Preliminary Results of the Safety of Immunotherapy with Gemtuzumab Ozogamicin following Reduced Intensity Allogeneic Stem Cell Transplant in Children with CD33+ Acute Myeloid Leukemia

Abstract

Purpose: Myeloablative allogeneic stem cell transplantation (SCT) has been successful in the treatment of childhood acute myeloid leukemia (AML), but may be associated with significant toxicity and recurrent disease. Reduced-intensity allogeneic SCT may offer a less toxic approach to patients with AML.Targeted immunotherapy with gemtuzumab ozogamicin has been shown to be safe, well tolerated in children, and, as a single agent, gemtuzumab ozogamicin has induced responses in 30% of patients with recurrent CD33 + AML. There are no safety data with gemtuzumab ozogamicin post allogeneic SCT in children. Therefore, we explored the feasibility and toxicity of targeted immunotherapy following reduced-intensity allogeneic SCT in children with CD33 + AML. Experimental Design: Eight patients with CD33+ AML received a reduced-intensity allogeneic SCT following fludarabine 30 mg/m 2 for 6 days and busulfan 3.2 mg/kg (<4 years, 4 mg/kg/d) for 2 days. Donor sources included six 6/6 HLA-matched related peripheral blood stem cells, one 6/6 sibling cord blood, and one 4/6 unrelated cord blood. Results: Day 30 and day 60 donor chimerisms in seven of eight evaluable patients were 96 F 2% (n = 7) and 94 F 3% (n = 6), respectively. Five of six patients (too early for one patient) received two doses of gemtuzumab ozogamicin and one patient received only one dose. After each dose, all patients developed grade 4 neutropenia, with recovery on median days 16 and 13, respectively, after dose 1 and dose 2. Grade 4 thrombocytopenia was only observed in 2 of 11 gemtuzumab ozogamicin courses. No patients have developed dose-limiting toxicity secondary to gemtuzumab ozogamicin. Conclusions: The administration of gemtuzumab ozogamicin post reduced-intensity allogeneic SCT in children with average risk AML is feasible and well tolerated with minimal toxicity.The maximal tolerated dose has yet to be determined for gemtuzumab ozogamicin post reduced-intensity allogeneic SCT in children with CD33 + AML. Additional studies in a larger group of patients will be required to adequately assess the safety of this approach.

Dose-related efficacy and toxicity of gemtuzumab ozogamicin in pediatric acute myeloid leukemia

“…Twenty-seven articles were included based on their abstracts. After reading full-text articles, 14 studies were included in this study [4,[21][22][23][24][25][26][27][28][29][30][31][32][33].…”

Reduced intensity allogeneic umbilical cord blood transplantation in children and adolescent recipients with malignant and non-malignant diseases

“…RI-UCBT should be considered for pediatric patients whose condition at the time of transplantation places them at a high risk of toxicity (co-morbidities) from myeloablative transplantation. Studies are ongoing to determine the place of RI-UCBT in standard-risk pediatric hematological malignancies, 62 pediatric solid tumors 63 and selected non-malignant diseases. 34 The optimal intensity of conditioning for individual diseases, particularly CML, HLH and b-thalassemia, remains to be elucidated.…”

Reduced-intensity conditioning for acute myeloid leukemia: is this strategy correct

“…These problems may be addressed by the incorporation of targeted agents into the reduced-intensity conditioning regimen, including 188 Rh-or 90 Yt-monoclonal antibodies. 19 Other strategies to improve this approach include the use post-transplant of monoclonal antibodies such as gemtuzumab ozogamicin 20 or to utilize DLI to induce a graft-versus-leukemia effect. The use of new immunomodulating monoclonal antibodies such as Campath may help reduce GVHD in this setting.…”