Genetic mutations do not hinder FLAG chemotherapy in rare blood cancer
Study shows high survival rates for CBF-AML treatment regimens
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In adults newly diagnosed with a type of blood cancer called core-binding factor acute myeloid leukemia (CBF-AML), genetic mutations present before treatment do not impact how well patients respond to FLAG-based chemotherapy or how long they survive, a new study shows.
“This regimen is now our standard frontline therapy for adults with core-binding factor AML, and these findings further strengthen the evidence supporting its use,” Gautam Borthakur, MD, a professor at The University of Texas MD Anderson Cancer Center and study author, said in a press release.
The study, “Integrated analysis of genomics, molecular responses and outcomes of CBF-AML with FLAG based therapy on a phase 2 trial,” was published in Blood Cancer Discovery by researchers at The University of Texas MD Anderson Cancer Center.
Relapse remains the leading cause of death in CBF-AML
CBF-AML is a group of AML subtypes defined by specific chromosomal changes affecting a protein complex called the core binding factor. These subtypes are thought to have more favorable outcomes than other forms of AML, with five-year survival rates above 50% using standard chemotherapy.
Studies suggest that adding the antibody-based treatment Mylotarg (gemtuzumab ozogamicin, GO) to a triple-combination chemotherapy regimen known as FLAG (fludarabine, cytarabine, and G-CSF) may improve outcomes.
Despite these favorable outcomes, relapse remains the leading cause of death in CBF-AML. Factors linked to higher relapse risk include an inability to tolerate full chemotherapy doses and specific genetic changes in leukemia cells.
An important tool for managing CBF-AML is measurable residual disease (MRD) monitoring, which uses a sensitive technique, quantitative PCR, to detect residual leukemia cells after treatment. Tracking how MRD changes over time can provide critical information about outcomes.
But the impact of pretreatment (baseline) mutations on MRD response patterns and survival outcomes among CBF-AML patients receiving FLAG remains unknown.
Optimal response achieved in nearly half of patients
Researchers examined 219 adults with newly diagnosed CBF-AML who were treated in a Phase 2 trial (NCT00801489). Half (51%) received FLAG combined with Mylotarg (FLAG-GO), and the rest received FLAG with the chemotherapy agent idarubicin (sold as Idamycin and generics, FLAG-IDA). Patients ranged in age from 19 to 80 years; 41 (18.7%) were age 60 or older.
About half (44.3%) of patients had a chromosomal change called t(8;21), and the remaining (55.7%) had one called Inv16. These are the two defining subtypes of CBF-AML. Some (42.9%) had an additional chromosomal abnormality, the most common being an extra copy of chromosome 8 (32.1%).
Additional mutations at trial enrollment were found in several genes: RAS, KIT, FLT3-TKD, FLT3-ITD, and TP53. When grouped into broader categories, kinase pathway mutations were present in half of the patients (48.5%), MAPK pathway mutations in half (44.3%), MDS-associated mutations in one-third (35.8%), and DAT mutations in one-tenth (11%).
After the first cycle of chemotherapy, the optimal MRD response, defined as less than 0.1% of residual leukemia signals, was achieved in half of the patients (47.7%). This rate was nearly twice as high among individuals treated with FLAG-GO compared with those treated with FLAG-IDA (61.6% vs. 34.1%).
After at least three cycles, an even deeper MRD response, below 0.01%, was reached in more than twice as many FLAG-GO patients as in FLAG-IDA patients (72.8% vs. 29.4%). Similar results were seen by the end of treatment after at least four cycles (90.9% vs. 59.5%).
In statistical analyses that adjusted for multiple factors, treatment with FLAG-GO was the single strongest predictor of achieving a deep response at every measured time point. Mutation groups did not significantly affect the chances of achieving an MRD response.
Five-year, relapse-free overall survival rate among highest observed
Overall, the five-year relapse-free survival rate (RFS), the proportion of patients alive without relapse at five years, was 67.1%, and the five-year overall survival (OS) rate was 74.2%. At eight years, these figures were 61.7% and 67.4%, respectively.
Patients treated with FLAG-GO had better outcomes than those treated with FLAG-IDA: five-year RFS (76.5% vs. 59.4%) and five-year OS (80.1% vs. 69.5%). Patients younger than 60 fared better than those ages 60 and older, with a higher five-year OS (79.1% vs. 62.1%).
“This is one of the highest reported five-year, relapse-free overall survival rates we have observed,” Borthakur said.
Neither CBF subtypes nor the presence of most other baseline mutations was significantly associated with differences in survival. Notably, KIT-mutated patients appeared to benefit particularly from FLAG-GO, with a better five-year OS (95.5% vs. 68.2%). Patients with an additional chromosomal abnormality also had a higher five-year RFS (76.7% vs. 60.7%) but similar OS compared to those without.
In this analysis of a large cohort of patients treated with [FLAG-based] regimens in a prospective non-randomized trial with long-term [follow-up], baseline myeloid mutations did not impact outcomes including achievement of MRD. Survival outcomes are significantly superior in patients who received [FLAG-GO] compared to FLAG-IDA.
Achieving an earlier MRD response was associated with better outcomes, the data showed. Patients who achieved such a response after the first cycle had a higher five-year RFS than those who did not (75.2% vs. 61.5%). Likewise, after cycle three, those with an MRD response had a better five-year RFS (82.1% vs. 54.3%) and five-year OS (84.3% vs. 66.0%).
Among patients who relapsed, most had not achieved an optimal MRD response after the first cycle, and the median residual leukemia signal at that point was more than twice as high as in patients who stayed in remission. A computer-based analysis identified a specific threshold: an initial MRD response above 0.04% was associated with a higher risk of subsequent relapse.
In an adjusted statistical analysis, younger age (below 60) and treatment with FLAG-GO were independently associated with improved RFS and OS. Mutation groups and CBF subtype were not independently significant.
“In this analysis of a large cohort of patients treated with [FLAG-based] regimens in a prospective non-randomized trial with long-term [follow-up], baseline myeloid mutations did not impact outcomes including achievement of MRD,” the team wrote. “Survival outcomes are significantly superior in patients who received [FLAG-GO] compared to FLAG-IDA.”
