Successful bone marrow transplantation for severe aplastic anemia following orthotopic liver transplantation: long-term follow-up and outcome

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.     

Enhancement by dimethyl myleran of donor type chimerism in murine recipients of bone marrow allografts

A major problem in using murine models for studies of bone marrow allograft rejection in leukemia patients is the narrow margin in which graft rejection can be analyzed. In mice irradiated with greater than 9 Gy total body irradiation (TBI) rejection is minimal, whereas after administration of 8 Gy TBI, which spares a significant number of clonable T cells, a substantial frequency of host stem cells can also be detected. In current murine models, unlike in humans, bone marrow allograft rejection is generally associated with full autologous hematopoietic reconstitution. In the present study, we investigated the effect of the myeloablative drug dimethyl myleran (DMM) on chimerism status following transplantation of T cell-depleted allogenic bone marrow (using C57BL/6 donors and C3H/HeJ recipients, conditioned with 8 Gy TBI). Donor type chimerism 1 to 2 months post-transplant of 1 to 3 x 10(6) bone marrow cells was markedly enhanced by using DMM one day after TBI and prior to transplantation. Conditioning with cyclophosphamide instead of DMM, in combination with 8 Gy TBI, did not enhance engraftment of donor type cells. Artificial reconstitution of T cells, after conditioning with TBI plus DMM, by adding mature thymocytes, or presensitization with irradiated donor type spleen cells 1 week before TBI and DMM, led to strong graft rejection and consequently to severe anemia. The anti-donor responses in these models were proportional to the number of added T cells and to the number of cells used for presensitization, and they could be neutralized by increasing the bone marrow inoculum. These results demonstrate the potential of DMM to facilitate engraftment in unsensitized mice in which the host stem cells may compete with donor type cells; the use of DMM to create models in which mechanisms of immune rejection can be studied without interference due to stem cell competition; and that bone marrow allograft rejection may be overcome by increasing the bone marrow inoculum in these stringent models.     

Porphyria cutanea tarda after allogeneic bone marrow transplantation for chronic myelogenous leukemia

A case of porphyria cutanea tarda (PCT) occurring after bone marrow transplantation (BMT) is reported. A 43-year-old male with chronic myelogenous leukemia received an human leukocyte antigen (HLA)-identical allogeneic transplantation with T-cell depleted marrow. Because of graft rejection, a second transplant was performed 4 months later. A grade II acute graft- vs.-host disease and a cytomegalovirus (CMV) infection were subsequently observed. Two years after the second transplant, cutaneous symptoms of PCT with typical biochemical abnormalities developed. Liver biopsy revealed signs of hepatitis with iron overload. CMV was isolated from liver tissue. The possible roles of underlying disease, BMT, and CMV liver disease are discussed in view of the recently reported cases of PCT in patients with AIDS or hematological disorders.     

Hepatitis C virus reinfection in allografts after orthotopic liver transplantation.

From September 1988 to May 1991, 160 orthotopic liver transplantations were performed in our hospital. Twenty-four patients had end-stage cirrhosis caused by chronic non-A, non-B hepatitis. Antibodies against hepatitis C virus were documented before and after orthotopic liver transplantation in 13 patients. Studies using the polymerase chain reaction demonstrated hepatitis C virus RNA in the serum and liver tissue of 17 patients (10 of whom tested positive for hepatitis C virus antibodies) before orthotopic liver transplantation. Tissue samples taken from liver grafts during the operation were hepatitis C virus RNA negative in every case. Ten of these 17 patients had positive hepatitis C virus RNA findings in serum and liver biopsy specimens within the first month after surgery. One patient died of Mucor sepsis 2 mo after orthotopic liver transplantation. Another patient died of multi-organ failure 3 mo after a retransplantation. Two patients underwent retransplantation for graft rejection at 2 and 3 mo, respectively. One year after orthotopic liver transplantation, hepatitis C virus RNA was demonstrated in allograft biopsy specimens in 13 of 15 patients. Two patients remained hepatitis C virus RNA negative in repeated biopsies up to 12 mo. Mild portal and lobular hepatitis developed within 6 months of orthotopic liver transplantation in four patients and within 1 yr in five additional patients. The data suggest that persistent hepatitis C virus reinfects the allograft in most cases, but the risk of acute organ damage caused by hepatitis C virus reinfection is low.     

