l fe a tu re s , la b o ra to ry fin d in g s a nd tre a tm e n t o u tc o m e of p a tie n ts w ho tra n s fo rm e d to RS.
PATIENTS A N D M ETHODS
Fifty fo u r p a tie n ts w ith C L L w e re e v a lu a te d in th is re tro s p e c tiv e study, w h e re re c o rd s o f all p a tie n ts w ith C LL, w h o a re fo llo w e d up at th e h a e m a to lo g y o u t p a tie n t clin ic s , w e re e x a m in e d in o rd e r to d e te rm in e w h e th e r R ic h te r tra n s fo rm a tio n had o cc u rre d at any tim e d u rin g th e c o u rs e o f th e d is e a s e .
In te rn a tio n a l W o rk in g G ro u p on C L L (IW C L L ) g u id e lin e s w e re a p p lie d fo r th e d ia g n o s is o f C L L (7). M o rp h o lo g ic a lly th e ly m p h o c y te s had to be m a tu re and th e b o n e m a rro w a s p ira te had to s h o w th a t g re a te r th a n 3 0 % of all n u c le a te d ce lls w e re lym p h o c y te s . C LL
(Received 30 June, 1999) Marmara Medical Journal 1999;12(4):183-185
Ahmet Toprak, et al
c la s s ific a tio n w a s d e te rm in e d a c c o rd in g to th e Rai sta g in g (8).
D ia g n o s is of RS w a s e s ta b lis h e d a c c o rd in g to the c lin ica l fe a tu re s as p re v io u s ly d e s c rib e d and also p a th o lo g ic a lly (2 ,3 ,6 ). T h e p a th o lo g ic a l d ia g n o s e s w e re b a se d on iym p h n o d e b io p s ie s in tw o p a tie n ts, an d b io p s y o f a p a ra v e rte b ra l m ass at th e tim e of p re s e n ta tio n o f C L L in o n e patient.
RESULTS
R ic h te r's s y n d ro m e w a s o b s e rv e d in 3 o u t of 54 p a tie n ts, g iv in g an in c id e n c e o f 5.6% . C lin ic a l d a ta for th e s e p a tie n ts is illu s tra te d in T a b le I. M ean a g e of th e C L L p a tie n ts w a s 65 y e a rs. T h irty on e p a tie n ts w e re m ale an d 23 p a tie n ts w e re fe m a le . M a jo rity of th e p a tie n ts (2 5 /5 4 ) w e re Rai s ta g e s I and II. F o u rte e n p a tie n ts w e re lo s t to fo llo w -u p . M e d ia n s u rv iv a l in th e re m a in in g p a tie n ts w a s 38 m o n th s. In a d d itio n to th e 3 p a tie n ts, w h o tra n s fo rm e d to RS, 5 C L L p a tie n ts had tra n s fo rm e d to p r o ly m p h o c y tic le u k e m ia (P L L ). M e d ia n d u ra tio n o f tim e fro m d ia g n o s is of C L L to RS w a s 27 m o n th s. T h e o u ts ta n d in g c lin ica l fe a tu re s of RS p rio r to d ia g n o s is w e re s y s te m ic s y m p to m s of m a la ise , w e a k n e s s , fe v e r and w e ig h t loss, ra p id ly p ro g re s s iv e ly m p h a d e n o p a th y and e le v a tio n of th e LD H to m o re th a n tw ic e th e u p p e r lim it o f no rm a l in all th re e p a tie n ts (T a b le II). T h e firs t tw o p a tie n ts w e re tre a te d w ith M in i-B E A M (c a rm u s tin e , e to p o s id e , cy ta ra b in e , m e lp h a la n ), a nd th e th ird p a tie n t, w ho p re s e n te d w ith a p a ra s p in a i m ass, re c e iv e d th re e c y c le s o f C H O P (c y c lo p h o s p h a m id e , d o x o ru b ic in , v in c ris tin e , p re d n is o n e ) c h e m o th e ra p y . N o n e o f th e
Table I. Clinical features of 54 patients with CLL
Clinical features No.
