Apparent cure of Graves-Basedow disease after sibling allogeneic bone marrow transplantation

Evidence that allogeneic bone marrow transplantation (BMT) can cure or alter the course of intractable autoimmune diseases comes from both extensive experimental work in animal models and anecdotal case reports in humans. We describe a female patient diagnosed as having severe aplastic anaemia (SAA), hyperthyroidism and ophthalmopathy of Graves-Basedow disease who received a BMT from her histocompatible sister. Fifty-three months after BMT, complete remission of hyperthyroidism and ocular signs persists. The SAA is cured and she is free of any chronic graft-versus-host disease (GVHD). In the early post-BMT period, PCR analysis of bone marrow and peripheral blood cells confirmed a complete chimerism of donor origin. Thus, it is plausible to attribute the resolution of the patient's thyroid hyperfunction and opththalmopathy to the replacement of the host immune system.     

Relapse of Graves' disease after successful allogeneic bone marrow transplantation.

As shown in many reports, allogeneic BMT can help cure autoimmune diseases. Conversely, we present a 24-year-old woman with Graves' disease, which was diagnosed just before BMT for CML. The Graves' disease remitted immediately after BMT but relapsed 18 months later. Since the donor was free from thyroid diseases and the patient showed a rapid shift to complete donor chimerism after BMT, the autoimmune problem seemed neither to arise directly from the donor nor simply from the recipient's residual lymphocytes. On the contrary, it was most likely compounded by chronic GVHD as suggested by the accompanying GVHD symptoms and the absolute donor karyotype in bone marrow cells. A Graves' disease-susceptible HLA allele was also shared between recipient and donor, possibly enhancing the chances of this condition developing. Thus, allogeneic BMT may facilitate relapses in autoimmune diseases as well as alleviating them.     

Adoptive autoimmune hyperthyroidism following allogeneic stem cell transplantation from an HLA-identical sibling with Graves' disease.

Autoimmune diseases which follow allogeneic BMT from a donor who is a patient or a carrier of an autoimmune condition are considered to be a paradigm of adoptive autoimmunity. Seven cases of autoimmune thyroiditis associated with clinical hyperthyroidism have been published to date. In the case reported here a 35-year-old female patient with AML of the M2 subtype received unmanipulated PBSC from her HLA-identical sister who had therapeutically controlled Graves' disease. Antithyroid antibodies, including thyrotropin receptor (TSHR) antibodies, appeared 1 year after transplant. Clinical hyperthyroidism requiring thyrostatic medication appeared after 2 years. The biological and clinical implications of adoptive, post-transplant autoimmunity are briefly discussed.     

Appearance of thyroid stimulating and blocking immunoglobulins after bone marrow transplantation: presentation of two contrasting cases

Two acute leukemia cases who presented autoimmune thyroid diseases after bone marrow transplantation (BMT) are described with reference to the pathogenesis of their autoimmune clones. A 37-year old Japanese woman developed Graves' hyperthyroidism 39 months after allogeneic BMT for acute myeloid leukemia (AML) donated from her sister. Although both donor and recipient were euthyroid and negative for thyroid autoimmunity before BMT, the donor was positive for anti-nuclear and anti-single strand DNA autoantibodies. Studies on polymorphism for variable number of tandem repeat region of T-cell receptor gene suggested that the lymphocytes responsible for the hyperthyroidism were of donor origin. The second case was a 12-year-old Japanese schoolboy who presented nongoitrous hypothyroidism 2 years after autologous BMT for acute lymphoblastic leukemia (ALL). He had been clinically euthyroid before transplantation. Family history revealed that his mother and sister had a history of Graves' disease. His serum was positive for thyroid-stimulation blocking antibody. It is highly likely that the autoimmune process was activated after transient immune suppression during peri-BMT period in this patient. Pathogenesis, incidence, and observed time lag between BMT and development of autoimmune thyroid diseases were discussed.     

