Allogeneic Hematopoietic Cell Transplantation Using Treosulfan-Based Conditioning for Treatment of Marrow Failure Disorders

Abstract

Hematopoietic cell transplantation (HCT) is effective in the treatment of inherited marrow failure disorders and other non-malignant diseases. Conventional myeloablative conditioning regimens have been associated with high transplant related mortality particularly in patients with co-morbid conditions. Here we report on 14 patients with marrow failure disorders (Shwachman-Diamond syndrome n=3, Diamond Blackfan anemia n=4, GATA2 deficiency n=2, paroxysmal nocturnal hemoglobinuria n=4, and an undefined marrow failure disorder n=1) who underwent HCT on a prospective phase II multi-center clinical trial. Patients were given HLA-matched related (n=2) or unrelated (n=12) grafts following conditioning with treosulfan (42 grams/m2), fludarabine (150 mg/m2), ± thymoglobulin (n=11; 6 mg/kg). All patients engrafted. At a median follow-up of 3 years, 13 patients are alive with complete correction of their underlying disease. These results indicate that the combination of treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with a low toxicity profile and excellent disease-free survival in patients with marrow failure disorders.

Treosulfan–fludarabine–thiotepa-based conditioning treatment before allogeneic hematopoietic stem cell transplantation for pediatric patients with hematological malignancies

“…After initial data on treosulfan-based conditioning in adult alloHSCT patients became available [9,10], several published studies reported on the efficacy and safety of treosulfan given as part of various conditioning regimens in children [12,13,15,16,20,31]. Here, we report the final results of the first prospective alloHSCT trial of a treosulfan/fludarabine/thiotepa combination regimen (FTT; 65 of 70 trial patients treated) administered to children and adolescents with hematological malignancies.…”

“…Clinical studies, including prospective phase III trials in adults with AML and MDS, have shown that treosulfan-based conditioning has myeloablative, immunosuppressive, and antineoplastic effects associated with a low non-relapse mortality (NRM) [6][7][8][9][10][11]. Furthermore, several reports have been published that show an indication for treosulfan-based conditioning in children undergoing alloHSCT for nonmalignant and malignant disorders [12][13][14][15][16][17][18][19][20][21]. In addition, pharmacokinetic (PK) investigations on treosulfan in children have been conducted in order to derive dose recommendations for all pediatric age groups [22][23][24][25].…”

Early Increase in Complement Terminal Pathway Activation Marker sC5b-9 Is Predictive for the Development of Thrombotic Microangiopathy after Stem Cell Transplantation

“…Our results about the remarkable strong association between early increase of complement activation (as reflected by sC5b-9 levels) and later development of TA-TMA are in line with this model. Therefore, due to the high proportion of treosulfanbased conditioning regimens (24 of 33) in our cohort the rate of significant early transplant-related complications was reasonably low [32][33][34], and nonrelapse mortality did not associate with TA-TMA (Table 1). After more aggressive or toxic conditioning regimens, more severe TA-TMA cases could be observed, and further studies would be needed to validate these observations on adult and on other conditioning regimen cohorts.…”

When should transplant physicians think about familial blood cancers?

“…There have also been several reports of patients with GATA2 deficiency syndrome who underwent successful HCT prior to the HM development . Tholouli et al described three patients, ranging in age from 12 to 34 years, with a history of recurrent severe infections and pathogenic germline GATA2 mutations that underwent HCT from a MUD .…”