Transforming the Treatment Landscape for AML and MDS With myeloMATCH

Harry Erba, MD, PhD

myeloMATCH is a trial that represents a significant shift in how acute myeloid leukemia (AML) is treated by addressing the disease's complexity and genetic diversity. By breaking down the therapeutic process and focusing on personalized medicine, myeloMATCH seeks to improve patient outcomes through targeted interventions.^1,2

The trial utilizes advanced genetic profiling, including Thermo Fisher's Ion Torrent Genexus System, to rapidly identify specific mutations in patients with AML and myelodysplastic syndromes (MDS) and assigns them to the most suitable clinical trials based on their unique genetic makeup.

This approach not only accelerates the treatment process but also ensures that patients receive the most effective therapies tailored to their individual needs.

In an interview with Targeted Oncology^TM, Harry Erba, MD, PhD, professor of medicine at Duke Cancer Institute, chair of the SWOG Leukemia Committee, and co-chair of the myeloMATCH Senior Science Council, provided his insights into the groundbreaking myeloMATCH trial and its influence on the treatment of AML and MDS.

Targeted Oncology: Can you provide some background on the myeloMATCH trial?

Erba: myeloMATCH is 1 of the 3 [National Cancer Institute (NCI)]-funded adult MATCH trials. The concept of myeloMATCH is to deconstruct all the elements of a patient’s therapeutic journey after an initial diagnosis of acute myeloid leukemia and try to optimize our interventions for initial therapy, follow-up treatment, the possibility to transplant, and maintenance. So, myeloMATCH attempts to develop clinical trials in each of these therapeutic steps to optimize outcomes for patients with acute myeloid leukemia.

Could you elaborate on the specific substudies included in myeloMATCH?

To improve outcomes for [patients] with acute myeloid leukemia and myelodysplastic syndromes, it is critical that we understand the heterogeneity of this patient population in terms of the drivers of the disease pathogenesis. We have a lot of information about the mutations that are present in patients with AML and MDS. Out of the 10s of 1000s of genes in each of our cells, there is only a handful, maybe 50 to 60, that are currently mutated in people with acute myeloid leukemia, and they fall into very distinct classes, such as splicing mutations, chromatin modifiers, DNA methylation, enzymes activating signals, transcription factors, cohesin molecules, and such. We truly believe that these mutations underlie a pathogenesis of the disease. We have already started to make great inroads into the treatment of acute myeloid leukemia by identifying some of these targets.

Some of the targets identified are more common like FLT3, IDH1, [and] IDH2. Other mutations are now targets for other therapies, such as the Menin inhibitors and patients with NPM1 mutations and KMT2A. myeloMATCH attempts to identify these mutations at the time of diagnosis and then assign patients to clinical trials meant to optimize the initial therapy and then subsequent therapy for these patients based on this mutational analysis.

Blood Cancer: © Hadi - stock.adobe.com

myeloMATCH activated on May 16, 2024, and we already have patients accrued to the study. The idea here is that after a patient is screened and the genetic profile is defined, the patient will then be assigned to an appropriate study. Now, we plan to have studies for every subtype that we identified and plan to develop studies for new targets that are identified. But at this point, myeloMATCH is activating with 2 studies: 1 from the Canadian Cancer Trials Group in intermediate-risk AML as defined by [European LeukemiaNet (ELN)] 2017 criteria, and a SWOG study of high-risk, poor-risk, or average-risk karyotype AML as defined by ELN 2017.

There are other studies coming. We are developing studies for NPM1, FLT3, for core binding factors, and those studies are coming for the initial treatment of younger patients with acute myeloid leukemia. We are doing a similar thing for older patients, identifying these mutations and then developing trials.

What treatment modalities are being explored?

