Gemtuzumab ozogamicin, once approved in 2000 for the treatment of acute myeloid leukemia (AML), was taken off the market in 2010 due to toxicity concerns. Idarubicin has been used in place of gemtuzumab ozogamicin in some chemotherapy regimens. Gemtuzumab ozogamicin was reintroduced to the market in 2017, with new dosing requirements and schedule, and it is now being combined with standard regimens for favorable-risk AML.
The chemotherapy regimen known as FLAG-GO (fludarabine, cytarabine, granulocyte colony-stimulating factor, and gemtuzumab ozogamicin) is used at The University of Texas MD Anderson Cancer Center, Houston, and other centers for induction treatment in favorable-risk AML. During the time gemtuzumab ozogamicin was off the market, idarubicin was used to replace it (FLAG-IDA). A study presented at the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition compared experience with FLAG-GO vs FLAG-IDA.1
Both regimens achieved high rates of remission as induction therapy in patients with favorable-risk AML, but FLAG-GO was associated with an improved relapse-free survival rate and achieved a greater reduction in minimal residual disease, using fusion transcription ratio as a surrogate measure. FLAG-GO also has the advantage of avoiding anthracyclines and their associated toxicity.
The FLAG-GO regimen produces a better fusion transcript reduction, and if we use FLAG-GO, we have the option to use idarubicin later.— Gautam M. Borthakur, MD
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“At the beginning of this study, we did not know what level of reduction in the fusion transcript ratio predicted for outcome. We found that the optimal fusion transcript reduction [> 4-log] predicted for overall survival benefit. The FLAG-GO regimen produces a better fusion transcript reduction, and if we use FLAG-GO, we have the option to use idarubicin later,” said lead author Gautam M. Borthakur, MD, Professor in the Department of Leukemia at MD Anderson. “If we find patients who are [semi-quantitative reverse-transcriptase polymerase chain reaction] (sQPCR)-negative [ie, show optimal reduction in fusion transcript level], they may not need more therapy,” he said.
“Patients with core-binding factor AML are considered favorable risk and highly responsive to high-dose cytarabine, such as used in FLAG-based regimens. In this group of patients, FLAG-based regimens are known to improve outcome, particularly when gemtuzumab ozogamicin or idarubicin is added,” Dr. Borthakur noted.
Dr. Borthakur and colleagues wanted to compare experience at MD Anderson with FLAG-GO and FLAG-IDA. “This was not a randomized trial,” he emphasized.
Methodology and Outcomes
The sQPCR assay was used to assess fusion transcripts during consolidation therapy. Fusion transcripts are chimeric RNAs resulting from gene fusions, and particular fusions are commonly produced by cancer cells. “sQPCR is informative of remission duration. Multilog reductions in fusion transcripts on sQPCR predict for better outcomes,” Dr. Borthakur explained.
The study included 153 patients who were newly diagnosed with core-binding factor AML and treated with FLAG-based regimens between 2017 and 2018. The median age was 49, and 15% were older than 65 years. Patients in both groups were comparable for age, cytogenetic subgroups, and presence of KIT mutations. In addition to comparing outcomes with the two regimens, the researchers wanted to study the impact of KIT and other kinase mutations on outcomes.
Of 153 patients with core-binding factor AML treated during those years, 50 received FLAG-GO and 103 received FLAG-IDA. At baseline, more KIT mutations were present in the FLAG-IDA group, and RAS mutations were more frequent in those treated with FLAG-GO.
The median follow-up was 6.5 years. Among all patients, 95% achieved complete remission. Six patients (4%) achieved complete remission with incomplete platelet recovery, and two died within 4 weeks. The median number of cycles delivered was five out of a planned seven, with cytopenias as the limiting factor.
The 5-year overall survival was 71%, and 5-year relapse-free survival was 75%. Overall survival was not significantly different between the two groups, but relapse-free survival at 5 years was significantly better with FLAG-GO: 87% vs 68% for FLAG-IDA (P = .02). There was no impact of KIT or any kinase mutations on relapse-free survival.
The only two predictors of relapse-free survival were age and level of reduction of fusion transcript ratio. A 3-log reduction of fusion transcript ratio at the end of induction and a 4-log reduction at the end of cycles 3 to 4 and at the end of all cycles were associated with improved relapse-free survival.
“FLAG-GO was the only factor associated with improved response,” Dr. Borthakur stated. The FLAG-GO regimen, but not cytogenetic subgroup, was associated with greater reduction in fusion transcript. Among those treated with FLAG-GO, 76% achieved reduction of fusion transcript to < 0.01 by midconsolidation vs 42% of those treated with FLAG-IDA (P = .002).
DISCLOSURE: Dr. Borthakur has been a consultant for PTC Therapeutics, Nkarta, and BioLineRx; has served on a board of directors or advisory committee for FTC Therapeutics, BioTheryX, Argenx, and BioLineRx; and has received research funding from AstraZeneca, Bayer Healthcare AG, Eli Lilly, Agensys, BMS, Cyclacel, Arvinas, Polaris, Cantargia AB, GSK, Janssen, AbbVie, TetraLogic Pharmaceuticals, Oncoceutics, Novartis, XBiotech USA, Eisai, Merck, BioLineRx, Incyte, and Strategia Therapeutics.
1. Borthakur GM, Cortes JE, Ravandi F, et al. Fludarabine, cytarabine, G-CSF and gemtuzumab ozogamicin (FLAG-GO) regimen results in better molecular response and relapse-free survival in core binding factor acute myeloid leukemia than FLAG and idarubicin (FLAG-Ida). 2019 ASH Annual Meeting & Exposition. Abstract 290. Presented December 7, 2019.
Chetasi Talati, MD
Chetasi Talati, MD, Assistant Member in the Department of Malignant Hematology at Moffitt Cancer Center, Tampa, Florida, commented on the study by Borthakur et al.
“[Core-binding factor] acute myeloid leukemia (AML) represents a favorable-risk group of patients who are...