Rapid NGS When Your Patients Need Answers

Dr. Alexander Craig Mackinnon

Chief of Genomic Diagnostics & Informatics Division, University of Alabama at Birmingham

Transcript

00:00:04

So when you're diagnosing and making the treatment plan for patients with these myeloid malignancies, these are like acute myeloid leukemias, almost all these diseases are defined by some type of molecular event.

00:00:17

It's really critical that you do a genetic analysis because it has implications on their treatment, their prognosis, and fundamentally their outcome.

00:00:28

So the first step in a diagnosis is getting a sample.

00:00:31

So it can be peripheral blood or bone marrow, oftentimes both.

00:00:35

And then from there, it's an amazing diagnostic odyssey with leukemia because it has multiple components to it.

00:00:42

It's important to get quick turnaround times when you're testing for acute myeloid leukemia is that often these times these patients present when they're ill.

00:00:49

These patients are not stable.

00:00:51

And in fact, there's certain types of leukemia where they're making so many malignant cells that it can actually cause coagulation problems and lead to strokes and can be fatal very rapidly.

00:01:04

There are reference labs in the United States where you can send your sample.

00:01:09

and they'll do the testing there, but there's delay.

00:01:12

You have to ship the sample.

00:01:14

The sample may arrive either, and it might be too scanty.

00:01:17

You might not actually have enough material or it could get damaged in shipping.

00:01:20

So in some ways, you know, the sample gets divvied up in these different labs, which may not even be in the same building, are doing these reports, and then the reports come back out.

00:01:30

One of the exciting things right now, especially with the technology with next-gen sequencing and the panels can get bigger and bigger, you can start to consolidate some of this testing so that the clinician, when they get these results back, has all the information they need to make a fully informed treatment decision.

00:01:46

Another instance, I think, where next-gen sequencing is going to be critical is when patients, the diagnosis is hard, it's not precise, and you find a certain mutation.

00:01:56

that can help clinch a diagnosis.

00:01:58

So the patient may have a disease that may resemble almost a lymphoma, for example, and then you find a mutation and it changes the diagnosis to a myeloid leukemia, which has a completely different treatment regimen.

00:02:11

And so there are instances where the mutation

00:02:15

can completely be the linchpin or the clincher in the diagnosis.

00:02:20

And you do see that, and that's exciting because a lot of times an oncologist will contact and go, oh, that's what I was thinking, but I couldn't really prove it, but this mutation really helped me out a lot.

00:02:29

And that had historically been a send-out test.

00:02:31

Now we can bring it back in-house, give more rapid results, and getting that level of sensitivity they need to really dial in the therapy and make sure it's working.

00:02:39

Now with amplicon-based testing, where I work,

00:02:42

We have a pretty large volume of heme malignancies, AMLs, coming through.

00:02:47

So the volume isn't a problem.

00:02:49

And we use an amplicon-based approach for testing our AML patients, where we make libraries using DNA and libraries making RNA, and then we sequence both of them.

00:02:59

So typically at the time of diagnosis, they'll order both DNA and RNA, and we kind of run them in parallel.

00:03:05

And we have very rapid turnaround time.

00:03:06

I'd say by the time the sample arrives in the lab, we're pushing reports out between two to four days.

00:03:13

We found at our institution that we have a very good close relationship with both our heme path people, the people actually working up making the diagnosis, and the oncologist who's fundamentally treating the patient, and then the molecular lab.

00:03:25

I think that type of communication is really important to making sure that the results are good, that the results make sense, that certain variants that may be at a low level are observed and appreciated because they might have a history of having that variant.

00:03:40

What I'm excited about the future is with automation and rapid testing is that it isn't just restricted to acute myeloid leukemias.

00:03:48

It can be happening in the germline space, and then you can consolidate labs, you can cross-chain your techs, technologists, and just be a lot more efficient and have redundancies built in that can make sure that you can deliver results when they're needed.

Dr. Amir Fathi

Leukemia Program Director, Massachusetts General Hospital

Dr. Valentina Nardi

Associate Director of Hematological Molecular Pathology, Mass General Brigham 

Transcript

00:00:05

Acute myeloid leukemia is an aggressive, potentially lethal cancer involving the blood and bone marrow, and particularly the myeloid precursors.

00:00:18

Let's say it's late at night, or oftentimes the middle of night, you get a call from the emergency room that a patient has been sent here from his primary care physician's office or a local emergency room.

00:00:32

He presented after significant bleeding or an infection of his teeth following a dentist appointment a few days prior.

00:00:41

They had done a blood count check in the emergency room and done some tests of his metabolic panel, found that his white count was elevated at 50,000 with circulating immature cells.

00:00:54

We send the blood at our hospital, generally,

00:00:58

for flow cytometry.

00:01:00

And flow cytometry can be expedited or rushed, so you can have a rapid result hopefully the next day.

00:01:08

We also at our hospital now have a rapid mutational test.

00:01:13

We didn't have this previously, we have this now.