Bone marrow transplantation in beta-thalassemia major. The Israeli experience

The present report summarizes our experience in applying a new approach in bone marrow transplantation for the treatment of beta-thalassemia major. Ex-vivo pretransplant T-lymphocyte depletion with CAMPATH-1 was used for prevention of acute and chronic graft versus host disease and total lymphoid irradiation was added for the conditioning regimen for abrogation of potential rejection of T-cell depleted marrow allografts. Ten patients with homozygous beta-thalassemia major were 9-48 months of age (median 18.5 months) and received HLA-identical allogeneic T-cell depleted marrow after treatment with total lymphoid irradiation, busulfan and cyclophosphamide. Seven patients are alive and free of disease, 3-46 months post-transplantation. The actuarial probability of survival and of disease-free survival at two years was 70%. Three patients died: one of intracranial hemorrhage post-transplantation, one from busulfan interstitial pneumonitis, and one who rejected the first graft and developed fatal chronic graft versus host disease after a second transplant. Seven patients are alive and well with follow-up of 3-45 months, with no signs of acute or chronic GVHD. We conclude that T-cell depleted bone marrow transplantation is indicated for homozygous transfusion dependent young patients with beta-thalassemia who are minimally transfused, particularly in areas where optimal conventional therapy is not feasible.     

Gastroesophageal reflux as a reversible cause of allograft dysfunction after lung transplantation

Gastroesophageal reflux (GER) is increasingly recognized as contributing to a number of pulmonary disorders. The relationship of GER to pulmonary allograft dysfunction after lung transplantation is unknown. In this report, we describe a lung transplant recipient who developed an acute decline in pulmonary function several months after a retransplantation for chronic rejection. A pulmonary workup at that time, including bronchoscopy with biopsy, revealed bronchial inflammation with no allograft rejection or infection. Because of increasing GI symptoms after retransplantation, the patient also underwent additional testing, which revealed severe acid reflux. The treatment of this patient's acid reflux with Nissen fundoplication surgery resulted in a prompt and sustained improvement in his pulmonary function. We suggest that GER should be considered among the potential causes of allograft dysfunction after lung transplantation.     

Bone Mrrow Transplantation in β-Twiassemia Major the Israeli Experience

The present report summarizes our experience in applying a new approach in bone marrow transplantation for the treatment of β-thalassemia major. Ex-vivo pretransplant T-lymphocyte depletion with CAMPATH-1 was used for prevention of acute and chronic graft versus host disease and total lymphoid irradiation was added for the conditioning regimen for aborgation of potential rejection of T-cell depleted marrow allografts. Ten patients with homozygous β-thalassemia major were 9–48 months of age (median 18.5 months) and received HLA-identical allogeneic T-cell depleted marrow after treatment with total lymphoid irradiation, busulfan and cyclophos-phamide. Seven patients are alive and free of disease, 3–46 months post-transplantation. The actuarial probability of survival and of disease-free survival at two years was 70%. Three patients died: one of intracranial hemorrhage post-transplantation, one from busulfan interstitial pneumonitis, and one who rejected the first graft and developed fatal chronic graft versus host disease after a second transplant. Seven patients are alive and well with follow-up of 3–45 months, with no signs of acute or chronic GVHD. We conclude that T-cell depleted bone marrow transplantation is indicated for homozygous transfusion dependent young patients with β-thalassemia who are minimally transfused, particularly in areas where optimal conventional therapy is not feasible.     

Transient B lymphocytosis associated to hepatitis B after allogeneic bone marrow transplantation

A 42-year-old male suffered from AML (M2) and achieved remission with chemotherapy. After that, he was successfully treated with allogeneic bone marrow transplantation. About eight months later, jaundice and general malaise developed and diagnosis of acute hepatitis B type was made based on laboratory findings. After 3 months of a conservative therapy, he recovered from the disease. During the clinical course of the hepatitis, B lymphocytes were increased to about 70% of peripheral blood lymphocytes (PBLs) transiently, and furthermore CD5 positive B lymphocytes occupied 12% of the PBLs at that time. This B lymphocytosis disappeared gradually along with the improvement of the hepatitis. The remarkable increase of B lymphocytes in PBLs was considered to be an abnormal reaction induced by HB virus infection, when his immune system was in the recovering phase after bone marrow transplantation.     

Transplantation with allogenic bone marrow from a donor with systemic lupus erythematosus (SLE): successful outcome in the recipient and induction of an SLE flare in the donor.

OBJECTIVE: To investigate the transfer of autoimmunity by allogenic bone marrow transplantation. METHODS: Bone marrow transplantation was performed in a 43 years old man with acute myeloid leukaemia (AML) in remission. The donor was his HLA identical brother who had a mild systemic lupus erythematosus (SLE). Autoantibodies, including antinuclear, anti-C1q, and anticardiolipin antibodies, were measured before and after transplantation. RESULTS: Transient mild graft versus host disease (GvHD) developed in the recipient in the weeks following transplantation. The donor had persistently high concentrations of anti-C1q antibodies to the collagenous region of the complement component C1q. Three months after transplantation the recipient developed antiC1q antibodies that persisted for two months. No other autoantibodies and no SLE-like manifestations appeared. Chronic GVHD started five months posttransplant and responded to intensified immunosuppressive treatment. Three years post-transplant the patient was in unmaintained remission. Within a few weeks after bone marrow donation the donor's disease was exacerbated with development of severe pulmonary alveolitis which required treatment with cyclophosphamide. CONCLUSIONS: When bone marrow transplantation was performed in a patient with AML with bone marrow from an HLA identical brother who had SLE, no evidence of transfer of disease was obtained. However, the recipient temporarily produced anti-C1q antibodies which was a characteristic feature of the donor's SLE and was probably produced by the transplant. The flare of the donor's SLE might be related to the bone marrow tap.     

