Successful application of epidermal growth factor for treatment of hemorrhagic cystitis after bone marrow transplantation

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Hemorrhagic cystitis (HC) is a common complication after bone marrow transplantation, with an incidence that varies from 7 to 68% in different reports. It can occur early or late after transplantation. Early onset of HC has been associated mainly with administration of cyclophosphamide and busulfan. These drugs can damage the uroepithelium directly, or through metabolites, whereas late onset (2–3 months after transplant) HC has been related instead to reactivation of virus infection.1

Initial treatment is usually forced diuresis and continuous bladder irrigation (CBI). Other measures like MESNA and prostaglandins are still under debate.2 Some authors reported encouraging results using hyperbaric therapy.3 Recently, recombinant human granulocyte–macrophage colony-stimulating factor (rhGM-CSF) in intravesical instillation has been reported for the treatment of HC.4 Generally, HC can be managed by medical therapy but in cases of refractoriness it may require cystotomy or cystectomy.

Until now various measures for prevention and treatment of HC have been reported, but the most effective treatment remains to be established.

Recombinant human epidermal growth factor (rh EGF) is a cytoprotective agent that acts as a potent stimulant for repair of cells in ex vivo and in vivo models. It has been useful in the protection and treatment of gastrointestinal, liver, renal, peripheral nervous system, corneal epithelium and skin injuries. The mechanism(s) by which EGF exerts these effects is, however, unclear. EGF influences multiple systems which might be important in mediating these effects, including upregulation of prostaglandins and mucus production, upregulation of superoxide dismutase (thereby reducing free radicals induced toxicity) and influencing stress-associated protein kinase.5

Here we report a 15 year-old boy diagnosed in May 2000 with Philadelphia positive chronic myeloid leukemia in chronic phase. In July of 2001, the patient received a bone marrow transplant from his HLA identical, but ABO major incompatible, sister. Conditioning regimen was busulfan (16 mg/kg × 4 days) and cyclophosphamide (60 mg/kg × 2 days); mesna (2-mercaptoethane-sulfonate) 40 mg/kg × 2 days; hyperhydration (dextrose 5% 3000 ml/m2/day) and forced diuresis (furosemide 2 mg/kg per day) were used for the prevention of HC. Renal function before transplantation was normal according to blood chemistry, ultrasonographic, and urine analysis.

The neutrophils rose to >500 × 109/l on day +19, and platelets >50 × 109/l on day +23. On day +12 the patient developed a gross hematuria with clots (HC grade II, according to Brugieres et al).6 Bacteriological and virological urine analyses were performed with negative results. Hyperhydration and CBI with saline solution were started. The patient showed slight improvement and symptoms became intermittent, but with frequent blood transfusions (25 units since the beginning of the hematuria) for support of blood loss. On day +45 the hematuria was severe and 2 days after the patient had a urethral obstruction (HC grade III). A cystotomy was performed with insertion of large suprapubic catheters and CBI, because of recurrent clot retention. During the surgical intervention, a large clot was removed from the bladder and several hemorrhage points in the bladder endothelium were detected.

On day +51 we started treatment with rh EGF supplied by HerberBiot SA (Havana, Cuba) in a dose of 2 mg /day in CBI, that was increased to 5 mg/day on day +55. After 4 days, the macroscopic and microscopic hematuria completely disappeared, and the dose of EGF was tapered off until day +67, (total duration of treatment was 12 days), when the suprapubic catheters were removed. No other treatments, except CBI, were used before EGF.

The patient has been followed for up to 5 months without HC recurrence. Neither systemic nor bladder side effects were observed.

To our current knowledge, no report has previously communicated the use of EGF in patients with HC. Our result suggests that intravesical instillation of EGF may be effective in the treatment of HC, but further studies are needed in order to confirm our observation.

References

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    Laslo D, Bosi A, Guidi S et al. Prostaglandin E2 bladder instillation for the treatment of hemorrhagic cystitis after allogenic bone marrow transplantation. Haematologica 1995; 80: 421–425.

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    Hughes AJ, Schwarer AP, Millar IL et al. Hyperbaric oxygen in the treatment of refractory haemorrhagic cystitis. Bone Marrow Transplant 1998; 22: 585–586.

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    Vela-Ojeda J, Tripp-Villanueva F, Sánchez-Cortes E et al. Intravesical rhGM-CSF for the treatment of late onset hemorrhagic cystitis after bone marrow transplant. Bone Marrow Transplant 1999; 24: 1307–1310.

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    Brugieres L, Hartmann O, Travagli JP et al. Hemorrhagic cystitis following high-dose chemotherapy and bone marrow transplantation in children with malignancies: incidence clinical course and outcome. J Clin Oncol 1989; 7: 194–199.

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Correspondence to E Dorticós.

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Dorticós, E., Pavón, V., Jaime, J. et al. Successful application of epidermal growth factor for treatment of hemorrhagic cystitis after bone marrow transplantation. Bone Marrow Transplant 31, 615–616 (2003) doi:10.1038/sj.bmt.1703877

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