General AML

The benefit of gemtuzumab ozogamicin in patients with AML depends on mutational status and level of CD33 expression

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

Study design

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). 

Main findings
Mutational profiling
  • In total, 94% of patients had at least one mutation
  • Frequently mutated genes (in ≥ 10% of patients) included
    • NPM1 (34%)
    • DNMT3A (29%)
    • FLT3 (28%)
      • FLT3-ITD (21%)
      • FLT3-TKD (8%)
    • TET2 (20%)
    • RUNX1 (16%)
    • NRAS (14%)
    • ASXL1, IDH2, and SRSF2 (13% each)
    • TP53 and IDH1 (11% each)
  • 30% of patients were classified as having favorable risk, 29% as intermediate, and 40% as adverse risk according to the European LeukemiaNet (ELN) 2017 risk classification
  • Control group and the GO group had balanced distribution of gene mutations, ELN risk categories, and CD33 expression
The benefit of GO in molecularly defined subgroups
  • There was no difference between the GO and control arms in complete remission (CR) rate, which was 71% overall
  • CR differed between ELN risk categories with no impact of GO
    • 86% in the favorable-risk group
    • 83% in the intermediate-risk group
    • 64% adverse-risk group
  • The 3-year event-free survival (EFS) was 25.7% (95% CI, 2.6–30.0)
  • Addition of GO improved outcomes in patients with favorable and intermediate risk (HR 54; 95% CI, 0.30–0.98 and HR 0.57; 95% CI, 0.33–1.00, respectively)
  • The impact of GO addition to standard chemotherapy by mutation status can be observed in Table 1
    • Patients with signaling mutations had significantly increased EFS with GO (p = 0.02; HR 0.36; 95% CI, 0.21–0.61) and a positive trend was seen in overall survival (OS; p = 0.07, HR 0.47; 95% CI, 0.26–0.83), compared to patients without signaling mutations (EFS HR 1.07; 95% CI, 0.53–2.16 and OS HR 1.11; 95% CI, 0.50–2.47)
    • Only patients with activating signaling mutations benefited from GO addition
    • There was no benefit of GO addition in patients with RUNX1, TP53, or ASXL1 mutations
  • Addition of GO improved EFS for patients independent of VAF for signaling mutations or allelic FLT3-ITD ratio

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)

Correlation between the benefit of GO and CD33 expression
  • Increased benefit in EFS after addition of GO was correlated with CD33 expression levels among the different mutations, especially with signaling mutations (Pearson correlation coefficient, −0.67)
  • In patients with epigenetic mutations, those with signaling mutations had significantly higher levels of CD33 expression compared to those without (98% vs 60%; p = 0.001)
Conclusion

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.

References
  1. Döhner H. et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017 Jan 26; 129(4):424–447. DOI: 10.1182/blood-2016-08-733196
  2. Fournier E., Duployez N. et al. Mutational profile and benefit of gemtuzumab ozogamicin in acute myeloid leukemia. Blood. 2020 Feb 20; 135(8):542–546. DOI: 10.1182/blood.2019003471
  3. Castaigne S. et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012 Apr 21; 379(9825):1508–16. DOI: 10.1016/S0140-6736(12)60485-1
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