Resolution of immune haemolytic anaemia with allogeneic bone marrow transplantation after an unsuccessful autograft

Autologous transplantation of lymphocyte-depleted peripheral blood stem cells (PBSC) has been proposed for treatment of patients with severe autoimmune disease. However, several patients have been reported to achieve only transient remissions. We report on a child with thalassaemia intermedia and immune-mediated haemolytic anaemia, given an autologous lymphocyte-depleted PBSC transplant, who relapsed 7 weeks after transplant. A complete remission, lasting 18 months to date, was obtained with allogeneic bone marrow transplantation (BMT) from an HLA-matched unrelated donor. This experience indicates that, in selected cases, allogeneic BMT may be the treatment of choice for life-threatening autoimmune disease. A graft-versus-autoimmunity effect may favour the eradication of the recipient autoaggressive lymphocytes.     

Late graft rejection and second infusion of bone marrow in children with aplastic anaemia

Late graft rejection following allogeneic bone marrow transplantation (BMT) for aplastic anaemia is a significant clinical problem and is associated with a high risk of mortality. We report two children with severe aplastic anaemia (SAA) who developed very late graft rejection 2 years and 4 months and 10 years respectively after allogeneic BMT from HLA-identical siblings. Following a second BMT from their initial donors, engraftment has been sustained in both cases. The patients are alive with full donor chimaerism, 18 and 19 years from initial transplant. These cases illustrate that graft failure can be an extremely late event after allogeneic BMT for SAA, and that long-term sustained engraftment can be achieved in these patients with second BMT from the original donors.     

Assessment of graft status following allogeneic bone marrow transplantation for haematological disorders in children using locus-specific minisatellite probes

We have examined peripheral blood or bone marrow DNA following allogeneic bone marrow transplantation (BMT) in children suffering from a variety of haematological disorders. Using either locus-specific minisatellite probes separately or in combination with a Y specific probe for sex-mismatched transplants, complete haematological chimaerism, autologous reconstitution, or mixed chimaeric states have been defined immediately post-BMT. We have also been able to identify emerging autologous cells or relapse prior to morphological diagnosis.
Forty-two children, mean age 6.4 years (range 9 months to 15 years), received an allogeneic BMT for: acute lymphoblastic leukaemia (ALL), n = 17; acute myeloid leukaemia (AML), n = 5; biphenotypic leukaemia, n = 1; myelodysplastic syndrome (MDS), n = 5; chronic granulocytic leukaemia (CGL), n = 1; severe aplastic anaemia (SAA), n = 7; familial erythrophagocytic lymphohistiocytosis (FEL), n = 2; beta thalassaemia major (beta thal), n = 1; and juvenile chronic myeloid leukaemia (JCML), n = 3. Immediately post-transplant, 78% had achieved complete haematological chimaerism, 12% had failed to engraft (DNA analysis confirmed autologous reconstitution) and 10% had mixed chimaerism. SAA was the underlying disease in two of the chimaeric cases, the third case having had a matched unrelated donor (MUD) BMT for MDS. In 3/4 cases which subsequently relapsed, DNA analysis showed re-emergence of autologous cells (indicative of relapse), prior to their morphological identification. We conclude that DNA analysis using minisatellite probes to assess graft status provides a useful contribution to patient management following allogeneic BMT.     

Resolution of psoriasis after allogeneic bone marrow transplantation for chronic myelogenous leukemia: late complications of therapy

Treatment of autoimmune disease with bone marrow transplantation (BMT) is under investigation. A few reports of patients undergoing allogeneic BMT for malignant conditions observed the resolution of psoriasis after BMT, with minimal late morbidity. We describe a patient with chronic myelogenous leukemia (CML) whose psoriasis resolved completely after allogeneic BMT. However, the patient's course was complicated by extensive chronic graft-versus-host disease (GVHD), recurrent serious infections, poor performance status and quality of life, and severe disability. The patient died 887 days post transplant due to infectious complications. The potential benefits and risks of treatment of autoimmune diseases with allogeneic BMT are discussed.     