In this first series of clinical trials that we have developed, we have chosen to study currently available therapies that appear to have activity in each of these disease states, but we really do not know the relative value in terms of efficacy and toxicity of each of these regimens. [For] example, in the SWOG study that our group is leading, we have 5 arms for these high-risk patients with acute myeloid leukemia who are under the age of 60. One is standard 7+3; we needed a control arm. Nothing has ever been shown to be better than 7+3. As much as that is not very attractive, it is the standard –of care. Then we have 4 experimental arms. One of them is 7+3 with a BCL2 inhibitor, venetoclax [Venclexta]. Another is the liposomal formulation of daunorubicin and cytarabine groups, CPX-351, either alone or with venetoclax, and we have phase 1 data and phase 2 data for both of those regimens. Then finally, the hypomethylating agent azacitidine and venetoclax. The purpose of this initial treatment protocol is to see which one of these arms of therapy, compared [with] 7+3, provides deeper and earlier remissions, which we believe translates into better outcomes and the least amount of toxicity. It is a combined end point. The primary end point is [minimal residual disease (MRD)]-negative remissions by flow cytometry. So, that is an example of what we are doing in the high-risk group of patients in the Canadian study. We are also studying venetoclax-based regimens for the intermediate-risk population as well. Other studies are being developed.

Beyond the initial screening, how does the trial possibly handle patients’ mutations changing over time?

That is one of the reasons why we launched myeloMATCH. We understand that not only do patients present with a certain mutational profile, but in that individual patient, there are likely subpopulations with various mutations. We could tell this is true by the variant allele frequencies, that some are low, some are higher, suggesting some of these mutations are in subsets. Then, we make a therapeutic intervention, and that therapeutic intervention may select for a clone of cells with a minor mutational profile or a new mutational profile. The goal of myeloMATCH is to study patients along their journey to identify these mutations that might be popping up, and then target them in subsequent tiers of the study. At the end of each tier, we collect samples from patients, in remission or not, and we do the same targeted cytogenetic and mutational analysis, and we are partnering with a vendor that looks at duplex DNA or error-corrected DNA sequencing, as well as high sensitivity flow cytometry, to identify small populations of cells, and then have studies available to them in what we call tier 4, to target those mutations with various therapies, whether they be targeted molecules or immunotherapeutic approaches.

Looking at the historical challenges and developing new therapies for AML, how does this trial, in terms of patient accrual personalization, address these challenges?

The myeloMATCH concept initiative has been in development since before January of 2019. But I will say 5 years ago, the leaders of leukemia committees of the NCI-funded Cooperative Groups [Program] in the United States and the Canadian Cancer Trials Group got together and decided that we needed to develop these studies in unison and put our patients in the United States and Canada on these studies. It is powerful; it gives us the power of the numbers as we start to look at smaller and smaller subsets of patients, especially patient subsets, where you are not just thinking about a single target, but how we handle patients who have 2 targets in their leukemia. These are going to be smaller and smaller subsets. We need to get together, and we all agreed to develop the myeloMATCH initiative so that we have the power of the number of patients with AML and MDS throughout North America. That is number 1.

Number 2, to have studies that, right from the start, are targeting those mutations that are drivers of the pathogenesis of these myeloid neoplasms, we need to know what those mutations are in each of those patients. That has been a second major challenge in rapid identification of a patient appropriate for the study. I would like to give [an] example of a study that I was co-chair of the steering committee, and that is the QuANTUM-First study [NCT02668653]. There were 3500 patients who gave consent to be part of a clinical trial trying to improve the outcomes of AML. Out of those 3500, only 500 were eligible because only those 500 had the mutation. What happens to the other 3000 patients who gave consent? They were probably treated with standard –of care, maybe they went on another clinical trial at that institution. So, it became quite obvious that even for the most common of the mutations, FLT3 [internal tandem duplication (ITD)] mutations found in 25%, maybe 30% of younger [patients with] AML, that we needed to be able to screen patients, but not lose patients who are agreeable to clinical research, which was happening in all of these studies.

