Treosulfan-fludarabine-thiotepa conditioning before allogeneic haemopoietic stem cell transplantation for patients with advanced lympho-proliferative disease. A single centre study.

In recent years, with the aim of reducing transplant-related mortality, new conditioning regimens have been explored in patients not eligible for conventional haemopoietic stem cell transplantation. In this setting, we investigated safety and feasibility of the treosulfan-fludarabine-thiotepa combination prior to allogeneic haemopoietic stem cell transplantation in patients with advanced lympho-proliferative diseases and at high transplant risk. Twenty-seven consecutive patients, median age 43 years (range 19-60), entered this study. All of them were affected by lympho-proliferative disease in advanced phase and have been heavily pre-treated. The median haemopoietic stem cell transplant co-morbidity index was 1 (range 0-3). Twenty-five patients had regular engraftment, while the remaining two patients were not evaluable for early deaths. Non-haematological toxicity was limited. No patient developed veno-occlusive disease. The estimated probability of overall survival and progression-free survival with a median follow-up of 40 months was 52% (95% confidence interval 33-73) and 50% (95% confidence interval 30-70) respectively. Six patients have relapsed; all of them were not in remission before transplantation. The treosulfan-fludarabine-thiotepa combination is a reduced toxicity but myeloablative regimen that can be proposed to patients not fitting criteria for conventional myeloablative transplant regimens. Longer follow-up and prospective randomized studies are necessary to evaluate this regimen.

Hematopietic stem cell transplantation in thalassemia and related disorders.

The basis of allogeneic hemopoietic stem cell (HSC) transplantation in thalassemia consists in substituting the ineffective thalassemic erythropoiesis with and allogeneic effective one. This cellular replacement therapy is an efficient way to obtain a long lasting, probably permanent, clinical effective correction of the anaemia avoiding transfusion requirement and subsequent complications like iron overload. The first HSC transplant for thalassemia was performed in Seattle on Dec 2, 1981. In the early eighties transplantation procedure was limited to very few centres worldwide. Between 17 December 1981 and 31 January 2003, over 1000 consecutive patients, aged from 1 to 35 years, underwent transplantation in Pesaro. After the pioneering work by the Seattle and Pesaro groups, this therapeutic approach is now widely applied worldwide. Medical therapy of thalassemia is one of the most spectacular successes of the medical practice in the last decades. In recent years advances in knowledge of iron overload patho-physiopathology, improvement and diffusion of diagnostic capability together with the development of new effective and safe oral chelators promise to further increase success of medical therapy. Nevertheless situation is dramatically different in non-industrialized countries were the very large majority of patients live today. Transplantation technologies have improved substantially during the last years and transplantation outcome is likely to be much better today than in the '80s. Recent data indicated a probability of overall survival and thalassemia free survival of 97% and 89% for patients with no advanced disease and of 87% and 80% for patients with advanced disease. Thus the central role of HSC in thalassemia has now been fully established. HSC remains the only definitive curative therapy for thalassemia and other hemoblobinopathies. The development of oral chelators has not changed this position. However this has not settled the controversy on how this curative but potentially lethal treatment stands in front of medical therapy for adults and advanced disease patients. In sickle cell disease HSC transplantation currently is reserved almost exclusively for patients with clinical features that indicate a poor outcome or significant sickle-related morbidity.

Myocardial iron overload assessment by T2* magnetic resonance imaging in adult transfusion dependent patients with acquired anemias.

Only limited data are available regarding myocardial iron overload in adult patients with transfusion dependent acquired anemias. To address this topic using MRI T2* we studied 27 consecutive chronic transfusion dependent patients with acquired anemias: (22 myelodysplastic syndrome, 5 primary myelofibrosis). Cardiac MRI T2* values obtained ranged from 5.6 to 58.7 (median value 39.8) milliseconds. Of the 24 analyzable patients, cardiac T2* correlated with transfusion burden (p=0.0002). No patient who had received less than 290 mL/kg of packed red blood cells (101 units=20 grams of iron) had a pathological cardiac T2* value (< 20 ms). All patients who had received at least 24 PRBC units showed MRI T2* detectable hepatic iron (liver T2* value

Treosulfan/fludarabine as an allogeneic hematopoietic stem cell transplant conditioning regimen for high-risk patients.

In recent years, new conditioning regimens have been explored in patients not eligible for conventional transplant with the aim to reduce transplant-related mortality. In a phase II multicentric prospective trial, we investigated the safety and feasibility of the treosulfan-fludarabine combination prior to allogeneic hematopoietic stem cell transplant in patients with various hematological malignancies not eligible for conventional regimens because of previous intensive treatment, older age, and comorbidities. Forty-six consecutive patients, median age 48 years (range 17-69), were enrolled. Sixteen of them were in complete remission, and 20 had a HSCT comorbidity index > or = 1. Forty-four patients had regular and sustained engraftment, and 39 out of 40 evaluable patients developed complete chimerism. Nonhematological toxicity was limited. Risk of transplant-related mortality was 9% (95% CI, 2-17%) at day +100 and plotted at 15% (95% CI, 7-22%) after 7 months. The estimated overall survival and progression-free survival with a median follow-up of 20 months were 51% and 38%, respectively. The estimated 30 months progression-free survival for patients transplanted in remission was 56%. The treosulfan-fludarabine combination is a reduced-toxicity but myeloablative regimen that can be proposed to patients not fitting criteria for conventional transplant regimens. Longer follow-up and further prospective studies are necessary to evaluate this regimen.