Successful treatment of cyclophosphamide induced intractable hemorrhagic cystitis with recombinant FVIIa (NovoSeven®) after allogenic bone marrow transplantation

Authors


Mehran Karimi, Hemostasis and Thrombosis Unit, Hematology Research Center, Department of Pediatrics, Nemazee Hospital, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
Tel.: +98 7116265024; fax: +98 7112359317; e-mail: karimim@sums.ac.ir

Hemorrhagic cystitis is considered a major cause of morbidity and mortality after allogenic bone marrow transplantation (BMT), and sometimes even invasive procedures, such as supravesical urinary diversion (ileal conduit) and cystectomy, may be needed [1]. It occurs after using high doses of cyclophosphamide as a condition regimen in patients who undergo BMT [1].

In this study, we evaluated the efficacy of recominant factor VIIa (rFVIIa) in patients with severe hemorrhagic cystitis following allogenic BMT, which can lead the patients to a better management, compared with risky procedures such as formalin instillation or artery ligation.

From May 1993 through September 2003, 182 patients underwent allogenic BMT in Nemazee Hospital, Shiraz, Southern Iran [(β-thalassemia major (n = 113), leukemia (n = 55), lymphoma (n = 6) and aplastic anemia (n = 8)]. Severe hemorrhagic was observed in eight patients (4.4%); one patient was expired, one needed suprapubic cystostomy and three underwent internal iliac artery ligation. The three remaining patients with severe hemorrhagic cystitis as well as the other one with mild hemorrhagic cystitis but with severe gastrointestinal bleeding received rFVIIa. These patients included three males of 21, 26 and 9 years of age and one 11-year-old female.

Patients received busulfan, 14–16 mg kg−1 plus cyclophosphamide, 200 mg kg−1 and ±-antilymphocyte globulin, 40–100 mg kg−1 for thalassemia major and leukemia as a conditioning regimen with written consent.

Continuous bladder irrigation was applied as well as red blood cell transfusions as the first line of hemorrhagic cystitis therapy for all four patients without any significant response.

In the five patients for whom invasive procedures were used, in order to stop gross hematuria as well as repeated red blood cell transfusions we administered a dose of 150–400 µg kg−1 of rFVIIa as a trial in four patients (three with severe hemorrhagic cystitis and one with mild hemorrhagic cystitis plus severe gastrointestinal bleeding) (Table 1).

Table 1.  rFVIIa (NovoSeven®) therapy in cyclophosphamide induced severe hemorrhagic cystitis in bone marrow transplantation
 Age/sexDiagnosisCondition Rx (mg g−1)Start of hematuria (day post BMT)Day and dose of NovoSeven® Rx (µg kg−1)Stopping of bleeding
  1. *CML, chronic myelogenous leukemia. †Treatment.

120/MCML*BU 16
CY 206
+ 23+ 26 (200)48 h later
226/MCMLBU 16
CY 200
+ 36 + 74 (100)+ 48 (100)48 h later
39/MThalassemia majorBU 15
CY 200
AGT 40
+ 22 + 56 (400) + 66 (400)+ 36 (400)24 h later
411/FThalassemia majorBU 15
CY 200
AGT 40
+ 30 + 17 (severe GI bleeding)+ 100 (150)12 h later

Several studies have used rFVIIa in non-hemophilic patients with bleeding [2–6] and in hemophilic patients with inhibitor [7–9]. Induction of severe hemorrhagic cystitis by cyclophosphamide was reported to occur in about 5% of patients who underwent BMT [10]. Thus, we had convincing reasons to start rFVIIa as a first experience before beginning invasive procedures, which [10,11] we had used previously for five patients who developed morbidity and mortality. Indeed, we had to use repeated red blood cell transfusions due to severe gross hematuria, which caused the risk of induced infections and was dangerous in these immunologically compromised patients. In case 3, we had to use a higher dose (200 µg kg−1) and more frequent intervals to achieve hemostatic effects (total 1200 µg kg−1) but in case 4, a single dose of 150 µg kg−1 of rFVIIa could stop the bleeding after 12 h.

When rFVIIa is administered, the risk of thrombotic events seems to be low even in high risk clinical situations [2]. Several studies, including Baudo et al. showed the use of rFVIIa to be safe [12,13]. Moreover, it cannot be totally excluded that a plaque rupture occurring at the time of high plasma concentration of rFVII might facilitate the promotion of a thrombose formation at the site of the rupture plaque [14]. In our study, we did not encounter any thromboembolic or other side effects.

We can conclude that treatment with rFVIIa in the mid-range of a total dose of 150–1200 µg kg−1 appears to be effective and safe in patients with severe hemorrhagic cystitis or mild hemorrhagic cystitis and severe gastrointestinal bleeding (three out of four) and recommend that other risky, painful and unacceptable procedures as well as repeated risky red blood cell transfusions should not be used.

Acknowledgements

We would like to thank the Office of the Vice Chancellor for Research and the Center for Development of Clinical Studies of the Shiraz University of Medical Sciences for financial support, Professor Ulla Hedner for her fruitful advice, and Dr Davood Mehrabani for editorial assistance. The authors received no financial support and have no financial relationship with Novo Nordisk.

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