Integrating resistance functions to predict response to induction chemotherapy in de novo AML

One of the standard induction regimens for patients with acute myeloid leukemia (AML) is the ‘7+3’ method, (100–200mg/m2 cytarabine for seven days, 12mg/m2 idarubicin for three days). This treatment regimen achieves up to a 70% complete response (CR) in newly diagnosed de novo AML.1 Chemoresistance of induction therapy is a huge complication in the treatment of AML, with patients who are unable to achieve CR after initial induction therapy having poorer outcomes.

The identification of patients who will fail the standard ‘7+3’ therapy is vital to prepare alternative treatment regimens. Yu-Chiao Chiu, from the Department of Medical Research, Taichung Veterans General Hospital, TX, and colleagues systematically identified resistance functions to examine their interactions in determining chemoresistance.

Study design

  • Retrospective study, looking at records of 373 consecutive patients diagnosed with de novo AML from 2004 to 2017
  • Patients who had completed initial ‘7+3’ treatment regimen, and had RNA extraction from bone marrow were included
    • Those under 20 years of age or those who died during therapy were excluded
  • The 52 patients analyzed were divided into two groups:
    • 35 in the CR group
    • 17 in the non-CR group
  • Treatment groups had similar baseline characteristics, with small non-significant differences in age (p=0.785), sex (p=0.278), percentage of blast cells in bone marrow (p=0.290) and initial leukocyte count (p=0.810)
    • Patients in the non-CR group had more high-risk cytogenetic features in accordance with the European Leukemia Network than patients in the CR group (p=0.002)

Study methods

Gene expressions were profiled using RNA sequencing, and gene set enrichment analysis (GSEA) was used to systematically identify molecular signatures responsible for chemoresistance-related cellular functions. The researchers also combined representative functions to determine whether these cellular functions predicted ‘7+3’ regimen chemoresistance.

The results were combined to develop a prediction model that scores genes to calculate the likelihood of chemoresistance. A value of 0 was set for CR, and 1 for non-CR. Higher scores predicted refractoriness to induction chemotherapy.

The model was validated through the area under the ROC curve (AUROC), and a permutation test was conducted to confirm its significance.

Results

Twenty-eight resistant functions that correlated with the ‘7+3’ regimen were identified. Half of these were also related to mTOR signalling, mitochondrial OXPHOS, myc targets and stem cell activities. Results were validated by comparing expressional differences of the CR group and the non-CR group with a cohort from another study.2

Despite the functions (mTOR, myc, OXPHOS, and stemness) identified all being associated with chemoresistance, the leading-edge component genes of each function were independent. Overall results showed that chemoresistance to the ‘7+3’ regimen is a multifactorial mechanism.

The four-function prediction model predicted ‘7+3’ chemoresistance better than the individual functions. ROC analysis showed the optimal cut-off for each predictor. Higher sensitivity was seen in myc (82%) than mTOR (71%), OXPHOS (41%) and stemness (71%), but myc (77%) had lower specificity than OXPHOS (94%). The Youden3 index indicated that the four-function model better predicted chemoresistance than single pathways.

A seven-gene scoring system was used to predict the achievement of CR through the ‘7+3’ treatment regimen. The score of this system correlated with that of the four-function score, and also predicted CR or non-CR in patients treated with the ‘7+3’ regimen.

Table 1: the seven-gene scoring model

Gene symbol

Gene name

Function category

Weight

CNOT7

CCR4-NOT transcription complex subunit 7

OXPHOS

0.11

DCUN1D4

Defective in cullin neddylation 1 domain containing 4

myc

-0.02

EXOSC2

Exosome component 2

myc

0.11

FKBP4

FKBP prolyl isomerase 4

myc

0.05

NDUFA8

NADH: ubiquinone oxidoreductase subunit A8

OXPHOS

0.10

PRDX4

Peroxiredoxin 4

myc

0.05

RPS27A

Ribosomal protein S27a

mTOR

0.28

OXPHOS, oxidative phosphorylation

Conclusion

The researchers found that the mTOR, myc, OXPHOS, and stemness pathways were all associated with chemoresistance of patients with de novo AML to the ‘7+3’ induction regimen.

Limitations for this study included the small number of patients involved, and as such an independent validation cohort to verify the seven-gene scoring model could not be provided. Other studies were used to reduce this limitation, however prospective studies, analyzing a larger number of patients, are required to validate both the seven-gene scoring model and the four-function model.

References

  1. Burnett A, et al., Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011 Feb 10;29(5):487-94. DOI: 1200/JCO.2010.30.1820
  2. Horibata S, et al., Heterogeneity in refractory acute myeloid leukemia. Proceedings of the National Academy of Sciences. 2019 May 21;116(21):10494-503. DOI: 1073/pnas.1902375116
  3. Chiu YC, et al., Integrating resistance functions to predict response to induction chemotherapy in de novo acute myeloid leukemia. European journal of haematology. 2019 Jul 29. DOI: 1111/ejh.13301
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