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The Impact of NGS in Hematology-Oncology

In aggressive forms of cancer such as acute myeloid leukemia (AML), accurate diagnosis is needed as soon as possible. Targeted therapies can offer better chances for patients with certain abnormalities or biomarkers, and next-generation sequencing (NGS) is quickly becoming the powerful tool of choice that can be used to examine a sample for multiple genetic abnormalities at once, allowing pathologists to quickly generate results that inform optimal therapy selection.

Thermo Fisher Scientific recently spoke to University of Pennsylvania’s Kojo Elenitoba-Johnson, MD, director of the Center for Personalized Diagnostics and Division of Precision and Computational Diagnostics at the Perelman School of Medicine, regarding the role of NGS in hematology-oncology, its impact on therapy selection and how he sees the technology supporting diagnosis.

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"There are several protocols, including extensive amounts of genetics and immunophenotyping, which are required to establish the appropriate approach to treat patients. The sooner we can get results and deliver treatment, the better the outcomes."

 

What is the impact of rapid turnaround time on diagnosis and disease management, particularly for AML?

Kojo Elenitoba-Johnson (KE): AML is an aggressive disease and, like some other cancers, tends to have unfavorable outcomes for patients. Recently, we have made tremendous progress in understanding the genetic abnormalities underlying the disease. This knowledge of how biology and genetics are the drivers of disease has matured to the point where a patient’s genetics are able to inform the proper treatment.

There are several protocols, including extensive amounts of genetics and immunophenotyping, which are required to establish the appropriate approach to treat patients. The sooner we can get results and deliver treatment, the better the outcomes. If a system can deliver genetic testing results quickly, it makes it possible to start treatment rapidly. AML is an example where patient outcomes benefit from rapid, accurate reporting of results. Commencing treatment within 24 hours of identifying the disease gives patients the best chance at promptly receiving appropriate treatment with implications for outcomes.

Given that STAT testing is common for acute malignancies, can you provide your perspective on how STAT test orders affect lab operations?

KE: If you receive a sample that is designated for STAT testing, that means it needs to be immediately run through the lab. Depending on the lab’s workflow, it can affect them differently. I would guess that each lab plans to include STAT testing, if needed, but the workflow also depends on what platform they are running. If a lab is running panel testing for NGS, a STAT test could have significant implications on the lab’s workflow since those platforms require you to do things in a cost-effective and practical manner. You may need to organize the workflow of these platforms such that they can accommodate a sufficient number of samples to start a run.

Our lab is fortunate to be well-established. When it was built, it was driven by the concept of precision oncology. We have a reasonably high volume NGS operation where we can incorporate STAT testing into our workflow, but we are always looking for opportunities to make our processes more efficient and deliver care in a clinically-relevant manner.

How have targeted therapies changed the treatment paradigm for AML patients in recent years? Can you elaborate on how NGS is providing more insight into therapy selection?

KE: In the case of AML, oncologists are really driven by the genetics of the disease when informing the treatment plan. Once an analysis comes back with the diagnosis of AML, decisions need to be made as to what subclassification it is since the disease is so heterogeneous. Within 24 hours or less it is necessary to know whether it falls under the category of AML with certain recurring structural aberrations. For example, AML with PML/RARA fusion requires specific therapy which is different from AML lacking that abnormality. While there are histopathologic and immunophenotypic correlates, genetic diagnosis remains the most specific. If genetic testing is not done, or if the results are delayed and a patient with this structural abnormality is may be inappropriately treated with suboptimal outcomes. Because of this, identifying this information right away is part of standard protocols for diagnosis the disease.

Do you typically see mutation-targeted therapies (e.g., FLT3 or IDH1 inhibitors) integrated into front line therapy regimens? 

KE: There is emerging evidence from trials indicating that FLT3 inhibitors may offer benefit to patients with AML carrying certain mutations in FLT3. This particular mutation defines a higher risk subset of patients with AML. Now that physicians have the capacity to test for these mutations in the context of others, we are seeing them assign patient for treatment with FLT3 inhibitors based on identification of the genetic mutation. The availability of an inhibitor that targets a specific gene definitely impacts how clinicians treat patients. However, each patient is different and has their own intrinsic risks. Treatment options need to be discussed with the patient to contextualize any co-morbidities or related risk factors. It’s not a one size fits all strategy but is a powerful tool that we can now employ.

Taking AML for example, how does the typical workup compare/contrast with and without NGS? In other words, are you able to reduce the overall number of individual tests that need to be performed per case? 
KE: The advantage of having NGS is that you can test for multiple targets at once. However, you need to weigh the ability to do this with the infrastructure needed and the ability to report clinical results in a relevant timeframe. The advantage is that instead of approaching each abnormality as a singular problem, you’re able to target them all and report in context. Your operations just need to permit a cost per base efficiency that allows you to do so.

Most of the institutions that operate at a tertiary level have built the structure to be able to accommodate NGS testing, but the vast majority of patients are not treated in an ivory tower. For us to improve overall outcomes, we will need to standardize these approaches so they can be easily performed at the community level and have accurate results.

With an ever-growing list of disease-associated biomarkers in hematology-oncology, can you discuss how labs are dealing with the challenge of keeping up? At what point does single-gene testing for so many markers become impractical? 

KE: The degree of progress we are experiencing far exceeds the rate that we’ve seen in the past. One solution people have utilized is to hire professionals to curate data and monitor the literature and clinical trials to stay up to date. Other solutions include electronic tools or applications that aggregate the data that’s been accumulated. It’s essentially become its own industry, which was not the case 20 years ago.

When single gene testing for so many markers becomes impractical is dependent on the size and threshold of the lab in question. With the volume of tests we see, NGS is a more appropriate solution for us.

Since NGS can detect multiple types of genetic abnormalities, do you foresee a time when it might eventually replace well established technologies like FISH? 

 KE: Whenever a new technology comes in, there are typically areas of overlap where different tests can be used to find the same result. This is especially helpful where one test is 99 percent accurate and you need to corroborate test results. Because of this, it’s not uncommon for both to be used in one lab so that, when presented with an abnormality, there is a separate in-lab validated test that can corroborate and confirm results.

When looking at whether NGS could eventually replace technologies like FISH, I could see it happening. If barriers to entry are lowered, the convenience of adoption and quality of results would make NGS the first choice. This is particularly true if in addition to high resolution mutational data, karyotyping information may be obtained from NGS. The goal is to deliver the best possible care for the patient and the removal of these barriers would translate to that.

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Mauricio Minotta
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Mauricio Minotta


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