Limited genetic susceptibility to severe Graves' ophthalmopathy: no role for CTLA-4 but evidence for an environmental etiology.

Graves' disease (GD) is an autoimmune thyroid disease (AITD) characterized by hyperthyroidism and by the occurrence of a distinctive ophthalmopathy (orbitopathy), which presents with varying degrees of severity. Graves' disease clusters in families but the importance of heredity in the pathogenesis of the associated ophthalmopathy is unclear. We have studied the family history of 114 consecutive, ethnically mixed patients with severe Graves' ophthalmopathy (GO). Patients were selected by unambiguous single ascertainment. Seventy-seven percent of patients were female and 59% smoked. The mean age at onset of their GD was 43 years (range 17-78 years). Forty-one patients (36%) had a family history of AITD, defined as a first- and/or a second-degree relative affected with either Graves' disease (GD) or Hashimoto's thyroiditis (HT). The segregation ratio for AITD in nuclear families in our ascertained Graves' ophthalmopathy families was 0.07 (0.12 in Caucasians only). Hence, the higher prevalence of AITD among relatives of Graves' ophthalmopathy patients agreed with the known genetic predisposition to AITD and this predisposition was stronger in women than in men. However, only 3 of the 114 patients had a family history of severe Graves' ophthalmopathy (all second-degree relatives) and the segregation ratio for GO was 0. These data did not support a major role for familial factors in the development of severe Graves' ophthalmopathy distinct from Graves' disease itself. In addition, we tested 4 candidate genes, human leukocyte antigen (HLA), tumor necrosis factor-beta (TNF-beta), CTLA-4 and the thyrotropin receptor (TSHR), for association with Graves' ophthalmopathy. These were negative except for the HLA and CTLA-4 genes, which were found to be weakly associated with GO giving similar relative risk (RR) as in GD patients without ophthalmopathy. These data suggested that environmental factors, rather than major genes, were likely to predispose certain individuals with AITD to severe Graves' ophthalmopathy. Smoking remains one example of such potential external insults.     

Donor lymphocyte infusion for childhood acute lymphoblastic leukaemia relapsing after bone marrow transplantation

Four children with acute lymphoblastic leukaemia (ALL) who relapsed after allogeneic bone marrow transplantation (BMT) were treated with donor lymphocyte infusion (DLI) without prior conditioning. Three patients had previously received a non-T-cell-depleted matched sibling BMT and the fourth had a T-cell-depleted matched unrelated BMT. Two patients developed grade III–IV acute graft-versus-host-disease (GVHD) of the skin, which required intervention. Both are alive in complete haematological remission 7 and 10 months from DLI with chronic GVHD of the skin requiring immunosuppressive therapy. A third patient went into haematological remission 6 weeks after DLI, but with no clinical evidence of GVHD. His bone marrow remained in remission 11 months post-DLI despite the disease (ALL) relapsing in extramedullary sites. The fourth patient showed no clinical or haematological response to three consecutive doses of DLI given at 4-weekly intervals and died from progressive disease 11 months after relapse. These preliminary observations indicate that in constrast to experience in adult ALL, DLI may be effective in inducing sustained remission in children with ALL relapsing after BMT, and a response may occur even in the absence of clinical evidence of GVHD.     

Prevention of hepatitis B flare-up using lamivudine in a patient with non-Hodgkin's lymphoma after allogeneic bone marrow transplantation

A 22-year-old man with non-Hodgkin's lymphoma (B-cell lymphoblastic lymphoma, Stage IVA) received chemotherapy and radiation therapy and achieved complete remission. He was admitted for allogeneic bone marrow transplantation (BMT) using a graft from his completely HLA-matched mother. Although he had HBV infection, allogeneic BMT was performed because he still had normal liver function and strongly requested the procedure. He developed both acute and chronic GVHD after the procedure, but showed no liver damage related to HBV. Treatment with lamivudine (150 mg/day) was started because the HBV-DNA level increased gradually after allogeneic BMT. Although the HBV-DNA then decreased gradually and there was no evidence of severe liver damage, the patient died following relapse of NHL. It seems that in this case, treatment of HBV with lamivudine may have prevented serious liver damage after allogeneic BMT. Therefore, allogeneic BMT may be done safely in patients with HBV infection if lamivudine is administered.     

