Encouraging Results in the Treatment of Haemorrhagic Cystitis with Estrogen – Report of 10 Cases and Review of the Literature

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Bone Marrow Transplantation (2000) 25, 981–985  2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt Encouraging results in the treatment of haemorrhagic cystitis with estrogen – report of 10 cases and review of the literature

R Ordemann, R Naumann, G Geissler, M Bornhauser, U Schuler and G Ehninger

Department of Medicine I, Technical University of Dresden, University Hospital ‘Carl Gustav Carus’, Dresden, Germany

Summary: been published.14–16 Few have shown an encouraging effect with acceptable side-effects. Case reports about oral estro- Haemorrhagic cystitis (HC) after allogeneic haematopo- gen as an effective treatment of HC have prompted us to ietic stem cell transplantation (HSCT) or high-dose try this modality in affected patients.17–19 cyclophosphamide (CP) chemotherapy is a severe side- effect and can cause signiﬁcant morbidity and mortality. In this report, we describe the clinical courses of 10 Patients and methods patients with HC and review the literature. The patients were treated with oral conjugated estrogen in an Ten consecutive cases of haemorrhagic cystitis after high- attempt to improve severe haemorrhagic cystitis. In dose chemotherapy and CP mobilisation were observed in seven patients positive effects were seen, haematuria the University Hospital of Dresden between 1 January 1997 resolved in all, but residual symptoms of dysuria and 31 December 1998. All patients treated with cyclophos- remained for longer periods. In one patient application phamide received mesna prophylaxis at a dose identical to of estrogen was interrupted because of hepatotoxicity. the CP dose for 24 h with an additional bolus of 40% before Two patients failed all treatment modalities including the start of CP infusion. Patients were required to have a oral estrogen because of terminal illness. We conclude normal serum bilirubin at the time of administration of oral that in the management of HC the administration of estrogen. Other causes of haematuria at this time were not oral conjugated estrogen should be considered. Bone seen. The clinical characteristics of the patients described Marrow Transplantation (2000) 25, 981–985. in this report are listed in Table 1. The severity of HC is Keywords: haemorrhagic cystitis; haematopoietic stem graded according to the scale published by Bearman and cell transplantation; cyclophosphamide; estrogen colleagues.13

Case 1 Haemorrhagic cystitis (HC) remains a well known complication after high-dose cyclophosphamide (CP) or ifosfam- A 27-year-old man with paroxysmal nocturnal haemoglobi- ide, but other causes such as busulfan, etoposide, nuria (PNH) complained of haematuria, dysuria and polyu- irradiation, acute GVHD, viruses such as adenovirus, poly- ria 21 days after unrelated HLA-matched peripheral blood oma BK virus, cytomegalovirus and age in the allogeneic stem cell transplantation. The conditioning regime included population have also been implicated.1–9 The reported fre- busulfan (16 mg/kg), CP (200 mg/kg) and ATG quency ranges from 5 to 40% despite various attempts to (10 mg/kg). At the beginning, the HC was treated with prevent this complication.10 It is known that metabolites of hydration and analgesics (metamizole, buprenorphine). the oxazaphophorines alkylating agents, CP and ifosfamide Because of persistent symptoms, oral estrogen therapy was can induce urothelial toxicity and microvascular damage begun at 6 mg daily and increased to 12 mg (4 mg three and leads to HC.11,12 The clinical course of this compli- times a day). Bleeding resolved after 2 weeks and no cation is heterogeneous. The manifestations vary from further transfusion was needed. A cystoscopic washout was asymptomatic and transient microhaematuria to repeated not required. After 4 weeks the dose could be reduced to episodes of macrohaematuria with blood clots and bladder 2 mg daily. No residual symptoms of dysuria remained. pain and spasms. Some patients develop bladder tamponade The patient is alive with persistent complete remission of with urinary tract obstruction.13 Often there is no corre- the PNH. lation between the extent of therapy and development of severe haematuria. No deﬁnitive and effective therapy for the severe form of HC has been established. Many different Case 2 conservative and aggressive treatment regimes for HC have A 39-year-old woman with multiple myeloma (MM) developed haematuria and irritative voiding symptoms 7 days after high dose CP (4 g/m2) for peripheral stem cell Correspondence: Dr G Ehninger, Department of Medicine I, Technical University of Dresden, University Hospital ‘Carl Gustav Carus’, Fetscher- mobilisation. After application of 2 mg estrogen three times stra␤e 74, 01307 Dresden, Germany daily haematuria and dysuria greatly improved. Afterwards Received 22 September 1999; accepted 1 February 2000 the patient received a conditioning regimen with high-dose Treatment of haemorrhagic cystitis with estrogen R Ordemann et al 982 Table 1 Clinical characteristics of the patients

