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.     

Complete remission of idiopathic myelofibrosis following donor lymphocyte infusion after failure of allogeneic transplantation: demonstration of a graft-versus-myelofibrosis effect

A patient with idiopathic myelofibrosis (IM) in the osteosclerotic phase received an allogeneic stem cell transplant. Hemopoietic engraftment was rapid, and full donor chimerism was observed on day +70. However, a few months later, replacement of donor hemopoiesis by the patient's 20q- cell clone was observed, followed by reappearance of the blood IM features, marrow fibrosis and osteosclerosis. At 8 months from transplant donor lymphocytes were infused, which induced chronic GVHD. This resulted in normalization of the blood, with disappearance of the fibrosis and osteosclerosis, effects which persisted 20 months later. This case provides evidence for a graft-versus-disease effect in IM.     

Reversal of severe bone marrow fibrosis and osteosclerosis following allogeneic bone marrow transplantation for chronic granulocytic leukaemia

S ummary . Severe marrow fibrosis and osteosclerosis gradually disappeared after a 33-year-old woman received an allogeneic bone marrow transplantation (BMT) as experimental treatment for chronic granulocytic leukaemia. Serial biopsies demonstrate gradual resolution of dense reticulin fibrosis, collagen fibrosis and osteosclerosis, and restoration of normal marrow architecture after transplantation. These changes correspond with histological and cytogenetic evidence of normal marrow engraftment and sustained complete remission from chronic granulocytic leukaemia. In this case severe marrow infiltration with reticulin and collagen fibrosis as well as severe derangement of marrow architecture and obliteration of the medullary cavity by osteosclerosis was an entirely reversible process after allogeneic bone marrow transplantation, and did not prevent successful engraftment, haemopoietic and cytogenetic reconstitution and complete remission from chronic granulocytic leukaemia.     

Cirrhosis as a consequence of graft-versus-host disease

A 28-yr-old woman with severe idiopathic aplastic anemia received an HLA-identical mixed lymphocyte culture nonreactive bone marrow transplant from her brother. In the months after successful engraftment, she developed cutaneous and hepatic graft-versus-host disease, associated with marked cholestatic jaundice. Despite a series of therapeutic maneuvers, cholestasis persisted but remained relatively stable over the ensuing 10 yr. However, serial liver biopsies revealed progressive biliary-type fibrosis culminating in cirrhosis. Subsequently, her clinical course deteriorated and she developed signs of hepatic failure, and ultimately died 10.5 yr after bone marrow transplantation. The evolution of chronic graft-versus-host disease to cirrhosis may be a limiting factor in the long-term survival of this group of bone marrow transplant recipients. The lack of correlation between the stable clinical or biochemical indices and the progressive hepatic disease underscores the need for sequential liver biopsies in patients with sustained liver function abnormalities after bone marrow transplantation.     

Metastatic papillary carcinoma of thyroid in a patient undergoing allogeneic BMT for CML

Summary. A 30-year-old woman underwent HLA-compatible bone marrow transplant for chronic myeloid leukaemia. Her post-transplant course was complicated by disseminated aspergillus and CMV infections resulting in death 65 d post transplant. At post-mortem, multiple pulmonary metastases of papillary carcinoma of the thyroid were found with a small (< 8 mm) primary carcinoma in the thyroid. It is suggested that the progression of this tumour was related to the patient's immunocompromised state.     

Second marrow transplantation following high dose busulfan, etoposide, and Ara-C after testicular relapse in a patient with AML]

Prognosis of second marrow transplantation after leukemia relapse is usually gloomy. We report a patient with AML who was successfully treated by the second marrow transplant following high dose busulfan, etoposide, and Ara-C for the testicular relapse after the first marrow transplantation. A 24-year-old man was diagnosed as having acute myeloid leukemia (AML) in September, 1988. In December of 1989 when he was in early relapse after his 2nd remission, he received the first allogeneic BMT from his HLA identical brother after high dose busulfan and cyclophosphamide conditioning. His posttransplant course was uneventful and graft versus host disease was not observed. Three months after BMT, he noticed swelling on right testicle. Leukemic cell infiltration was confirmed by aspiration cytology. The testicular relapse was followed by marrow relapse. After successful remission induction chemotherapy, he received 17.5 Gy testicular irradiation and second marrow transplantation using high dose busulfan, etoposide, and Ara-C conditioning. Although his posttransplant period was complicated by severe mucositis, high fever and bronchopneumonia, hematologic recovery was obtained by 3 weeks after the second transplant. He is now continuing in complete remission 18 months after the second BMT. This case report suggests that the combination of high dose busulfan, etoposide, and Ara-C could be a choice as a conditioning regimen for resistant AML relapsing after BMT.     

