Decision-making in adult thalassemia patients undergoing unrelated bone marrow transplantation: quality of life, communication and ethical issues.

Bone marrow transplantation (BMT) represents a potentially curative treatment of thalassemia. For patients without an HLA-identical sibling donor, recourse to an unrelated donor is a practicable option but the candidates and their families are faced with a difficult decision. They can either choose to continue the supportive therapy, with no chance of definitive cure, or they accept the mortality risk of BMT in the hope of obtaining a definitive resolution of the disease. We investigated the communication strategies and the post transplantation quality of life (QoL) in 19 adult thalassemia patients surviving after an unrelated donor BMT. The patients were given two questionnaires: a questionnaire to evaluate pre-transplantation communication factors and the EORTC QLQ-C30 questionnaire to assess global QoL. All patients were satisfied with the communication modalities employed by the physicians. The global post transplantation QoL in our patient cohort was found to be good. The approach used in this study may offer a contribution to understanding the decision-making process leading to the choice of a treatment with a high mortality risk for a chronic, non-malignant disease. Finally, some ethical issues of this therapeutic approach are briefly addressed.

Unrelated donor stem cell transplantation in adult patients with thalassemia.

Allogeneic SCT remains the only potential cure for patients with thalassemia. However, most BMT candidates lack a suitable family donor and require an unrelated donor (UD). We evaluated whether BMT using UDs in high-risk adult thalassemia patients can offer a probability of cure comparable to that reported employing an HLA-compatible sibling as donor. A total of 27 adult thalassemia patients (15 males and 12 females, median age 22 years) underwent BMT from a UD selected by high-resolution HLA molecular typing. The conditioning regimen consisted of Busulphan (BU, 14 mg/kg) plus Cyclophosphamide (CY, 120 or 160 mg/kg) in 12 cases and BU (14 mg/kg), Thiotepa (10 mg/kg) and CY (120-160 mg/kg) in the remaining 15 cases. Cyclosporine-A and short-term Methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. In all, 19 patients (70%) are alive and transfusion-independent after a median follow-up of 43 months (range 16-137). A total of 10 patients (37%) developed grade II-IV acute GVHD and six (27%) chronic GVHD. Eight patients (30%) died from transplant-related causes. UD-BMT can cure more than two-thirds of adult thalassemia patients, and is a particularly attractive option for patients who are not compliant with conventional treatment.

Extracorporeal photochemotherapy for the treatment of graft-versus-host disease.

Photopheresis is an extracorporeal photochemotherapy (ECP) used for the treatment of oncological and autoimmune diseases. Lymphocytes are drawn from the patients by leukapheresis, treated with 8-methoxypsoralen (8-MOP) and ultraviolet light A (UVA) in an extracorporeal system; then, reinfused to the host. Because skin exposure to 8-MOP and UVA (PUVA) has been shown to improve cutaneous GVHD, we evaluated in a pilot study, if ECP might be beneficial for patients with GVHD unresponsive to conventional protocols. In this study, we enrolled 9 children or young adults, with acute (no = 1) or chronic extensive GVHD (no. = 8). A significant improvement was observed in three of the 5 patients with scleroderma-like lesions and in one patient with severe liver involvement. Karnofsky performance score improved from 30-50% to 90% in the 4 responders. The better control of GVHD in these patients allowed a reduction of the immunosuppressive therapy that was, finally, discontinued in two. No significant side effects were observed during ECP. Our results suggest that ECP is a nonaggressive treatment that may benefit patients with c-GVHD unresponsive to standard immunosuppressive therapies.

Indications and results for splenectomy for beta thalassemia in two hundred and twenty-one pediatric patients.

