Treosulfan-based conditioning and hematopoietic cell transplantation for nonmalignant diseases: a prospective multicenter trial

Abstract

Hematopoietic cell transplantation is an effective treatment for 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 comorbid 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 after conditioning with treosulfan (total dose, 42 g/m(2)), fludarabine (total dose, 150 mg/m(2)), ± 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 to IV and III to 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 grades III to IV acute GVHD (0% versus 33%; P = .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.

Keywords: Allo-transplantation; Clinical results in inherited disorders; Conditioning regimen; Nonmalignant diseases; Reduced-intensity conditioning.

Figure 1. CD3+ and CD33+ donor chimerism in 31 patients conditioned with treosulfan and fludarabine

Shown are the percent donor chimerism of sorted peripheral blood CD3+ (panel A) and CD33+ (panel B) subsets according to day after transplant. The open circles represent percent donor chimerism measured for patients who were given thymoglobulin (n = 22), and the closed circles represent percent donor chimerism measured for patients who were not given thymoglobulin (n = 9) in the regimen. Spline smoothed regression lines reflect the trend in mean chimerism over time, for patients given thymoglobulin (dashed line) and for patients not given thymoglobulin (solid line). Overlapping points at day 28, day 84, day 180, and 1 year, and at 100% chimerism, are jittered slightly to improve visibility.

Figure 2. Acute and chronic graft-vs.-host disease (GVHD)

Shown is the cumulative incidence of acute GVHD grades II-IV (panel A) and acute GVHD grades III-IV (panel B) according to whether patients were given thymoglobulin (dashed line, n = 22) or not given thymoglobulin (solid line, n = 9) in the regimen. Panel C shows the cumulative incidence of chronic GVHD. Panel D shows the cumulative incidence of discontinuation of systemic immune suppression following HCT.

Figure 3. Overall survival, disease-free survival, and transplant-related mortality (n=31)

Shown are the Kaplan Meir estimates of overall survival (solid line) and disease-free survival (dashed line), and the cumulative incidence of transplant-related mortality (dotted line).