Peripheral stem cell transplantation in a child with amegakaryocytic thrombocytopenia

Congenital amegakaryocytic thrombocytopenia (CAMT) is an unusual cause of thrombocytopenia without radial or other congenital anomalies in the newborn. Generalized bone marrow dysfunction developing later in life has been reported. We present a 13-month-old girl who was diagnosed as having congenital amegakaryocytic thrombocytopenia and was successfully treated with allogeneic peripheral stem cell transplantation (PSCT) from her fully matched sibling donor. The neutrophil engraftment was on post transplant day 12 and platelet engraftment was on day 14. Her last hemogram revealed platelets of 168 x 10(9)/l 20 months post transplant.     

Atypical leukemia accompanied by vitamin B12 deficiency]

A 76 year old female with atypical leukemia complicated by vitamin B12 deficiency demonstrated marked fluctuation in blast percentage and hemopoiesis over 8 month period. She underwent surgical removal of pancreas head cancer 5.5 years ago. In January 1989 severe pancytopenia and mild increase of bone marrow blast were found. Blood transfusions and inadvertent administration of Vitamin B12 resulted in alleviation of pancytopenia and decrease in blast percentage. Several months later her bone marrow blast exceeded 30%, when serum B12 concentration was below 90 pg/ml. B12 injection and blood transfusion resulted in significant improvement in her hematological condition, but shortly thereafter she died of fulminant hepatitis. Her bone marrow cells showed a polyclonal constitution, as assessed by the RFLP-methylation technique using the PGK gene as a probe. The coexistence of leukemic- and normal clones under Vitamin B12 deficiency conditions and the differing behavior of such clones to B12 supplementation may explain the unusual clinical course observed in this patient.     

Recurrent graft failure following syngeneic bone marrow transplantation for aplastic anaemia

We present the case of a 60-year-old woman with drug-induced aplastic anaemia with a healthy monozygotic twin. Proof of monozygosity was confirmed by studies using the hypervariable minisatellite probe to obtain identical DNA fingerprints in donor and recipient. In vitro co-culture studies performed showed no evidence of a recipient-derived cellular or humoral inhibitor of donor haemopoiesis. Despite this, there was no engraftment following simple marrow infusion without preconditioning. A second syngeneic transplant following high dose cyclophosphamide therapy produced trilineage engraftment but severe thrombocytopenia developed at 3 months, followed later by pancytopenia with generalized marrow failure. Following a third syngeneic transplant with cyclophosphamide and total lymphoid irradiation there was good initial engraftment but graft failure occurred at 14 weeks. A fourth transplant using Campath 1G as preconditioning resulted in no engraftment and the patient died of septicaemia 8 weeks following her fourth transplant. We suggest that the cause of the recurrent aplastic anaemia in this case was a defect of marrow stroma as neither an inhibitor of donor haemopoiesis nor an intrinsic defect of donor stem cell growth could be demonstrated in vitro.     

Effective treatment of Jo-1-associated polymyositis with T-cell-depleted autologous peripheral blood stem cell transplantation

A patient with Jo-1 antibody-associated polymyositis (Jo-1 PM) had a Karnofsky score of 40% and severe muscle, liver and lung damage that was refractory to standard therapy. The female patient received an autologous T-cell-depleted haematopoietic stem cell transplant (HSCT) after myeloablative conditioning. The transplant procedure was complicated by severe adult respiratory distress syndrome (ARDS) and adenovirus-associated haemorrhagic cystitis as well as cytomegalovirus (CMV) reactivation. The patient's creatinine phosphokinase (CPK) and alanine transaminase (ALT) values were normal on day 21. The patient's strength has improved remarkably and her dyspnoea is subjectively improved. At 15 months after the transplant, the patient was well with a Karnofsky score of 80% and had been off any therapy, including steroids, for 14 months.     

