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Mesna versus forced diuresis to prevent cyclophosphamide induced haemorrhagic cystitis in marrow transplant patients (preliminary data)
Cancer Treatment Reviews (1983) 10 ( Supplement A), 53-56
M e s n a v e r s u s f o r c e d d l u r e s i s to p r e v e n t c y c l o p h o s p h a m i d e i n d u c e d h a e m o r r h a g i c c y s t i t i s in marrow transplant patients (preliminary data) j . H o w s , A. M e h t a a n d E. C. G o r d o n - S m i t h Royal Post-Graduate Medical School, Hammersraith Hospital, London S ~ t 1 2 OHS, U.A".
Introduction High-dose c y c l o p h o s p h a m i d e t ( H D C ) alone or in combination with total body irradiation is the c o n v e n t i o n a l i m m u n o s u p p r e s s i v e t h e r a p y used to p r e p a r e patients for atlogeneic b o n e m a r r o w t r a n s p l a n t a t i o n (4). T h e most f r e q u e n t serious side-effect o f H D C is h a e m o r r h a g i c cystitis (H.C). T h i s occasionally requires blood transfusions a n d even bilateral n e p h r o s t o m i e s for t r e a t m e n t (3). T h e s t a n d a r d m e t h o d o f r e d u c i n g H C is to dilute the toxic metabolites o f c y c l o p h o s p h a m i d e in the urine by forced diuresis (FD) a n d ] o r c o n t i n u o u s b l a d d e r irrigation. T h e s e m e t h o d s are difficult to m a n a g e a n d can lead to serious m e t a b o l i c a n d infective complications, W e h a v e carried out a r a n d o m i s e d trial o f mesna~ versus F D in m a r r o w t r a n s p l a n t recipients to a n s w e r the following questions: ( 1) Is m e s n a as effective as F D in p r e v e n t i n g H C ? (2) Are t h e r e a n y specific side-effects o f m e s n a ? (3) Does m e s n a interfere with the i m m u n o s u p p r e s s i v e action o f c y c l o p h o s p h a m i d e ?
Patients and methods T h i r t y - f o u r consecutive patients w e r e r a n d o m i s e d to receive m e s n a or F D as p r o p h y l a x i s against H C (Figure 1). T h e aplastic patients received c y c l o p h o s p h a m i d e 50 m g / k g i.v. × 4. T h e l e u k a e m i c patients received c y c l o p h o s p h a m i d e 60 m g / k g i.v. × 2 a n d T B I 1000-1200 c : G y in 5 - 6 fractions. M e s n a a n d F D w e r e given as s h o w n in Figure 2. T h e m e s n a patients received 3 - 4 litres o f i n t r a v e n o u s fluid e a c h d a y , details o f the F D are s h o w n in T a b l e 1. E a r l y m o r n i n g u r i n e samples w e r e e x a m i n e d daily" for m a c r o s c o p i c a n d microscopic t Uromitexan® (Boehringer lngelheim Hospital Division, U.K. and Eire, and Asta-Werke AG, F.R.G.). Endoxana® (Boehringer Ingelheim Hospital Division, U.K. and Eire) and Endoxan® (Asta-Werke AG, F.R.G.). t~) 1983 Academic Press Inc. (London) Limited
0305-7372/83/10A0053 + 04 $03.00/0 53
54
J. HOWS E T AL. 3 4 Patients
16 FAD
18 mesno
8 SAA
9 CGL I AML
8 SAA
8 CGL
Figure 1. Randomised trial: mesna vs. forced alkaline diuresis.
h a e m a t u r i a . Daily b l o o d c o u n t s were p e r f o r m e d . T h e lowest l y m p h o c y t e c o u n t in the 10 days following c y c l o p h o s p h a m i d e t h e r a p y was t a k e n as a n i n d i c a t o r o f the i r n m u n o s u p pressive activity o f c y c l o p h o s p h a m i d e , in the aplastic t r a n s p l a n t patients.
Results T h e i n c i d e n c e o f h a e m o r r h a g i c cystitis in the 34 p a t i e n t s is s h o w n in T a b l e s 2 a n d 3. M e s n a was statistically s u p e r i o r to F D in p r e v e n t i n g m a c r o s c o p i c h a e m a t u r i a (p ----- < 0 . 0 5 chi T r i a l protocol : mesno vs' forced a l k a l i n e diureeis
EMU
Cyclophosphomide x m g / kg i.v.
0930 FAD
I000
t
6 t i.v. over 2 4 h + N o H C 0 3 + frusemide
frusemide diamox
EMU
1
Cyclophosphomide x m g / kg i.v.
1300
1600
1900 M esno
l
1000
mesn0 0-4 x xmg/kg i.v.
mesno
mesno
Figure 2. Trial protocol: mesna ~s. forced alkaline diuresis.
