scholarly journals 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 ◽  
Vol 113 (11) ◽  
pp. 3181-3185 ◽  
Author(s):  
Gautam Borthakur ◽  
Hagop Kantarjian ◽  
Xuemei Wang ◽  
William K. Plunkett ◽  
Varsha V. Gandhi ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Event Free Survival ◽  
Core Binding Factor ◽  
Free Survival ◽  
Binding Factor ◽  
Acute Myelogenous ◽  
Stimulating Factor

Impact of Granulocyte Colony-Stimulating Factor during Induction Therapy in Children with Acute Myelogenous Leukemia: Results from the Prospective and Randomized Trial AML-BFM 98.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2911-2911 ◽  
Author(s):  
Thomas Lehrnbecher ◽  
Martin Zimmermann ◽  
Dirk Reinhardt ◽  
Michael Dworzak ◽  
Jan Stary ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Infectious Complications ◽  
Myelogenous Leukemia ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Event Free Survival ◽  
Free Survival ◽  
Acute Myelogenous ◽  
To Receive ◽  
Stimulating Factor

Abstract Background: Treatment for acute myelogenous leukemia (AML) is one of the most intensive treatment modalities in pediatric oncology. Infection-related mortality is particularly high among these patients during chemotherapy-induced neutropenia. Granulocyte colony-stimulating factor (G-CSF) expands the circulating pool of neutrophils by stimulating proliferation and maturation of myeloid progenitor cells. Although G-CSF is widely used for the prevention of infectious complications in cancer patients, no larger randomized study has evaluated the effect of G-CSF in pediatric cancer patients undergoing treatment for AML. Patients and Methods: The impact of G-CSF on hematopoetic recovery, infectious complications and five-year event-free survival (5-EFS) was prospectively evaluated in the multicenter clinical trial AML-BFM 98. Patients (inclusion criteria: primary diagnosis of AML, age 0–18 years) were randomized to receive or not to receive G-CSF (5 μg/kg/day) after induction 1 (cytarabine, idarubicin, etoposide; AIE) and induction 2 (high-dose cytarabine and mitoxantrone; HAM). Patients who had more than 5% blasts in the bone marrow on day 15 were excluded from randomization. Patients with Down Syndrome were included in the clinical trial, but received only 60% of idarubicin in induction 1 and no second induction (HAM). Results: Between July 1998 and June 2003, 546 patients entered the clinical trial AML-BFM 98 (Down Syndome: n=45). Three-hundred-and-twenty-seven patients were eligible for randomization. Hundred-fifty eight of these patients were randomized to receive G-CSF, and 169 patients not to receive G-CSF. Both groups did not differ in their clinical characteristics. The G-CSF group had a significantly shorter duration of neutropenia (ANC<500/μl) both after induction 1 (16.3 vs 20.0 days, P=.019) and after induction 2 (12.4 vs 16.3 days, P=.0024). The time of thrombocytopenia (<20,000/μl) was similar in both groups (9.3, 9.4, 5.5, and 6.3 days, respectively). No impact of G-CSF was found on the incidence of grade II infections (fever without an identified pathogen) and grade III/IV infections (fever due to an identified pathogen/sepsis syndrome). Five-year event-free survival (5-EFS) did not significantly differ between the groups with and without G-CSF (65.6% + 3.9% vs 65.7% + 3.8%, P-logrank=.86). No significant difference was found when comparing the results of children randomized for G-CSF (intended-to treat) and of children who actually received the hematopoietic growth factor. Children with Down Syndrome showed also similar 5-EFS with and without G-CSF (P-logrank=.72). Conclusion: G-CSF significantly shortens the duration of neutropenia in children undergoing induction therapy for AML, but does not influence the incidence of infectious complications nor outcome (5-EFS probability). Whether there is a subgroup of children with AML who benefit from the administration of the hematopoetic growth factor has to be evaluated.

Effect of fludarabine, cytarabine, filgrastim, and gemtuzumab ozogamicin (FLAG-GO) on relapse-free survival in patients with newly diagnosed core-binding factor acute myelogenous leukemia.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6528-6528
Author(s):  
Gautam Borthakur ◽  
Jorge E. Cortes ◽  
Susan Mary O'Brien ◽  
Tapan M. Kadia ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Gemtuzumab Ozogamicin ◽  
Myelogenous Leukemia ◽  
Newly Diagnosed ◽  
Relapse Free Survival ◽  
Core Binding Factor ◽  
Platelet Recovery ◽  
Free Survival ◽  
Binding Factor ◽  
Acute Myelogenous

6528 Background: Prior modulation with fludarabine increases cytarabine-triphosphate (ara-CTP) accumulation and granulocyte-colony-stimulating factor (G-CSF) increases the fludarabine-triphosphate (F-ara-ATP) levels in leukemic blasts. Our front-line regimen of fludarabine, cytarabine and filgrastim (FLAG) based on this rationale showed improved event-free survival compared to anthracycline and cytarabine based regimens in patients (pts) with core-binding factor acute myelogenous leukemia (CBF-AML). Medical Research Council AML 15 trial reported survival benefit from addition of gemtuzumab ozogamicin (GO) to chemotherapy regimens in patients with favorable-risk cytogenetics AML. Methods: In a clinical trial combining GO (3 mg/m2 IV) with FLAG (FLAG-GO) in newly diagnosed CBF-AML, pts received GO on day 1 of induction and of post-remission cycles 2 or 3 and 5 or 6 in addition to FLAG. FLAG regimen was comprised of fludarabine 30 mg/m2 and cytarabine 2 gm/m2 IV daily (both for 5 days in induction and 3-4 days in post-remission cycles) with filgrastim started on day-1 and continued till neutrophil recovery. Pts who received one non-FLAG-GO induction could enroll irrespective of their remission status. Results: Fifty pts [30 with t(8;21) and 20 with Inv16] have been enrolled [5 of 50 (10%) were in remission at enrollment from prior induction]. Median age is 48 years (range, 19-76), median WBC count 12.3 x106/L (range, 1.3-97.2); 12 patients (24%) were >60 years of age and frequency of kit mutation is 8%. Complete remission with or without platelet recovery (CR/CRp) was achieved in 43/45 (96%) pts with 2 deaths in induction. With 6 planned consolidations, the median number of consolidation treatments received is 5 (range, 0-6). Two-thirds of pts needed dose reduction during post-remission cycles. Seven (14%) pts [t(8;21)= 5, Inv 16=2] relapsed and with a median follow-up of 34 months (range, 15-54 months) the relapse-free survival rate is 83%. Conclusions: FLAG-GO is a highly effective regimen and has resulted in high rate of relapse-free survival in pts with newly diagnosed CBF AML.

scholarly journals 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

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3993-3993 ◽  
Author(s):  
Gautam Borthakur ◽  
Jorge E. Cortes ◽  
Guillermo Garcia-Manero ◽  
Keyur Patel ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Research Funding ◽  
Gemtuzumab Ozogamicin ◽  
Myelogenous Leukemia ◽  
Newly Diagnosed ◽  
Relapse Free Survival ◽  
Core Binding Factor ◽  
Free Survival ◽  
Binding Factor ◽  
Acute Myelogenous

Abstract 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.

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