Addition of Gemtuzumab Ozogamicin (GO) to Fludarabine, Cytarabine and G-CSF (FLAG) Based Induction Regimen Results in Better Early Molecular Response and Relapse Free Survival Compared to Idarubicin (FLAG-Ida) in Newly Diagnosed Core Binding Factor Leukemia
Authors: Borthakur Gautam , Cortes Jorge E. , Garcia-Manero Guillermo , Patel Keyur , Ravandi Farhad , Kadia Tapan M. , Pemmaraju Naveen , Daver Naval G. , Yilmaz Musa , Estrov Zeev E. , Ohanian Maro N. , Maduike Rita , Kantarjian Hagop M. 
Published: October 2019

Background: Fludarabine, cytarabine and G-CSF (FLAG) based regimens have resulted in marked improvement in newly diagnosed core binding factor (CBF) acute myelogenous leukemia (AML)(1-3). Addition of gemtuzumab ozogamicin (GO) to chemotherapy has also improved survival outcomes in CBF-AML(4). In 2007 we initiated a frontline study of FLAG-GO in newly diagnosed CBF-AML but after withdrawal of GO from US market, GO was replaced with idarubicin (FLAG-Ida). We report on mature data including early molecular response in patients treated in these sequential protocols.

Methods: One hundred and forty five patients [Median age, 48 years (range, 19-78 years) were treated in these sequential protocols (FLAG=GO=50, FLAG-Ida= 95 patients). The treatment groups were comparable for age and distribution of cytogenetic (T8;21 or Inv16) subgroups (p≥0.5). FLAG regimen has been published before(2), GO was administered at 3 mg/m2 on day 1 in induction and in 2 consolidations out of planned 6 and idarubicin was administered at 6 mg/m2 on days 3 and 4 in induction and on day 2 in one of the consolidation cycles out of planned 6. Serial assessment of fusion transcript product relevant to the cytogenetic abnormality was performed in bone marrow samples at baseline, end of induction and every 2-3 cycles thereafter.

Results: All except 3 patients (2 induction deaths) achieved remission (98%). After median follow up of 5 years, 5 year overall survival (OS) and relapse free survival (RFS) for the entire cohort is 77% and 72% respectively. There were no differences in OS among FLAG-GO vs FLAG-Ida (p=0.3) and Inv16 vs T(8;21) (p=0.6). While RFS was similar among Inv 16 and T(8;21) subgroups, it was significantly better among the cohort treated with FLAG-GO compared to FLAG-Ida (p=0.04)(Fig 1). We confirmed our earlier report of higher than 3 log reduction of fusion transcript ratio at end of induction(5) being most indicative of sustained RFS (p=0.006) (Fig 2) and this end point was more frequently achieved in the FLAG-GO cohort (57%) compared to FLAG-Ida cohort (29%) (p=0.002). On the other hand, within each regimen there was no difference in RFS between Inv 16 andf T(8;21) subgroups (p=0.3) (Fig. 3).

SAEs were mostly related to cytopenias and associated infectious complications for both regimens and no hepatic veno-occlusive disease (VOD) was encountered. Presence of KIT, RAS, FLT3 mutations individually or in combination did not have any impact on outcomes.

Conclusion: Compared to idarubicin, GO when added to FLAG based frontline induction/consolidation regimen results in better early molecular responses and improved relapse free survival in CBF AML. Our current frontline protocol is exploring safety and efficacy of addition of both GO and Ida to FLAG based regimen.

ReferencesBorthakur G, Cortes JE, Estey EE, Jabbour E, Faderl S, O'Brien S, et al. Gemtuzumab ozogamicin with fludarabine, cytarabine, and granulocyte colony stimulating factor (FLAG-GO) as front-line regimen in patients with core binding factor acute myelogenous leukemia. Am J Hematol. 2014;89(10):964-8.Borthakur G, Kantarjian H, Wang X, Plunkett WK, Jr., Gandhi VV, Faderl S, et al. Treatment of core-binding-factor in acute myelogenous leukemia with fludarabine, cytarabine, and granulocyte colony-stimulating factor results in improved event-free survival. Cancer. 2008;113(11):3181-5.Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, et al. Optimization of Chemotherapy for Younger Patients With Acute Myeloid Leukemia: Results of the Medical Research Council AML15 Trial. Journal of Clinical Oncology. 2013;31(27):3360-8.Hills RK, Castaigne S, Appelbaum FR, Delaunay J, Petersdorf S, Othus M, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. The Lancet Oncology. 2014;15(9):986-96.Boddu P, Gurguis C, Sanford D, Cortes J, Akosile M, Ravandi F, et al. Response kinetics and factors predicting survival in core-binding factor leukemia. 2018.

Disclosures

Cortes: novartis: Research Funding. Ravandi:Jazz: Honoraria; Sunesis: Honoraria; Jazz: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Xencor: Research Funding; Orsenix: Honoraria; Xencor: Research Funding; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Sunesis: Honoraria; Orsenix: Honoraria. Kadia:Novartis: Consultancy; Celgene: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Amgen: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy; Novartis: Consultancy; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Takeda: Consultancy. Pemmaraju:SagerStrong Foundation: Research Funding; Affymetrix: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding. Daver:ARIAD: Research Funding; Daiichi-Sankyo: Research Funding; Kiromic: Research Funding; Alexion: Consultancy; Otsuka: Consultancy; Sunesis: Consultancy; Karyopharm: Consultancy; BMS: Research Funding; Karyopharm: Research Funding; Pfizer: Research Funding; Pfizer: Consultancy; Incyte: Consultancy; Sunesis: Research Funding; Novartis: Consultancy; Novartis: Research Funding; Incyte: Research Funding; ImmunoGen: Consultancy.