title: A Phase I study of gemtuzumab ozogamicin (GO) in combination with busulfan and cyclophosphamide (Bu/Cy) and allogeneic stem cell transplantation in children with poor-risk CD33+ AML: a new targeted immunochemotherapy myeloablative conditioning (MAC) regimen.
abstract: Children with high-risk acute myelogenous leukemia (AML) (induction failure [IF], refractory relapse [RR], third complete remission [CR3]) have dismal outcomes. Over 80% of AML patients express CD33, a target of gemtuzumab ozogamicin (GO). GO is an active drug in childhood AML but has not been studied in a myeloablative conditioning regimen. We sought to determine the safety of GO in combination with busulfan/cyclophosphamide (Bu/Cy) conditioning before allogeneic hematopoietic stem cell transplantation (alloSCT). GO was administered on day -14 at doses of 3.0, 4.5, 6.0, and 7.5 mg/m(2), busulfan on days -7, -6, -5, -4 (12.8-16.0 mg/kg), and cyclophosphamide on days -3 and -2 (60 mg/kg/day). GVHD prophylaxis consisted of tacrolimus and mycophenolate mofetil. We enrolled 12 patients: 8 IF, 3 RR, 1 CR3; median age: 3 years (1-17); median follow-up: 1379 days (939-2305). Nine received umbilical cord blood (UCB), 2 matched unrelated donors (MUDs) and 1 HLA-matched sibling donor: 3 patients each at GO doses of 3.0, 4.5, 6.0, or 7.5 mg/m(2). No dose-limiting toxicities secondary to GO were observed. Day 100 treatment-related mortality (TRM) was 0%. Myeloid and platelet engraftment was observed in 92% and 75% of patients at median day 22 (12-40) and 42 (21-164), respectively. Median day +30 donor chimerism was 99% (85%-100%). The probability of grade II-IV acute graft-versus-host disease (aGVHD) was 42% and chronic GVHD (cGVHD) was 28%. One-year overall survival (OS) and event-free survival (EFS) was 50% (95% confidence interval [CI], 20.8-73.6). GO combined with Bu/Cy regimen followed by alloSCT is well tolerated in children with poor-risk AML. GO at 7.5 mg/m(2) in combination with Bu/Cy is currently being tested in a phase II study.
authors.affiliation: Department of Pediatric, New York Presbyterian Morgan Stanley Children's Hospital, Columbia University, New York, NY, USA.
authors.forename: Prakash
authors.initials: P
authors.lastname: Satwani
authors.forename: Monica
authors.initials: M
authors.lastname: Bhatia
authors.forename: James H
authors.initials: JH
authors.lastname: Garvin
authors.forename: Diane
authors.initials: D
authors.lastname: George
authors.forename: Filemon
authors.initials: F
authors.lastname: Dela Cruz
authors.forename: John
authors.initials: J
authors.lastname: Le Gall
authors.forename: Zhezhen
authors.initials: Z
authors.lastname: Jin
authors.forename: Joseph
authors.initials: J
authors.lastname: Schwartz
authors.forename: Deirdre
authors.initials: D
authors.lastname: Duffy
authors.forename: Carmella
authors.initials: C
authors.lastname: van de Ven
authors.forename: Sandra
authors.initials: S
authors.lastname: Foley
authors.forename: Ria
authors.initials: R
authors.lastname: Hawks
authors.forename: Erin
authors.initials: E
authors.lastname: Morris
authors.forename: Lee Ann
authors.initials: LA
authors.lastname: Baxter-Lowe
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Cairo
mesh_terms: D000293:Adolescent; D000617:Aminoglycosides / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002066:Busulfan / Q000008:administration & dosage* / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D000079982:Gemtuzumab; D006086:Graft vs Host Disease / Q000401:mortality / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000401:mortality / Q000628:therapy*; D008297:Male; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D019653:Myeloablative Agonists / Q000008:administration & dosage* / Q000009:adverse effects; D012307:Risk Factors; D063268:Sialic Acid Binding Ig-like Lectin 3; D035781:Siblings; D015996:Survival Rate; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects; D014019:Tissue Donors; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods*; D014184:Transplantation, Homologous
chemical_list: D000617:Aminoglycosides; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000970:Antineoplastic Agents; C571163:CD33 protein, human; D007166:Immunosuppressive Agents; D019653:Myeloablative Agonists; D063268:Sialic Acid Binding Ig-like Lectin 3; D003520:Cyclophosphamide; D000079982:Gemtuzumab; D002066:Busulfan; D009173:Mycophenolic Acid; D016559:Tacrolimus