To determine the advantages and complications of splenectomy in the treatment of beta thalassemia, 221 splenectomies for thalassemia performed upon pediatric patients from 1971 to 1982 are evaluated. There were 125 boys and 96 girls with a mean age of 8.2 +/- 2.5 years at the time of the operation. Sixty-one other patients who underwent splenectomy for other diseases served as the controls. Early and late complications after splenectomy are considered with a follow-up study of ten years. Hemoglobin (Hb) value, transfusional quotients and mean of transfused blood previous to surgical treatment are matched with the same parameters evaluated during the follow-up period. The effect of treatment with salicylates and dipyridamole upon the incidence of early complications after operation is analyzed. The postoperative complications in patients with thalassemia were 43.4 versus 3.2 per cent (p less than 0.01) registered in control patients. Late complications occurred with an incidence of 10.7 per cent and were due principally to sepsis. Six patients died of sepsis during the follow-up period, but the mortality rate for sepsis in the patients we studied was significantly lower than that reported by others in 73 instances of splenectomy for beta thalassemia. Blood consumption dropped from 270 +/- 99 to 155 +/- 31 milliliters per kilogram per year postoperatively (p less than 0.01) and Hb levels rose from 9.7 +/- 1.3 to 11.2 +/- 0.7 grams per milliliter. These results suggest that, even though splenectomy for beta thalassemia causes a relevant incidence of complications and fatalities, surgical treatment permits an improvement in the quality of the lives of patients with beta thalassemia and significantly reduces blood consumption. Prophylactic antibiotic therapy can reduce the incidence of sepsis, as was observed in the patients we studied.

High-dose intravenous immunoglobulin in the management of autoimmune hemolytic anemia complicating thalassemia major.

Patients with thalassemia major due to red blood cell autoantibodies may develop an increase in transfusional blood consumption. In this study we report the results of treatment with high intravenous immunoglobulin (Ig) in 4 patients who developed an increase in blood consumption related to the presence of autoantibodies of defined or undefined specificities. Three patients showed a normalization of the blood consumption. No adverse effects were detected. These results indicate that high-dose intravenous Ig therapy is indicated in patients with thalassemia major manifesting an increase in blood consumption following the development of red cell autoantibodies.

Human immunodeficiency virus infection in multi-transfused patients with thalassaemia major.

We investigated the incidence, clinical and immunological characteristics of human immuno-deficiency virus (HIV) infection in a group of multi-transfused patients with thalassaemia major who were exposed to transfusion-associated HIV infection. Seropositivity to HIV by Western blot and immunofluorescence analysis was detected in 26 out of 590 patients. At a follow up 21-40 months later, none of these seropositive patients had developed acquired immuno-deficiency syndrome (AIDS), and six manifested the AIDS related complex (ARC). ARC was unusually mild and consisted of moderate laterocervical and submandibular lymph node enlargement associated with hypergammaglobulinaemia and a reduced CD4/CD8 ratio resulting from the decreased number of CD4 lymphocytes. These findings suggest that multi-transfused patients with thalassaemia major are relatively resistant to the development of severe manifestations of HIV infection, presumably because their immune status is relatively better preserved than that of other infected populations. Longer follow up is, however, necessary to determine whether the incidence of AIDS will be lower in this population or whether overt AIDS merely takes longer to develop.

Erythropoiesis following bone marrow transplantation from donors heterozygous for beta-thalassaemia.

This study shows a marked and protracted activation of HbF synthesis in homozygous beta.-thalassaemia patients transplanted from HLA identical siblings heterozygous for beta-thalassaemia, as compared to patients transplanted from normal donors. HbF synthesis in recipients was much higher in relation to the corresponding bone marrow donor values either normal or heterozygous for beta thalassaemia. gamma-chain synthesis and G gamma/A gamma ratio were also studied in peripheral blood BFU-E from recipients and their donors. BFU-E from donors heterozygous for beta-thalassaemia showed higher gamma chain synthesis as compared to normal donors. Peripheral blood BFU-E gamma/beta + gamma ratios and G gamma percentage were higher in recipients than in their corresponding donors both normal or heterozygotes. The marked and protracted reactivation of HbF synthesis in recipients of heterozygous beta-thalassaemia bone marrow most likely results from an increased erythropoietic stress on erythroid progenitors. In order to obtain adequate Hb levels heterozygous beta-thalassaemia bone marrow should produce more red blood cells to compensate for the low MCH. The magnitude of activation of HbF synthesis was very variable. This variability may result from inherited differences in the capacity of reactivation of HbF synthesis of red cell progenitors from heterozygous beta-thalassaemia under stressed erythropoiesis.

Auditory involvement in thalassemia major.

