Bone Marrow Transplantation (2008) 42, 57–58 & 2008 Macmillan Publishers Limited All rights reserved 0268-3369/08 $30.00
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LETTER TO THE EDITOR
Successful bone marrow transplantation in a girl with Fanconi anemia and preterminal renal failure Bone Marrow Transplantation (2008) 42, 57–58; doi:10.1038/bmt.2008.43; published online 10 March 2008 Fanconi anemia is a hereditary disorder characterized by congenital defects, including urogenital anomalies, progressive bone marrow failure and a high incidence of cancer. Allogeneic BMT is the therapy of choice for Fanconi patients with progressive pancytopenia. Because most conditioning regimens contain potentially nephrotoxic agents, BMT in Fanconi patients with both hematological and renal problems is a challenging procedure. We describe a girl with Fanconi anemia and chronic renal failure who was successfully transplanted from an HLA-identical sibling after an adjusted conditioning regimen consisting of fludarabine and thoracoabdominal irradiation. A 5-year-old girl with Fanconi anemia, diagnosed by a mytomycin C test, in whom a mutation in the FANC-A gene was found, suffered from chronic renal failure (creatinin clearance 22 ml/min/1.73 m2), caused by bilateral vesicoureteral reflux grade V, which is commonly associated with renal dysplasia. Because of progressive bone marrow failure and transfusion dependency, she had an indication for BMT. Her conditioning regimen consisted of fludarabine 15 mg/m2 for 3 days and thoracoabdominal irradiation 4 Gy once. She received unmanipulated full graft bone marrow from her HLA identical sister, with 1.4 106/kg CD34 þ cells and 4.7 107/kg CD3 þ cells. GVHD prophylaxis consisted of mycophenolate mofetil 1800 mg/ m2/day and prednisone 1 mg/kg/day. The post transplant period was uncomplicated. She did not suffer from mucositis or infection in neutropenia. There were no signs of acute GVHD. Renal function remained stable. She engrafted on day þ 37. Chimerism studies, performed from day þ 13, initially showed 28% donor signal, which gradually improved 70 days after transplantation to 95% donor signal and remained stable afterwards (see Table 1). At this moment, 1 year after transplantation, she is in good clinical condition without signs of chronic GVHD, has normal cell counts and has undergone surgical correction of her vesicoureteral reflux. Fanconi anemia is a rare hereditary condition, characterized by progressive bone marrow failure, congenital anomalies, growth retardation and a high susceptibility to several malignancies.1,2 The urinary tract is involved in about 30% of patients with Fanconi anemia.2 However, renal failure is rarely encountered. When pancytopenia arises, BMT is indicated. Results of matched sibling donor transplantations are good with 5
years event-free survival rates of approximately 80%.3 With matched unrelated donor transplantation, recent studies show a 5-year survival of 50–60% if fludarabine-based conditioning is given.4 Because of the increased sensitivity to chemotherapeutic agents and radiation of these patients, doses of conditioning agents have to be reduced to avoid severe toxicity. In our center, we use fludarabine 30 mg/m2 for 5 days (total dose 150 mg/m2), CY 10 mg/kg for 3 days (total dose 30 mg/kg) and antithymocyte globulin (ATG; Genzyme) 2.5 mg for 4 days in both matched sibling donor and matched unrelated donor transplantations. GVHD prophylaxis consists of CYA and short course MTX. The potential nephrotoxic consequences of bone marrow transplantation are well known. Acute renal failure is a frequent event after bone marrow transplantation, occurring in 30–80% of patients.5 Several mechanisms contribute to renal injury: tubular necrosis during sepsis, exposure to nephrotoxic drugs, veno-occlusive disease and transplantassociated microangiopathy can all cause acute renal failure. Radiation nephritis and chronic GVHD associated glomerulonephritis can cause chronic renal failure. CYA contributes markedly to the occurrence of acute renal failure by influencing renal hemodynamics as well as facilitating the occurrence of transplant-associated microangiopathy. All these factors will make BMT in patients already experiencing renal failure a challenging procedure with a serious risk of further deterioration of renal function. To our knowledge, no reports have been published describing allogeneic BMT in children suffering from renal failure prior to transplantation. Only a few case reports regarding adults have been published. Gerrie et al.6 describe three adults with severe aplastic anemia and renal impairment due to IgA nephropathy or CYA toxicity. One patient, conditioned with CY and ATG, died of multi organ failure after significant regimen-related toxicity. The two other patients received a reduced dose of fludarabine, low dose CY (10 mg/kg for 4 days) and alemtuzumab. Mycophenolate mofetil was used as GVHD prophylaxis. Both patients survived and showed 97 and 100% donor engraftment. Hamaki et al.7 described a patient, also suffering from severe aplastic anemia and IgA nephropathy requiring dialysis. He received melphalan 60 mg/m2, ATG 15 mg/kg for 3 days and total lymph node irradiation 4.0 Gy in 2 fractions. GVHD prophylaxis consisted of CYA and prednisolone. He had an uneventful clinical course with full donor engraftment and normal cell counts. Bischoff et al.8 described a patient with Philadelphia chromosome-positive chronic myeloid leukemia and malignant nephrosclerosis. In first chronic phase a matched unrelated donor (MUD)–BMT was performed. He received
Letter to the Editor
58 Table 1
Blood counts and chimerism studies of our patient during the BMT and recovery period
Time point
Hb (mmol/l)
Thrombocytes ( 109/l)
Leukocytes ( 109/l)
Neutrophils ( 109/l)
Chimerism studies (% donor, peripheral blood)
Before start conditioning Day 0 Day +11 (nadir) Day +20 Day +37 (engraftment) Day +51 Day +100 6 months 1 year
3.0 (TD) TD TD TD TD TD 6.2 9.2 8.1
15 TD TD TD TD 24 47 100 150
1.2 0.4 0.3 1.0 1.0 1.5 3.2 5.1 7.9
0.39 0.29 0.17 0.49 0.67 0.94 2.65 4.18 6.45
28 (day +13) 58 77 87 93 96 94
Abbreviation: TD ¼ transfusion dependent.
