Duncavage 2021 NEJM on AML: Abstract vs ChatGPT Summary

 Duncavage et al. NEJM 2021, WGS in AML

https://www.nejm.org/doi/full/10.1056/NEJMoa2024534

Blog  https://www.discoveriesinhealthpolicy.com/2023/08/first-approval-of-whole-genome-test-in.html

Abstract 260 words

BACKGROUND

Genomic analysis is essential for risk stratification in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). Whole-genome sequencing is a potential replacement for conventional cytogenetic and sequencing approaches, but its accuracy, feasibility, and clinical utility have not been demonstrated.

METHODS

We used a streamlined whole-genome sequencing approach to obtain genomic profiles for 263 patients with myeloid cancers, including 235 patients who had undergone successful cytogenetic analysis. We adapted sample preparation, sequencing, and analysis to detect mutations for risk stratification using existing European Leukemia Network (ELN) guidelines and to minimize turnaround time. We analyzed the performance of whole-genome sequencing by comparing our results with findings from cytogenetic analysis and targeted sequencing.

RESULTS

Whole-genome sequencing detected all 40 recurrent translocations and 91 copy-number alterations that had been identified by cytogenetic analysis. In addition, we identified new clinically reportable genomic events in 40 of 235 patients (17.0%). Prospective sequencing of samples obtained from 117 consecutive patients was performed in a median of 5 days and provided new genetic information in 29 patients (24.8%), which changed the risk category for 19 patients (16.2%). Standard AML risk groups, as defined by sequencing results instead of cytogenetic analysis, correlated with clinical outcomes. Whole-genome sequencing was also used to stratify patients who had inconclusive results by cytogenetic analysis into risk groups in which clinical outcomes were measurably different.

CONCLUSIONS

In our study, we found that whole-genome sequencing provided rapid and accurate genomic profiling in patients with AML or MDS. Such sequencing also provided a greater diagnostic yield than conventional cytogenetic analysis and more efficient risk stratification on the basis of standard risk categories.

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                    CHAT GPT (660 words)

Detailed Summary of the Study on Whole-Genome Sequencing in AML and MDS Patients

Objective: The study investigated the clinical utility of whole-genome sequencing (WGS) for genomic evaluation in patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS), comparing it against conventional testing techniques.

Methods:

• 263 patients (both AML and MDS) were evaluated.
• For AML samples, conventional cytogenetic analysis and FISH assays were used alongside targeted sequencing. The results were then compared against those from WGS to evaluate the diagnostic yield of the latter.

Key Findings:

1. Conventional Testing Results for AML Patients:

• Diagnosis of acute promyelocytic leukemia with PML–RARA fusion gene in 5 patients.
• 27 patients were assigned to the adverse-risk group, 10 to intermediate, and 19 to favorable-risk based on established guidelines.
• 7 patients had inconclusive cytogenetic analysis.
• 4 patients were categorized into risk groups solely due to FISH results for either PML–RARA or del(5q).

1. Whole-Genome Sequencing Outcomes:

• WGS on the same cohort samples detected new abnormalities in 17 of the 68 AML patients (25%). These were not identified in karyotype analysis or reported by FISH.
• These new findings ranged from cryptic chromosomal rearrangements to new copy-number alterations and identification of a normal karyotype.
• Using only WGS data and a PCR assay for FLT3-ITD, 10 of the 68 AML patients (excluding those with acute promyelocytic leukemia) were reassigned to a different risk group. Similarly, of the 42 prospective MDS patients, 12 had new findings or inconclusive results on WGS.
• Combining both groups, 19 out of 117 patients had a reclassified risk-group assignment, a total of 16.2%.

1. Predictive Value Using Existing Genetic-Risk Categories:

• The study evaluated the potential of WGS to predict clinical outcomes based on existing genetic risk groups.
• Analysis was performed on 71 AML patients who did not undergo stem-cell transplantation.
• Risk-group assignments based on conventional methods matched WGS results for 63 out of 71 patients (89%). 8 were re-categorized, with 5 showing new adverse-risk findings through WGS.
• WGS provided a slightly improved identification of patients with adverse risk compared to conventional testing. Hazard ratios for death were 0.32 by WGS compared to 0.66 by conventional methods.

1. Genetic Profiling in Patients Without Cytogenetic Results:

• The study theorized that WGS would be particularly beneficial for patients without available cytogenetic results at diagnosis, which comprises up to 20% of AML patients.
• Among 27 such AML patients not treated with stem-cell transplantation, WGS identified risk-defining chromosomal abnormalities in 4 patients.
• Risk predictions based on WGS correlated with actual patient outcomes.

Discussion and Implications:

• Clinical Utility:

WGS demonstrated a comparable, if not superior, analytical performance and clinical applicability against conventional testing.

WGS detected 100% of clinically significant abnormalities identified by cytogenetic analysis and FISH assays.

The diagnostic yield of WGS would vary depending on laboratory-specific karyotyping practices and the utilization of FISH or other tests. However, WGS can provide a holistic understanding of clinically relevant genomic events through a single test.

Reports can be generated in as little as 3 days due to accelerated laboratory methods and focused automated data analysis.

• Cost Considerations:

Major implementation barriers have been the cost associated with WGS. As the cost of sequencing continues to decrease, WGS is becoming increasingly comparable to the costs of current testing platforms, ranging between $1,000 to $2,000 per patient.

Calculations suggest that WGS will likely reach price parity with conventional testing as sequencing costs drop below $5 per Gbp.

WGS offers additional genetic information that might be obtained through other genetic assays, bringing the possibility of cost savings for some patients.

• Global Implications:

  • Implementing WGS can standardize the process across laboratories, reducing bias and ensuring a consistent approach worldwide.
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  • Beyond myeloid cancers, the study indicates the potential benefits of WGS for other cancers, especially solid tumors. WGS might simplify genomic testing and potentially enhance the yield of clinically relevant findings, refining treatment approaches for various cancer patients.

In conclusion, the study underscores the transformative potential of whole-genome sequencing in cancer diagnostics, risk stratification, and treatment decisions, particularly for patients with AML or MDS.