Treatment of Severe Hemorrhagic Cystitis after Allogeneic Stem Cell Transplantation with Palifermin, a Recombinant Human Keratinocyte Growth Factor (2007)

Hemorrhagic cystitis (HC) is common after high-dose therapy and allogeneic stem cell transplantation [1Nevo S. Swan V. Enger C. et al.Acute bleeding after bone marrow transplantation (BMT)—incidence and effect on survival A quantitative analysis in 1,402 patients.Blood. 1998; 91: 1469-1477PubMed Google Scholar, 2El-Zimaity M. Saliba R. Chan K. et al.Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: donor type matters.Blood. 2004; 103: 4674-4680Crossref PubMed Scopus (97) Google Scholar]. The severity of this complication ranges from asymptomatic macrohematuria to excessively painful and sometimes life-threatening bleeding. Direct toxicity from cytotoxic agents like cyclophosphamide and reactivation of a latent infection with polioma or adenovirus during episodes of profound immunosuppression are supposed to be involved in its pathogenesis [3deVries C.R. Freiha F.S. Hemorrhagic cystitis: a review.J Urol. 1990; 143: 1-9Crossref PubMed Scopus (192) Google Scholar, 4Tsuboi K. Kishi K. Ohmachi K. et al.Multivariate analysis of risk factors for hemorrhagic cystitis after hematopoietic stem cell transplantation.Bone Marrow Transplant. 2003; 32: 903-907Crossref PubMed Scopus (46) Google Scholar]. Once diagnosis has been made, the treatment of hemorrhagic cystitis is polypragmatic and often ineffective. Palifermin is a recombinant human keratinocyte growth factor (KGF), a member of the fibroblast growth factor (FGF) family, which binds specifically to the human KGF receptor and induces proliferation and differentiation of epithelial cells, including gastrointestinal epithelial cells, hepatocytes, type II pneumocytes, and transitional urothelial cells [5Finch P.W. Rubin J.S. Miki T. Ron D. Aaronson S.A. Human KGF is FGF-related with properties of a paracrine effector of epithelial cell growth.Science. 1989; 245: 752-755Crossref PubMed Scopus (815) Google Scholar]. It has been approved for prophylaxis of oral and gastrointestinal mucositis in the context of high-dose therapy and autologous as well as allogeneic stem cell transplantation [6Gorczynska E. Turkiewicz D. Rybka K. et al.Incidence, clinical outcome, and management of virus-induced hemorrhagic cystitis in children and adolescents after allogeneic hematopoietic cell transplantation.Biol Blood Marrow Transplant. 2005; 11: 797-804Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar]. We here describe the first successful treatment of severere hemorrhagic cystitis with Palifermin. A-24-year old man suffered from refractory T-acute lymphoblastic leukemia (ALL). He achieved a first remission after experimental treatment with Ara-G, and received an allogeneic stem cell transplant from an unrelated donor following conditioning with Fludarabine, high-dose Cytarabine, Amsacrine, and total body irradiation (TBI) (12 Gy). The early clinical course was uneventful and the patient had hematopoietic reconstitution of white blood cells (WBC) on day +14. The patient’s blood was weekly screened for cytomegalovirus (CMV), Ebstein-Barr virus (EBV), adenovirus, herpes simplex virus type-1 and -2, human herpes virus 6, and BK-virus (BKV) infections with all negative results. Twenty-five days after transplantation, he developed acute graft-versus-host disease (aGVHD) III grade of the skin and gastrointestional (GI) tract, which responded to combined therapy with steroids and basiliximab. Steroids could be discontinued on day +33 with resolving of GVHD of the GI tract. The GVHD of the skin did not resolve completely, but became chronic and needed an ongoing posttransplant immunosuppression with Cyclosporin A (CSA), maintaining serum levels between 150 and 50 mg/dL. Because of this prolonged immunosuppressive therapy, immune reconstitution is still incomplete within all T-lymphocyte subsets. On day +33 the patient developed painful hematuria. At that time, urine was positive for BKV (1.5 × 108 copies/mL). The treatment was initiated promptly and consisted of permanent bladder irrigation (200 L/day), Cidofovir (375 mg) (on days +33, +40, +57, +75, and +85) and intravenous immunoglobulins (30 g per dose). Cystoscopic evaluation showed diffuse multifocal inflammation and bleeding. Clinical and laboratory findings were consistent with the diagnosis of severe posttransplant hemorrhagic cystitis. Despite treatment, the