Severe aplastic anemia (SAA) is well described in children following liver transplantation for fulminant hepatic failure (FHF) secondary to non-A, non-B, non-C hepatitis, and is associated with a high mortality rate. Successful immunosuppressive treatment of SAA following liver transplantation has been reported, but death from infectious complications is not uncommon. We report the 8-year follow-up of a 3.5-year-old boy who underwent successful HLA-identical sibling donor bone marrow transplant for SAA 7 months following orthotopic liver transplant for non-A, non-B, non-C hepatitis. His post-bone marrow transplantation course was uneventful with no evidence of liver toxicity. Eight months following BMT he developed renal cell carcinoma metastatic to lymph nodes which was treated surgically. Six years following BMT he developed a mucoepidermoid carcinoma of the parotid gland also treated surgically. Despite these malignancies, he is currently well 8 years following liver and bone marrow transplantation, without signs of GVHD, growth failure or liver graft rejection. This is the first report of long-term follow-up of bone marrow transplantation for SAA following liver transplantation. The occurrence of two subsequent malignancies in this child underscores the need for close follow-up of future similar cases. Bone Marrow Transplantation (2001) 28, 523–526.
Severe aplastic anemia (SAA) has been reported in as many as one-third of children who undergo liver transplantation for fulminant hepatic failure (FHF) secondary to non-typeable viral hepatitis.1,2 This complication has been noted to be significantly more frequent among children than adults, and mortality is high. Clinical experience suggests that aplastic anemia is a complication of the underlying disease which led to hepatic failure, rather than due to the process of transplantation, as SAA does not generally occur following liver transplantation for other reasons. The cause of non-A, non-B, non-C hepatitis is unclear; parvovirus B19 has been suggested as an etiologic candidate for at least some cases.3 Outcomes for patients whose aplastic anemia was treated with immunosuppressive agents have varied.1,2 Full hematologic recovery following immunosuppression has been reported, however time to recovery is often on the order of several months to years.1,2 Sato et al4 recently described a child successfully treated with growth factors and immunosuppression for SAA which developed following living-related orthotopic liver transplantation for FHF. The patient remained well at 1-year follow-up. However, others have reported mortality rates of 40–50% during courses of immunosuppressive therapy, due primarily to infectious complications.1,2 In this report, we describe the 8-year follow-up of an 11-year-old boy who underwent orthotopic cadaveric liver transplantation at the age of 3.5 years for fulminant hepatic failure secondary to non-A, non-B, non-C hepatitis, followed by sibling donor BMT for SAA.
In April 1993, a 3.5-year-old boy presented to his local hospital with jaundice, acholic stools, and dark yellow urine. Initial laboratory studies revealed markedly elevated alanine aminotransferase (1836 U/l), aspartate aminotransferase (1876 U/l), bilirubin (26.8 mg/dl), ammonia (96 μmol/l), and abnormal coagulation studies (PTT = 49.6 s (normal range 23–34 s), PT = 20 s (normal range 11–13.5 s)). Complete blood counts, metabolic panel, abdominal ultrasound and CT of the liver were within normal limits. Serology for hepatitis A, B and C were negative. He was disoriented and combative, and was transferred to the University of Minnesota for further evaluation.
The patient was diagnosed with fulminant hepatic failure (FHF) of unknown etiology. Ten months prior to the development of FHF he was exposed to a mixed chemical spill which occurred following a train derailment; benzene comprised 44% of the chemicals involved.5 One month after presenting with FHF, the patient underwent orthotopic cadaveric liver tranplantation. The patient's and liver graft's ABO typing were both O+. Pathologic evaluation of his liver showed massive necrosis with no identifiable hepatocytes, and lymphocytic inflammation involving both the extrahepatic and intrahepatic biliary ductular epithelium. He tolerated the procedure well without complication. He was treated with azathioprine and prednisone for immunosuppression. In the immediate post-liver transplant period, he had an episode of enterococcus bacteremia, a questionable seizure episode, and a liver biopsy-proven CMV infection treated with ganciclovir.