The auditory function of 75 children affected by homozygous beta0-thalassemia, managed with a low transfusion scheme and treated irregularly with low doses of desferrioxamine, and of 75 controls were examined. In 12 patients a mild bilateral conductive hearing impairment due to bony hypertrophy and/or adenoid hypertrophy was found. In 43 cases a moderate monolateral or bilateral sensory-neural hearing loss at high frequencies with recruitment phenomenon was observed. Ferritin levels were determined in a randomly chosen group of these patients with (14) and without heaing loss (11). In the subjects with sensory-neural hearing loss the mean ferritin levels were significantly higher than in those with no hearing defect. There was no obvious relation between sensory-neural damage on the one hand and Hb levels and unit of blood transfused on the other. The results of this study suggest that iron overload could be a cause of damage in the high frequency elements of the auditory mechanism. Intermittent hypoxia and slow 8th nerve compression due to bony hypertrophy as causes of auditory involvement are also discussed.

Serum ferritin, liver iron stores, and liver histology in children with thalassaemia.

Serum ferritin, liver iron stores, and liver histology were studied in 38 children with thalassaemia major who were being treated by regular blood transfusions. There was no correlation between serum ferritin levels and either the number of transfusions or the amount of iron deposited in the liver. However, for a given level of iron stores, ferritin levels were higher in patients with chronic hepatitis (including chronic aggressive and chronic persistent forms) than in those with hepatic siderosis only. We conclude that serum ferritin reflects tissue iron deposits in regularly transfused thalassaemic patients, only in the absence of hepatitis.

Evaluation of antibodies to hepatitis C virus in a long-term prospective study of posttransfusion hepatitis among thalassemic children: comparison between first- and second-generation assay.

During an 8-year prospective study of post-transfusion hepatitis conducted at the Thalassemic Center of Cagliari (Italy), including 135 newly diagnosed thalassemic children on long-term transfusion maintenance, 83 children (61%) developed non-A, non-B hepatitis (NANBH). Resolution of NANBH was observed in 17 (20%) cases, and chronicity in 57 (69%), whereas the remaining 9 (11%) experienced one or two additional bouts of acute NANBH. Of the 83 children with NANBH, 75 (90%) showed anti-hepatitis C virus (HCV) seroconversion when tested by second-generation enzyme-linked immunosorbent assay (ELISA), whereas first-generation ELISA showed anti-HCV in only 59 (71%) cases (p = 0.003). Moreover, the newly developed assay allowed an earlier detection of anti-HCV response in most of the patients who seroconverted by both assays, reducing significantly the mean onset-seroconversion interval (5 +/- 9.4 weeks vs. 14.5 +/- 20.8 weeks, p < 0.05). It was significantly more sensitive for the identification of HCV infection, not only in resolving NANBH, but also in NANBH progressing to chronicity (79 vs. 35%, respectively, p = 0.008; and 93 vs. 79%, p = 0.028). The pattern of antibody response with first-generation assay was characterized by clearance of anti-HCV with time, in most of the patients who recovered, and by persistence of anti-HCV in the majority of those who progressed to chronicity, whereas second-generation ELISA usually showed persistence of anti-HCV over time, regardless to the outcome of the disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Depletion of trace elements and acute ocular toxicity induced by desferrioxamine in patients with thalassaemia.

High doses of intravenous desferrioxamine infused over a short period of time induce a large faecal and urinary iron excretion but also produce retinal abnormalities that are characterised by decreased amplitude on electroretinography and defective dark adaptation. This regimen also results in high faecal iron, zinc, and copper excretion, and reduced granulocyte zinc concentrations and alkaline phosphatase activity. The retinal abnormalities may be related to the zinc and copper deficiency and/or iron depletion 'per se' which interferes negatively with critical iron dependent enzymes.

Molecular analysis of beta zero-thalassemia intermedia in Sardinia.

