Contemporary Conditioning Regimen before Allogeneic Stem Cell Transplantation for Children with Non-Malignant Diseases

Non-malignant diseases (NMD) include a wide spectrum of either congenital or acquired disorders occurring in early and later childhood. The primary goal of conditioning in NMD is either the replacement of missing cells as in severe aplastic anaemia (SAA) or severe combined immunodeficiencies (SCID) or the exchange of a deficient blood cell compartment as in hemoglobinopathies, hemophagocytic syndromes or metabolic disorders. The right choice of a conditioning regimen before allogeneic hematopoietic stem cell transplantation (HSCT) is crucial for the outcome of patients with NMD, many of whom are often critically ill due to infections, organ dysfunctions, vascular complications or metabolic problems. As a consequence of a highly activated immune-system and no pre-treatment with chemotherapy, graft rejection is a known severe complication in these patients. To get up-to-date information on the most commonly used conditioning regimen for children with NMD, we performed an EBMT- registry-based analysis: 2187 patients from 39 countries with a congenital or acquired NMD below the age of 18 years who underwent first allogeneic HSCT between January 2010 and December 2014 registered in the EBMT database were included. 51% of children were transplanted before 4 years of age, 489 patients were less than 12 months old, and 61.5% were male. Majority of patients (32,2%) underwent HSCT for hemoglobinopathies (463 thalassemia major, 127 sickle cell disease), the second most common disease type was SCID with 17.4%, followed by other primary immunodeficiencies, chronic granulomatous disease and bone marrow failure syndromes (excluding Fanconi anaemia): 13.2%, 11% and 10.4%, respectively.

The given conditioning regimen was under discretion of the treating physician. The most common conditioning regimen consisted of a combination of busulfan (bu)/fludarabine (flu) in 1063 patients, of treosulfan (treo)/flu in 422 patients; 473 patients received a combination of treo/flu/thiotepa (tt) and 229 patients received bu/flu/tt. The median total dose of the respective conditioning drugs was comparable (treo: 41 g/m2 or 42g/m2; bu: 160 mg/m2; tt: 201 and 205 mg/m2).

In univariate analysis, overall survival (OS) was significantly different between the conditioning groups (p = 0.0032): 2y-OS 87.7% [84.3%-91.2%] for treo/flu/tt vs. 82.4% [78.5%-86.5%], 81.8% [77.8%-86.0%] for treo/flu, 80.8% [78.1%-83.5%] and 78.2% [75.2%-81.3%] for bu/flu and 81.3% [75.9%-87.0%] and 80.4% [74.9%-86.4%] for bu/flu/tt, respectively. Transplant-related mortality (TRM) was significantly different between the conditioning groups (p = 0.0015): day-100 TRM was lowest after treo/flu/tt: 4.8% [2.8%-6.7%] compared to 9.2% [6.3%-12.0%] after treo/flu, 7.9% [6.2%-9.5%] after bu/flu and 9.9% [5.9%-13.8%] after bu/flu/tt. TRM at 1 year post-transplant: 8.3% [5.5%-11.0%] for treo/flu/tt, 16.2% [12.2%-20.0%] after treo/flu, 16.9% [14.2%-19.4%] after bu/flu and 14.9% [9.7%-19.8%] after blu/flu/tt, respectively. In multivariate analysis, the HR was adjusted on age groups at HSCT, underlying disease, year of HSCT, stem cell source and donor types. 1-y OS was significantly better after treo/flu/tt (89.5 [86.5 - 92.6], CI 95%, p 0.0032) than with treo/flu, bu/flu or bu/flu, respectively. Day 100- and 1-year TRM was lower after treo/flu/tt compared to the other three conditioning combinations.

A pairwise testing of the different treatment groups revealed no statistical significant difference in OS, TRM, disease-free survival (DFS) for bu/flu vs. treo/flu, bu/flu vs. bu/flu/tt and bu/flu/tt vs. treo/flu; a significant better OS, DFS and less TRM for treo/flu/tt vs. bu/flu, treo/flu/tt vs. treo/flu and a better DFS for treo/flu/tt vs. bu/flu/tt with a trend for better OS and less TRM for treo/flu/tt vs. bu/flu/tt. No statistically significant differences were found among the 4 conditioning regimens for acute or chronic GVHD.

Conclusion: For children with NMD, a variety of conditioning regimen are in use to facilitate engraftment, prevent rejection, and enable sufficient cell function. Beside treo and bu, flu and tt are established drugs to eradicate lymphocytes. In this analysis, the combination of treo/flu/tt shows promising outcome results and should be further evaluated in diseases specific prospective trials.