Experience of Endocrine Late Effects in Children with Haemolobinopathies Post Thiotepa Based Haematopoetic Stem Cell Transplant (HSCT) Regimens
Authors: Trikha Roochi , Hurley Catherine , Alexander Saji , de la Fuente Josu , Karnik Leena 
Published: October 2019

Abstract
Sickle cell disease and b-Thalassaemia major comprise the most prevalent haemoglobinopathies in the world. Despite significant advances in the supportive care, including effective iron chelation therapy, major complications still characterises the course of these illnesses. Allogeneic haematopoietic stem cell transplantation (HSCT) offers the only definitive cure at present. Based largely on goals in cancer treatment, myeloablative regimens such as busulpan/cyclophosphamide (Bu/Cy) were accepted as standard conditioning treatments for HSCT. However, significant side effects associated with Bu/Cy and increasing recognition of the benefit of graft Vs leukaemia/tumour effect brought reduced intensity conditioning with thiotepa to the fore. The relatively low early toxicity of thiotepa based regimens has widened its use to patients with co-morbidities who would have previously been deemed unfit for HSCT. This is especially pertinent in paediatric haemoglobinopathy patients where a regimen with low acute toxicity and importantly few late effects is required. Use of thiotepa/treosulphan based conditioning regimens in haemoglobinopathies was adopted by some groups less than 10 years ago.
There is paucity of data looking at endocrine late effect in paediatric patients. It has previously been reported that busulphan based chemotherapy was associated with significant endocrine abnormalities, including thyroid dysfunction and primary ovarian failure in girls. As thiotepa based regimens acquire longevity, their late effects will become more apparent.
Here we examine the endocrine late effects of thiotepa based conditioning in children who underwent a HSCT at St Mary Hospital, London in 2010 to 2014. The conditioning regimen comprised thiotepa 10mg/kg, fludarabine 150-160 mg/m2, treosulphan 42 g/m2 and ATG (thymoglobulin) 4.5 - 11.25 mg/kg. Sirolimus or Ciclosporin and MMF were used as GVHD prophylaxis. In patients who had haplo-identical HSCTs, in addition, 2 Gy TBI (low dose) and cyclophosphamide were used as part of the conditioning regimen and further cyclophosphamide post cell infusion as GVHD prophylaxis. In our cohort of 39 patients, 34 patients received stem cells from a related donors (25 matched sibling bone marrow, seven haploidentical from parents and two 9/10 mismatched relatives) and five from unrelated donors (four fully matched and one 9/10 mismatch). Median follow up in clinic was 3.1 years.
Of the 39 patients studied, two showed biochemical evidence of thyroid dysfunction and needed thyroid replacement therapy and 23 needed Vitamin D replacement. In this cohort, 19 patients (7 girls and 12 boys) were of pubertal age going into the transplant. There was evidence of gonadal failure in 6 (four girls and two boys) of the 19 patients ie 31% (as evidenced by high FSH and low testosterone levels). Four patients (two girls and two boys) ie 21% required pubertal induction. Of note, only one of the 6 patients with gonadal failure had had low dose TBI as part of the conditioning treatment.
Preliminary analysis of this cohort of patients suggests that thiotepa based conditioning chemotherapy that causes fewer early transplant related complications1, may also have a favourable late effects profile in terms of endocrine function. Our data, though precocious, shows at the very least that thiotepa based conditioning is no worse than the Bu/Cy regimens used before. It has previously been shown that approximately half of the patients given Bu/Cy had evidence of gonadal failure2. Clearly long-term follow of patients within this cohort is required for more accurate analysis of level of endocrine dysfunction. As the survivorship in post HSCT haemoglobinopathy patients is excellent, there is a pressing need to understand and set up services to manage these long-term complications.
References
1. O'Boyle F, Harrington Y, O'Brien N, et al. Fludarabine/Treosulfan/Thiotepa/ATG Conditioning Leads To High Rates Of Long-Term Engraftment and Low Toxicity Enabling The Use Of Mismatched and Unrelated Donors For Transplantation In Haemoglobinopathies. Blood. 2013;122(21):2041-2041.
2. Baki Y, Chakravorty S, Bridges N, et al. G95 Endocrine Late-Effects Post-Haematopoietic Stem Cell Transplant(HSCT) in Children with Haemoglobinopathies. Archives of Disease in Childhood. 2013;98(Suppl 1):A46-A47.

Disclosures
No relevant conflicts of interest to declare.