In this study we have carried out alpha- and beta-globin gene analysis and defined the beta-globin gene polymorphisms in a group of patients with thalassemia intermedia of Sardinian descent. A group of patients (109) with thalassemia major of the same origin served as control. Characterization of the beta-thalassemia mutation showed either a frameshift mutation at codon 6 or a codon 39 nonsense mutation. We found that homozygotes for the frameshift mutation at codon 6 or compound heterozygotes for this mutation and for the codon 39 nonsense mutation develop thalassemia intermedia more frequently than thalassemia major. The frameshift mutation at codon 6 was associated with haplotype IX that contains the C-T change at position -158 5' to the G gamma globin gene implicated in high gamma chain production and thus the mild phenotype. In patients' homozygotes for codon 39 nonsense mutation, those with thalassemia intermedia more frequently had the two-gene deletion form of alpha-thalassemia, or functional loss of the alpha 2 gene as compared with those with thalassemia major. In a few siblings with thalassemia major and intermedia, the thalassemia intermedia syndrome correlated with the presence of the -alpha/-alpha genotype. No cause for the mild phenotype was detected in the majority of patients who had not inherited either haplotype IX or alpha-thalassemia.

Deferoxamine-induced growth retardation in patients with thalassemia major.

In the retrospective study reported here, we compared the longitudinal growth in three groups of children with thalassemia major who received a similar transfusion program but different schedules of chelation treatment. In those patients who initiated deferoxamine (DF) administration by daily subcutaneous infusion (50 to 80 mg/kg/day) simultaneously with the beginning of transfusion (at 8 +/- 6 months), mean height at 2 to 6 years of age was significantly reduced in comparison (1) with those patients who initiated DF subcutaneous treatment after 3 years at similar doses and (2) with those who were treated intramuscularly with small doses. In the patients treated at an early stage, those with more marked stunted growth had a clinical and radiologic ricketslike syndrome associated with joint stiffness. Mineral metabolism studies in these patients showed a reduction of hair and leukocyte zinc levels and leukocyte alkaline phosphatase activity. Our findings indicate that DF administration at high doses by continuous infusion before iron overload has been established adversely affects longitudinal growth. By contrast, after 3 years of age, even large doses (in the order of 100/mg/kg/day) did not result in growth retardation. The growth retardation observed may be related to chelation of other trace elements, including zinc, in the presence of low iron burden, to the direct toxic effect of unchelated DF by interference with critical iron-dependent enzymes, or both. These results indicate that in patients with thalassemia major, DF administration should be initiated only after iron accumulation is established, namely, around 3 years of age, after 20 to 30 transfusions, which are usually associated with ferritin levels in the range of 800 to 1000 ng/ml. At this age, deferoxamine doses should be established on the basis of iron balance studies and dose response curves. Doses higher than 50 to 60 mg/kg do not adversely affect growth but produce toxic side effects on acoustic and visual pathways and therefore should not be used. Longitudinal growth monitoring of DF-treated patients is warranted.

Methyl-prednisolone treatment of serum HBsAg negative chronic active hepatitis occurring in transfusion-dependent thalassemia major.

We report the results of a two-year non randomized prednisolone trial carried out in 18 thalassemia major patients with chronic active hepatitis and in 16 controls. We found a beneficial effect on the biochemical remission rate and on the extent of liver inflammation with no significant side effects and no overt reactivation of possible latent HBV infection at three-year follow-up. However, a more prolonged longitudinal study is necessary in order to evaluate whether steroid treatment can impede the evolution to cirrhosis without determining long-term consequences, depending on virus-host interactions such as liver cell carcinoma.

Hepatitis C virus in multiple episodes of acute hepatitis in polytransfused thalassaemic children.

We investigated the course of distinct episodes of acute non-A, non-B (NANB) hepatitis in three polytransfused thalassaemic children. In each case, the first episode was associated with the appearance of serum hepatitis C virus (HCV) RNA and anti-HCV seroconversion. The second episode was accompanied by the reappearance of HCV viraemia, which in two patients was due to reinfection with a different HCV strain and in the third could be the result of either reactivation of primary infection or reinfection with a new but closely related strain. Thus HCV infection may not induce protective immunity, which has implications for vaccine development.

Chronic liver disease in transfusion-dependent thalassemia: liver iron quantitation and distribution.

