1.
Impact of treosulfan exposure on early and long-term clinical outcome in pediatric allogeneic HSCT recipients: a prospective multicenter study
van der Stoep, Myec, Bertaina, A., Moes, Djar, Algeri, M., Bredius, R. G. M., Smiers, F. J. W., Berghuis, D., Buddingh, E. P., Mohseny, A. B., Guchelaar, H. J., et al
Transplantation and cellular therapy. 2021
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Editor's Choice
Abstract
BACKGROUND Treosulfan-based conditioning has gained popularity in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) because of its presumed favorable efficacy and toxicity profile. Treosulfan is used in standardized dosing regimens based on body surface area. The relationship between systemic treosulfan exposure, early and long term clinical outcome in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for non-malignant diseases is as yet unresolved. OBJECTIVE In this study we assessed the association between treosulfan exposure and early, and in particular, long term clinical outcomes. STUDY DESIGN We conducted a multicenter, prospective observational study and included 110 pediatric patients with non-malignant diseases transplanted between 2011 and 2019 in Leiden, The Netherlands and Rome, Italy. Blood samples were collected and treosulfan area under the curve (AUC(0-8)) was estimated as a measure of exposure. Cox proportional hazard survival analyses were performed to assess the relationship between treosulfan exposure, OS and EFS. The predictive value of systemic treosulfan exposure for the occurrence of toxicity within 28 days is evaluated using a multivariable logistic regression analysis. RESULTS In the overall cohort, overall survival (OS) and event-free survival (EFS) at 2 years were 89.0% and 75.3%, respectively, with an excellent OS of 97% in children under the age of 2 years. The occurrence of grade II-IV aGvHD, the level of 1-year whole blood chimerism, and 2-year OS and EFS were not correlated with treosulfan exposure. The occurrence of skin toxicity (odds ratio (OR) 3.97, 95% confidence interval (CI) 1.26-13.68, p=0.02) and all grade mucositis (OR 4.43, 95%CI 1.43-15.50, p=0.02), but not = grade 2 mucositis (OR 1.51, 95%CI 0.52-4.58, p=0.46) was related to high treosulfan exposure (>1750 mg*h/L). CONCLUSION Our study demonstrates that standardized treosulfan-based conditioning results in a favorable OS and EFS in infants and children with non-malignant diseases, independent of interindividual variation in treosulfan exposure. These outcomes can be achieved without the need for therapeutic drug monitoring (TDM), thereby emphasizing the advantage of treosulfan use in this category of patients. Although higher treosulfan exposure increases the risk of skin toxicity, there is no absolute necessity for therapeutic drug monitoring if proper preventive skin measures are taken. More research is needed to assess whether de-escalation of treosulfan doses is possible in order to minimize early and long term toxicity without compromising efficacy.
PICO Summary
Population
Children with non-malignant diseases who received allogeneic HSCT at two centres in the Netherlands and Italy (n=110)
Intervention
Treosulfan conditioning
Comparison
None
Outcome
In the overall cohort, overall survival (OS) and event-free survival (EFS) at 2 years were 89.0% and 75.3%, respectively, with an excellent OS of 97% in children under the age of 2 years. The occurrence of grade II-IV aGvHD, the level of 1-year whole blood chimerism, and 2-year OS and EFS were not correlated with treosulfan exposure. The occurrence of skin toxicity (odds ratio (OR) 3.97, 95% confidence interval (CI) 1.26-13.68, p=0.02) and all grade mucositis (OR 4.43, 95%CI 1.43-15.50, p=0.02), but not = grade 2 mucositis (OR 1.51, 95%CI 0.52-4.58, p=0.46) was related to high treosulfan exposure (>1750 mg*h/L).
2.
Treatment of steroid resistant acute graft versus host disease with an anti-CD26 monoclonal antibody-Begelomab
Bacigalupo, A., Angelucci, E., Raiola, A. M., Varaldo, R., Di Grazia, C., Gualandi, F., Benedetti, E., Risitano, A., Musso, M., Zallio, F., et al
Bone marrow transplantation. 2020
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Editor's Choice
Abstract
We have treated 69 patients with steroid refractory acute graft versus host disease (SR-aGvHD), with an anti-CD26 monoclonal antibody (Begelomab): 28 patients in two prospective studies (EudraCT No. 2007-005809-21; EudraCT No. 2012-001353-19), and 41 patients on a compassionate use study. The median age of patients was 42 and 44 years; the severity of GvHD was as follows: grade II in 8 patients, grade III in 33, and grade IV in 28 patients. There were no adverse events directly attributable to the antibody. Day 28 response was 75% in the prospective studies and 61% in the compassionate use patients, with complete response rates of 11 and 12%. Response for grade III GvHD was 83 and 73% in the two groups; response in grade IV GvHD was 66 and 56% in the two groups. Non relapse mortality (NRM) at 6 months was 28 and 38%. Overall there were 64, 56, 68% responses for skin, liver, and gut stage 3-4 GvHD. The overall survival at 1 year was 50% for the prospective studies and 33% for the compassionate use patients. In conclusion, Begelomab induces over 60% responses in SR-aGvHD, including patients with severe gut and liver GvHD, having failed one or more lines of treatment.
PICO Summary
Population
Patients with steroid refractory acute graft versus host disease (n=69)
Intervention
Begelomab, an anti-CD26 monoclonal antibody in prospective study (n=28)
Comparison
Begelomab, an anti-CD26 monoclonal antibody in compassionate use (n=41)
Outcome
Day 28 response was 75% in the prospective studies and 61% in the compassionate use patients, with complete response rates of 11 and 12%. Response for grade III GvHD was 83 and 73% in the two groups; response in grade IV GvHD was 66 and 56% in the two groups. Non relapse mortality (NRM) at 6 months was 28 and 38%. Overall there were 64, 56, 68% responses for skin, liver, and gut stage 3-4 GvHD. The overall survival at 1 year was 50% for the prospective studies and 33% for the compassionate use patients. There were no adverse events directly attributable to the antibody