British journal o/ Haemutofogy, 1995, 90, 473-475

SHORT REPORT

Dapsone for refractory chronic idiopathic thrombocytopenic purpura

FERNANDO HERNANDEZ,* MARIANO LINARES,* PEDRO C O L O M I N A , ~ EMILIO PASTOR,$ ANTONIO CERVBR~),* AMALIA PEREZ? A N D MATILDE PERELLA$ Departments of Haematology, *Hospital General Universitario, Valencia, tHospita1 Virgen de 10s Lirios, Alcoy, and $Hospital Lluis Alcanyis, Xativa, Spain

Received 30 December 1994; accepted for publication 17 March 1995

Summary. Fifteen patients with refractory chronic idiopathic thrombocytopenic purpura (ITP) were treated with dapsone (lOOmg/d) for 1-31 months. The overall response rate to dapsone was 40%. Five patients responded in 1 month and one patient in 2 months. No pretreatment characteristics - sex, age, platelet count or duration of ITP - were correlated with response to dapsone.

Treatment was well tolerated. The most frequent adverse

effect was dose-related haemolytic anaemia. In our experi- ence, dapsone provides an inexpensive and well-tolerated alternative for patients with ITP who had inadequate reponses to conventional therapy.

Keywords: idiopathic thrombocytopenic purpura, dapsone, immune thrombocytopenia.

The cornerstone of therapy in adult idiopathic thrombo- cytopenic purpura (ITP) remains corticosteroids and splenectomy, but several alternative treatments are avail- able for unresponsive patients (Manoharan, 199 1).

Dapsone has been advocated for the treatment of refractory ITP (Durand et al, 1991; Godeau et al, 1993). Our preliminary results suggested a role for this approach (Linares et al, 1994).

We now report the results on the use of dapsone in 1 5 patients with chronic ITP.

PATIENTS AND METHODS

Fifteen patients with chronic ITF' were treated orally with dapsone (1 00 mg/d). No other drug active in ITP was used in conjunction with dapsone. All patients had normal levels of glucose-&phosphate dehydrogenase. To be eligible, patients had to have platelet counts consistently < 30 x 109/1 or higher with clinical bleeding.

The diagnosis of ITP was made according to the usual criteria (Karpatkin, 1985). There were 10 females and five males. The mean age at the onset of treatment with dapsone was 54.5 years (range 16-84). The median duration of

Correspondence: Dr Fernando Hernandez. Hospital General {Jniversitario. Servicio de Hematologia, Avenida Tres Cruces s.n., 46014 Valencia. Spain.

0 1995 Blackwell Science Ltd

thrombocytopenia before dapsone therapy was 29 months (range 12-131).

Previous therapy had included prednisone (1 mg/kg/d) in all patients (with nine transient responses and six failures) and azathioprine (100-1 50 mg/d) in seven patients (three responses and four failures). Four of the patients had previously undergone splenectomy. Details of the patients are presented in Table I.

Platelet counts were done every 2 weeks for the first month and every 1-2 months thereafter.

The following criteria were used in classifying responses: a complete response (CR) was defined as a platelet count increase to 100 x 109/1 or more, for at least 2 months: a partial response (PR) was defined as a platelet count at least doubled from initial levels and > 50 x 109/1 for at least 2 months; no response included none of the above.

The mean values were compared using the Mann- Whitney IJ test.

RESULTS

Results are summarized in Table I. Six patients (40%)) achieved response (four CR and two PR). After 1 month, patient 9 refused further treatment. Dapsone was withdrawn because of haemolysis (patient 10) or splenectomy (patient 11). Dapsone was continued for at least 3 months in the other 12 patients. The time to obtain response was 1 month in five patients and 2 months in one patient. Of the

473

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rc)

in

Tab

le I.

Sum

mar

y of

clin

ical

det

ails

and

resp

onse

to th

erap

y.

Plat

elet

cou

nt (x

10~11)

Hae

mog

lobi

n (g

/l)

Prev

ious

ther

apy

Dur

ingt

D

urat

ion

of

Dur

atio

n of

D

urin

gt

Befo

re

Mea

n M

axim

um

Befo

re

(min

imum

) da

pson

e (m

onth

s)

Patie

nt

Sex/

age

(yr)

IT

P (m

onth

s)

Pred

niso

ne

Aza

thio

prin

e

1 2*

3 4. 5 6 7 8*

9

1 o*

11

12

13

14

15

F/61

MI1

6 F/73

FJ53

MIS1

F/67

F/43

F/2 7

F/5l

MI5

8 MI65

F/33

F/70

MI65

F/84

48

120

107

41

17

26

131

108

24

49

60

15

28

12

18

NR

NR

CR

CR

CR

RP

NR

NR

PR

PR

CR

PR

NR

CR

NR

NR

15

NR

14

PR

7 28

PR

44

16

NR

16

NR

7 48

PR

13

14

18

42

10

43

77 f 21

114

52 z!c

35

117

49 i 14

80

57&

17

75

84f23

118

72 f 29

112

26 f 14

57

1554

23

- 57

2252

24

15fl

16

4fl

3 37f 10

48

21+9

36

18 + 13

40

152

141

138

128

167

152

131

114

131

139

152

139

143

156

121

108

135

109

117

141

125

129

110

120

100

150

126

119

139 99

>31 8

>13

>6

>3

>4

10

10

1 2 1 3 6 6 6

CR:

com

plet

e res

pons

e; PR p

artia

l res

pons

e: NR: n

o re

spon

se.

