Treatment of High Risk Inherited Lysosomal and Peroxisomal Disorders Using Reduced Intensity Hematopoietic Cell Transplantation.

Several treatment approaches have been utilized for inherited metabolic diseases (IMD), including enzyme replacement therapy and hematopoietic cell transplantation (HCT). Because enzyme replacement therapy is of minimal use in lysosomal and peroxisomal diseases that affect the central nervous system (CNS), HCT has been the mainstay of therapy for diseases such as metachromatic leukodystrophy (MLD) and X-linked cerebral adrenoleukodystrophy (ALD). Unfortunately, these diseases may be difficult to diagnose and patients are often not referred for definitive therapy until there has been significant neurologic damage. These high risk patients fare poorly with standard myeloablative HCT, perhaps due to additional neurologic toxicity associated with the preparative regimen. To offer therapy for these high risk patients with no other treatment options, we developed a reduced intensity preparative regimen that was designed to be minimally toxic to the CNS.

Between 2007 and January 2009, 20 patients with high risk IMD primarily affecting the CNS (13 ALD, 4 MLD, 3 other) were treated with a reduced intensity allogeneic HCT regimen at the University of Minnesota. All were conditioned with campath-1H (0.3mg/kg on days -12 through -8), clofarabine (40mg/m² on days -7 through -3), melphalan (140mg/m² on day -2) and total body irradiation (TBI 200cGy, n=14) or total lymphoid irradiation (TLI 500cGy, n=6) (day -1). Campath-1H blood levels were drawn on day -1. Cyclosporine and mycophenolate mofetil were used for graft versus host disease (GVHD) prophylaxis. All patients received standard antimicrobial prophylaxis and supportive care measures.

The median age at HCT was 8 years (range 0.1–44) with a median follow-up of 504 days (range 177-885). Graft sources consisted of matched sibling bone marrow (n=6) and unrelated donor umbilical cord blood (n=14; 5 single, 9 double). The median time to neutrophil engraftment was 18 days (range 10-26). Overall survival at 100 days was 100%. Fifteen patients achieved full (>80%, n=9) or mixed (10-80%, n=6) donor chimerism. There was a higher proportion of patients achieving full and mixed donor chimerism and less graft failure (GF) in those patients who received TBI as compared to TLI (12/14 [86%] vs. 3/6 [50%] and 2/14 [14%] vs. 3/6 [50%], respectively). Three patients with mixed chimerism have received donor lymphocyte infusions. Two patients (10%) developed steroid responsive GVHD, both after day 100. All five patients with graft failure (GF) had autologous recovery. Of those, 2 received a second HSCT and successfully engrafted. The median campath-1H area under the curve was 3.29 and was not different between those with successful engraftment and those with GF.

Patients with advanced cerebral manifestations of lysosomal and peroxisomal disorders have limited therapeutic options. This reduced intensity transplant regimen designed to be minimally toxic to the CNS was very well tolerated with excellent overall survival. Donor engraftment appears to be better when TBI is utilized in the conditioning regimen. The incidence of GVHD is low, perhaps secondary to persistence of campath-1H. In summary, HCT with reduced intensity conditioning is feasible and should be considered for patients with high risk IMD.

Off Label Use: Clofarabine is an antineoplastic agent approved for use in relapsed/refractory pediatric ALL, but was used in our patients as part of the pre-HCT conditioning regimen .