Allogeneic Stem Cell Transplantation For Patients With Adrenoleukodystrophy. Nationwide Retrospective Study In Japan

Adrenoleukodystrophy (ALD) is an autosomal recessive disorder with progressive neurodegeneration caused by the mutation of ABCD1 gene and allogeneic stem cell transplantation (SCT) at its early stage is recognized as the only effective treatment modality to control the neurological symptoms. But the transplant outcome according to the conditioning regimen is not well understood so far. Here we analyzed the transplant outcome of patients with ALD using the clinical data accumulated in the Japan Society of Hematopoietic Cell Transplantation and tried to find the favorable conditioning regimen.

From 1988 to 2010, 76 patients with ALD were transplanted and their age at transplant was 1-34 years old (median 8). Stem cell sources the patients received were bone marrow (sibling 26, non-sibling related donor 5, unrelated volunteer donor 17), and cord blood (sibling 1, unrelated 28). Conditioning regimen was classified into four categories of A: busulfan + cyclophosphamide +/- others, (n=25), B: melphalan + total lymphoid irradiation (TLI) / thoraco-abdominal irradiation (TAI) +/- fludarabine +/- anti-thymocyte globulin (n=23), C: fludarabine + melphalan +low dose total body irradiation (TBI) (n=18), and D: others (n=10).

Sustained engraftment was obtained in 59 patients (77.8%) and it was significantly higher in bone marrow transplant (BMT) patients than cord blood transplant (CBT) patients (87.8% vs 60.7%, P=0.001). The incidence of acute graft-versus-host disease (GVHD), chronic GVHD and treatment related mortality of all patients were 7.9%, 19.3%, and 11.9%, respectively. Ten year overall survival (OS) and event free survival (EFS) of all patients were 83.7% and 64.1%, respectively. Ten patients died of either disease progression (n=2), or transplant related complications (n=8). Five year OS and EFS according to the conditioning regimen was A: 91.6% and 75.8%, B: 85.7% and 60.9%, C: 100% and 83.3%, D: 77.8% and 48.0%, respectively and they were not significant (P=0.379 in OS and P=0.183 in EFS, respectively). TBI was given to 22 patients with median dose of 4Gy (range 2-10.2) and sustained engraftment was obtained in 19 patients and all of 22 patients are alive. In patients who were not given TBI (n=54), 41 patients obtained engraftment and 44 patients are alive. OS according to presence or absence of TBI was 100% with TBI (n=22) and 86.1% without TBI (n=54) (P=0.091). By multivariate analysis for EFS, BMT and TBI were identified as good prognostic factors compared to CBT or non-TBI (HR 3.303, P=0.005, and HR 3.257, P=0.038, respectively), but OS of CBT was improved after 2005 compared to before 2004 (94.7% vs 68.6%, P=0.090).

Our results showed that conditioning regimen which includes TBI, even at low dose could provide better transplant outcome and the result of CBT improved after 2005 even though it was proved to be a significantly poor risk factor in the analysis of entire cohort. CBT enables urgent SCT when family donor is not available, and immediate transplant is essential for patients with ALD because of its nature. More precise assessment with brain MRI and neuropsychological examination is mandatory to evaluate the transplant outcomes of patients with ALD.

No relevant conflicts of interest to declare.