Coronary artery disease following bone marrow transplantation

A 19-year-old woman died suddenly 30 months after allogeneic bone marrow transplantation for refractory leukemia. On postmortem examination severe coronary artery disease and acute myocardial infarction were found. The patient had previously been given chemotherapy including daunorubicin for treatment of her leukemia. She received high dose cyclophosphamide and total body irradiation (1260 cGy) for her transplant. Diffuse chronic graft-versus-host disease, mainly affecting skin, subsequently developed, and was resistant to various therapies. The possible association of coronary artery disease and allogeneic bone marrow transplantation is discussed.     

Successful non-myeloablative stem cell transplantation for a heavily transfused woman with severe aplastic anemia complicated by heart failure.

A 30-year-old Japanese woman weighing 35 kg with severe hemochromatosis due to multiple transfusions was referred to our clinic for treatment of severe aplastic anemia (SAA). The patient had heart failure with an ejection fraction of 36% requiring diuretics and a severe liver dysfunction with an indocyanine green clearance rate of 18%, as well as other transfusion-related complications such as chronic hepatitis due to hepatitis C virus and diabetes mellitus. She was treated with a non-myeloablative preparative regimen that included fludarabine monophosphate (Flu, 120 mg/m(2)), cyclophosphamide (CY, 1200 mg/m(2)) and antithymocyte globulin (ATG, 15 mg/kg) followed by allogeneic peripheral blood stem cell transplantation (PBSCT) from her HLA-matched sister. The regimen was well tolerated, and engraftment rapidly occurred without any therapy-related complications. Chimerism analysis on day 14 after transplant showed reconstitution with 100% donor cells. She no longer needed transfusion after day 23 and has been well in 90% Karnofsky status at 4 months post transplant. The clinical course of this patient indicates that this preparative regimen enables SAA patients with severe organ failure to safely undergo allogeneic stem cell transplantation.     

A case report of thrombotic thrombocytopenic purpura and severe acute renal failure post non-myeloablative allogeneic peripheral blood stem cell transplantation treated with plasma exchange and hemodialysis

A 59-year-old-woman received related non-myeloablative allogeneic peripheral blood stem cell transplantation (PBSCT) subsequent to autologous PBSCT in our hospital five years after she was diagnosed as oligo-secretory myeloma. She was admitted to our hospital because of vomiting and grayish diarrhea 4 months after non-myeloablative allogeneic PBSCT (mini-alloPBSCT). Although her initial symptoms improved after admission, she gradually showed thrombocytopenia, anemia, and oliguria during the 2 weeks after admission. Our diagnosis was thrombotic thrombocytopenic purpura (TTP) and acute renal failure (ARF) secondary to mini-alloPBSCT. After cessation of cyclosporine administration, we began to treat her with plasma exchange (PE) and hemodialysis. During the three and a half months after we started PE, the TTP gradually improved. Although PE had been reported to be ineffective for TTP post bone marrow transplantation, we could finally discontinue PE. In contrast, since her anuria continued, she was managed with hemodialysis. One month after PE was started, her activity of von Willebrand factor-cleaving protease was 41% (normal range, >50%) and the ultrasonographic investigation of both kidneys was normal. She could be discharged after four and a half months hospitalization and lived well as an outpatient for a further two months. She died shortly after readmission from multiple organ failure without the relapse of TTP. The patient's clinical course would suggest that TTP post mini-alloPBSCT could be treated with PE in some cases, despite the development of dialysis-requiring severe ARF being a poor prognostic factor.     

Four year follow-up of a case of fucosidosis treated with unrelated donor bone marrow transplantation