Treatment of adults with severe aplastic anemia: primary therapy with antithymocyte globulin (ATG) and rescue of ATG failures with bone marrow transplantation.

PURPOSE: To evaluate a policy of immunosuppression with antithymocyte globulin (ATG) as primary therapy for adults with severe aplastic anemia (SAA) regardless of the availability of an HLA-identical bone marrow donor. PATIENTS AND METHODS: Thirty-one consecutive adults with SAA who satisfied the age criteria for allogeneic bone marrow transplantation (BMT) (age less than 51 years) were treated with ATG 20 mg/kg/day for 10 days along with high-dose corticosteroids. Patients with an HLA-identical donor received a transplant if they did not respond to ATG or if they developed life-threatening complications during or soon after ATG administration. Eight patients with no response to ATG were also treated with oral cyclosporine 12.5 mg/kg/day. RESULTS: Eleven patients had a complete and five a partial response to ATG; two patients improved with cyclosporine treatment, resulting in an overall response rate of 58% to immunosuppression. Nine of 14 patients with donors received a BMT: seven because they did not respond to ATG and two because of serious infections. Seven grafts were obtained from related and two from unrelated donors. There was no significant difference in survival between those with and without a related HLA-identical donor (log-rank p value = 0.969). At a median follow-up of 58 months, 26 of 31 are alive with an actuarial survival of 80% at 5 years. Two patients died of infection, two died from complications of BMT, and one remains transfusion-dependent. One patient died of refractory leukemia at 30 months; one patient relapsed with hypoplasia 95 months after initial therapy with ATG. He showed a complete response to treatment with cyclosporine. No other late hematologic events have occurred. CONCLUSIONS: This treatment approach resulted in the restoration of hematopoiesis and independence from transfusion in 80% of patients with SAA entered into the study. The efficacy of allogeneic BMT in salvaging cases in which ATG failed does not appear to be compromised. Follow-up for the development of clonal hematologic disorders remains an important part of this treatment policy.     

Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease

The 8q24 locus, which contains the thyroglobulin (Tg) gene, was previously shown to be strongly linked with autoimmune thyroid disease (AITD). We sequenced all 48 exons of the Tg gene and identified 14 single-nucleotide polymorphisms (SNPs). Case control association studies demonstrated that an exon 10-12 SNP cluster and an exon 33 SNP were significantly associated with AITD (P < 0.01). Haplotype analysis demonstrated that the combination of these two SNP groups was more significantly associated with AITD (P < 0.001). Gene-gene interaction studies provided evidence for an interaction between HLA-DR3 and the exon 33 SNP, giving an odds ratio of 6.1 for Graves' disease. We then sequenced exons 10,12, and 33 of the mouse Tg gene in 19 strains of mice. Fifty percent of the strains susceptible to thyroiditis had a unique SNP haplotype at exons 10 and 12, whereas none of the mouse strains that were resistant to thyroiditis had this SNP haplotype (P = 0.01). We concluded that Tg is a susceptibility gene for AITD, both in humans in and in mice. A combination of at least two Tg SNPs conferred susceptibility to human AITD. Moreover, the exon 33 SNP showed evidence for interaction with HLA-DR3 in conferring susceptibility to Graves' disease.     

