title: Gemtuzumab-ozogamicin in combination with fludarabine, cytarabine, idarubicin (FLAI-GO) as induction therapy in CD33-positive AML patients younger than 65 years.
abstract: BACKGROUND
  The addition of gemtuzumab-ozogamicin (GO) to an induction regimen including synergistic drugs, such as intermediate dose of cytarabine (Ara-C), idarubicin and fludarabine (FLAI), could reduce treatment failure in acute myeloid leukemia (AML) patients. Nevertheless, the role and safety of this antibody target-therapy in first-line chemotherapy in patients younger than 65 years has not yet been defined.
  
  
  METHODS
  The primary goal of this prospective phase II pilot study was to evaluate the efficacy and the safety profile of FLAI plus GO as induction regimen. Thirty consecutive AML patients were included. All patients were younger than 65 with a median age of 53 years and CD33 expression exceeded 20% in all cases. The M/F ratio was 16/14 and 21/30 (70%) of patients were poor-risk at diagnosis. The induction regimen (FLAI-GO) included fludarabine (30mg/m(2)) and Ara-C (2g/m(2)) on days 1-5, idarubicin (10mg/m(2)) on days 1, 3, and 5 and GO (3mg/m(2)) on day 6. Hematopoietic stem cell transplant (HSCT) was planned for all high risk AML patients in first complete remission (CR) after consolidation with intermediate doses of Ara-C and idarubicin (IDAC-IDA). Cytogenetic, multidrug-resistance phenotype, FLT3 mutation status, and WT1 quantitative expression analyses were performed at diagnosis in all patients. WT1 expression and cytogenetic (in positive cases) analyses were performed after induction to detect and follow minimal residual disease.
  
  
  RESULTS
  Patients were evaluated for response rate, treatment-related adverse events, overall survival and relapse free survival. After induction with FLAI-GO, CR rate was 90% (26 of 29 evaluable pts); one patient achieved partial remission and two were resistant. There was only one case of death during induction (DDI). After FLAI-GO, the mean value of WT1 dropped from 4200+/-2777 copies/10(4)ABL to 192+/-399 copies/10(4)ABL. The toxicity of FLAI-GO was acceptable; 57% of patients experienced transient and reversible GO infusion-related adverse events (especially fever and chills), but no cases of veno-occlusive disease occurred during CHT or after HSCT. After a median follow-up of 16 months (range 2-25), 24/30 (80%) patients are alive (24/24 in CR). The probability of 1-year OS and RFS was 90 and 85%, respectively. Allogeneic and autologus HSCT was performed in 19 (63%) and 4 (13%) patients, respectively.
  
  
  CONCLUSIONS
  These preliminary results suggest that FLAI-GO is an effective and well tolerated induction regimen for CD33 positive AML patients younger than 65 years, with a high complete response rate, favourable safety profile, low DDI. These results encourage the testing of this regimen in a multicenter prospective trial.
authors.affiliation: Division of Hematology, Bone Marrow Transplantation Unit, Department of Clinical and Morphological Research, University Hospital, Udine, Italy. candoni.anna@aoud.sanita.fvg.it
authors.forename: Anna
authors.initials: A
authors.lastname: Candoni
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.forename: Eleonora
authors.initials: E
authors.lastname: Toffoletti
authors.forename: Alexia
authors.initials: A
authors.lastname: Chiarvesio
authors.forename: Mario
authors.initials: M
authors.lastname: Tiribelli
authors.forename: Michele
authors.initials: M
authors.lastname: Malagola
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Piccaluga
authors.forename: Angela
authors.initials: A
authors.lastname: Michelutti
authors.forename: Erica
authors.initials: E
authors.lastname: Simeone
authors.forename: Daniela
authors.initials: D
authors.lastname: Damiani
authors.forename: Domenico
authors.initials: D
authors.lastname: Russo
authors.forename: Renato
authors.initials: R
authors.lastname: Fanin
mesh_terms: D000328:Adult; D000368:Aged; D000617:Aminoglycosides / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000032:analysis*; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D003561:Cytarabine / Q000008:administration & dosage; D005260:Female; D000069585:Filgrastim; D000079982:Gemtuzumab; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins; D012074:Remission Induction; D063268:Sialic Acid Binding Ig-like Lectin 3; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D055815:Young Adult
chemical_list: D000617:Aminoglycosides; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D011994:Recombinant Proteins; D063268:Sialic Acid Binding Ig-like Lectin 3; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D000079982:Gemtuzumab; D014740:Vidarabine; C024352:fludarabine; D000069585:Filgrastim; D015255:Idarubicin