T
mesno
PREVENTION
OF HAEMORRHAGIG
CYSTITIS
55
squared). H o w e v e r , m a c r o s c o p i c h a e m a t u r i a did o c c u r in two patients in the m e s n a g r o u p and one r e q u i r e d nephrostomies and multiple blood transfusion. O n e p a t i e n t in the F D g r o u p also r e q u i r e d nephrostomies. N o specific side-effects of m e s n a w e r e noted. T h e incidence o f c y c l o p h o s p h a m i d e i n d u c e d v o m i t i n g was similar in the two groups. T a b l e 4 shows p e r i p h e r a l blood d a t a . T h e r e was no significant difference in the n a d i r o f the l y m p h o c y t e c o u n t in m e s n a or F D treated patients. T a b l e 5 shows e n g r a f t m e n t d a t a on the aplastic transplants. Five out of 16 aplastie patients suffered episodes of graft failure. All 5 patients h a d received mesna.
T a b l e 1. F o r c e d d i u r e s i s
Fluid Electrolytes
6 litres over 24 h 50 mmol N a H C O 3 / I 20 mmol KCI/I
Diuretics
Diamox 150 mg/m 2 Frusemide 20 mg/rn 2 } pre cyclophosphamide Frusemide 10 mg[l o f fluid
T a b l e 2.
Results: mesna
vs. FD
Haematuria
None
Micro
Macro
All patients Mesna FD
11 9 (50%) 2 (13%)
14 7 7
9 2 (11%) 7 (44%)
<0.05
--
<0.05
p
T a b l e 3.
Results: mesnavs. FD
Haematuria
None
Micro
Macro
5 2
4 4
1 2
4 0
3 3
1 5
CGL/AML Mesna FD
SAA Mesna FD
T a b l e 4.
Peripheral blood lymphocytes
(aplastics)
Mesna
FD
Pre R . lymphs x I09/I
1.2 (0.4-2.6)
0.9 (0.5-2. I)
Nadir lymphs x 109/1
0.14 (0-0.35)
0.12 (0-0.31)
No. of patients
8
8
56
J. HOWS E T AL. Table 5. Engraftment following BMT: rnesna vs. FD
Initial graft failure Late graft failure (:> 3/12 post BMT) No. aplastic BMT
Mesna
FD
2 3 8
0 0 8
Conclusions
The preliminary conclusions from this study are, firstl~, that mesna is statistically superior to FD in preventing cyclophospharnide induced haemorrhagic cystitis although treatment failures have occurred in the mesna group. Secondly, mesna is simple to give and we have not seen obvious side-effects at the time of administration. The high incidence of graft failure in the small group of aplastic patients treated with mesna is worrying. In this preliminary study five episodes ofgraft failure occurred in the 16 aplastic patients transplanted (Table 6). All the episodes of graft failure occurred in the mesna treatment group. The aplastic patients do not receive total body irradiation in the pretransplant immunosuppressive regimen and are dependent on the immunosuppressive effect of H D C P therapy alone to prevent marrow graft rejection. In vivo animal studies have shown that the antitumour effect of cyclophosphamide is unaffected by mesna (1). This author suggests that mesna is inactivated by auto-oxidation in the plasma and therefore cannot inactivate cyclophosphamide metabolites in the circulation. This group also states mesna is reduced to the active sulphydryl form in the renal epithelium and forms an addition compound with the toxic metabolite of cyclophosphamide, acrolein, within the urinary tract (2). There have been no randomised studies in man involving the use ofmesna in cases where HDGP is given principally for its immunosuppressive effect, as in our transplant patients with severe aplastic anaemia. Because of the clinical association between mesna and graft failure in a small number ofpatients described above we propose to study more patients. In addition, we intend to investigate the effect o f m e s n a in vitro on the growth of bone marrow colony forming cells and on peripheral blood lymphocytes treated with cyclophosphamide metabolites. T h e results of these investigations will be reported in due course.
References
1. Brock,N. (1980) The developmentofmesna for the inhibition ofurotoxic side-effectsofcyclophosphamide, ifosfamideand other oxazaphosphorinecytostatics. Recent Results Cancer Res. 74: 270. 2. Brock, N., Pohl, J. & Stekar, J. (1981) Dctoxification of urotoxic oxazaphosphorines by sulphydryl compounds.~7. CancerRes. Clin. Oncol. 100:311. 3. George,P. (1963) Haemorrhagiccystitisand cyclophosphamide.Lancet ii: 942. 4. Thomas, E. D., Storb, R., Cliff, R. A., Fefer, A.,Johnson, F. L., Nor~l~an,P., Lerner, K. G., GlucksbergH. & Buckner, C. C. (1975) Bonemarrow transplantation..At. Engl..7. Med. 292: 832.
