P. De Stefano

A moderate transfusion regimen may reduce iron loading in beta‐ thalassemia major without producing excessive expansion of erythropoiesis

BACKGROUND: Hypertransfusion with a baseline hemoglobin of 10 to 12 g per dL is still considered by many to be the mainstay of conservative therapy for beta‐thalassemia major. However, this regimen is frequently associated with manifestations of transfusion iron overload, despite regular chelation therapy with subcutaneous desferoxamine. STUDY DESIGN AND METHODS: To verify whether a transfusion regimen with a target pretransfusion hemoglobin level between 9 and 10 g per dL can allow a significant reduction in blood consumption, while still effectively suppressing erythropoiesis, the records were reviewed of 32 beta‐ thalassemia major patients, who were maintained at a pretransfusion hemoglobin of 11.3 +/− 0.5 g per dL between 1981 and 1986. These patients were switched at the beginning of 1987 to a transfusion regimen with pretransfusion hemoglobin of 9.4 +/− 0.4 g per dL. The degree of erythroid marrow activity was evaluated in these patients and in 32 subjects with beta‐thalassemia intermedia through the simple measurement of serum transferrin receptor. RESULTS: After the adoption of the moderate transfusion regimen, transfusion requirements decreased from 137 +/− 26 to 104 +/− 23 mL per kg per year of red cells (p < 0.0001), and mean serum ferritin decreased from 2448 +/− 1515 to 1187 +/− 816 micrograms per L (p < 0.0001), with one‐half of patients achieving serum ferritin levels lower than 1000 micrograms per L. The proportion of patients having spontaneous pubertal development increased significantly (p < 0.01), as a result of less iron‐related gonadotropin insufficiency. At the lower pretransfusion hemoglobin, erythroid marrow activity did not exceed two to three times normal levels in most subjects. CONCLUSION: As compared with hypertransfusion, moderate transfusion may allow more effective prevention of iron loading, with higher likelihood of spontaneous pubertal development and without producing excessive expansion of erythropoiesis.

Relationship between transfusion regimen and suppression of erythropoiesis in β-thalassaemia major

In the management of β‐thalassaemia major, different transfusion schemes are employed with baseline haemoglobin levels ranging from 8 to over 12 g/dl. We studied the relationship between transfusion regimen and suppression of erythropoiesis in 52 patients with β‐thalassaemia major whose mean pretransfusion haemoglobin levels ranged from 8.6 to 10.9 g/dl. Multiple, regression analysis showed that serum transferrin receptor was the parameter more closely related to mean pretransfusion haemoglobin (r = ‐0.77, P < 0.001). As measured through serum transferrin receptor, erythroid activity was 1‐2 times normal for pretransfusion haemoglobin levels between 10 and 11 g/dl, 1‐4 times normal for levels from 9 to 10 g/dl, and 2‐6 times normal for levels from 8.6 to 9 g/dl. Mean pretransfusion haemoglobin was also inversely related to serum erythropoietin (r = ‐0.72, P < 0.001), whereas it showed no or a weak relationship with Hb F, reticulocyte count, or circulating nucleated red cell count. This study suggests that serum transferrin receptor is a reliable indicator of suppression of erythropoiesis in β‐thalassaemia major. On the basis of our findings, pretransfusion haemoglobin values of ≦ 9 g/dl should be adopted with caution, because these levels can be associated with an insufficient inhibition of erythroid marrow expansion. However, a transfusion programme, with a baseline haemoglobin of 9‐10 g/dl, may provide enough suppression of erythropoiesis and allow a reduction in blood consumption as compared with the classic hyper‐ or supertransfusion schemes. Since fixed haemoglobin levels may not be the best target for transfusion treatment in all thalassaemic patients, assay of serum transferrin receptor may be helpful for individualizing the transfusion regimens.