* Spl

enec

tom

ized

pat

ient

s. f V

alue

s rea

ched

dur

ing

trea

tmen

t: M

ean f st

anda

rd d

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max

imum

or

min

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W

tp

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w

I tp

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0

Short Report 475 responders, five patients are still on treatment. Dapsone was reduced to 50mg/d in two responders (patients 1 and 3) because of the decrease in the haemoglobin value, but response was maintained. The drug was stopped in patient 2 because of cyanosis with methaemoglobinaemia. The platelet count decreased after drug suppression in this patient.

As seen in Table I, no patient characteristic was correlated with response to dapsone. The overall responses were similar for women and men. No statistically significant difference was observed between responders and non-responders with regard to mean age (responders 53-5 f 20.2 years, non- responders 55.1 f 18.3: P = 0.49), mean platelet count before therapy (responders '20.7 f 13.3 x 109/1, non- responders 23.4 f 16.1; P = 0.49) or mean decrease in haemoglobin (responders 23.8 f 13.6 g/l, non-responders 14.9 f 12.2; P = 0.43). Similarly, the efficacy of dapsone was not related to duration of ITP (59.8 rt 43.2 months in responders and 49.4 rt 43.1 in non-responders; P = 0.48) or response to previous therapy (Table I).

Treatment with dapsone was well tolerated. Haemolysis was observed in most patients. A decrease in haptoglobin was observed in all patients. Bilirubin was increased in 11/ 12 patients and LDH in 4/8 of patients. The haemoblogin level was decreased by >20g/l in seven patients but only one patient required discontinuance of dapsone therapy. No other side-effects were seen.

DISCUSSION

This study demonstrates that treatment with dapsone can raise and maintain the platelet count at haemostatic levels for several months in about 40% of adults with refractory chronic ITP. Similar optimal responses have also been observed by Godeau et a1 (1993) in 13/27 autoimmune thrombocytopenic patients (six HIV infected).

The mechanism of action of dapsone is unclear. A blockade of the reticuloendothelial system by excessive red blood cell destruction has been proposed (Durand et al, 1991). However, in our experience, in agreement with Godeau et a1 (1993), the increase in datelet count did not correlate with the decrease in the haemoglobin level.

Durand et al(l991) observed response in all of five elderly patients with chronic ITP. These more favourable results might be explained, by the difference in patient characteristics. In the study by Durand et a1 (1991) none

of the patients had previously undergone splenectomy, and two patients had not received previous therapy. Our patients had been more refractory to conventional treatment.

No pretreatment characteristic (age, sex, duration of ITP, previous splenectomy. platelet count before treatment, or response to previous treatments) was correlated with response to dapsone. Godeau et al (1993), in contrast to our findings, observed that platelet counts before initiation of dapsone therapy were significantly higher in the responders.

The most frequent adverse effect of dapsone was dose- related haemolytic anaemia. Nevertheless, our experience suggests that haemolysis associated with dapsone rarely limits its usage.

The dose of dapsone in our study was based on previous reports: Durand et aZ(1991) used 75 mg/d and Godeau et a1 (1993) used 100mg/d. The optimum duration therapy and the maintainance dose in the responders remain to be determined. In our experience, if patients have had sustained responses with dapsone that last several months, or if they experience side-effects, the dosage can be gradually tapered.

The treatment for chronic ITP is still controversial if splenectomy has failed or is contraindicated. Several alternative treatments are available: however, none of these therapies have been compared in randomized trials. The choice of therapy has to be based on response rate and duration, side-effects and cost of treatment. In our opinion, dapsone provides an inexpensive, well-tolerated, alternative for patients with ITP who have had an inadequate response to conventional therapy.

REFERENCES

Durand, J.M.. Lefevre, P., Hovette, P., Mongin, M. & Soubeyrand, J. (1 991) Dapsone for idiopathic autoimmune thrombocytopenic purpura in elderly patients. British Journal of Haematology, 78,

Godeau, B., Oksenhendler, E. & Bierling. P. (1993) Dapsone for autoimmune thrombocytopenic purpura. American Journal of Hematology, 44, 70-72.

Karpatkin, S. (1985) Autoimmune thrombocytopenic purpura. Seminars in Hematology. 22, 260-288.

Linares, M., Cerver6, A., Pastor, E. & Colomina. P. (1994) Dapsone for idiopathic thrombocytopenic purpura. American journal of Hematology, 46, 371.

Manoharan, A. (1991) Treatment of refractory idiopathic thrombo- cytopenic purpura in adults. British Journal of Haematology, 79,

459-460.

143-147.

0 1995 Blackwell Science Ltd, British Journal of Haematology 90: 473-475