Refractory Evans' syndrome treated with allogeneic SCT followed by DLI. Demonstration of a graft-versus-autoimmunity effect

Evans' syndrome, a combination of autoimmune haemolytic anaemia and autoimmune (idiopathic) thrombocytopenic purpura, is generally harder to treat and more refractory than the single entities. In a male patient with refractory disease, predominantly thrombocytopenic, an allogeneic reduced intensity BMT from his human leukocyte antigen (HLA)-identical sister was followed by a dramatic platelet peak while he was still experiencing initial engraftment (presumably of autologous origin), but subsequently by progressive relapse associated with mixed chimerism. Five gradually incremental DLI achieved complete donor chimerism, which was associated not only with grade II graft-versus-host disease (GVHD), but also with complete clinical and biological remission for 2 years post-transplant. Long-term FU is necessary before claiming that allogeneic stem cell transplantation (SCT) is capable of curing an autoimmune blood disease. However, there is evidence for a graft-versus-autoimmunity effect in this case.     

In vitro evidence for disappearance of erythroid progenitor T suppressor cells following allogeneic bone marrow transplantation for severe aplastic anemia

In vitro coculture studies were performed in five patients with severe aplastic anemia (SAA) and their normal HLA-matched donors before and after allogeneic bone marrow transplantation (BMT) to determine whether the erythropoietic function of T cells is abnormal in this disorder. These coculture studies used fresh or cryopreserved marrow T lymphocytes with fresh or cryopreserved marrow T cell-depleted target cells. Four of five aplastic patients had little or no transfusion exposure before studies. The composite results showed that, in comparison to the erythropoietic effects of normal HLA-identical marrow T lymphocytes or engrafted T lymphocytes, T lymphocytes collected from the aplastic patients before BMT consistently suppressed or failed to support CFUE and BFUE growth optimally from autologous marrow, HLA- identical marrow, or engrafted aplastic T cell-depleted marrows. This T cell abnormality was not observed in four multiply transfused leukemics and three patients with myelodysplastic syndrome. Marker analyses of SAA marrow T lymphocytes performed before and after BMT suggested that the erythropoietic functional abnormality was due to abnormal marrow T cell composition reflecting an excess of activated Tac+, T3+, T11+ lymphocytes. Collectively, these in vitro studies provide firmer in vitro evidence implicating T cells in the pathogenesis of SAA. The erythropoietic T cells abnormalities in SAA are fully corrected by allogeneic BMT.     

Complete remission of tumour with interleukin 2 therapy in a patient with non-Hodgkin's lymphoma post allogeneic bone marrow transplant associated with polyclonal T-cell bone marrow lymphocytosis

A patient with low-grade non-Hodgkin's lymphoma (NHL) who relapsed shortly after an allogeneic bone marrow transplant (BMT) is reported. The patient was treated with interleukin 2 (IL-2), which resulted in a flare-up of graft-versus-host disease followed by disease control, with disappearance of peripheral lymphadenopathy. Sequential bone marrow testing showed the disappearance of bone marrow involvement with disease but occurrence of T-cell aggregates post IL-2 that were identified as polyclonal by molecular methods. The patient remains in complete remission 37 months following allogeneic BMT.     

Unusual complications after bone marrow transplantation for dyskeratosis congenita

Dyskeratosis congenita (DC) is a rare inherited disorder often associated with aplastic anaemia. We report the cases of five boys transplanted with an HLA-identical related donor for severe aplastic anaemia (SAA) associated to DC; in all cases successful engraftment was observed. Three patients died 2–8 years after bone marrow transplantation (BMT) with signs of endothelial cell damage syndrome (kidney microangiopathy and liver veno-occlusive disease). Another boy died 1 year after BMT from Evans syndrome and invasive aspergillosis. One boy currently presents anaemia, polyarthritis of unknown origin, pulmonary fibrosis and gut malabsorption 7.5 years after BMT. SAA associated with DC can be successfully treated by allogeneic BMT. However, these early and late complications observed are very unusual after BMT and probably reflect the association of transplanted-related factors, evolution of the underlying disease, and increased sensitivity of endothelial cells. Modified conditioning approaches, advances in supportive care and surveillance of these unusual complications offer the possibility of improved outcome for these patients.     

