Eugenia Piras

Allogeneic hematopoietic stem cell transplantation in thalassemia major: results of a reduced-toxicity conditioning regimen based on the use of treosulfan

Sixty thalassemia patients (median age, 7 years; range, 1-37) underwent allogeneic hematopoietic stem cell transplantation (HSCT) after a preparation combining thiotepa, treosulfan, and fludarabine. Before HSCT, 27 children were assigned to risk class 1 of the Pesaro classification, 17 to class 2, and 4 to class 3; 12 patients were adults. Twenty patients were transplanted from an HLA-identical sibling and 40 from an unrelated donor. The cumulative incidence of graft failure and transplantation-related mortality was 9% and 7%, respectively. Eight patients experienced grade II-IV acute GVHD, the cumulative incidence being 14%. Among 56 patients at risk, 1 developed limited chronic GVHD. With a median follow-up of 36 months (range, 4-72), the 5-year probability of survival and thalassemia-free survival are 93% and 84%, respectively. Neither the class of risk nor the donor used influenced outcome. This treosulfan-based preparation proved to be safe and effective for thalassemia patients given allogeneic HSCT.

Unrelated Bone Marrow Transplantation for β‐Thalassemia Patients: The Experience of the Italian Bone Marrow Transplant Group

Abstract: Bone marrow transplantation (BMT) remains the only potentially curative treatment for patients with thalassemia major. However, most candidates for BMT do not have a suitable family donor. In order to evaluate whether BMT from an HLA‐matched unrelated volunteer donor can offer a probability of cure comparable to that obtained when the donor is a compatible sibling, we carried out a study involving 68 thalassemia patients transplanted in six Italian BMT Centers. Thirty‐three males and 35 females (age range, 2‐37 years; median age, 15) were transplanted from unrelated volunteer donors, all selected using high‐resolution molecular typing of both HLA class I and II loci. Fourteen patients were classified in risk class 1; 16 in risk class 2; and 38 in risk class III of the Pesaro classification system. Nine patients (13%) had either primary or secondary graft failure. Fourteen patients (20%) died from transplant‐related causes. Grade II‐IV acute graft‐versus‐host disease (GVHD) developed in 24 cases (40%), and chronic GVHD in 10 cases (18%). Overall survival (OS) in the cohort of 68 patients was 79.3% (CI 67‐88%), whereas the Kaplan‐Meier estimates of disease‐free survival (DFS) with transfusion independence was 65.8% (CI 54‐77%). In the group of 30 thalassemic patients in risk classes 1 and 2, the probability of OS and DFS were 96.7% (CI 90‐100%) and 80.0% (CI 65‐94%), respectively, whereas in the 38 patients in class 3 OS was 65.2% (CI 49‐80%) and DFS was 54.5% (CI 38‐70%). These data show that when donor selection is based on stringent compatibility criteria, the results of unrelated transplantation in thalassemia patients are comparable to those obtained when the donor is a compatible sibling.

Unrelated donor stem cell transplantation in adult patients with thalassemia

Summary: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.

Treosulfan‐based conditioning regimen for allogeneic haematopoietic stem cell transplantation in patients with thalassaemia major

The safety and efficacy of a preparation with treosulfan/thiotepa/fludarabine were explored in 20 thalassaemia patients given allogeneic marrow transplantation. Seventeen patients were transplanted from unrelated donors after receiving anti‐thymocyte globulin. The regimen was well tolerated. Two patients experienced secondary graft failure; one died of acute graft‐versus‐host disease. Cumulative incidence (95% confidence interval, CI) of transplantation‐related mortality and graft failure was 5% (95% CI, 0–34%) and 11% (95% CI, 3–43%), respectively. Two‐year probability of survival and thalassaemia‐free survival was 95% (95% CI, 85–100%) and 85% (95% CI, 66–100%), respectively. This regimen might find elective application in patients at high risk of developing life‐threatening complications.

The human leucocyte antigen-G 14-basepair polymorphism correlates with graft-versus-host disease in unrelated bone marrow transplantation for thalassaemia

The presence of the 14‐bp insertion polymorphism of the human leucocyte antigen (HLA)‐G gene (HLA‐G) promotes immune tolerance through increased synthesis of HLA‐G molecules. We investigated this polymorphism in a large cohort of 53 thalassaemia patients transplanted from an unrelated donor. Sixteen patients (30·2%) homozygous for the 14‐bp deletion had a higher risk of developing acute graft‐versus‐host disease (aGvHD) than patients homozygous for the 14‐bp insertion (−14‐bp/−14‐bp vs +14‐bp/+14‐bp: Relative Risk = 15·0; 95% confidence interval 1·59–141·24; P = 0·008). Therefore, the 14‐bp polymorphism could be an important predictive factor for aGvHD following bone marrow transplantation.

Long-term health-related quality of life evaluated more than 20 years after hematopoietic stem cell transplantation for thalassemia

The principal aim of our study was to investigate whether patients transplanted more than 20 years ago for β-thalassemia major had a different health-related quality of life (HRQoL) compared with the general population. The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) were received from 109 ex-thalassemia patients who underwent hematopoietic stem cell transplantation (HSCT) during the 1980s and 1990s. Adjusted comparisons were performed separately for patient age at HSCT and the presence or absence of graft-versus-host disease (GVHD). Sociodemographic and clinical variables were also analyzed. The median age of our cohort at HSCT and the time of the survey was 12 years (range, 1-36) and 34 years (range, 21-48), respectively, with a median follow-up age of 22.8 years (range, 11.7-30.3). Statistical analysis of data collected more than 20 years after HSCT showed that the long-term HRQoL of ex-thalassemia patients was very similar to that of the general population. Clinical meaningful differences were only found for the general health (GH) scale (-8.9; 95% CI, -15.0 to 2.7, P = .005). Mental health, education level, employment status, marital status, living arrangements, and birth rate were compatible with normal living patterns. The development of GVHD and older age at transplantation were important impairing factors. Additional analyses performed to evaluate HRQoL in an age-sex-matched cohort of 124 patients receiving conventional treatment of β-thalassemia revealed poorer outcomes compared with the cohort of transplanted patients.

