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Acute myeloid leukemia (AML) is a complex heterogeneous disease. In the last decade, increased understanding of treatment interactions with cytogenetic and molecular aberrations in AML have enabled the stratification of patients according to predicted response to chemotherapy.1 New drugs against specific aberrations are being developed and approved, changing the AML treatment landscape. However, the predictive value of a patient’s genetic background and the interaction with new therapies remains to be assessed. Incorporation of this information into decision making on the optimal treatment regimen that would target antigens and pathways specific for each disease subtype is being evaluated.
Elsie Fournier and Nicolas Duployez et al. recently published a paper on this topic in Blood. In a retrospective study, the authors evaluated whether molecular events could predict the benefit of adding gemtuzumab ozogamicin (GO) to standard frontline chemotherapy.2
Mutational analysis was performed on samples from 235 patients with non–core binding factor (CBF) AML. Patients came from a cohort enrolled on ALFA-0701 (NCT00927498), a phase III trial evaluating the efficacy of addition of gemtuzumab ozogamicin (GO) to standard frontline chemotherapy.3 Samples were analyzed for molecular aberrations, including FLT3-internal tandem duplication (ITD), recurrent gene rearrangements, KMT2A–partial tandem duplication, and CD33 expression. The signaling mutations were defined as the presence of at least one mutation in FLT3, NRAS, KRAS, PTPN11, JAK2, RIT1, or CBL, regardless of the variant allelic frequency (VAF).
Table 1. Impact of GO addition to standard chemotherapy by mutation status
|
HR (95% CI) |
Mutated gene |
|
NPM1 |
0.48 (0.28–0.83) |
FLT3 FLT3-ITD FLT3-TKD |
0.36 (0.18–0.72) 0.20 (0.05–0.78) |
NRAS |
0.43 (0.19–0.95) |
KRAS |
0.27 (0.09–0.84) |
SRSF2 |
0.28 (0.12–0.65) |
IDH2 |
0.43 (0.16–1.17) |
ASXL1 |
1.57 (0.68–3.58) |
Mutation type |
|
Activating signaling |
0.43 (0.28–0.65) |
Epigenetic |
0.68 (0.48–0.97) |
Spliceosome deregulation |
0.44 (0.24–0.80) |
The authors of the original article demonstrated that the benefit of GO in AML depends on underlying molecular abnormalities. The findings from the ALFA-0701 suggest that the addition of GO to standard chemotherapy predominantly improves outcomes for patients with signaling mutations coupled with high CD33 expression.3 Therefore, this retrospective study reiterates that treatments, even with novel therapies, should be tailored based on patient genetic profile. The drug was approved for the use in previously untreated AML patients by FDA and EMA without limiting its use to any specific genetic subtypes. The NICE recommendation is also for a whole population of patients with untreated AML.
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