Outcomes of Thalassemia Patients Undergoing Hematopoietic Stem Cell Transplantation by Using a Standard Myeloablative versus a Novel Reduced-Toxicity Conditioning Regimen According to a New Risk Stratification

Abstract

Improving outcomes among class 3 thalassemia patients receiving allogeneic hematopoietic stem cell transplantations (HSCT) remains a challenge. Before HSCT, patients who were ≥ 7 years old and had a liver size ≥ 5 cm constitute what the Center for International Blood and Marrow Transplant Research defined as a very high–risk subset of a conventional high-risk class 3 group (here referred to as class 3 HR). We performed HSCT in 98 patients with related and unrelated donor stem cells. Seventy-six of the patients with age < 10 years received the more conventional myeloablative conditioning (MAC) regimen (cyclophosphamide, busulfan, ± fludarabine); the remaining 22 patients with age ≥ 10 years and hepatomegaly (class 3 HR), and in several instances additional comorbidity problems, underwent HSCT with a novel reduced-toxicity conditioning (RTC) regimen (fludarabine and busulfan). We then compared the outcomes between these 2 groups (MAC versus RTC). Event-free survival (86% versus 90%) and overall survival (95% versus 90%) were not significantly different between the respective groups; however, there was a higher incidence of serious treatment-related complications in the MAC group, and although we experienced 6 graft failures in the MAC group (8%), there were none in the RTC group. Based on these results, we suggest that (1) class 3 HR thalassemia patients can safely receive HSCT with our novel RTC regimen and achieve the same excellent outcome as low/standard-risk thalassemia patients who received the standard MAC regimen, and further, (2) that this novel RTC approach should be tested in the low/standard-risk patient population.

Hematopoietic stem cell transplantation for homozygous β-thalassemia and β-thalassemia/hemoglobin E patients from haploidentical donors

“…Further, we employed a high-dose of peripheral blood progenitor cells (PBPC) rather than bone marrow to be able to consistently target a large number of CD-34+ progenitor cells in the graft. This strategy has been working well; so far all patients (n=26) who had at most a one HLA-antigen mismatched donor engrafted (10, 11), and ultimately it resulted in an event-free survival (EFS) of over 90%. In contrast to previous reports, we found no increased risk for (serious) treatment-related complications associated with unrelated donors (10, 11).…”

“…This strategy has been working well; so far all patients (n=26) who had at most a one HLA-antigen mismatched donor engrafted (10, 11), and ultimately it resulted in an event-free survival (EFS) of over 90%. In contrast to previous reports, we found no increased risk for (serious) treatment-related complications associated with unrelated donors (10, 11). Our data indicated, that this new approach would be an improvement over the existing allo-SCT standard of care when applied with HLA-compatible donors.…”

Oxaliplatin-induced hepatic sinusoidal obstruction syndrome in a patient with gastric cancer: A case report

“…It is histologically characterized by sinusoidal dilatation, hepatocyte necrosis and obliterated hepatic venules due to damage to the sinusoidal endothelial cells (4). Sinusoidal changes induced by chemotherapeutic agents or pyrrolizidine alkaloid-containing herbals are caused by a direct toxicity to sinusoidal endothelial cells (12). In addition, toxic agents have an adverse effect on bone marrow progenitors of endothelial cells that are responsible for the repair of sinusoidal lesions (15).…”

Cure for thalassemia major – from allogeneic hematopoietic stem cell transplantation to gene therapy

“…19,20 Patients over 7 years of age with hepatomegaly of more than 5cm have been identified as an especially high-risk group who are candidates for/require novel approaches, particularly with regard to their conditioning regimen and preparation for transplant. 21,22 Two approaches have been taken in this regard, one based on pre-transplant immunosuppression using fludarabine, and the other by introducing a longer gap between the use of busulfan and cyclophosphamide during conditioning 23,24 or using less toxic myeloablative agents such as treosulfan and avoiding cyclophosphamide completely. 11 All these modifications have led to significantly improved survival rates of nearly 80-90% in these high-risk patients (Table 1).…”

“…11 All these modifications have led to significantly improved survival rates of nearly 80-90% in these high-risk patients (Table 1). 10,11,15,19,20,[23][24][25][26][27] While we have to appreciate the impact of successful alloHSCT on the lives of these patients, we need to continue to recognize the many challenges that persist with respect to the still significant morbidity and mortality associated with this procedure. All over the world a major constraint is the lack of access to this therapy related to the lack of a suitable donor.…”