00:01:16

If there is a circulating blast population, we can send that rapid test off the BLOT2, and that can return in one to two days.

00:01:24

So for cases where acute leukemia is suspected, at least in my institution, in my practice, we usually receive a page, a rush page saying suspected acute leukemia.

00:01:37

And that rush page is received by both pathologists, by the core laboratory, the hematology laboratory, by the flow cytometry laboratory.

00:01:47

So everyone is alerted there is a specimen that needs, you know, to be prioritized.

00:01:53

The pathologist will try to review either the peripheral blood or the bone marrow aspirate, within the hour or the couple of hours after the rush page.

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And at that point, if the pathologist agrees that there is an acute leukemia, we often initiate also the ultra-rapid NGS testing.

00:02:14

Some type of NGS

00:02:16

requires still quite some hands-on time and sort of more skilled technologists to set up the assay and then require bioinformatician for the analysis.

00:02:28

But the ultra-rapid NGIS, for example, we have implemented has really minimal hands-on time and does not require a skilled technologist to set up the assay.

00:02:39

Also, the assay already performs also the analysis, so it does not require also a

00:02:45

bioinformatician to generate a report to review the test results.

00:02:51

So from that point of view, it sort of frees out the texts in the laboratory to perform more manual assays.

00:02:58

The ultra-rapid NGS certainly has had a big impact.

00:03:02

Many times, we are able to test patients with suspected acute leukemias, whether they are still in the emergency room, and by the time they reach the floor because a bed has become available, we already have genetic results back, which means we can give a much more...

00:03:19

specific and informative report to our oncologist.

00:03:25

And they can sort of start treating the patient right away.

00:03:29

I think the patient had been happier, not having to wait a long time for their final diagnosis and to start treatment.

00:03:36

And the oncologists also are not wasting any time and starting treatment sooner may mean also that the patient can leave the hospital sooner and therefore that another patient can also

00:03:49

admitted.

00:03:50

One of the biggest challenges in healthcare right now is beds, bed utilization.

00:03:58

Every time I walk into my hospital, these days the emergency room is packed.

00:04:03

The hospital rooms are often taken.

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It's hard for patients to sort of go through and get the care that they need on the hospital floors.

00:04:12

To be able to start treatment sooner, to understand what the disease is sooner, also means that patients can leave the hospital sooner.

00:04:18

That has, in my view, huge implications for the practice, at least at our hospital.

00:04:23

I certainly think that having NGS in-house is key to having a rapid turnaround time, and certainly having also a great communication with the oncologist for which patient, you know, it's necessary to have rapid results.

00:04:40

Having this conversation with the oncologist, where it really does matter.

00:04:44

I think is key, and many times also informing them whether or not they need to pursue additional testing.

00:04:50

It helps to have an in-house hematopathology team, because you can pick up the phone and discuss the case.

00:04:56

Having to have a pathology team outside your hospital whom you don't know, who may change all the time, to have to wait a week, two weeks, three weeks for a result, that obviously would be much less desirable.

00:05:11

The availability of rapid testing has been a game changer for us.

00:05:15

We, within two to three days, have a general idea of what the disease is, and that helps us plan.

00:05:23

It helps us reach out to the patient's insurance, get prior approval of authorization if needed, get the drug in hand, because many of these drugs are expensive and not necessarily on inpatient formularies.

00:05:35

If they're candidates for clinical trials, this is a huge advance because you can make a determination to consent and enroll a patient.

00:05:42

And I always tell patients, there is not much I can do to take away this sting and the pain and the trauma of a new diagnosis of AML.

00:05:51

But what often makes things easier as you move forward is information.

00:05:55

So the more you know, and the more you understand the plan, and the more concrete that plan is,

00:06:01

the better you feel.

00:06:02

So certainly having that information sooner, earlier, having the ability to make a plan and a strategy for the management of the disease, I think overall makes everybody comfortable.

Dr. Rajeev Gupta

Clinical Lead for Haematology, Health Services Laboratories

Rob Baker

Molecular Haematology Operations Manager, Health Services Laboratories

Transcript

00:00:03

You tell somebody that they have a condition that is going to kill them if we don't do anything, but we're going to wait a couple of days for the genetics so we can decide an appropriate treatment.

00:00:13

Even though that individual is busy having heart scans and

00:00:17

PICC lines put in and whatnot and having various other tests.

00:00:20

The fact that they are not being treated is always at the back of the mind.

00:00:23

So being able to come back to your patients with, yes, the genetics are X, Y, Z, whatever, and this is going to be the treatment plan, I think takes a big pressure off our patients psychologically.

00:00:36

It allows them to prepare for what's ahead.

00:00:39

Having treatment for AML is a bit like running a marathon without doing any training.

00:00:44

Even if you're a 25 year old, it takes it out of you.

00:00:46

I think having the additional fretting about genetics on top of that, it's just an extra complication that a lot of people can do without.

00:00:58

Acute myeloid leukaemia is a medical emergency.

