Brain Sparing Conditioning Regimen and Umbilical Cord Blood Transplantation for Inherited High Risk Neurologic Metabolic Diseases.
Authors: Tolar Jakub , Jacobson Pamala , Charnas Lawrence , Orchard Paul J. 
Published: October 2019

In addition to the well established role of hematopoietic stem cell transplantation (HSCT) in the treatment of malignancies, HSCT is utilized for a number of neurologic metabolic diseases (typically, enzyme deficiencies) due to the ability of donor graft to provide an ongoing source of enzyme that can be taken up by recipient’s cells. Many of these diseases damage the white matter of the brain, and after onset of symptoms are characteristically progressive and lethal. Major limitations to the success of HSCT as therapy for these diseases are graft failure and toxicity to the brain from conditioning, resulting in disease progression. Thus, we reasoned that it would be advantageous to develop a less intensive conditioning regimen that minimally contributed to central nervous system toxicity while providing sufficient immunosuppressive to permit engraftment from unrelated cord blood donors. We are testing a reduced intensity regimen including Campath 1H (1.5 mg/kg), clofarabine (200 mg/m2), melphalan (140 mg/m2), and low dose total body irradiation (200 cGy) for this patient population. To gain insight into the persistence of Campath 1H, we measured serum levels within 30 hours prior to the cord blood infusion. We report outcomes in three adults and three children:

Diagnosis Age (years) UCB Graft; HLA match NC dose (×108/kg CD34+ dose (×106/kg) Campath 1H serum level* Donor Engraftment 1 MLD 44 dUCB; 4/6, 5/6 0.44 0.68 Undectectable 0% 2 ALD 9 dUCB; 5/6, 5/6 0.90 1.43 699 100% 3 ML 1 dUCB; 5/6, 5/6 1.43 3.04 1,575 100% 4 TS 1 sUCB; 6/6 0.97 1.33 2,250 100% 5 MLD 42 dUCB; 5/6, 6/6 0.76 0.94 2,728 60% 6 MLD 42 dUCB; 5/6, 5/6 0.22 0.24 Not done 100%

Legend: MLD, metachromatic leukodystrophy; ALD, adrenoleukodystrophy; ML, mucolipidosis type II; TS, Tay-Sachs disease; NC, nucleated cell; dUCB, double unit umbilical cord blood; sUCB, single unit umbilical cord blood; ND, not detected; Eng, engraftment; HLA matching is reported for antigen level HLA-A, B and allele level DRB1. *Campath 1H levels (nanograms/mL) are reported as an average of two measurements of samples diluted 10x. Cumulative doses for both UCB units are shown. The most recent donor chimerism is reported. To decrease the risk of graft rejection and prevent graft versus host disease (GvHD) patients received cyclosporine and mycophenolate mofetil. Patient 2 developed grade II skin and gastrointestinal acute GvHD, treated successfully with systemic and topical steroids. All patients are alive; none experienced progressive deterioration of neurologic function in the peri-transplant period. Our data suggest that this conditioning regimen is minimally toxic to the brain. The two subjects with the lowest Campath 1H concentrations had autologous recovery (patient 1) and GvHD (patient 2), suggesting that in vivo T cell depletion with Campath 1H may be beneficial. These results suggest that novel modifications in the transplant process may provide opportunities to decrease neurologic toxicity and maintain optimal neurologic function in this high risk population.