clinical condition worsened and the patient needed up to 8 units of packed red blood cells (PRBCs) per day to maintain a hemoglobin level of >5 g/dL. At this time point we decided to introduce a combined treatment with oral estrogens (5 mg/day) and Palifermin (60 μg/kg, 3 days a week). Estrogens had to be stopped after 7 days because of severe liver toxicity, but KGF was well tolerated. A few days after starting Palifermin, bleeding severity improved and repeated cystoscopy now showed more localized leasons that were tried to coagulate. In addition, Uropol S, a chondroitin sulphate, was given intravesically on several occasions. However, bleeding intermittently continued and the patient received 12 more doses of Palifermin. Finally, bleeding stopped and bladder irrigation could be discontinued after 96 days. A few days later hematuria reappeared, but resolved after additional treatment with Palifermin (see Figure 1). At present, the patient is alive in remission without HC 463 days after transplantation. Hemorrhagic cystitis is a severe and potentially life-threatening complication after allogeneic stem cell transplantation [1Nevo S. Swan V. Enger C. et al.Acute bleeding after bone marrow transplantation (BMT)—incidence and effect on survival A quantitative analysis in 1,402 patients.Blood. 1998; 91: 1469-1477PubMed Google Scholar]. Pathogenesis is not fully understood, but there is some evidence that three elements are essential for the development of HC: damage to the bladder epithelium, BK-virus replication, and alloimmunity [7Priftakis P. Bogdanovic G. Kokhaei P. Mellstedt H. Dalianis T. BK virus (BKV) quantification in urine samples of bone marrow transplanted patients is helpful for diagnosis of hemorrhagic cystitis, although wide individual variations exist.J Clin Virol. 2003; 26: 71-77Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 8Sencer S.F. Haake R.J. Weisdorf D.J. Hemorrhagic cystitis after bone marrow transplantation Risk factors and complications.Transplantation. 1993; 56: 875-879Crossref PubMed Scopus (126) Google Scholar]. Consequently, treatment has tried to aim at virus replication, which has been successful in some cases. However, a large proportion of patients do not respond to antiviral therapy, and the remaining therapeutic options are rather empiric and include systemic estrogens, instillation of formalin, or even cystektomy [9Garderet L. Bittencourt H. Sebe P. et al.Cystectomy for severe hemorrhagic cystitis in allogeneic stem cell transplant recipients.Transplantation. 2000; 70: 1807-1811Crossref PubMed Scopus (41) Google Scholar]. Once established, there is constant destruction of urothelium either because of viral replication or as a result of alloimmune cytolytic mechanisms. KGF may be able to modify this process and improve wound healing as has been shown in other experimental models of bladder injury. Palifermin is a human KGF that acts on several epithelial tissues. It has been approved to reduce mucositis after high-dose therapy and stem cell transplantation. Several authors have demonstrated a proliferative and antiapoptotic effect on human urothelium. Using an animal model, Ulich et al. [10Ulich T.R. Whitcomb L. Tang W. et al.Keratinocyte growth factor ameliorates cyclophosphamide-induced ulcerative hemorrhagic cystitis.Cancer Res. 1997; 57: 472-475PubMed Google Scholar] could demonstrate that HC induced by cyclophosphamide could almost completely be prevented by the application of KGF before chemotherapy. It is tempting to suggest, that a combination of antiviral therapy and protection of the bladder epithelium by Palifermin may be more successful than conventional therapy for HC. We have used KGF to treat severe HC late in the course of the disease in a patient where antiviral and supportive therapy alone was not effective. KGF may be even more effective when used earlier, that is, at first occurrence of hematuria or even prophylactically in patients with extraordinary high BKV titers. Although unlikely, we cannot rule out that the short course of estrogens, coagulation, or instillation of Uropol S also contributed to the final resolution of HC in our patient. However, timing of these interventions and the known cytoprotective and proliferative effects of KGF suggests, that Palifermin may be an important component in a combined modality approach combining antiviral and growth factor therapy to treat HC after allogeneic stem cell transplantation.