M e s n a v e r s u s f o r c e d d l u r e s i s to p r e v e n t c y c l o p h o s p h a m i d e i n d u c e d h a e m o r r h a g i c c y s t i t i s in marrow transplant patients (preliminary data) j . H o w s , A. M e h t a a n d E. C. G o r d o n - S m i t h Royal Post-Graduate Medical School, Hammersraith Hospital, London S ~ t 1 2 OHS, U.A".
Introduction High-dose c y c l o p h o s p h a m i d e t ( H D C ) alone or in combination with total body irradiation is the c o n v e n t i o n a l i m m u n o s u p p r e s s i v e t h e r a p y used to p r e p a r e patients for atlogeneic b o n e m a r r o w t r a n s p l a n t a t i o n (4). T h e most f r e q u e n t serious side-effect o f H D C is h a e m o r r h a g i c cystitis (H.C). T h i s occasionally requires blood transfusions a n d even bilateral n e p h r o s t o m i e s for t r e a t m e n t (3). T h e s t a n d a r d m e t h o d o f r e d u c i n g H C is to dilute the toxic metabolites o f c y c l o p h o s p h a m i d e in the urine by forced diuresis (FD) a n d ] o r c o n t i n u o u s b l a d d e r irrigation. T h e s e m e t h o d s are difficult to m a n a g e a n d can lead to serious m e t a b o l i c a n d infective complications, W e h a v e carried out a r a n d o m i s e d trial o f mesna~ versus F D in m a r r o w t r a n s p l a n t recipients to a n s w e r the following questions: ( 1) Is m e s n a as effective as F D in p r e v e n t i n g H C ? (2) Are t h e r e a n y specific side-effects o f m e s n a ? (3) Does m e s n a interfere with the i m m u n o s u p p r e s s i v e action o f c y c l o p h o s p h a m i d e ?
Patients and methods T h i r t y - f o u r consecutive patients w e r e r a n d o m i s e d to receive m e s n a or F D as p r o p h y l a x i s against H C (Figure 1). T h e aplastic patients received c y c l o p h o s p h a m i d e 50 m g / k g i.v. × 4. T h e l e u k a e m i c patients received c y c l o p h o s p h a m i d e 60 m g / k g i.v. × 2 a n d T B I 1000-1200 c : G y in 5 - 6 fractions. M e s n a a n d F D w e r e given as s h o w n in Figure 2. T h e m e s n a patients received 3 - 4 litres o f i n t r a v e n o u s fluid e a c h d a y , details o f the F D are s h o w n in T a b l e 1. E a r l y m o r n i n g u r i n e samples w e r e e x a m i n e d daily" for m a c r o s c o p i c a n d microscopic t Uromitexan® (Boehringer lngelheim Hospital Division, U.K. and Eire, and Asta-Werke AG, F.R.G.). Endoxana® (Boehringer Ingelheim Hospital Division, U.K. and Eire) and Endoxan® (Asta-Werke AG, F.R.G.). t~) 1983 Academic Press Inc. (London) Limited
0305-7372/83/10A0053 + 04 $03.00/0 53
54
J. HOWS E T AL. 3 4 Patients
16 FAD
18 mesno
8 SAA
9 CGL I AML
8 SAA
8 CGL
Figure 1. Randomised trial: mesna vs. forced alkaline diuresis.
h a e m a t u r i a . Daily b l o o d c o u n t s were p e r f o r m e d . T h e lowest l y m p h o c y t e c o u n t in the 10 days following c y c l o p h o s p h a m i d e t h e r a p y was t a k e n as a n i n d i c a t o r o f the i r n m u n o s u p pressive activity o f c y c l o p h o s p h a m i d e , in the aplastic t r a n s p l a n t patients.
Results T h e i n c i d e n c e o f h a e m o r r h a g i c cystitis in the 34 p a t i e n t s is s h o w n in T a b l e s 2 a n d 3. M e s n a was statistically s u p e r i o r to F D in p r e v e n t i n g m a c r o s c o p i c h a e m a t u r i a (p ----- < 0 . 0 5 chi T r i a l protocol : mesno vs' forced a l k a l i n e diureeis
EMU
Cyclophosphomide x m g / kg i.v.
0930 FAD
I000
t
6 t i.v. over 2 4 h + N o H C 0 3 + frusemide
frusemide diamox
EMU
1
Cyclophosphomide x m g / kg i.v.
1300
1600
1900 M esno
l
1000
mesn0 0-4 x xmg/kg i.v.
mesno
mesno
Figure 2. Trial protocol: mesna ~s. forced alkaline diuresis.