Mean age (years) 65±9
Sex Female 23 Male 31 Rai staging 0 12 I. II 25 III. IV 17 Bulky disease 9
Median survival (months) 38
Lost-to-follow-up 14
Infectious complications 20
Immune Hemolytic Anemia 1
Immune Thrombocytopenia 1
Total number of deaths 13
due to disease progression 8
other 5
PLL transformation 5
Richter's Syndrome 3
p a tie n ts re s p o n d e d to th e s y s te m ic c h e m o th e ra p y . T h e firs t p a tie n t d ie d fo llo w in g 3 m o n th s , an d th e o th e r tw o p a tie n ts d ie d fo llo w in g 4 m o n th s a fte r th e d ia g n o s is o f RS.
Table II. Characteristics of 3 patients with Richter's Syndrome
Patient 1 2 3
Age (years) 61 48 70
Sex Female Male Male
Rai stage II II III
Prior regimens chlorambucil adriablastina. ara-c chlorambucil, CHOP, fludarabine None Reason tor prior chemotherapy Rapid lymphocyte doubling time Rapid lymphocyte doubling time
-Systemic symptoms Yes Yes Yes
Bulky disease Yes Yes Yes
Extranodal disease No No paravertebral mass
WBC count at AS (ttfl/t) 33.6 75.1 11.3
LDH>twice normal Yes Yes Yes
Monoclonal gammopathy No No No
Lymph node pathology accelerated phase CLL with prolymphocytes and immunoblasts diffuse, high-grade malignant lymphoma Paravertebral mass high-grade malignant lymphoma
Treatment tor RS Mini-BEAM Mini-BEAM CHOP
Survival (months) 3 4 4 WBC: white blood cell: LDH: lactate dehydrogenase;
ara-c: cytosine arabinoside: CHOP: cyclophosphamide, adriamycine, vincristine, prednisone; Mini-BEAM: carmustine, etoposide, cytarabine, melphalan
DISCUSSION
C h ro n ic L y m p h o c y tic L e u k e m ia (C L L ) is a ly m p h o p ro life ra tiv e d is o r d e r c h a ra c te riz e d by p ro life ra tio n o f s m a ll, m a tu re -a p p e a rin g ly m p h o c y te s , u s u a lly o f B -ce ll ty p e . C L L m a y tra n s fo rm into large c e ll ly m p h o m a (L C L ) in 3 -5 % , p ro ly m p h o c y tic le u k e m ia (P L L ) in 10% , a c u te ly m p h o b la s tic le u k e m ia (A LL) in le s s th a n 1% , an d m u ltip le m y e lo m a in less th a n 1% o f th e s e p a tie n ts (9). Is o la te d c a s e s o f C LL, tra n s fo rm in g in to s m a ll n o n c le a v e d c ell ly m p h o m a , ly m p h o b la s tic ly m p h o m a , h a iry c ell le u k e m ia , and H o d g k in ’s d is e a s e h a v e b e e n re p o rte d (10). T he d e v e lo p m e n t o f a s e c o n d h ig h e r-g ra d e ly m p h o m a in p a tie n ts w ith p re -e x is tin g C L L is c a lle d R ic h te r's S y n d ro m e (R S ).
T h e in c id e n c e of R S in C L L p a tie n ts in th is s tu d y w as 5.6 % , w h ic h is c o n s is te n t w ith p re v io u s re s e a rc h e s re p o rtin g an in c id e n c e in th e ra n g e o f 3 -1 0 % (2,3). T he th re e p a tie n ts w h o u n d e rw e n t R ic h te r's tra n s fo rm a tio n , d e v e lo p e d s y s te m ic s y m p to m s , p ro g r e s s iv e ly m p h a d e n o p a th y , fo llo w e d b y ra p id c lin ic a l d e te rio ra tio n , c h e m o th e ra p y re s is ta n c e a n d d e a th w ith in 4 m o n th s. T w o p a tie n ts ha d Rai s ta g e II, and o n e p a tie n t h a d R ai s ta g e III at th e tim e o f tra n s fo rm a tio n . P re v io u s ly s e rie s illu s tra te th a t s ta g in g
Richter's syndrome in chronic lymphocytic leukemia
o f th e C L L p a tie n ts m a y n o t be re le v a n t, as e ven th o s e p a tie n ts w ith m in im a l re s id u a l d is e a s e ca n tra n s fo rm to RS (3).