Successful treatment with allogeneic peripheral blood stem cell transplantation and granulocyte transfusion for severe aplastic anemia with sinusitis

A 43-year-old woman with severe aplastic anemia (SAA) received anti-thymocyte globulin and cyclosporin A (CyA) and achieved hematological remission. Although she had maintained hematological remission, the disease relapsed 10 months after arbitrary discontinuance of maintenance therapy with CyA. Resumption of CyA therapy was not effective, and her condition became complicated with progressive sinusitis with bone destruction, which was refractory to antibiotics, antifungal agents, granulocyte colony-stimulating factor, and surgical drainage. Because of the necessity for early neutrophil recovery (to resolve the infection), we proceeded with a combination therapy using allogeneic peripheral blood stem cell transplantation (PBSCT) promptly followed by granulocyte transfusion (GTX) from the same human leukocyte antigen-identical donor rather than carrying out a second immunosuppressive therapy. The patient showed temporal resolution of infection on the second day after a single GTX. Although the patient had pneumonia on day 11, it was resolved promptly after engraftment on day 16. This report suggests the clinical utility of a salvage therapy with allogeneic PBSCT followed by GTX in a particular case of recurrent SAA with refractory infections.     

Late onset post-transplantation lymphoproliferative disease of recipient origin following cytogenetic relapse and occult autologous haematopoietic regeneration after allogeneic bone marrow transplantation for acute myeloid leukaemia

A post-transplantation lymphoproliferative disease (PTLD) of recipient origin was identified in one of 376 consecutive cases of allogeneic bone marrow transplantation (BMT). This occurred in a 36-year-old woman who received an allogeneic BMT for acute myeloid leukaemia in relapse. At 15 months after BMT, recipient haematopietic and leukaemic cells were found in the bone marrow, which disappeared on withdrawal of immunosuppression. However, severe graft-versus-host disease (GVHD) necessitated the continuation of immunosuppression, leading to the occurrence of PTLD in the liver and lung 12 months afterwards. Fluorescence in situ hybridisation showed that the neoplastic cells were of recipient origin. Although the PTLD also responded completely to withdrawal of immunosuppression, the patient finally died from the complications of GVHD. This case of late onset PTLD post-BMT showed features similar to those in solid organ transplantation, in that the tumour was of recipient origin and responded well to the withdrawal of immunosuppression. Of further interest is that recipient lymphoid regeneration had accompanied autologous haematopoietic regeneration and become a target for subsequent neoplastic transformation.     

Long-term remission of APL with a second allogeneic BMT after CNS relapse following HLA-identical allogeneic BMT

Second allogeneic bone marrow transplantation (BMT) for AML relapsing after an initial BMT has a poor prognosis, with a probability of a 2-y disease-free survival below 30 per cent, caused both by treatment-related mortality (TRM) and high relapse rate. While TRM is most likely due to heavy pretreatment, AML relapse after BMT may be due to resistant disease or to a poor graft-versus-leukaemia (GvL) effect of the transplant. The degree of GvL may depend on individual donor/recipient immunoreactivity. In most published cases of second allogeneic BMT, both transplants were performed from the same donor. Here, we describe a patient who was first transplanted for acute promyelocytic leukaemia (APL) (AML FAB M3v) from his HLA-identical brother and received intensive immunotherapy including donor lymphocytes and IL2. He remained free from GvHD >I degrees, but developed CNS relapse. After a second BMT from another HLA-identical brother, he spontaneously developed GvHD III degrees, and has now been disease free for nearly 3 years. In this patient, long-term remission of AML relapsing after BMT was achieved by combining remission induction using an individual chemotherapy protocol with a second BMT from an alternative matched related donor and transient GvHD III degrees, which probably conferred a GVL effect.