T
mesno
PREVENTION
OF HAEMORRHAGIG
CYSTITIS
55
squared). H o w e v e r , m a c r o s c o p i c h a e m a t u r i a did o c c u r in two patients in the m e s n a g r o u p and one r e q u i r e d nephrostomies and multiple blood transfusion. O n e p a t i e n t in the F D g r o u p also r e q u i r e d nephrostomies. N o specific side-effects of m e s n a w e r e noted. T h e incidence o f c y c l o p h o s p h a m i d e i n d u c e d v o m i t i n g was similar in the two groups. T a b l e 4 shows p e r i p h e r a l blood d a t a . T h e r e was no significant difference in the n a d i r o f the l y m p h o c y t e c o u n t in m e s n a or F D treated patients. T a b l e 5 shows e n g r a f t m e n t d a t a on the aplastic transplants. Five out of 16 aplastie patients suffered episodes of graft failure. All 5 patients h a d received mesna.
T a b l e 1. F o r c e d d i u r e s i s
Fluid Electrolytes
6 litres over 24 h 50 mmol N a H C O 3 / I 20 mmol KCI/I
Diuretics
Diamox 150 mg/m 2 Frusemide 20 mg/rn 2 } pre cyclophosphamide Frusemide 10 mg[l o f fluid
T a b l e 2.
Results: mesna
vs. FD
Haematuria
None
Micro
Macro
All patients Mesna FD
11 9 (50%) 2 (13%)
14 7 7
9 2 (11%) 7 (44%)
<0.05
--
<0.05
p
T a b l e 3.
Results: mesnavs. FD
Haematuria
None
Micro
Macro
5 2
4 4
1 2
4 0
3 3
1 5
CGL/AML Mesna FD
SAA Mesna FD
T a b l e 4.
Peripheral blood lymphocytes
(aplastics)
Mesna
FD
Pre R . lymphs x I09/I
1.2 (0.4-2.6)
0.9 (0.5-2. I)
Nadir lymphs x 109/1
0.14 (0-0.35)
0.12 (0-0.31)
No. of patients
8
8
56
J. HOWS E T AL. Table 5. Engraftment following BMT: rnesna vs. FD
Initial graft failure Late graft failure (:> 3/12 post BMT) No. aplastic BMT
Mesna
FD
2 3 8
0 0 8
Conclusions
The preliminary conclusions from this study are, firstl~, that mesna is statistically superior to FD in preventing cyclophospharnide induced haemorrhagic cystitis although treatment failures have occurred in the mesna group. Secondly, mesna is simple to give and we have not seen obvious side-effects at the time of administration. The high incidence of graft failure in the small group of aplastic patients treated with mesna is worrying. In this preliminary study five episodes ofgraft failure occurred in the 16 aplastic patients transplanted (Table 6). All the episodes of graft failure occurred in the mesna treatment group. The aplastic patients do not receive total body irradiation in the pretransplant immunosuppressive regimen and are dependent on the immunosuppressive effect of H D C P therapy alone to prevent marrow graft rejection. In vivo animal studies have shown that the antitumour effect of cyclophosphamide is unaffected by mesna (1). This author suggests that mesna is inactivated by auto-oxidation in the plasma and therefore cannot inactivate cyclophosphamide metabolites in the circulation. This group also states mesna is reduced to the active sulphydryl form in the renal epithelium and forms an addition compound with the toxic metabolite of cyclophosphamide, acrolein, within the urinary tract (2). There have been no randomised studies in man involving the use ofmesna in cases where HDGP is given principally for its immunosuppressive effect, as in our transplant patients with severe aplastic anaemia. Because of the clinical association between mesna and graft failure in a small number ofpatients described above we propose to study more patients. In addition, we intend to investigate the effect o f m e s n a in vitro on the growth of bone marrow colony forming cells and on peripheral blood lymphocytes treated with cyclophosphamide metabolites. T h e results of these investigations will be reported in due course.
References
1. Brock,N. (1980) The developmentofmesna for the inhibition ofurotoxic side-effectsofcyclophosphamide, ifosfamideand other oxazaphosphorinecytostatics. Recent Results Cancer Res. 74: 270. 2. Brock, N., Pohl, J. & Stekar, J. (1981) Dctoxification of urotoxic oxazaphosphorines by sulphydryl compounds.~7. CancerRes. Clin. Oncol. 100:311. 3. George,P. (1963) Haemorrhagiccystitisand cyclophosphamide.Lancet ii: 942. 4. Thomas, E. D., Storb, R., Cliff, R. A., Fefer, A.,Johnson, F. L., Nor~l~an,P., Lerner, K. G., GlucksbergH. & Buckner, C. C. (1975) Bonemarrow transplantation..At. Engl..7. Med. 292: 832.