fractionated TBI (total dose 13.5 Gy) and CY (total dose 120 mg/kg). Follow-up data were not supplied. In our patient, we decided to adjust the conditioning regimen to her poor renal function and to omit potentially nephrotoxic drugs as much as possible to prevent further renal deterioration. Though some authors suggest that CY can be safely given to patients with renal failure, others, including Gerrie et al.,6 describe decreased clearance in patients with renal impairment resulting in severe systemic toxicity.9 For these reasons, we decided to omit CY in our patient. Instead of CY, we added thoracoabdominal irradiation to the conditioning regimen, excluding the kidneys from the radiation field. CYA has been used safely for GVHD prophylaxis in patients with renal failure. However, serious renal toxicity can occur using CYA. Therefore, we decided to give mycophenolate mofetil as GVHD prophylaxis. Because Fanconi patients have a higher risk of developing malignancies later in life when experiencing GVHD,10 we also added prednisone instead of the potentially nephrotoxic MTX. Finally, we adjusted the fludarabine dose and dosages of prophylactic antibiotics to her creatinine clearance. Regarding the initially mixed chimerism, as we expected, our conditioning regimen was not fully myeloablative. However, as the patient is fully engrafted at this moment, this did not adversely influence the outcome of our patient. In conclusion, our case shows that allogeneic BMT after an adjusted conditioning regimen may be feasible in children with Fanconi anemia and significant renal impairment. KMJ Heitink-Polle´1, MR Lilien2 and MB Bierings1 Department of Pediatric Hematology/Oncology, UMCU/ Wilhelmina Children’s Hospital, Utrecht, The Netherlands and 2 Department of Pediatric Nephrology, UMCU/Wilhelmina Children’s Hospital, Utrecht, The Netherlands E-mail:
[email protected] 1
Bone Marrow Transplantation
References 1 Alter BP. Cancer in Fanconi anemia, 1927–2001. Cancer 2003; 97: 425–440. 2 De Kerviler E, Guermazi A, Zagdanski AM, Gluckman E, Frija J. The clinical and radiological features of Fanconi’s anaemia. Clin Radiol 2000; 55: 340–345. 3 Dufour C, Rondelli R, Locatelli F, Miano M, Digirolamo G, Bacigalupo A et al. Stem cell transplantation from HLAmatched related donor for Fanconi’s anaemia: a retrospective review of the multicentric Italian experience on behalf of AIEOP-GITMO. Br J Haematol 2001; 112: 796–805. 4 Wagner JE, Eapen M, MacMillan ML, Harris RE, Pasquini R, Boulad F et al. Unrelated donor bone marrow transplantation for the treatment of Fanconi anemia. Blood 2007; 109: 2256–2262. 5 Noe¨l C, Hazzan M, Noe¨l-Walter MP, Jouet JP. Renal failure and bone marrow transplantation. Nephrol Dial Transplant 1998; 13: 2464–2466. 6 Gerrie A, Marsh J, Lipton JH, Messner H, Gupta V. Marrow transplantation for severe aplastic anemia with significant renal impairment. Bone Marrow Transplant 2007; 39: 311–313. 7 Hamaki T, Katori H, Kami M, Yamato T, Yamakado H, Itoh T et al. Successful allogeneic blood stem cell transplantation for aplastic anemia in a patient with renal insufficiency requiring dialysis. Bone Marrow Transplant 2002; 30: 195–198. 8 Bischoff ME, Blau W, Wagner T, Wagenmann W, Do¨rner O, Basara N et al. Total body irradiation and cyclophosphamide is a conditioning regimen for unrelated bone marrow transplantation in a patient with chronic myelogenous leukemia and renal failure on hemodialysis. Bone Marrow Transplant 1998; 22: 591–593. 9 Haubitz M, Bohenstengel F, Brunkhorst R, Schwab M, Hofmann U, Busse D. Cyclophosphamide pharmacokinetics and dose requirements in patients with renal insufficiency. Kidney Int 2002; 61: 1495–1501. 10 Rosenberg PS, Socie´ G, Blanche PA, Gluckman E. Risk of head and neck squamous cell cancer and death in patients with Fanconi anemia who did and did not receive transplants. Blood 2005; 105: 67–73.
