Treosulfan-Based Conditioning and Hematopoietic Cell Transplantation for Nonmalignant Diseases: A Prospective Multicenter Trial

Abstract

Hematopoietic cell transplantation (HCT) is effective in the treatment of patients with nonmalignant diseases and for many is the only known cure. Conventional myeloablative regimens have been associated with unacceptably high early transplant-related mortality (TRM) particularly in patients with co-morbid conditions. This prospective multicenter trial was designed to determine the safety and engraftment efficacy of treosulfan-based conditioning in patients with nonmalignant diseases. Thirty-one patients received HLA-matched related (n=4) or unrelated (n=27) grafts following conditioning with treosulfan (total dose: 42 g/m2), fludarabine (total dose: 150 mg/m2), ± thymoglobulin (6 mg/kg; n=22). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. All patients engrafted. Day-100 TRM was 0%. With a median follow-up of 2 years, the 2-year survival was 90%. Three patients died of GVHD, recurrent hemophagocytic lymphohistiocytosis, and a surgical complication, respectively. The cumulative incidences of grades II–IV and III–IV acute GVHD at day 100 and chronic GVHD at 2 years were 62%, 10% and 21%, respectively. Patients who received thymoglobulin had a significantly lower incidence of grade III-IV acute GVHD (0% versus 33%; P = 0.005). These results indicate that the combination of treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with low toxicity and improved survival in patients with nonmalignant diseases, and support the need for future disease-specific clinical trials.

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

“…In 2014 we reported the preliminary results of a U.S. multicenter prospective phase I/II trial of a treosulfan-based reduced intensity conditioning regimen for treatment of life-threatening nonmalignant disorders [5]. We observed a low incidence of both toxicity and TRM, consistent with that reported in a number of large retrospective studies [6–10].…”

“…Toxicity and survival data on 8 of the 14 patients with marrow failure were reported previously [5]. The protocol was approved by the Institutional Review Boards of all participating institutions and monitored by an independent Data Safety Monitoring Board (DSMB).…”

Treosulfan-based conditioning for allogeneic HSCT in children with chronic granulomatous disease: a multicenter experience

“…[14][15][16][17][18] It has a low-toxicity profile, with the most commonly reported acute toxicities being skin, including nappy rash; diarrhea; mucositis; and hepatic toxicity; however, these are generally mild, and importantly, venoocclusive disease (VOD) is very rare. 19 Long-term effects are not welldocumented because of the relatively recent introduction of the drug for conditioning for HSCT.…”

Treosulfan-based conditioning regimens for allogeneic haematopoietic stem cell transplantation in children with non-malignant diseases

“…Further, a multivariate analysis was performed to study the impact of possible confounding factors on the defined outcomes. Cox regression 11,12 was used to model the time to transplantrelated mortality and OS. The statistical analysis was done with SAS System V9.2 (2008, SAS Institute, Cary, NC, USA).…”

“…Since then, treosulfan has increasingly been used for paediatric patients undergoing HSCT for both malignant and nonmalignant diseases. [5][6][7][8][9][10][11][12] An increasing number of patients with non-malignant disorders are eligible for HSCT and these patients present different challenges compared with those with malignant diseases: children with inherited disorders such as SCID often come to transplant as infants under 1 year of age with organ damage and co-morbidities. GvHD, which may be associated with a beneficial GvL effect in patients with high-risk haematological diseases, is of no added value in controlling the underlying genetic illness and may adversely affect subsequent immune reconstitution and have an unnecessarily negative impact on HSCT-related morbidity and quality of life in the short and long term.…”