FLAG-IDA Has Significant Activity As Frontline Induction or Salvage Therapy for Patients with High Risk and/or Relapsed or Refractory Acute Myeloid Leukemia (AML)
Authors: Bhella Sita D. , Atenafu Eshetu G , Schuh Andre C , Minden Mark D , Schimmer Aaron D , Gupta Vikas , Seftel Matthew D. , Alam Naheed , Lutynski Andrzej , Rostom Amr , Rydlewski Anna , Yee Karen 
Published: October 2019

Abstract
Background: Therapy for patients (pts) with high risk and/or relapsed or refractory AML remains unsatisfactory. Retrospective studies have demonstrated activity of fludarabine, cytarabine, granulocyte colony stimulating factor and idarubicin (FLAG-IDA) as salvage therapy in pts with relapsed or refractory AML. Furthermore, a recent randomized trial has indicated high complete remission (CR) rates with improved relapsed-free survival when FLAG-IDA is administered as frontline induction chemotherapy (Burnett et al. J Clin Oncol 2013). Therefore, since January 2011, we have employed FLAG-IDA as first line therapy in pts with high risk AML (i.e. poor risk cytogenetics, antecedent myeloproliferative neoplasm or myelodysplastic syndrome, or therapy-related AML), or as first salvage in pts with primary refractory or relapsed AML, in an attempt to improve CR rates and permit more patients with AML to advance to allogeneic hematopoietic stem cell transplantation (alloSCT).
Methods: A retrospective review was conducted of the 62 consecutive patients with high risk AML or primary refractory or relapsed AML treated with FLAG-IDA between January 2011 to December 2013 at the Princess Margaret Cancer Centre to determine the CR rate and overall survival (OS) associated with FLAG-IDA remission induction chemotherapy.
Results: Baseline characteristics of the patients are listed in Table 1. Fourteen pts received FLAG-IDA as first induction, whereas 48 pts received FLAG-IDA as salvage (39 as first salvage and 9 as second salvage).
The overall CR rate (i.e. CR + CR with incomplete platelet recovery [CRi]) using FLAG-IDA as frontline therapy was assessed in 13 patients, as one pt died during induction therapy and therefore, was not evaluable. Of the 13 evaluable patients, all achieved CR or CRi. The overall CR rate for the salvage induction group was 73% (i.e. 31% CR and 42% CRi). The CR duration was censored at time of transplant. The CR duration for pts receiving FLAG-IDA as first induction was 3 mos (range, 0-15 mos). For pts receiving FLAG-IDA as salvage therapy, the CR1 duration for primary refractory AML pts was 6 mos (range, 2-58 mos) and CR2 duration for relapsed AML pts was 4 mos (range, 1-12 mos). 76% of patients (n=10) who received frontline FLAG-IDA induction chemotherapy, and achieved CR/CRi, had a donor identified, but only 40% of those pts underwent alloSCT. 85% of pts (n=30) who received salvage FLAG-IDA, and achieved CR/CRi, had a donor identified, but only 53% of those pts proceeded to alloSCT.
The length of hospital stay during the first FLAG-IDA induction was 33 days (range, 17-96 days), whereas the length of hospital stay for salvage FLAG-IDA induction was 43 days (range, 10-305 days). Fourteen percent of pts in the first induction group were admitted to the ICU during their induction, compared to 17% of pts in the salvage induction group. The median ICU stay was 39.5 days and 14 days, respectively. There was a 14% death rate during FLAG-IDA induction for both groups.
The median follow up time from diagnosis for both groups was 15.28 mos (range, 2-70.4 mos). Overall survival at 1 and 2 years in the upfront FLAG-IDA induction group was 65% and 41%, respectively, while OS at 1 and 2 years for the salvage FLAG-IDA group was 60% and 35%, respectively.
Conclusions: The toxicities associated with FLAG-IDA induction, including induction death rates and ICU admission rates, are acceptable and similar in the untreated and heavily pre-treated groups. FLAG-IDA induction can result in durable CR rates, permitting patients with high risk AML or patients with primary refractory or relapsed AML to proceed to allogeneic transplantation.
Table 1: Patient Characteristics Front-LineN=14 SalvageN=48 Median age, y (range) ≥70y (%) ≥60y (%) 65.5 (21-76) 2 (14%) 10 (71%) 50 (18-76) 2 (4%) 10 (21%) Gender 7M : 7F 22M : 26F Secondary/Therapy-related Prior MDS Prior MPN 14 (100%) 2 (14%) 2 (14%) 17 (35%) 8 (17%) 2 (4%) Cytogenetic risk group Good Intermediate Poor 0 4 (28%) 10 (71%) 3 (6%) 28 (58%) 17 (35%) Molecular abnormalities cKit mutated FLT3-ITD mutated 0 1 (7%) 2 (4%) 5 (10%) Median no. prior treatment regimens (range) 0 1 (1-2) Prior chemotherapy regimen Daunorubicin + cytarabine NOVE-HiDAc Other NA NA NA 43 (90%) 11 (23%) 3 (6%) Disease status Primary refractory Relapsed CR1 duration <12 months NA NA NA 17 (35%) 31 (65%)23 (74%)
NA – not applicable; NOVE-HiDAc – mitoxantrone, etoposide and cytarabine

Disclosures
No relevant conflicts of interest to declare.