APLASTIC ANEMIA: ANALYSIS OF TWO METHODS OF TREATMENT

Between 1981 and 1985, 27 patients with aplastic anemia have been treated by immunosuppression with antilymphocyte globulin and prednisolone or allogeneic bone marrow transplantation. Fifteen have undergone bone marrow transplantation and have an actuarial survival at 54 months of 65%± 12% (95% confidence limits). There have been four deaths from graft rejection, septicemia (two), and graft-versus-host disease. Twelve have received antilymphocyte globulin and have an actuarial survival at 56 months of 67%± 21 %. Five of these now have a normal blood count and two have had good partial responses and are self supporting. Of the five non-responders, three survived, two with persistent aplasia and one after allogeneic bone marrow transplantation. Two are dead, one of hemorrhage and one after mismatched bone marrow transplantation. In this study antilymphocyte globulin produced survival equivalent to bone marrow transplantation although only 58% of patients had a response to the antilymphocyte globulin. The advantages and disadvantages of these two methods of treatment are discussed. (Aust NZ J Med 1986; 16: 470–474.)     

Organ tolerance following cadaveric liver transplantation for chronic graft-versus-host disease after allogeneic bone marrow transplantation

A paediatric patient was treated with orthotopic liver transplantation after he developed cirrhosis of the liver due to chronic graft-versus-host disease (GVHD) following allogeneic bone marrow transplantation. His pre-existing chronic GVHD of the skin disappeared and immunosuppressive therapy could be gradually tapered and finally withdrawn 71 months after liver transplantation. Two and a half years after discontinuation of all immunosuppressive therapy, the patient is in excellent condition with neither signs of chronic GVHD nor rejection of the liver graft.     

Current concepts on cytomegalovirus infection after liver transplantation

Cytomegalovirus (CMV) is the most common viral pathogen that negatively impacts on the outcome of liver transplantation. CMV cause febrile illness often accompanied by bone marrow suppression, and in some cases, invades tissues including the transplanted allograft. In addition, CMV has been significantly associated with an increased predisposition to allograft rejection, accelerated hepatitis C recurrence, and other opportunistic infections, as well as reduced overall patient and allograft survival. To negate the adverse effects of CMV on outcome, its prevention, whether through antiviral prophylaxis or preemptive therapy, is regarded as an essential component to the medical management of liver transplant patients. Two recent guidelines have suggested that antiviral prophylaxis or preemptive therapy are similarly effective in preventing CMV disease in modest-risk CMV-seropositive liver transplant recipients, while antiviral prophylaxis is the preferred strategy over preemptive therapy for the prevention of CMV disease in high-risk recipients [CMV-seronegative recipients of liver allografts from CMV-seropositive donors (D+/R-)]. However, antiviral prophylaxis has only delayed the onset of CMV disease in many CMV D+/R- liver transplant recipients, and at least in one study, such occurrence of late-onset primary CMV disease was significantly associated with increased mortality after liver transplantation. Therefore, optimized strategies for prevention are needed, and aggressive treatment of CMV infection and disease should be pursued. The standard treatment of CMV disease consists of intravenous ganciclovir or oral valganciclovir, and if feasible, one should also reduce the degree of immunosuppression. In one recent controlled clinical trial, valganciclovir was found to be as effective and safe as intravenous ganciclovir for the treatment of mild to moderate CMV disease in solid organ (including liver) transplant recipients. In this article, the authors review the current state and the future perspectives of prevention and treatment of CMV disease after liver transplantation.     

Rapid Development of Lymphoma following Liver Transplantation in a Recipient with Hepatitis B and Primary Hemochromatosis

We report a case of a posttransplant lymphoproliferative disorder (PTLD) which presented in a liver allograft shortly after transplantation. The patient, who had been transplanted because of cirrhosis due to primary hemochromatosis and chronic hepatitis B infection (HBV), developed early recurrent HBV in the graft, and 2 months after transplantation, liver biopsies showed a malignant large-cell lymphoma. The neoplastic cells demonstrated Epstein-Barr virus DNA by in situ hybridization. The patient died 3.5 months post-transplant due to liver failure. At autopsy, the liver showed nodules of malignant lymphoma, massive hepatic necrosis, and iron overload, but no evidence of rejection. This report suggests that the grafted liver can be the site of PTLD in recurrent HBV and hemochromatosis.     

