The hepatic iron concentration is a reliable indicator of total body iron stores in patients with thalassemia major. In patients with transfusion-related iron overload, repeated determinations of the hepatic iron concentration can provide a quantitative means of measuring the long-term iron balance.

We reviewed the results of transplantation of allogeneic marrow from HLA-identical donors in patients with beta-thalassemia who were less than 16 years old. Among the 222 consecutive patients who had received transplants since 1983, survival and event-free-survival curves leveled off about one year after transplantation, at 82 and 75 percent, respectively. Pretransplantation clinical characteristics were examined for their impact on survival, event-free survival, and the recurrence of thalassemia in the 116 consecutive patients who were treated with our current regimen, in use since June 1985. In a multivariate analysis, portal fibrosis and either the presence of hepatomegaly or a history of inadequate chelation therapy were significantly associated with reduced probabilities of survival and event-free survival. The patients were divided into three classes on the basis of the presence of hepatomegaly or portal fibrosis (class 1 had neither factor, class 2 had one, and class 3 had both). For class 1 patients the three-year probabilities of survival, event-free survival, and recurrence were 94, 94, and 0 percent, respectively. For class 2 patients the probabilities were 80, 77, and 9 percent, and for class 3 patients 61, 53, and 16 percent. We conclude that for patients under 16 years of age, transplantation of bone marrow from an HLA-identical donor offers a high probability of complication-free survival, particularly if they do not have hepatomegaly or portal fibrosis.

The high probability of cure with little early or late morbidity and mortality suggests that patients with class 1 thalassemia who have HLA-identical donors available should be treated by bone marrow transplantation. However, this was not a controlled trial, so we cannot directly compare the outcome with that of conventional treatment.

When prepared for transplantation with busulfan (BU) 14 mg/kg and cyclophosphamide (CY) 120 to 160 mg/kg, patients with thalassemia in risk class 3, aged younger than 17 years, who receive transplants from HLA-identical donors, had a 30% incidence of transplant rejection with recurrence of thalassemia. This, relatively poor, outcome was ascribed to insufficient immune suppression or to inadequate eradication of the thalassemic marrow, or both. In an attempt to enhance both immune suppression and eradication of the thalassemic clones, hydroxyurea, azathioprine, and fludarabine were added to the BU and CY. This regimen, called protocol 26, was applied to 33 consecutive patients with class 3 thalassemia aged younger than 17 years and was well tolerated with 93% survival. The incidence of recurrent thalassemia after the transplantation decreased from 30%

We report the reliability and safety of percutaneous liver biopsy in the evaluation of hepatic iron loading and histology in patients with homozygous /3thalassaemia prior to and in serial biopsies following allogeneic bone marrow transplantation for this disorder. 501 thalassaemic patients aged 11 + 4.5 years (range 1-32

Thalassemia patients can be categorized as class 1 (minimal liver damage and iron overload), class 3 (extensive liver damage from iron overload), and class 2 (intermediate). These categories are prognostic for treatment outcome after marrow transplantation. Class 3 patients have more transplant-related mortality than other patients. This study examines transplantation outcome for class 3 patients. Records were reviewed of 215 patients in class 3 who received transplants in Pesaro from HLA-identical related donors between May 1, 1984 and May 1, 1994. The influence of pretransplant, peritransplant, and posttransplant variables on survival, relapse, and transplant-related mortality was examined by product-limit and proportional-hazards multivariate analysis. Age and conditioning regimen were influential on survival, and regimens with less than 200 mg/kg cyclosporine (CY) were associated with 5-year survival probabilities of .74 and .63 patients younger than 17 years and older patients, respectively. Transfusion history and regimen were influential on rejection with 5 year probabilities of .53 and .24 in patients who received less than or greater than 100 red blood cell transfusions before transplantation and regimens containing less than 200 mg/kg CY. Results of transplantation for patients with advanced thalassemia treatment have improved with the introduction of conditioning regimens with less CY. This has been associated with an increase in rejection (particularly in patients who have received < 100 red blood cell transfusions before transplant). Efforts at reducing the rejection rate by modifying the conditioning regimen should be concentrated on younger patients who have received a small number of transfusions. Patients with thalassemia who have HLA-identical family members should be transplanted before they are in class 3.