The quantitative and/or qualitative distribution of liver iron was assessed in 81 transfusion-dependent thalassemia major patients with chronic liver disease (36 with chronic active hepatitis, 23 with chronic persistent hepatitis, 22 with siderosis). Viral marker studies showed only 3 cases with both HBsAg and anti-HBc positivity in the serum, while the others had anti-HBc and anti-HBs or only anti-HBs or no B viral markers. A significantly higher iron overload was found in chronic hepatitis, particularly chronic active hepatitis, than in siderosis. The increased iron overload may be due to less intensive chelation treatment, higher intestinal absorption secondary to lower mean Hb levels, and/or to liver inflammation-dependent iron deposition. The liver iron overload in turn amy facilitate the development or persistence of chronic progressive liver disease.

Photopheresis in paediatric patients with drug-resistant chronic graft-versus-host disease.

Photopheresis (ECP) is a new type of photochemotherapy, used for the treatment of oncological and autoimmune diseases. Lymphocytes are drawn from the patients by leukapheresis, treated with 8-methoxypsoralen (8-MOP) and ultraviolet light A (UVA) in an extracorporeal system and then reinfused. Skin exposure to 8-MOP and UVA (PUVA) has been shown to relieve cutaneous symptoms of graft-versus-host disease (GVHD) in bone marrow transplant (BMT) recipients. ECP, which is similar in some ways to PUVA, has been used in this study to treat four paediatric patients who developed chronic GVHD following BMT and in whom GVHD had failed to respond to conventional immunosuppressive therapy. Following ECP, skin lesions cleared almost completely and pulmonary function tests improved in two of three patients with cutaneous and lung involvement. Serum bilirubin and transaminases gradually normalized, and gammaGT decreased considerably in the remaining patient who had a severe cholestatic hepatopathy. The Karnofsky performance score increased to 90% in the three patients with positive responses to ECP and remained unchanged (40%) in the patient who did not respond. Immunosuppressive therapy was reduced in three patients and eventually discontinued in two. No significant side-effects were observed during the treatment. Our results suggest that ECP is a non-aggressive treatment that may benefit patients with chronic GVHD who do not respond to standard immunosuppressive therapy.

Hematopoietic stem cell transplantation in childhood: report from the bone marrow transplantation group of the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP).

BACKGROUND AND OBJECTIVE: Transplantation of hematopoietic stem cells from different sources is being increasingly used to treat a variety of diseases in children. Transplant procedures and indications have changed considerably during recent years. Monitoring of information about these changes is useful for interpretation of nationwide collected data. DESIGN AND METHODS: Since 1985, Centers belonging to the AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica), performing hematopoietic stem cell transplants (HSCT) in children, and members of the AIEOP-Bone Marrow Transplant (BMT) Group annually report data on their transplant activity to the AIEOP-BMT Registry employing specially prepared patient-oriented forms. RESULTS: From January 1985 to December 1998, a total of 2,474 bone marrow (BM), peripheral blood (PB) or umbilical cord blood (CB) transplants were reported: 1,296 (52%) were allogeneic (Allo) and 1,178 (48%) autologous (Auto) transplants. These transplants were performed in 19 Italian Centers on 2,249 patients aged less than 17 years. Among Allo-transplants, 1,198 (92%) were performed using BM progenitor cells, whereas 49 (4%) CB, 42 (3%) were PB, 4 BM plus PB, and 3 BM plus CB allografts; they were performed using HLA-identical sibling donors in 867 cases (67%) and alternative donors (i.e. partially-matched relatives or unrelated donors) in the remaining 429 (33%) cases. Allogeneic transplants were performed on 786 (67%) patients with malignancy and on 395 (33%) patients with non-malignant disorders. In the last 6 years, the number of Allo-transplants per year exceeded that of Auto-transplants. Of the Auto-transplants, 775 (66%) were performed using BM, and 403 (34%) using PB alone or combined with BM hematopoietic stem cells. Indications for Auto-BMT were myelo-lymphoproliferative disorders in 524 (49%) cases, solid tumor in 533 (50%) cases and non-malignant disease in 11 (1%) cases. In the last 5 years, the use of PB for autografts has increased from 7% to 70%. INTERPRETATION AND CONCLUSIONS: These data reflect the development and present status of HSCT in Italy and provide a basis for patient counseling and health care planning.