Treosulfan-based conditioning regimen for children and adolescents with hemophagocytic lymphohistiocytosis

Lehmberg, Kai; Albert, Michael H.; Beier, Rita; Beutel, Karin; Gruhn, Bernd; Kröger, Nicolaus; Meisel, Roland; Schulz, Ansgar; Stachel, Daniel; Woessmann, Wilhelm; Janka, Gritta; Müller, Ingo

doi:10.3324/haematol.2013.094730

Cited by 58 publications

(61 citation statements)

References 21 publications

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“…We observed a low incidence of both toxicity and TRM, consistent with that reported in a number of large retrospective studies [6–10]. Several European groups have evaluated treosulfan in combination with fludarabine for conditioning of patients with primary immune deficiency disorders [7], hemophagocytic lymphohistiocytosis [8], and thalassemia [11, 12]; however, limited data have been published regarding the use of treosulfan-based conditioning for patients with bone marrow failure disorders. Here we report on a cohort of patients with marrow failure disorders treated on a prospective U.S. study.…”

Section: Introductionsupporting

confidence: 87%

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

Burroughs

Shimamura

Talano

et al. 2017

Biology of Blood and Marrow Transplantation

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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.

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Section: Introductionsupporting

confidence: 87%

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

Burroughs

Shimamura

Talano

et al. 2017

Biology of Blood and Marrow Transplantation

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“…Our results may also suggest that some disorders may be more resistant to engraftment with this regimen, as 2 of 6 patients with HLH experienced relapsed disease in the setting of mixed chimerism, one of whom required a second HCT and 1 of 4 patients with sickle cell disease required a second HCT for correction of secondary graft failure. While these numbers are too small to draw firm conclusions, several studies support the feasibility of intensifying the regimen without excessive toxicity through the addition of thiotepa, particularly in patients with thalassemia major and HLH [42–45]. …”

Section: Discussionmentioning

confidence: 99%

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

Burroughs

Nemecek

Torgerson

et al. 2014

Biology of Blood and Marrow Transplantation

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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.

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“…5,6,9,14,20,21 In this retrospective EBMT study, we evaluated the toxicity profile and outcome of 316 patients with non-malignant diseases undergoing HSCT, following treosulfan-based conditioning. To our knowledge, this is the largest such study to date.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Boztug

Pötschger

et al. 2015

Bone Marrow Transplant

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An increasing number of children with non-malignant diseases can be cured by allogeneic haematopoietic stem cell transplantation (HSCT). Treosulfan (L-treitol-1,4-bis-methanesulfonate) is being used more frequently for conditioning, owing to its' lower toxicity profile compared with conventional myeloablative regimens. A retrospective analysis was performed of children registered in the EBMT database, who received treosulfan before HSCT between January 2005 and 2010, to identify possible doserelated toxicity and determine the incidence of engraftment, treatment-related mortality and overall survival (OS). Results from 316 transplants from 11 different countries are presented. Ninety-five (30%) were under 1 year of age at the time of transplant. OS was 83% and event-free survival was 76%; 3-year OS and event-free survival of infants below 1 year were 79% and 73%, respectively. No association was found with age at transplant, dose of treosulfan given, other agents used in combination with treosulfan, donor type, stem cell source, or second or subsequent transplant. In this report of the largest number of children to date receiving treosulfan for non-malignant diseases, treosulfan is shown to be a safe and effective agent even for those under 1 year of age at the time of transplant. Further prospective studies are needed using precisely defined protocols with pharmacokinetic monitoring and detailed chimerism analysis. In addition, long-term studies will be vital to determine long-term effects, for example, on fertility in comparison with other regimens.

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Treosulfan-based conditioning regimen for children and adolescents with hemophagocytic lymphohistiocytosis

Cited by 58 publications

References 21 publications

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

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

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

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

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