No. Patient Age/Sex Diagnosis Therapy HC Responder Virus study

1 27/M PNH Unrelated PBSCT Mild Yes Negative 2 39/F MM High dose CP Mild Yes Negative 3 52/F MM Related PBSCT Severe Yes Negative 4 40/F CML Unrelated BMT Mild No Negative 5 31/M CML Related PBSCT (2 AG mismatch) Severe No Negative 6 28/M ALL Related PBSCT Severe Yes BK virus positive 7 38/M AML Unrelated BMT Severe Yes Negative 8 38/M AML Unrelated BMT Severe Yes Negative 9 24/F CML Unrelated PBSCT Moderate Yes BK virus positive 10 40/M CML Unrelated BMT Mild No BK virus positive

melphalan (200 mg/m2) followed by an autologous PBSCT did not disappear in the next 2 weeks until death from without any complications. recurrent leukaemia.

Case 3 Case 6 A 52-year-old woman developed gross haematuria with A 28-year-old man received total body irradiation (12 Gy), polyuria, dysuria and clots 30 days after receiving CP CP (120 mg/kg) and etoposide (45 mg/kg) as conditioning (120 mg/kg) and busulfan (16 mg/kg) before allogeneic regime for allogeneic related peripheral blood stem trans- related peripheral blood stem cell transplantation for mul- plantation for refractory relapse of ALL. Already during tiple myeloma. Cystoscopy was required because of a tran- the high-dose chemotherapy the patient developed haemor- sient postrenal kidney failure. During the next 8 weeks the rhagic cystitis with blood clots and urinary retention. Urine patient was treated with 4 mg estrogen three times daily. PCR testing showed polyoma BK virus to be present. Mul- The bleeding resolved and no further transfusion was tiple cystoscopic washouts and blood transfusion were needed. However, residual symptoms of dysuria remained required. 6 mg estrogen daily was started on day 7 after for a longer period. During the next 2 months complaints transplantation. The patient showed initial improvement have not recurred on a maintainance dose of 1 mg daily. and the estrogen dose was decreased. A relapse of HC Until now the patient lives in a stable remission of the occurred 24 days later. The estrogen dose was increased to multiple myeloma. 4 mg three times daily and the patient responded again until he died from recurrent leukaemia on day 81 post transplant. Case 4 Case 7 A 40-year-old woman with CML received high dose CP (200 mg/kg), busulfan (16 mg/kg) and ATG (10 mg/kg). A 38-year-old man had a severe macrohaematuria with Thirty days after matched unrelated bone marrow transplan- repeated bladder tamponade. The haemorrhagic cystitis tation the patient complained of haematuria, polyuria and began at day 5 after CP (120 mg/kg), busulfan (10 mg/kg) dysuria. After application of 4 mg estrogen three times and thiotepa (750 mg/m2) and allogeneic unrelated bone daily for 5 days the administration was interrupted because marrow transplantation for AML. Bleeding responded tran- of histological proven drug induced hepatosis. The macro- siently to continuous bladder irrigation and multiple cysto- haematuria continued for about 4 weeks. Residual symp- scopic washouts, diathermies and laser coagulations. Mul- toms of dysuria lasted for another month and then discon- tiple units of transfused packed red blood cells were tinued. The patient died from chronic GVHD on day 360 required. The clinical course was complicated by a post transplant. Coombs-positive autoimmune haemolytic anaemia and postrenal kidney failure which required transient haemo- Case 5 dialysis. Altogether the patient received 112 units of transfused packed red blood cells and more than 150 platelet A 31-year-old man with CML in blast crisis had severe HC transfusions. At day 70 post transplant estrogen therapy was 20 days after related two antigen mismatched peripheral started with 6 mg and increased to 12 mg daily (4 mg three blood stem cell transplantation for which he had received times daily). Haematuria improved slowly 11 days later and high-dose chemotherapy with CP (120 mg/kg), busulfan no further transfusion and cystoscopy were needed. (12.4 mg/kg) and ATG (10 mg/kg). Various therapies, including continuous bladder irrigation, repeated cysto- Case 8 scopic bladder washouts and platelet transfusions failed to control the haemorrhage, which required between 2 and 4 A 38-year-old man presented with gross haematuria and units of transfused packed red blood cells daily. The patient irritative voiding at day 4 after high-dose chemotherapy received 4 mg estrogen three times daily, but haematuria with CP (200 mg/kg), busulfan (16 mg/kg) and ATG