Fucosidosis is a rare autosomal recessive lysosomal disorder caused by alpha-fucosidase deficiency. We report a child with fucosidosis, second daughter of non-consanguineous parents, for whom biochemical diagnosis followed clinical evidence of the disease in her older sister. Based on previous experiences, the indication to transplant was considered. Since she lacked a matched sibling, an unrelated marrow donor was found. At pre-hematopoietic stem cell transplantation evaluation, first signs of neurological involvement were clinically detectable. MRI showed diffuse hypomyelination and auditory brainstem responses and somatic-sensorial evoked potentials were altered. Visual evoked potentials were normal, tortuosity in the retinal veins and peripapillary hemorrhages were detected. Bone marrow transplantation conditioning was with a regimen of busulphan, thiotepa and cyclophosphamide; in vivo Campath 1G, cyclosporin A and short course methotrexate were given to prevent graft-versus-host disease. The patient engrafted rapidly and her post-transplant course was complicated by moderate graft-versus-host disease, transient episodes of idiopathic thrombocytopenic purpura, repeated septic complications and recurrent episodes of Sweet's syndrome. Sequential short tandem repeat polymorphisms on peripheral blood and bone marrow cells documented the persistence of donor engraftment. Follow-up showed a progressive rise of enzymatic levels. Psychomotor development improved, as confirmed by evaluation of evoked potentials and by MRI scanning.     

Successful therapy with ribavirin of late onset respiratory syncytial virus pneumonitis complicating allogeneic bone transplantation.

A 21-year-old patient developed interstitial pneumonitis nine months post bone marrow transplant for acute myeloblastic leukaemia. Immunofluorescence of broncheoalveolar lavage fluid revealed the presence of respiratory syncytial virus (RSV). Aerosolized ribavarin therapy resulted in rapid resolution of the pneumonitis with full recovery without any side effects. Ribavarin therapy should be considered early in the management of BMT patients who develop RSV pneumonitis.     

Successful therapy with ribavarin of late onset respiratory syncytial virus pneumonitis complicating allogeneic bone transplantation

Summary A 21-year-old patient developed interstitial pneumonitis nine months post bone marrow transplant for acute myeloblastic leukaemia. Immunofluorescence of broncheoalveolar lavage fluid revealed the presence of respiratory syncytial virus (RSV). Aerosolized ribavarin therapy resulted in rapid resolution of the pneumonitis with full recovery without any side effects. Ribavarin therapy should be considered early in the management of BMT patients who develop RSV pneumonitis.     

Discontinuation of immunosuppression for prevention of kidney graft rejection after receiving a bone marrow transplant from the same HLA identical sibling donor

Induction of tolerance in solid organ transplant recipients has been a long sought goal so that patients will not need lifelong immunosuppression. In this case report we review a patient who received a kidney transplant from an HLA matched related sibling and developed acute leukemia as a consequence of her immunosuppression. The patient was then treated with an allogeneic bone marrow transplant from her kidney donor. After the bone marrow transplant, all immunosuppression therapy for graft rejection and graft versus host disease was stopped. Six months after the bone marrow transplant, the patient's kidney function had no deterioration as a consequence of stopping immunosuppression. This illustrated that a combined solid organ/bone marrow transplant can help to induce tolerance. In fact, the tolerance to the bone marrow transplant for prevention of graft versus host disease may have been accomplished by the prior kidney transplant.     

One antigen mismatched related donor bone marrow transplant in a patient with acute lymphoblastic leukaemia and beta-thalassaemia major: potential cure of both marrow disorders

We report a case of a 34-year-old man with T-ALL and beta-thalassaemia major who underwent a one antigen mismatched related donor bone marrow transplant. Five months post transplant chimeric studies revealed full donor haemopoiesis and the patient remains leukaemia and thalassaemia free at 12 months post transplant. Cumulative risk factors contributing to the increased transplant-related mortality in patients with two different marrow disorders are discussed.     

Accelerated bone formation causing profound hypocalcemia in acute leukemia

A patient with acute monocytic leukemia and fibrosis presented with severe hypocalcemia producing tetany, myocardial failure, and ventricular tachycardia with torsades de pointes configuration. Hypophosphatemia, hypomagnesemia, an elevated alkaline phosphatase level, and osteosclerosis were also present. Bone marrow biopsy samples showed fibrosis and thickened bony trabeculae lined with large osteoblasts. Tetracycline labeling showed an increased rate of calcification. Complete remission of the leukemia and fibrosis was achieved with a single 3-week course of low-dose cytarabine and hydroxyurea, with resolution of the hypocalcemia and hypophosphatemia. Calcitriol and etidronate disodium were also administered. The calculated left ventricular ejection fraction increased from 15% to 55% with correction of the hypocalcemia. The hypocalcemia and hypophosphatemia in this patient probably resulted from accelerated bone formation stimulated by the leukemic cells. The high dose of calcitriol that this patient received may have contributed to the remission of the leukemia.