Two months following transplantation, pancytopenia was noted at a routine follow-up visit (WBC = 1.5, Hb = 9.9, platelets = 140). Azathioprine and trimethoprim-sulfamethoxazole were held and his immunosuppressive regimen was changed to low-dose prednisone and CsA. His pancytopenia continued to worsen (WBC = 2.2, Hb = 8.3, platelets = 16) and a bone marrow biopsy was performed. The findings were consistent with severe aplastic anemia with cellularity of less than 5%, and no evidence of malignancy or myelodysplasia. His aplasia showed no response to treatment with courses of G-CSF, ATG, prednisone and CsA.
Seven months following liver transplantation, the patient underwent a 6/6 HLA-A, B, DRB1-matched bone marrow transplantation from his brother. As mentioned above, the patient's ABO typing was O+; his brother's was A+. His preparative regimen consisted of total lymphoid irradiation (TLI, 750 rads) and cyclophosphamide (200 mg/kg). His transplanted liver was not shielded from irradiation. GVHD prophylaxis consisted of four doses of methotrexate and CsA. His immediate post-BMT course was relatively uncomplicated with no evidence of veno-occlusive disease of the liver, liver rejection or hepatic GVHD. In the immediate post-BMT period, CSA levels were maintained in the 200–400 μg/l range. Subsequently, CSA dosing was adjusted and continues as immunosuppression for his liver graft with levels kept in the 40–100 μg/l range. Low-dose prednisone (0.4 mg/kg) was continued during BMT, and continues now for liver prophylaxis (0.08 mg/kg).
Eight months after BMT (15 months post liver transplantation), an abnormal density in the anterior mid portion of the right kidney was noted on CT scan. CT-guided biopsy revealed renal cell carcinoma. Chest CT and bone scan showed no evidence of distant metastases. This tumor arose in an area which was shielded during the previous TLI. He underwent partial nephrectomy with removal of a 5-cm renal cell carcinoma. A hilar lymph node was found to be positive for renal cell carcinoma. One month following surgery he was found to have a new mass and lymph nodes in the area of the previous renal cell carcinoma. Two months following the original partial nephrectomy he underwent right radical nephrectomy and lymph node dissection. The excised lymph nodes contained metastatic renal cell carcinoma. He recovered well from surgery and follow-up scans have remained negative with no further evidence of renal cell carcinoma.
The patient remained well until 10 years of age (6 years post-BMT) when he developed a swelling in his left cheek. CT scans revealed a parotid mass, which was resected completely and found to be low-grade mucoepidermoid carcinoma (MEC) of the parotid gland. This tumor developed outside the field of previous TLI. At annual review, he is currently well with full donor hematopoiesis, normal blood counts and liver function tests, and no evidence of malignancy. He is in age-appropriate schooling and receives treatment for attention-deficit disorder. He continues on CsA and prednisone for immunosuppression for his liver transplant.
Successful allogeneic bone marrow transplantation in pediatric patients developing severe aplastic anemia following orthotopic liver transplantation has been described in three previous cases.6,7,8 Preparative regimens have consisted of cyclophosphamide and ATG. None of these cases have been reported to have developed any signs of GVHD or liver graft rejection, and these patients were reported to be well 1 to 3 years following bone marrow transplantation. This report is the first to describe longer-term follow-up after sequential liver and bone marrow transplantation, and to describe the occurrence of secondary malignancies. Despite the occurrence of two separate carcinomas, one metastatic to lymph nodes, the patient is currently free of disease with an excellent quality of life.