On the other hand, patients with acute myeloid leukemia are often sick at the time of diagnosis [with] neutropenic infections, thrombocytopenic bleeding or fatigue from anemia, and often because of the nature of the disease, are sent to emergency rooms, and then admitted to the hospital. We know it is okay to wait for mutational analysis. We can support patients for a short period of time; this has been shown in multiple retrospective studies. However, there is a practical issue. These patients are in the hospital waiting for therapy. They all have to deal with length of stay, [and]patients are eager to get started, so we need this information quickly. And not just on 1 single mutation or 1 clinical trial, but all the mutations. This is where our partnership in the cooperative groups, with the NCI, and then vendors such as Thermo Fisher have been so critically important. We are able to provide, within a 72-hour turnaround, the full mutational profile of patients with acute myeloid leukemia and MDS using a next-generation sequencing platform that gives us the information on the recurrently mutated genes in AML. Also, fusion protein genes in AML and MDS, and through the work of our own people in the Cooperative Groups’ cytogenetic analysis in Seattle, and flow cytometry as well. Flow cytometry is being run and spearheaded by Brent Wood, MD, PhD, at [University of California, Los Angeles (UCLA)] Children's Hospital, the cytogenetics and FSH effort being spearheaded by Min Jin, MD, in Seattle. This is an amazing partnership where the NCI academics and industry have come together to provide the information we need rapidly to assign patients to the initial tier of studies and then subsequent studies, answering question about maintenance, identifying those mutations that may be present, and then putting them on a tier 4 study or a tier 2 study, which is an MRD research study. We are building out AML therapy in this deconstructed fashion.

How do you think the trial will contribute to a broader understanding of AML biology and potential future treatment strategies?

This is such an amazing international resource. We are collecting samples on all of these patients. These patients will be coming from academic and community practices, so it is a broad representation of patients in the United States. Hopefully through this, we will be able to have information on patients of smaller ethnic and racial groups that are often misrepresented or underrepresented in clinical trials. That is number 1.

Number 2, we will have the samples and will be able to look at how therapies impact on the mutational profile and this heterogeneity of the patient sample so that we can target small subsets of disease that may be still present that we need to take care of before the relapse. We hope it will improve outcomes by extending survival without evidence of cancer and potentially curing the disease. Our goal is to understand the biology of this disease over the entire treatment course so that we can make interventions that will ultimately cure the patient with AML.

What are the long-term plans for myeloMATCH?

myeloMATCH is starting out slowly; it took 5 years to get to this point. We have 3 clinical trials that have been approved by the central [internal review board (IRB)] and have gone out to sites for activation: 1 for FLT3-mutated AML in older patients, and 2 for younger patients with AML, which are intermediate- and high-risk studies from the Canadian Cancer Trials Group. We still have a lot of work to do. We have already been designed and vetted through a Senior Science Counsel of myeloMATCH, in concert with our industry colleagues who have agreed to provide investigational drugs for each of these areas. Additionally, the artificial intelligence agrees that these studies are worthy of being part of the myeloMATCH concept.

myeloMATCH is not intended to be a large phase 3 study. In most cases, we are looking for signals at each step in the patient's journey to improve outcomes. We aim to piece together these steps into a curative path for individual patients. This approach differs from large phase 3 studies where patients receive various consolidations and types of transplants, complicating interpretation. Approvals for drugs from such studies often take a decade, and we cannotafford to wait that long. We have new therapies coming for patients and need to develop earlier endpoints, which we are doing in myeloma. One of the major goals of myeloMATCH is to validate high-sensitivity flow cytometry, done in a single [Clinical Laboratory Improvement Amendments (CLIA)]-certified lab, as I mentioned at UCLA Children's Hospital under the supervision of Brent Wood. We have prepared an [investigational device exemption (IDE)] application for this assay, so data from these studies can inform large phase 3 studies if industry partners choose to pursue that. This data may be impactful enough for clinicians to apply it to their patients.

We are also working to validate assays for measurable residual disease, flow cytometry, error-corrected double-stranded DNA sequencing, and next-generation sequencing. This is another long-term goal of myeloMATCH. We are starting with a portfolio of clinical trials that are already active or soon to be active. As you might imagine, new therapies will emerge, and we will gather information from these studies. myeloMATCH, in concert with the NCI, industry partners, and the FDA, will design the next level of studies to continuously refine our therapeutic approach for this very aggressive cancer.

REFERENCES:

1. Thermo Fisher Scientific to help advance myeloid cancer clinical research and treatment utilizing Next generation sequencing technology. News release. Thermo Fisher Scientific. July 11, 2024. Accessed July 29, 2024. https://tinyurl.com/3zu2h647

2. myeloMATCH: The Next Revolution in the NCTN. News release. SWOG. May 10, 2024. Accessed July 29, 2024. https://tinyurl.com/mye35zek