The safety and efficacy of clofarabine in combination with high-dose cytarabine and total body irradiation myeloablative conditioning and allogeneic stem cell transplantation in children, adolescents, and young adults (CAYA) with poor-risk acute leukemia.

Acute leukemias in children with CR3, refractory relapse, or induction failure (IF) have a poor prognosis. Clofarabine has single agent activity in relapsed leukemia and synergy with cytarabine. We sought to determine the safety and overall survival in a Phase I/II trial of conditioning with clofarabine (doses 40 - 52 mg/m2), cytarabine 1000 mg/m2, and 1200 cGy TBI followed by alloSCT in children, adolescents, and young adults with poor-risk leukemia. Thirty-seven patients; Age 12 years (1-22 years); ALL/AML: 34:3 (18 IF, 10 CR3, 13 refractory relapse); 15 related, 22 unrelated donors. Probabilities of neutrophil, platelet engraftment, acute GvHD, and chronic GvHD were 94%, 84%, 49%, and 30%, respectively. Probability of day 100 TRM was 8.1%. 2-year EFS (event free survival) and OS (overall survival) were 38.6% (CI95: 23-54%), and 41.3% (CI95: 25-57%). Multivariate analysis demonstrated overt disease at time of transplant (relative risk (RR) 3.65, CI95: 1.35-9.89, P = 0.011) and umbilical cord blood source (RR 2.17, CI95: 1.33-4.15, P = 0.019) to be predictors of worse EFS/OS. This novel myeloablative conditioning regimen followed by alloSCT is safe and well tolerated in CAYA with very poor-risk ALL or AML. Further investigation in CAYA with better risk ALL and AML undergoing alloSCT is warranted

Expression of human adenosine deaminase in nonhuman primates after retrovirus-mediated gene transfer.J. Exp. Med

The development of retroviral vectors capable of efficient insertion of genes into mammalian hematopoietic cells (1-7) has generated interest in gene therapy as a potential approach for the treatment of lethal genetic disease (8, 9). The cloning of a cDNA for the human adenosine deaminase enzyme (h-ADA) ' (10-12) has made the ADA deficient form of severe combined immunodeficiency (SCID) a potential candidate for such therapy. We recently described (13) a retroviral vector called SAX that contains the h-ADA cDNA (Fig. 1). Using this vector, the h-ADA gene was transferred into ADA-deficient human T cells that had been previously immortalized with human T cell leukemia virus (HTLV-1). After gene transfer, the T cells produced the ADA enzyme from the new gene at levels similar to those seen in normal cells. This level of expression was sufficient to make the treated cells resistant to levels of deoxyadenosine that are toxic to untreated ADA-deficient T cells in vitro (13). Therefore, the SAX retroviral vector appears to function efficiently in T cells cultured in vitro from ADA-deficient patients