Allogeneic bone marrow transplantation after the treatment of alpha-IFN and high-dose SNMC in two cases of acute myeloblastic leukemia with post-transfusional non-A, non-B hepatitis

Two patients of acute myeloblastic leukemia (M2) with post-transfusional hepatitis (non-A, non-B) were treated with alpha-IFN and high-dose SNMC before allogeneic bone marrow transplantation. Bone marrow transplantation from HLA identical and MLR negative sibling donor was carried out when their hepatic functions were almost normalized. In the early phase after bone marrow transplantation, the hepatic function in both two cases has been stable, thus indicating that this treatment should be tried for reducing hepatic dysfunction and for safety bone marrow transplantation.     

Successful T-cell-depleted,related haploidentical peripheral blood stem cell transplantation in a patient with Fanconi anaemia using a fludarabine-based preparative regimen without radiation

Haematopoietic stem cell transplantation (HSCT) represents the treatment of choice for severe bone marrow failure in patients with Fanconi anaemia (FA). When the donor is a compatible relative, the chance of being cured with an allograft is in the order of 70%. However, for FA children lacking an HLA-identical sibling, the results of HSCT from an alternative donor are less satisfactory because of a higher risk of graft rejection, graft-versus-host-disease (GVHD) and regimen-related toxicity. We report on a 12-year-old girl with FA, who was treated by T-cell-depleted (TCD) peripheral blood HSCT from her haploidentical uncle, using a novel fludarabine-based preparative regimen without radiation. She had rapid engraftment with no toxicity and no GVHD. Progressive recovery of both numbers of lymphocyte and of proliferative response to polyclonal activators occurred over time. At 18 months after transplantation, she is well with 100% donor chimerism and has recovered normal immune function.     

Different repopulation kinetics of erythroid (BFU-E), myeloid (CFU-GM) and T lymphocyte (TL-CFU) progenitor cells after autologous and allogeneic bone marrow transplantation

Marrow recovery of erythroid (BFU-E), myeloid (CFU-GM) and T-lymphocyte (TL-CFU) progenitor cells was studied at various time intervals after autologous bone marrow transplantation in 10 patients with acute myeloid leukaemia in remission. These data were compared with those in 14 recipients of T-cell depleted allogeneic marrow grafts. The results indicate markedly different repopulation kinetics of BFU-E, CFU-GM and TL-CFU after autologous and allogeneic bone marrow transplantation. Following autografting reduced numbers of BFU-E and CFU-GM were always present at 2 months after transplantation. Between 2-6 and 6-24 months a gradual increase occurred, although reduced BFU-E and CFU-GM values were still noted in 50% of the cases in spite of normal bone marrow cellularity and restoration of peripheral blood counts. In contrast, in the allograft recipients normal BFU-E numbers appeared within 2 months after transplantation. In addition, CFU-GM values had become normal in 35% of the tests performed at 1-2 months and respectively in 66% and 100% at 2-6 and 6-24 months. The recovery pattern of TL-CFU differed from that of the other haemopoietic progenitor cells. TL-CFU showed a fast recovery, i.e. within 1 month after autologous bone marrow transplantation which was much more rapid than that of BFU-E and CFU-GM. After allografting, however, TL-CFU regenerated at a slower rate and reached normal levels between 2 and 6 months after transplantation. We suggest that the delayed restoration of myeloid and erythroid progenitor cells after autologous transplantation is related to a proliferative defect of the graft as a result of the preceding cytotoxic chemotherapy, the underlying malignant disease and/or cryopreservation. The slower recovery of the T lymphocyte precursors after allografting might be due to the immunological interactions between graft and host, the immuno-suppressive therapy and/or the in vitro T cell depletion of the graft.     

Recovery of splenic function after gvhd-associated functional asplenia

An adolescent male patient developed functional asplenia in the course of graft versus host disease (GVHD) after successful allogeneic bone marrow transplantation (BMT) for aplastic anemia. Coincident with the onset of the asplenia, amelioration of the ongoing GVHD was observed. Unexpectedly, after 34 months of functional asplenia, the organ regained its function without evidence of graft rejection or reactivation of GVHD.     

Obstructive jaundice after bone marrow transplantation.

Jaundice after bone marrow transplantation is usually a consequence of graft versus host disease. Reported is a patient who presented with obstructive jaundice several months after a successful marrow allograft. Despite a benign bone marrow examination, abdominal ultrasound, upper gastrointestinal series, and endoscopic biopsy were utilized to diagnose recurrent leukemia at the pancreatic head and descending duodenum. The entities of graft versus host disease as related to jaundice, and gastrointestinal leukemia, in the presence of a "remission" bone marrow, are reviewed.