00:01:01

If you don't do anything, most patients will die within, in some cases, days.

00:01:06

So we have to select treatment that is appropriate as rapidly as possible.

00:01:11

So understanding the

00:01:13

biological risk, which is predicated on molecular profiling, is absolutely essential.

00:01:19

And those data have to be in the hands of the treating physicians within two to three days of the patient presenting.

00:01:26

It's really important to know exactly what the genetic abnormalities are, because they will tell you the intensity of initial chemotherapy and whether or not a transplant is in order.

00:01:37

We have an amplicon-based approach.

00:01:39

First of all, we have our rapid pathway.

00:01:41

So we have our rapid NGS through which we put all our new query diagnosis of acute leukaemias, things like chronic myeloid leukaemias and anything else that's deemed clinically urgent by the clinicians.

00:01:56

And alongside those, we run all our myeloproliferative neoplasm samples, so we maximise the runs.

00:02:05

We quote a 72-hour turnaround time from receiving the sample to issuing the final report.

00:02:12

In reality, what that will look like in the laboratory will either be 24 hours or 48 hours usually, depending on when the sample hits the laboratory.

00:02:23

The advantage of using the rapid myeloid NGS and RNA-seq is that we can produce a full result

00:02:31

within the time frame it takes from a patient presenting to being able to start therapy.

00:02:36

So therefore they get the most appropriate therapy from the start.

00:02:40

You can't afford to go in too lightly if intensive treatment is required.

00:02:46

And if intensive treatment is not required, you can cause considerable hematotoxicity and considerable systemic toxicity by selecting initial therapy that is too strong.

00:02:57

What can often happen is that you have people who are, we're waiting for genetics, we don't have them.

00:03:03

This is really a historic problem and we start on something that is inappropriate and we only ever find out that it's inappropriate because we have an inadequate clinical response.

00:03:12

What NGS has enabled us to do is to consolidate all this test into one rapid pathway which generates a whole lot more valuable information for the conditions than we could previously produce.

00:03:24

It's equally important with the NGS that we can now identify those negatives so you can identify patients who can be discharged from clinic much faster.

00:03:34

Well, the immediate benefit to patients has been that they know the deal, they know what the mutations are at a much earlier stage.

00:03:42

Expediting all of this is key.

00:03:44

It's been transformative in our practice to be able to do that.

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Our outcomes are as good as anybody.

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certainly in the Western world.

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And what underpins our excellent clinical outcomes is rock-solid diagnostics.

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Key to everything is a close collaboration between the clinical team and the laboratory team.

00:04:05

The closer that is, the easier it is to make these sort of things happen.

David M. Swoboda, MD

Tampa General Hospital Cancer Institute, Tampa, Florida

Transcript

0:00
So how does rapid sequencing change the flow of how we take care of our AML patients?

0:07
So the goal would be to admit patients or receive them from a transfer, diagnose those patients so have a pathologist review their morphology, get all our FISH testing back and actually simultaneously get our sequencing back with all the mutations that we need to make them most appropriate diagnosis, understand the patient's prognosis and all to deliver the best precision based treatment for our patient.

0:36
And so then we initiate our therapy with all of that information and ultimately discharge patients now in about 30 to 39 days.

0:46
And so how does this improve our patient care both from the patient standpoint and also the hospital standpoint?

0:54
So it's pretty obvious that from a patient standpoint and a provider standpoint for that matter, we now have the correct molecular diagnosis and we're able to provide the correct treatment, whether it be standard of care or on a clinical trial up front for our patients, which is very important, especially in AML, which as I've talked about is can be a very high risk and scary disease for patients.

1:25
We have no treatment delays due to testing.

1:28
We have no unnecessary outpatient blood transfusions, Dr.

1:32
visits or other sort of situations that we have to have the patient out of the hospital and back in the hospital.

1:38
And important for our patients is really the increased days outside of the hospital.

1:44
And so if you've ever taken care or and no providers that have taken care of AML patients, what the biggest thing that you see over the course of their care is they tend to bounce in and out of the hospital, whether it be from infections, blood transfusions or other, you know, sort of challenges that arise over the course of their therapy.

2:06
So anytime a way that we can provide our patients more times with their families is really important in the care of AML patients and we do that by decreasing the amount of time that they're in the hospital.

2:21
And So what about the advantages to the hospital system as a whole?

2:25
So as as you can obviously see, we are able to decrease days that patients are in the hospital.

2:34
So we get all the information early and we ultimately improve our length of state measurements That overall leads to cost reduction for both the patients and also the hospital system as a whole.

2:48
And that also opens up bed availability for other patients that you know, could be sick and, and need need those resources.

2:58
It decreases the need for additional outpatient services.

3:01
So now we also open up sort of those blood transfusions, the clinic visits so that our providers can see, you know, more patients or really just have a better, you know, ability to see the existing patients that they have in their clinic.

3:16
And then for the patient and the provider and the system, it's really better patient care and better patient satisfaction.