Acute Myeloid Leukemia: Evolving Perspectives on Testing, Targeted Therapies, and Transplantation - Episode 2

Molecular Testing in Community Practices

January 15, 2021
Harry P. Erba, MD, PhD, Duke University School of Medicine

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Alexander E. Perl, MD, University of Pennsylvania

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Eunice Wang, MD, Roswell Park Comprehensive Cancer Center

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Adam Bagg, MD, University of Pennsylvania

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Corey S. Cutler, MD, MPH, FRCPC, Dana-Farber Cancer Institute

Harry P. Erba, MD, PhD: It appears that, although testing rates are improving over time, there is still a need to improve the rate of testing, especially in community practice. My colleague Dan Pollyea has published for the Connect MDS [myelodysplastic syndrome]/AML [acute myeloid leukemia] Disease Registry with a series of patients in that registry, and the registry results are showing that molecular testing is done in only 70% of patients in the community and government sites. I was wondering, Adam, if you would like to comment on the need for testing. Then we’ll move to turnaround times. Adam?

Adam Bagg, MD: Yes, thanks Dr Erba. The point you brought up about FISH [fluorescence in situ hybridization] analysis and cytogenetics was something I was going to embrace as well, and although we are focusing on the importance of so-called molecular testing, I don’t think we should be talking about molecular testing in isolation. We should talk broadly about genetic testing, turnaround times, and impact on therapy to make sure that people don’t think that molecular testing is going to replace cytogenetics and FISH analysis. Absolutely not; we still need karyotyping in all patients.

To get to your point regarding patients who may benefit from gemtuzumab or who may benefit from liposomal ara-C [cytarabine] and daunorubicin, we routinely screen all patients when they come in for CBF [cerebral blood flow] FISH analysis, so we can tell from the day the leukemia is diagnosed by FISH results whether they have a chromosomal translocation of 8;21 or chromosomal inversion at 16 by FISH analysis more rapidly than we can by cytogenetics, so they can benefit from that form of therapy.

Similarly, as you alluded to, because our cytogenetic chromosomal turnaround time is longer than we would like, in a patient who may benefit from such liposomal therapy—who does not have a history of MDS, who does not have a history of prior therapy—we want to diagnose AML with myelodysplasia-related changes [MRC] by cytogenetic testing, so we do a rapid FISH panel. We’ll look for abnormalities in chromosome 5, abnormalities in chromosome 7, and deletion of 17p, getting these results on the same day to make decisions about how to administer the 7+ 3 conventionally or in a liposomal formulation.

With regard to molecular testing, it’s also important for practitioners to be cognizant of the different technologies that are involved. Everyone talks NGS [next-generation sequencing] these days: next generation sequencing or MPS [massively parallel sequencing]. This technology, although important and used in most myeloid and lymphoid malignances, is time consuming. The results generated by massively parallel sequencing are unlikely to be back in time to affect early therapy.

Therefore, the tests that are likely to impact early therapy are usually done as single gene assays like the FLT3, CEBP-alphas, NPM1 in some instances, and IDH2 assays. If you need a test, and the result is going to be required to make a therapeutic decision within a week, next-generation sequencing is not the test to do to give you that answer in the short term. For that reason, although the mutations I’ve mentioned are covered on most NGS panels, you want a fairly rapid, usually PCR [polymerase chain reaction]–based single gene assay to pick up a FLT3 mutation, an IDH1/2 mutation, if necessary to pick up an NPM1 mutation, and so on.

Alexander E. Perl, MD, MS: Especially in the relapsed/refractory setting, where certain drugs have their best efficacy shown with a specific mutational complement, whether it’s a FLT3 inhibitor like gilteritinib or an IDH1/2 inhibitor like ivosidenib or enasidenib. Those mutations can sometimes change from diagnosis to relapse. In that setting, we need a rapid turnaround time. I absolutely agree with Adam: For most of the things we find on a next-generation sequencing panel, we can wait a bit of time. But it has not replaced karyotyping, and it has not replaced getting a full genetic analysis in terms of cytogenetics.

Harry P. Erba, MD, PhD: I agree. Sasha, since you have the floor, let me turn to you from the clinical perspective. You’re going to be waiting some amount of time, and we’ve all been trained that you don’t go to sleep until you write for the 7+3 chemotherapy on that newly admitted patient. What should we be doing? How much treatment delay is allowable? Are there any data that help us and inform us?

Alexander E. Perl, MD, MS: “Don’t just stand there. Do something” is what we are feeling, but “Don’t just do something. Stand there” is potentially the right answer because you want to know that you’re giving the best regimen for your patient. If the results from some of this testing lead you from 1 regimen to another, it is important to be right. What the data have shown is that, for certain patients, picking the right regimens can lead to a survival benefit, so you don’t want to rush into something too quickly. That being said, I don’t think we can say, “You’ve got AML. Come back in a few weeks, and we’ll treat you” and not expect that a good number of patients will get sicker.

With close monitoring of patients, it is safe to follow them during that time. We have data that Christoph Röllig and colleagues published in the past year that showed a delay of up to a couple of weeks—with close monitoring in the context of patients ultimately treated with intensive therapy—was not associated with a lower remission rate or impaired survival. If you need to choose a regimen based on the genetic data, and you’re closely monitoring your patient, and your patient is not developing potentially life-threatening complications under your watch, then you can delay that without impairing the ability of the new regimen to give you that benefit.

Harry P. Erba, MD, PhD: One of the challenges I face is that these patients are often identified in emergency departments in the community. They get shipped into our inpatient service, and there is a lot of “Why aren’t you doing something?” We’re just waiting, and this adds to the length of stay. We’ve started getting in the practice of potentially discharging patients if they are stable enough and waiting for that evaluation to come back.

It’s important to discuss this with the pathologist. When I got to Duke, they talked about their limited resources, and we have to take that into account. Pathology departments also have constraints on what they can do. We set up a program so we have a way of identifying newly diagnosed patients and relapsed/refractory patients for whom a treatment decision needs to be made. We can distinguish them from others where there can be more time from the bone marrow biopsy to the actual report. We get FISH analysis results back quickly as well as the PCR panel for FLT3 and for IDH in that regard.

Adam, what conversations do you have with Sasha at Penn and our other colleagues, Selina Luger and David Porter and the like?

Adam Bagg, MD: We have frequent communications regarding new patients. We have open channels of communication. We’ve also worked intently to work up and develop pathways. For each time a new patient with AML comes in, we’ve got a pathway that we follow in terms of what the standard laboratory testing is going to be, along the lines of what I alluded to regarding FISH analysis, cytogenetics, and molecular testing. We didn’t talk about PML [promyelocytic leukemia]/RARA [retinoic acid receptors] or translocations in chromosomes 15;17, but we do that as well. We have standard, quite well-formulated pathways each time a new patient with acute leukemia comes in, AML in particular, more robustly than for patients with ALL [acute lymphoblastic leukemia]. We also recognize early on patients who come in who are relapsed. We communicate rigorously, vigorously, and frequently. Beyond that, we have established pathways and guidelines for how to do the tests we need to do.

Transcript Edited for Clarity