Acute Myeloid Leukemia: Evolving Perspectives on Testing, Targeted Therapies, and Transplantation - Episode 1

Role of Molecular Testing in AML

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

,
Alexander E. Perl, MD, University of Pennsylvania

,
Eunice Wang, MD, Roswell Park Comprehensive Cancer Center

,
Adam Bagg, MD, University of Pennsylvania

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

Harry P. Erba, MD, PhD: Hello, and welcome to this OncLive® Peer Exchange® titled “Acute Myeloid Leukemia: Evolving Perspectives on Testing, Targeted Therapies, and Transplantation.” I am Dr Harry Erba from Duke University School of Medicine in Durham, North Carolina.

Joining me in this discussion are my colleagues Dr Alexander Perl from the University of Pennsylvania Perelman School of Medicine in Philadelphia, Pennsylvania; Dr Eunice Wang from Roswell Park Comprehensive Cancer Center in Buffalo, New York; Dr Adam Bagg, a hematologic pathologist from the University of Pennsylvania Perelman School of Medicine in Philadelphia, Pennsylvania; and Dr Corey Cutler, a transplant specialist from the Dana-Farber Cancer Institute in Boston, Massachusetts.

We’re going to discuss a number of topics pertaining to contemporary treatment of acute myeloid leukemia [AML]. We’ll discuss the latest research in the field and the impact of recent clinical trials on making decisions around treatment selection. Let’s get started with our first topic.

In the first section, we’re going to discuss molecular testing in AML, which is clearly going to rely heavily on our interactions with our pathologists. Before we get there, it’s important that we help inform our pathologists as clinicians what we need in caring for patients. For this, I’m going to turn to Eunice. Talk about what molecular testing should be done according to NCCN [National Comprehensive Cancer Network] 2021 recommendations and then what you do at Roswell Park. Eunice?

Eunice S. Wang, MD: Thanks, Harry. I appreciate the opportunity to speak to the audience. In the past, when we made a diagnosis of acute myeloid leukemia, we relied on morphology and flow cytometry, as well as conventional cytogenetics. In the current era, given the development of many targeted therapies for acute myeloid leukemia, we are required to perform molecular testing, and the NCCN 2021 recommendations have stated explicitly that there are certain actionable mutations that should be expedited at the time of AML diagnosis for therapeutic reasons. These include CEBP-alpha, FLT1-ITD and -TKD, IDH1, IDH2, and NPM1 mutations. It is explicitly stated in the guidelines that these are immediately actionable mutations, meaning that we would potentially treat patients differently and offer treatment approaches based on the presence or absence of these mutations.

What does expedite mean? That’s a great question, Harry, because we know that some of our colleagues in the community vs academia may have different timelines. At our center, we like to have those results back within 3 to 5 days of obtaining the sample. That sample can be the peripheral blood if there are a significant number of blasts or a marrow sample. So if there is a significant amount of disease in the periphery, there is no need to wait to do a bone marrow biopsy. In fact, we sometimes send peripheral blood first, then do the marrow and wait for those marrow results a couple of days later. In the community, it could take 1 to 2 weeks, and we would advise potentially collaborating with the individuals—Dr Bagg can discuss this later—about how to best facilitate obtaining those results in a timely fashion.

Harry P. Erba, MD, PhD: Can you give me a couple of examples of specifically what mutations and changes you’re looking for and how you would select therapy? What are the most urgently required tests that you need to start therapy?

Eunice S. Wang, MD: That’s a great question. I’ll give an example. I had a young patient come to see me the other day, a 20-year-old undergraduate student who ran on the cross-country team. She was having progressive anemia, weakness, and symptoms over the last few months right before returning home for the Thanksgiving holiday. She went to employee health and had a CBC [complete blood count] drawn. Unfortunately, that showed about 40% peripheral blasts. We brought her in to see us in our clinic, and we made a diagnosis based on her peripheral blood that she had acute myeloid leukemia. She was admitted, and given that she was 20 years old, we deemed her eligible for intensive chemotherapy. We sent peripheral blood at the time of initial encounter for FLT3 mutation testing. She was admitted a couple of days later and was receiving 7+3 chemotherapy when we got the results that she was FLT3 mutant.

In that situation, obtaining that result in the first 3 to 5 days of the diagnosis is crucial because we would be obligated based on that result to start a FLT3 inhibitor like midostaurin or an experimental inhibitor on day 8 of her treatment regimen. In that case, expediting the results in a young patient fit to receive intensive chemotherapy could not only alter the initiation of therapy on time on day 8 but also drive us to consider more seriously performing a bone marrow or allogeneic stem cell transplantation once she achieves a complete remission [CR]. Based on that FLT3 result in the setting of a normal karyotype, we have also started typing her siblings and are planning to move forward with a transplant in CR1.

Harry P. Erba, MD, PhD: I completely agree, but I want to throw in a couple of other examples that may not come from the mutation analysis. Let’s go back to cytogenetics and FISH [fluorescence in situ hybridization] analyses, which are still important. According to the meta-analysis of 5 large, randomized trials of chemotherapy with gemtuzumab ozogamicin, the anti-CD33 antibody, patients with core-binding factor leukemias—those with a translocation between chromosomes 8;21 or an inversion in chromosome 16—had a survival benefit when gemtuzumab was added to chemotherapy in some dose and in some schedules. It varied between the protocols, and it should be done with chemotherapy. You need that result even quicker than the FLT3 results, with which you’re going to start midostaurin on day 8.

The other place I use it is with a FISH panel that may show me changes associated with AML with myelodysplasia-related changes based on cytogenetics. It appears to be de novo, but it may have cytogenetic changes. So we can have a different discussion about liposomal daunorubicin-cytarabine or, as we’ll talk about later, hypomethylating agents with venetoclax in that population of patients. I agree, it is important to get this information.

Transcript Edited for Clarity