Long Term Outcome of Allogeneic Hematopoietic Stem Cell Transplantation for Beta Thalassemia Major

Introduction:Allogeneic hematopoietic stem cell transplantation (HSCT) cures beta thalassemia major (TM). Such individuals, ex-thalassemics, have good long term survival. However, there is limited data on long term outcome (LTO) of this therapy. This is particularly relevant as these patients often have organ dysfunction pre-transplant due to secondary hemosiderosis apart from the impact of post-transplant factors such as chronic GVHD, chimerism status and iron depletion therapy (IDT). In this report, we describe the LTO of patients with TM who underwent HSCT with busulfan (Bu) and cyclophosphamide (Cy) conditioning at our center from 2000 to 2011 and had a minimum of 2 year follow-up.

Method: Data was extracted from prospectively maintained standardized case record forms for details of HSCT and long term follow-up with particular reference to GVHD, chimerism (evaluated at day +30, +60, +100 and thereafter as indicated), IDT (initiated at variable periods post-HSCT) and metabolic and endocrine disorders evaluated on physician discretion or as per clinical indications.

Results:A total of 190 patients underwent matched related donor HSCT from 2001 to 2011 with Bu/Cy based conditioning. After excluding those who expired or had primary graft failure or did not have at least 2 years of follow-up, 124 patients were available for analysis of LTO. 44 patients (35.5%) class 3, 69 patients (55.6%) class 2 and 11 patients (8.9%) class 1. The median age was 7 years (range: 2-24) with 81 males (65.3%). The median follow-up was 7 years (range: 2 to 14). Chronic GVHD was present in 22 patients (17.7%]. Mixed chimerism (MC) occurred in 40 patients (32%) in the first year after HSCT: level I in 21 (52.5%), level II in 10 (25%), level III in 7 (17.5%), and level unknown in 2(5%). At last follow-up, 20/40 (50%) patients with MC went on to CC, 18 maintained stable MC (level I-5, level II-9 and level III-4) with hemoglobin of 11.35g/dl (range: 9-13.5), while 2 (5%) with level 3 MC remained transfusion dependent. Median serum ferritin (SF) at HSCT was 2367 ng/ml (range: 685-7660). IDT was initiated in 90 (72.6%) patients at a median of 15 months (range: 6-53) post-HSCT - 13 patients (14.4%) were treated with phlebotomy alone, while 39 (43.3%) received chelation and 38 (42.2%) the combination. Reduction in SF/month [absolute quantity (ng/ml/month) and percent] was as follows: 40.5 (range: 11.68 - 125.78); 1.67% (range: 0.5-4.58), 54.9 (range: 9.3- 278.7); 2.1% (range: 0.41- 13.8) and 36.6 (range: 3.51-590.7); 1.3% (range: 0.42-42.99), in the phlebotomy, chelation and combination groups, (p=0.077 & 0.017, respectively). SF level of <300 ng/ml was achieved in 33 patients (31%) at last follow-up. Anthropometry measurements (at last follow up) revealed short stature in 53 patients (42.7%; 38M/15F), underweight in 32 patients (25.8%; 20M/12F) and overweight in 14 (11.3%) patients (11M/3F). A total 48 patients (38.7%) had the following endocrine disorders: hypogonadism in 33 (73.3%), primary hypothyroidism in 9 (18.8%), hypopituitarism in 4 (8.3%), diabetes mellitus in 3 (6.2%), and hypoparathyroidism, dyslipidemia and hypertension in 1 patients each. 40 patients were vitamin D deficient (83.3%). Endocrine complications were more common in female patients (55.8% versus 29.6%; p=0.006). Two patients (1.3%) developed malignancies at 7 and 8 years, post-HSCT. Among different patient, donor and graft characteristics, there were no predictors of MC, nor did the ferritin levels or chelation therapy post-HSCT affect the incidence of endocrine complications in this cohort.

Conclusion: Our data shows that even though the long term survival of ex-thalassemics is extremely good, at least 40% of them suffer from several co-morbidities related to iron overload and various metabolic and endocrine disorders which requires a coordinated plan for their management. The aim therefore should be to transplant these patients as early as possible before such complications occur and implement IDT intensively early after HSCT.