Bone Marrow Transplantation Treatment of haemorrhagic cystitis with estrogen R Ordemann et al 983 (10 mg/kg) and allogeneic unrelated bone marrow trans- causing urinary tract obstruction (severe) occurred. plantation for AML in second remission. Cystoscopic Polyoma BK virus was implicated in three cases. washout was required because of bladder tamponade on day We started with 6 mg estrogen daily in three divided 19 post transplant. Continuous bladder irrigation could not doses and escalated until improvement of symptoms control the haematuria. At day 21 after transplantation, occurred. The highest dose given was 12 mg daily. Seven 12 mg estrogen daily (4 mg three times daily) were admin- of our 10 patients responded to oral estrogen. HC treated istered. Gross haematuria and dysuria improved. Estrogen with estrogen resolved in two of four patients with mild was reduced after improvement at day 30 and stopped at and four of ﬁve with severe HC. Estrogen was well day 51. Because of renewed macrohaematuria at day 62 the tolerated. Beside the hepatosis mentioned above, other patient was treated again with estrogen 4 mg three times side-effects like ﬂush symptoms were not observed. daily in the outpatient clinic. The dosage was tapered until day 87. The patient is alive with persistent complete haematological remission. Discussion

Case 9 Haemorrhagic cystitis is still an important complication after high-dose chemotherapy for HSCT and stem cell A 24-year-old woman complained of polyuria and dysuria mobilisation with CP and can cause significant morbidity with macrohaematuria and clots 101 days after unrelated, and mortality. The incidence of severe HC is high HLA-matched peripheral blood stem cell transplantation for especially after allogeneic bone marrow transplantation. CML in accelerated phase. The patient had received CP Direct urothelial toxicity seems to be most responsible for (200 mg/kg), busulfan (13.2 mg/kg) and ATG (10 mg/kg) the clinical manifestation of HC, which is caused not only as conditioning regime. Urine PCR detected polyoma BK by cytostatic drugs but also by irradiation and virus infec- virus. Six days after the start of symptoms, 4 mg estrogen tions like adenovirus, polyoma BK virus and cytomegalo- three times a day was initiated. Three days later clots disap- virus. Trotman et al7 emphasised the immunosuppression peared and macrohaematuria improved, estrogen was of acute GVHD as an important factor in the multifactorial stopped at day 14 of the administration. The patient remains pathogenesis of the HC. Thrombopenia after conditioning in persistent remission of her disease. treatment can increase the risk of bleeding. The prevention of HC includes sufficient oral and parenteral hydration.7–10 et al20 Case 10 Hows reported a lower incidence of cyclophosphamide-induced HC in marrow transplantation with 2-mercap- A 40-year-old man had mild HC with polyuria, dysuria and toethane sulfonate (mesna). Mesna binds to acrolein, which microhaematuria after receiving CP (200 mg/kg), busulfan is responsible for urothelial toxicity as a urinary metabolite (13.2 mg/kg) and ATG (10 mg/kg) for allogeneic, unrelated of cyclophosmamide.21 However Trotman et al7 described HLA-mismatched bone marrow transplantation because of no benefit in application of mesna for prevention of HC. CML in chronic phase. The symptoms began at day 27 post Different options for treatment of HC are known. The transplant. The virological examination revealed polyoma therapy is usually initiated by intensive intravenous BK virus. On day 30 estrogen was initiated in a dose of hydration and forced diuresis. Most patients require anal- 6 mg daily which was increased to 12 mg daily. Fluctuating gesics (sometimes even opioids) and spasmolytic drugs. In symptoms of HC required dose adjustment. For a short time cases of severe macrohaematuria with clots bladder irri- the patient needed intermittent opioids because of severe gation is a general treatment to avoid bladder tamponade. bladder spasms. On