Health related quality of life in Middle Eastern children with beta-thalassemia

BackgroundThalassemia is a common disorder worldwide with a predominant incidence in Mediterranean countries, North Africa, the Middle East, India, Central Asia, and Southeast Asia. Whilst substantial progress has been made towards the improvement of Health related quality of life (HRQoL) in western countries, scarce evidence-based data exists on HRQol of thalassemia children and adolescents living in developing countries.MethodsWe studied 60 thalassemia children from Middle Eastern countries with a median age of 10 years (range 5 to 17 years). HRQoL was assessed with the Pediatric Quality of Life Inventory (PedsQL) 4.0. The Questionnaire was completed at baseline by all patients and their parents. The agreement between child-self and parent-proxy HRQoL reports and the relationship between HRQoL profiles and socio-demographic and clinical factors were investigated.ResultsThe scores of parents were generally lower than those of their children for Emotional Functioning (mean 75 vs 85; p = 0.002), Psychosocial Health Summary (mean 70.3 vs 79.1; p = 0.015) and the Total Summary Score (mean 74.3 vs 77.7 p = 0.047). HRQoL was not associated with ferritin levels, hepatomegaly or frequency of transfusions or iron chelation therapy. Multivariate analysis showed that a delayed start of iron chelation had a negative impact on total PedsQL scores of both children (p = 0.046) and their parents (p = 0.007).ConclusionsThe PedsQL 4.0 is a useful tool for the measurement of HRQoL in pediatric thalassemia patients. This study shows that delayed start of iron chelation has a negative impact on children’s HRQoL.

Prospective Assessment of Health-Related Quality of Life in Pediatric Patients with Beta-Thalassemia following Hematopoietic Stem Cell Transplantation

Although hematopoietic stem cell transplantation (HSCT) has been widely used to treat pediatric patients with beta-thalassemia major, evidence showing whether this treatment improves health-related quality of life (HRQoL) is lacking. We used child-self and parent-proxy reports to prospectively evaluate HRQoL in 28 children with beta-thalassemia from Middle Eastern countries who underwent allogeneic HSCT in Italy. The PedsQL 4.0 Generic Core Scales were administered to patients and their parents 1 month before and 3, 6, and 18 months after transplantation. Two-year overall survival, thalassemia-free survival, mortality, and rejection were 89.3%, 78.6%, 10.9% and 14.3%, respectively. The cumulative incidence of acute and chronic graft-versus-host disease (GVHD) was 36% and 18%, respectively. Physical functioning declined significantly from baseline to 3 months after HSCT (median PedsQL score, 81.3 vs 62.5; P = .02), but then increased significantly up to 18 months after HSCT (median score, 93.7; P = .04). Agreement between child-self and parent-proxy ratings was high. Chronic GVHD was the most significant factor associated with lower HRQoL scores over time (P = .02). The child-self and parent-proxy reports showed improved HRQoL in the children with beta-thalassemia after HSCT. Overall, our study provides preliminary evidence-based data to further support clinical decision making in this area.

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.

Comparison between an artificial neural network and logistic regression in predicting acute graft-vs-host disease after unrelated donor hematopoietic stem cell transplantation in thalassemia patients.

OBJECTIVE There is growing interest in the development of prognostic models for predicting the occurrence of acute graft-vs-host disease (aGVHD) after unrelated donor hematopoietic stem cell transplantation. A high number of variables have been shown to play a role in aGVHD, but the search for a predictive algorithm is still ongoing. Artificial neural networks (ANNs) represent an attractive alternative to multivariate analysis for clinical prognosis. So far, no reports have investigated the ability of ANNs in predicting HSCT outcome. MATERIALS AND METHODS We compared the prognostic performance of ANNs with that of logistic regression (LR) in 78 beta-thalassemia major patients given unrelated donor hematopoietic stem cell transplantation. Twenty-four independent variables were analyzed for their potential impact on outcomes. RESULTS Twenty-six patients (33.3%) developed grade II to IV aGVHD. In multivariate analysis, homozygosity for donor KIR haplotype A (p = 0.03), donor age (p = 0.05), and donor homozygosity for the deletion of the human leukocyte antigen-G 14-bp polymorphism (p = 0.05) were independently significantly correlated to aGVHD. The mean sensitivity of LR and ANNs (capability of predicting aGVHD in patients who developed aGVHD) in test datasets was 21.7% and 83.3%, respectively (p < 0.001); the mean specificity (capability of predicting absence of aGVHD in patients who did not develop aGVHD) was 80.5% and 90.1%, respectively (p = NS). CONCLUSION Although ANNs are unable to calculate the weight of single variables on outcomes, they were found to have a better performance than LR. A combination of these two methods could be more efficient in predicting outcomes and help tailor GVHD prophylaxis regimens according to the predicted risk of each patient. Whether ANN technology will provide better predictive performance when applied to other datasets remains to be confirmed.