Clinical Profile and Outcome of Patients with Graft Rejection Following Related HLA Matched Allogeneic Stem Cell Transplant for β Thalassemia Major

Allogeneic stem cell transplant (SCT) remains the only curative option for patients with β thalassemia major (TM). Graft rejections post SCT are unfortunately a common problem in this condition. There is limited data on the clinical profile and long term outcome of patients who have had a graft rejection post allogeneic SCT.

From October, 1991 to April, 2013, 400 HLA matched related transplants for TM was done at our center. The median age was 8 years (range: 1-24) and there were 250 (62.5%) males. 154 (38.5%) were Lucarelli Class II and 229 (57.2%) were in the Class III risk group. Majority (72%) received a busulfan based conditioning regimen while 22% received a treosulfan based regimen. Bone marrow was the source of stem cells in 81% and PBSC in the rest.

There were 48 (12%) graft rejections in this cohort. Among these 26 (54%) were primary graft failures (PGF) while 22 (46%) were secondary graft failures (SGF). The median time to a SGF was 122 days (range: 40 - 2210). Of the 26 PGF, 9(34.6%) had autologous recovery with recurrence of transfusion dependence while 17(65.4%) had pancytopenia. 11(42.3%) of PGF died prior to second transplant, 10 (38.5%) had a second transplant and the rest had recurrence of TM but were alive and well. Among the 22 SGF, 10(45.5%) had autologous recovery. Of the SGF's, 2 died prior to a second transplant while 9 had a second transplant and the remaining (n=11) had recurrence of TM and were on conservative management.

Among the 29 cases that did not receive a second transplant 14 died at a median time of 20 days (range: 0-3268). The major cause of death in this group was graft failure with infection (n=10) and regimen related toxicity (RRT; n=4). The remaining cases (n=14) are alive and well on conservative management (transfusion dependent, one with pancytopenia).  

19 (39.%) of the patients with graft rejection underwent a second allogeneic SCT. Conditioning regimen for second SCT was busulfan based in 5(26.3%), treosulfan based in 5(26.3%) and the rest received non-myeloablative conditioning regimens (fludarabine based, low dose TBI, OKT3, Cy-OKT3) in view of pancytopenia. The source of stem cells was BM in 7(36.84%) and PBSC in the rest. All cases conditioned with treosulfan based regimen received a PBSC graft. The OS and EFS of the patients that had a second transplant was 41.4±12.8% and 37.6±12.2% respectively. None of the patients conditioned with a treosulfan based regimen died or had a second graft rejection. Of the remaining 14 patients 11 died of second graft rejection while 3 (all busulfan based conditioning) are alive and well at 3, 23 and 81 months from second transplant.

In conclusion graft rejection following allogeneic SCT for patients with TM are associated with poor clinical outcomes. A treosulfan based reduced toxicity myeloablative regimen with a PBSC graft has potential to significantly improve the outcome in this group of patients.