Total-Body Irradiation and Melphalan Is a Safe and Effective Conditioning Regimen for Autologous Bone Marrow Transplantation in Children With Acute Myeloid Leukemia in First Remission

PURPOSE To evaluate the safety and efficacy of a preparative regimen consisting of fractionated total-body radiation (9.9 to 12 Gy) and melphalan (140 mg/m(2) in a single dose) in children with acute myeloid leukemia in first complete remission (CR) given autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS Fifty-three children (30 males and 23 females; age range, 1.5 to 18 years) were enrolled onto the study. The median time from first CR to ABMT was 3.5 months (range, 1.4 to 13 months), with 45 patients (85%) undergoing transplantation within 6 months from the diagnosis. Forty-five patients received in vitro marrow purging with standard-dose mafosfamide (100 microg/mL), seven patients were treated with interleukin-2 before marrow collection, and in the remaining child, the marrow was unmanipulated. The median infused cell dose was 1.8 x 10(8)/kg (range, 0.4 to 5.8 x 10(8)/kg). RESULTS All patients but one achieved hematopoietic engraftment, with a median time to neutrophil recovery of 24 days (range,11 to 66 days). Treatment-related toxicity was moderate and consisted mainly of mucositis. One patient died from cytomegalovirus interstitial pneumonia, and one died from pulmonary hemorrhage. Fourteen patients (26%) relapsed at a median time of 6 months after ABMT (range, 2 to 17 months), with a cumulative relapse probability of 29% (95% confidence interval, 16% to 42%). The 5-year Kaplan-Meier estimate of survival for all 53 patients was 78% (range, 65% to 90%), whereas the overall 5-year disease-free survival was 68% (range, 55% to 81%), with a median follow-up duration of 40 months (range, 7 to 130 months). CONCLUSIONS These data suggest that, in our cohort of patients, the combination of total-body irradiation and melphalan is safe and associated with good antileukemia activity, making ABMT an appealing alternative for postremission therapy in children with acute myeloid leukemia in first CR.

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.

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

Summary: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.

Accelerated erythroid repopulation with no stem-cell competition effect in children treated with recombinant human erythropoietin after allogeneic bone marrow transplantation.

Summary. We carried out a pilot study on the use of recombinant human erythropoietin (rHuEPO) to accelerate erythropoietic engraftment in paediatric patients undergoing allogeneic BMT. rHuEPO was administered intravenously at a dose of 75 U/kg per day for 30 d after transplant. Erythroid repopulation, evaluated sequentially through the serum transferrin receptor, was faster in 15 patients receiving rHuEPO than in 16 historical controls (P= 0·0003). This faster erythroid engraftment resulted in a reduction in the total number of red blood cell units required to reach transfusion independence (2·7 ± 1·2 v 4·2 ± 2·3, P= 0·027). No significant difference in leucocyte or platelet regeneration was observed. These findings indicate that rHuEPO administration can accelerate erythroid recovery after allogeneic BMT and reduce red cell transfusion requirements with no stem‐cell competition effect.

Study of Vinyl Polymerization by Proton Magnetic Relaxation

A study of molecular motion during the process of polymer formation has been performed with measurements of proton magnetic relaxation. The presence of two distinct relaxation processes for the protons of the monomer molecules and those of the polymer chains has been observed. During the polymerization the spin‐lattice relaxation time T1 of the monomer protons decreases very slowly while the flow viscosity of the sample increases greatly; this reveals that the motions responsible for the relaxation are mainly rotational. These motions can be considered to be thermally activated: the activation energies increase as the polymerization proceeds. The results we have obtained can be explained by assuming that there is a motion which has a predominant effect upon the relaxation and that a distribution of correlation frequencies, the width of which increases as the polymerization proceeds, is present. By making certain assumptions it has been possible to obtain some information about this distribution.

Penicillin compliance in splenectomized thalassemics.

Compliance with penicillin prophylaxis after splenectomy was studied in 42 thalassemic children and adolescents. Urine samples were tested five times per patient for the presence of penicillin by the Sarcina lutea inhibition test. Only 7% of patients were found to be absolute noncompliers, while an additional 14% had a compliance considered to be insufficient. Noncompliers tended to have been splenectomized more than 5 years before, while couples of affected siblings were uniformly full-compliers. No relation was found with age, presence of healthy siblings in the household, chronic disease or previous severe infections. Knowledge of the risks of severe infection after splenectomy was uniformly good. We conclude that compliance with penicillin prophylaxis in splenectomized thalassemics is good (79%) and that close contact between patients and medical staff is important in its promotion.