day 65 post transplant the patient was The situation may necessitate multiple blood transfusions without bladder complaints and estrogen therapy was as well. Hyperbaric oxygen offers another noninvasive stopped. The patient is doing well and is in a persistent therapeutic alternative in the management of radiation remission of the CML. induced HC not responding to standard treatment.22 The severe HC associated with urinary tract obstruction is a potentially life-threatening complication. Often invasive Results therapy includes cystoscopic washouts to remove blood clots. Endoscopic cauterisation of bleeding mucosal areas Ten patients (four female, six male) were treated with estro- can be effective. Bladder instillation with formalin and gen in an attempt to improve haemorrhagic cystitis. The other toxic substances has been reported. Further escalation duration of estrogen administration varied from 5 days to of therapy involves application of a helmstein hydrostatic 16 weeks with a median duration of 5.5 weeks. One patient pressure balloon, cystotomy and cystectomy. However, received high-dose CP for stem cell mobilisation because these aggressive treatments cause a high incidence of hyd- of scheduled high-dose chemotherapy with autologous stem ronephrosis, bladder rupture and even death. Despite these cell transplantation. Nine patients developed HC after allo- various approaches to control HC, the therapeutic inter- geneic (three related, six unrelated) PBSCT/BMT (five ventions are frequently of little efficacy. Case reports about PBSC, four BM). All patients complained of gross haema- estrogen as a potential treatment of HC have prompted us turia and irritative voiding symptoms. Four patients to try this modality in affected patients. developed macrohaematuria without clots (mild), one Potentially adverse effects of long-term exposure to patient complained of macrohaematuria with clots estrogens include an increased risk of cancer. Metabolites (moderate) and in five patients macrohaematuria with clots of estrogens may function as initiators for preneoplastic

Bone Marrow Transplantation Treatment of haemorrhagic cystitis with estrogen R Ordemann et al 984 transformation, because recent evidence in cellular and 6 Foad B, Hess EV. Urinary bladder complications with CY molecular oncology revealed that estrogens act by genetic therapy. Arch Intern Med 1976; 136: 616–619. and epigenetic mechanisms on cancer cells.23–25 However, 7 Trotman J, Nivison-Smith I, Dodds A. Haemorrhagic cystitis: the potential carcinogenicity of high-dose estrogen adminis- incidence and risk factors in a transplant population using hyp- tration in a short-term setting is unknown. Short-term estro- erhydration. Bone Marrow Transplant 1994; 23: 797–801. 8 Spencer SF, Haake RJ, Weisdorf DJ. Hemorrhagic cystitis gen use has been associated with other adverse effects 26 after bone marrow transplantation: risk factors and compli- especially hypercoagulability. cations. Transplantation 1993; 56: 875–879. The potential effect of estrogen in resolving HC remains 9 Seber A, Shu XO, Defor T et al. Risk factors for severe unclear, but there is some evidence that estrogen has a pro- hemorrhagic cystitis following BMT. Bone Marrow Trans- found effect on the cellular and cytokine immune response plant 1999; 23: 35–40. during inflammation.27 Some authors reported that estradiol 10 Klein FA, Smith M. Urinary complications of cyclophospham- enhances the healing of tissue damaged by trauma.28,29 ide therapy: etiology, prevention and management. South Med It is known that estradiol promotes endothelial cell J 1983; 76: 1413–1416. activities.30,31 11 Brock N, Stekar J, Pohl J et al. Acrolein, the causative factor In our group, the duration of estrogen administration of urotoxic side-effects of cyclophosphamide, ifosfamide, tro- fosfamide and sulfosfamide. Arzneim Forsch 1979; 29: 659– varied from 5 days to 16 weeks with a median duration of 661. 5.5 weeks. 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