An increased frequency of malignancy after bone marrow transplantation has been described in a number of studies.9,10,11,12,13 The cumulative risk of developing any malignancy following BMT has ranged from 10 to 14%.9,10,11,12 The nature of second malignancies following BMT changes with time from transplantation. The period of greatest risk for developing post-transplant lymphoproliferative disorders (PTLDs) appears to be immediately following BMT, with a plateau 4 years after transplant.11 By contrast, risk of solid tumors following BMT increases progressively with time, and sharply increases 8 to 15 years after transplant.9,10,11,12 The only well-established risk factor associated with the development of solid tumors (most commonly cutaneous, brain and thyroid cancers), is having received irradiation.9,10,11,12,13 Other factors less consistently reported to be associated with risk for the development of solid tumors include younger age at transplantation,9 acute GVHD,10,12 the diagnosis of Fanconi anemia,12 azathioprine therapy,12 and male sex.12 Chronic GVHD may10,12 or may not9,11 place patients at an increased risk. In patients who have received thoraco-abdominal irradiation for severe aplastic anemia, solid tumors have been reported to occur more commonly at the margin of the radiation field.13
Ongoing immunosuppression after liver transplantation might also contribute to the occurrence of these neoplasms. Malignancy developing de novo following solid organ transplantation has been well described.14,15,16,17,18,19,20,21 In renal transplant patients, the overall incidence has been reported to be between 2.3 and 8.9%.15,16,18,19 Data on primary neoplasms after liver transplantation are relatively similar.14,20,21 Specific tumor type varies; overall a higher frequency of cutaneous tumors and lymphoproliferative disorders is observed. Of interest, a Japanese study found their renal transplant patients were susceptible primarily to malignancies of the gastrointestinal tract, with relatively low incidence of skin cancers or lymphomas.16 Overall incidence increases with time, with rates reported as high as 3.9–13% by 10 years post transplantation, and 13.9–34% at 20 years post transplant.16,19 Metastatic renal cell carcinoma following kidney transplant has been previously described in an adult 12 months following transplantation.22
This patient's experience of two carcinomas before the age of 10 years seems greater than would be expected from past reports. It is unclear whether his toxic exposure may have been associated with his liver failure or subsequent malignancies as benzene exposure has usually been associated with hematological malignancy.23 MEC comprises 16% of all salivary gland neoplasms in children, 51% of all malignant salivary tumors.24 Tumors are graded according to a three-tiered system: low, intermediate and high grade. Although prognostic factors in MEC in pediatric patients have not been well defined, histocytologic gradings of low and intermediate are associated with a favorable prognosis compared with high grade. This tumor has been described as a second malignant neoplasm in children with a history of prior radiotherapy and chemotherapy.24,25
It is possible that the combined risk of malignancy associated with both BMT and solid organ transplant increases an individual's overall risk more than the sum of the risk of each procedure alone. In addition, this child might have an otherwise undescribed genetic susceptibility to malignancy, which may also have contributed to susceptibility to FHF and SAA.
This patient was transplanted with a radiation-containing preparative regimen as part of a treatment protocol investigating the use of limited-field radiation in aplastic anemia. Reports from some institutions have implicated radiation in malignancy post bone marrow transplantation;9,10,11,12,13 in this case the parotid malignancy clearly arose at a site outside the radiation field. A study of long-term follow-up of patients with aplastic anemia treated at the University of Minnesota with TLI-containing regimens, in which this patient did not participate, reported no cases of secondary malignancy with a median of 17 years follow-up.26 The use of TLI in the preparative regimen had no adverse effects on the tranplanted liver, and subsequent orthotopic liver transplant recipients transplanted with unrelated donor hematopoietic stem cells at the University of Minnesota have received total body irradiation incorporating the liver without unusual toxicity (unpublished data). Successful transplantation of well-matched stem cells has been reported in patients with aplastic anemia using non-radiation-containing regimens and might be considered in future cases.27
In conclusion, successful sibling bone marrow transplantation for severe aplastic anemia following orthotopic liver transplantation is possible without rejection of the liver graft or excessive liver toxicity. A distinct etiology for the development of this patient's fulminant liver failure, severe aplastic anemia, or ensuing malignancies remains undefined. This case demonstrates the need for careful long-term follow-up of this child and any similar patients receiving solid organ and marrow grafts to document their risk of subsequent malignancy.
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Cite this article
Perkins, J., Neglia, J., Ramsay, N. et al. Successful bone marrow transplantation for severe aplastic anemia following orthotopic liver transplantation: long-term follow-up and outcome. Bone Marrow Transplant 28, 523–526 (2001). https://doi.org/10.1038/sj.bmt.1703177
- fulminant hepatic failure
- non-A, non-B, non-C hepatitis
- orthotopic liver transplantation
- severe aplastic anemia
- bone marrow transplantation
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