Early trials of allogenic bone marrow transplantation (BMT) for homozygous beta thalassemia and the analyses of results of transplantation in patients under 17 years of age have allowed us to identify 3 classes of risk using the criteria of degree of hepatomegaly, the degree of portal fibrosis, and the quality of the chelation treatment given before the transplant. Patients for whom all 3 criteria were adverse constituted Class 3, patients with none of the adverse criteria constituted Class 1, and patients with 1 or various associations of 2 of the adverse criteria formed Class 2. Most patients older than 16 years have disease characteristics that place them in Class 3, with very few in Class 2. For all the patients with an HLA identical donor we are actually using 2 protocols to which the patient is assigned on the basis of the Class he belongs to at the time of BMT and independently from the age of the patient. For 104 patients in Class 1 and for 262 patients in Class 2 prepared for the transplant with busulfan 14 mg/kg, cyclophosphamide 200 mg/kg and cyclosporine alone, the probabilities of survival and of event-free survival are 95% and 90% for Class 1 and 87% and 84% for Class 2. For 33 Class 3 patients prepared for the transplant with busulfan 14 mg/kg, cyclophosphamide reduced to 160 mg/kg, cyclosporine, and "short" methotrexate, the probabilities of survival and event-free survival are 89% and 64%. For 57 adult patients (17 to 35 years), who underwent the transplant after preparation with the same protocol used for Class 3, the probabilities of survival and of event-free survival are 70% and 68%, respectively. BMT remains the only form of radical treatment for thalassemia in those patients with an HLA-identical donor.

Summary:Twenty-nine patients with thalassemia and a median age of 6 years (range 1.1-33 years) were given a BMT from an alternative donor. Six of the 29 donors were HLA-phenotypically identical and two were mismatched relatives, 13 were mismatched siblings and eight were mismatched parents. Six patients received no antigen (relatives), 15 patients one antigen, five patients two antigen and three patients three antigen disparate grafts. Twenty-three patients were in class 2 or class 3, whereas six patients were in class 1. Thirteen patients were given BUCY, nine patients BUCY plus ALG, six patients BUCY plus TBI or TLI and one patient BUCY with prior cytoreductive-immunosuppressive treatment as conditioning. As GVHD prophylaxis four patients received MTX, 22 CsA ؉ MTX ؉ methylprednisolone (MP) and three patients CsA ؉ MP. Thirteen of 29 patients (44.8%) had sustained engraftment. The probability of graft failure or rejection was 55%. There were no significant differences between antigen disparities and graft failure. The incidence of grade II-IV acute GVHD was 47.3% and chronic GVHD was 37.5%. The incidence of acute GVHD was higher in patients receiving one or two antigen disparate in the GVHD direction grafts (vs no antigen) (P EQ 0.04; odds ratio 10.8; 95% CI 1.5-115). The probability of overall and event-free survival was 65% and 21%, respectively, with median follow-up of 7.5 years (range 0.6-17 years) for surviving patients. The degree of HLA disparity between patient and donor did not have a significant effect on survival. The incidence of nonhematologic toxicity was low. Transplant-related mortality was 34%. GVHD (acute or chronic) was a major contributing cause of death (50%) followed by infections (30%). We conclude that at present, due to high graft failure and GVHD rates, BMT from alternative donors should be restricted to patients who have poor life expectancies because they cannot receive adequate conventional treatment or because of alloimmunization to minor blood antigens. Keywords: bone marrow transplantation; phenotypically identical related donor; mismatched related donor; graft failure; GVHD Currently, bone marrow transplantation (BMT) from an HLA-identical related donor has been established as the only curative therapy for thalassemia, with long-term eventfree survival in 53-94% of patients according to the class of risk.1-4 One major limitation of BMT is the lack of suitable donors. Since only 30-35% of potential transplant candidates have HLA-identical siblings, attention has turned to alternative donor transplants including those using a partially mismatched related donor 5-8 or phenotypically matched unrelated donor. 9,10 In general, the results of BMT from unrelated donors are inferior to those using matched sibling donors due to an increased incidence and severity of GVHD, rejection, and infections.9-11 In a non-malignant BMT setting such as aplastic anemia, the results of unrelated BMT for adults are generally unsatisfactory, although improved survival in younger patients has been repor...