Reduced Intensity Conditioning and Allogeneic Stem Cell Transplantation Followed By Targeted Consolidation Immunotherapy with Gemtuzumab Ozogamicin in Children and Adolescents with CD33+ Acute Myeloid Leukemia

Background: Myeloablative conditioning and AlloSCT in children with AML in CR1 is associated with a 60% event-free survival (EFS) but may be associated with significant acute toxicity and late effects (Woods et al; Blood, 2001). Reduced-intensity conditioning (RIC) and AlloSCT in children is safe, feasible and may be associated with less adverse effects (Del Toro/Cairo et al, BMT, 2004; Satwani/Cairo, BBMT, 2013). Gemtuzumab ozogamicin (GO) has been demonstrated to induce response in 30% CD33+ pediatric relapsed/refractory AML (Sievers et al, JCO, 2001). The dose of GO is significantly lower when combined with chemotherapy (Aplenc, JCO, 2008).

Objective: We examined the feasibility and toxicity of RIC-AlloSCT followed by GO targeted immunotherapy in children with CD33+ AML in CR1/CR2. 

Methods: Conditioning consisted of fludarabine 30mg/m² x 6 days and busulfan 3.2-4mg/kg x 2 days ± rabbit ATG 2mg/kg x 4 days followed by AlloSCT from matched related/unrelated donors. GO was administered ≥55 days post-AlloSCT in 2 doses (8 weeks apart), following a dose escalation design (4.5, 6, 7.5 and 9 mg/m²).  

Results: Thirteen patients with average risk AML received RIC AlloSCT: median age of 14.5 years at transplant (range: 11-21); M:F:7:6; disease status at AlloSCT: 10 CR1, 3 CR2.  Eleven patients received AlloSCT from 5-6/6 HLA matched family donors: 8 received PBSCs, 2 received BM and 1 received umbilical cord blood transplantation (UCBT). Two patients received an unrelated graft (HLA matching 1 4/6 and 1 9/10) from UCBT and BM, respectively. Neutrophil engraftment and platelet engraftment was observed in 13 patients (100%) and was achieved at a median of 14 days (range 7-31) and 18 days (range 10-52), respectively. Three patients received GO at dose level 1 (4.5 mg/m²/dose), 5 at dose level 2 (6 mg/m²/dose), 3 at dose level 3 (7.5 mg/m²/dose) and 2 at dose level 4 (9 mg/m²/dose).  The first dose of GO was administered after 55 days post-transplant. One patient experienced grade III transaminitis which resolved; no grade IV transaminitis, no grade III/IV hyperbilirubinemia or VOD. Twelve and 7 patients experienced grade 4 myeloid toxicity and grade 4 thrombocytopenia, respectively.  Following the first dose of GO, neutrophil and platelet recovery was achieved at median of 14 days (range 9-18) and 11 days (range 6-17), respectively. The second dose of GO was given at a median of 143 days (range: 120-209) post-transplant. The probability of grade II-IV aGVHD was 15.4%.   Probability of overall survival following RIC-AlloSCT and GO consolidation at 1 and 3 years was 83.3% and 65.6%, respectively.  There have been no DLTs observed in this cohort during this time period.

 Conclusion: This preliminary data demonstrates that RIC followed by AlloSCT and consolidation with GO appears to be safe in children with CD33+ AML in CR1/CR2. A larger cohort with longer follow-up is required to determine the long-term clinical significance.