P ro lo n g e d or in te n s iv e c y to to x ic th e ra p y fo r e ith e r n e o p la s tic o r n o n -n e o p la s tic c o n d itio n s is kn o w n to in c re a s e th e ris k o f d e v e lo p in g a h e a m a to lo g ic a l m a lig n a n c y . A c u te m y e lo id le u k e m ia , d iffu s e h is tio c y tic ly m p h o m a , d iffu s e u n d iffe re n tia te d ly m p h o m a , a n d p rim a ry in tra c r a n ia l h is tio c y tic ly m p h o m a a re m a lig n a n c ie s w h ic h a re m o s t c le a rly re la te d to p rio r c y to to x ic a n d /o r ra d ia tio n th e ra p y . A lth o u g h it is p o s s ib le th a t p rio r c y to to x ic th e ra p y m ay in c re a s e th e risk of R S tra n s fo rm a tio n in s o m e p a tie n ts w ith C LL, T ru m p et al s h o w e d th a t n e a rly o n e -th ird of RS p a tie n ts h ad n e v e r re c e iv e d tre a tm e n t fo r C L L (2). In o u r stu d y, p a tie n t 3 re c e iv e d no tre a tm e n t fo r C LL p rio r to th e R ic h te r’s tra n s fo rm a tio n , b u t he still d ied 4 m o n th s fo llo w in g th e d ia g n o s is d e s p ite th e ra p y . It is th e re fo re u n lik e ly th a t p re v io u s c h e m o th e ra p y is a s ig n ific a n t in flu e n c in g fa c to r in th e tra n s fo rm a tio n of C L L to R S . R S m a y o c c u r as a re s u lt o f a tra n s fo rm a tio n o f th e C LL clo n e , o r it m a y o c c u r as a m a lig n a n c y a ris in g fro m a s e c o n d d is tin c t an d in d e p e n d e n t c lo n e (11, 12)
T h e p ro g n o s is o f p a tie n ts w h o p ro g re s s to RS is m uch w o rs e th a n th e p ro g n o s is o f u n c o m p lic a te d C LL. T h is w a s illu s tra te d by o u r s tu d y , w h ic h s h o w e d th a t th e m e d ia n s u rv iv a l in R S p a tie n ts w a s 4 m o n th s d e s p ite tre a tm e n t in c o m p a ris o n w ith . th e re m a in in g C L L p a tie n ts , w h o s e m e d ia n s u rv iv a l w a s 38 m o n th s. N one o f th e RS p a tie n ts in th is s tu d y a c h ie v e d a re m is s io n w ith c h e m o th e ra p y . T ru m p et a l's s tu d y s u p p o rts the fin d in g s o f th is re p o rt b y s ta tin g a m e d ia n s u rv iv a l of 4 m o n th s, an d a p o o r re s p o n s e to c h e m o th e ra p y w ith o n ly 14% c o m p le te re m is s io n ra te fo r th e RS p a tie n ts (2). T h o s e fe w p a tie n ts w h o re s p o n d to c h e m o th e ra p y a p p e a r to h a v e lo n g e r d u ra tio n s o f s u rv iv a l even th o u g h th e c h a n c e s o f a c u re is a ra rity (2,13). T h is is in c o n tra s t w ith th e d ia g n o s is o f p rim a ry high g ra d e ly m p h o m a , w h ic h is c u ra b le in n e a rly 4 0 % of the p a tie n ts (14). In c o n c lu s io n , e a rly d ia g n o s is of RS is p o s s ib le w ith th e re c o g n itio n o f th e w a rn in g s y m p to m s an d signs, b u t tr e a tm e n t re m a in s u n s a tis fa c to ry . T h e s tu d y h ig h lig h ts th e n e e d to d e v e lo p n e w s tra te g ie s fo r th e s u c c e s s fu l tre a tm e n t o f RS.
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