Guenther Koehne, MD, PhD, Shares Details on New FDA-Approved Trials in AML

In an interview with Oncology Learning Network, Guenther Koehne, MD, PhD, Deputy Director and Chief of Blood and Marrow Transplant and Hematologic Oncology at the Miami Cancer Institute, part of Baptist Health South Florida, highlights 2 new FDA-approved clinical trials, including a pilot study on CPX351 plus midostaurin followed by an allogeneic stem cell transplant (ASCT) for fms-like tyrosine kinase 3 (FLT3)-positive acute myeloid leukemia (AML), and the phase 1 dose trial of lymphocyte infusions following CD34-selected ASCT for the same patient population.

Transcript:

Hi, my name is Dr. Guenther Koehne. I'm the Deputy Director of Miami Cancer Institute. I'm the Chief of Blood and Marrow Transplantation and Immunotherapies in Hematologic Oncology at Miami Cancer Institute.

Oncology Learning Network: Can you share details about the 2 new FDA-approved clinical trials?

Dr Koehne: I'm happy to report that over the last year and a half or so, I submitted these 2 investigator-initiated clinical trials to the FDA, and they are both are now approved and prepared for enrollment of patients for these novel innovative clinical trials.

The first one, the CPX351 plus midostaurin followed by an C34 selected allogeneic stem cell transplantation (ASCT) is particularly focusing on the treatment of patients with a FLT3-positive AML, which is a higher risk AML, acute myeloid leukemia.

About 30% of patients get diagnosed with the FLT3-positive AML. To my understanding, we need to stratify these patients from the very beginning of how to treat.

In other words, if you have a higher risk disease, higher risk means relapse and subsequently pass away from the disease. You may want to be a little bit more aggressive from the very beginning on in order to improve and provide the overall survival (OS) that you would have had with a not so aggressive AML. That’s the baseline here.

The scientific evidence is that the CPX351 (Vyxeos) showed improvement in the outcome of patients undergoing induction chemotherapy for newly diagnosed AML when compared to the standard of care, which is 7+3 chemotherapy. This has been the standard for many, many years. Now with the development of new drugs, there are new opportunities to improve on certain subcategories of AML.

What struck me when the study performed, comparing CPX351 to 7+3 induction chemotherapy, had an improved response in patients with FLT3 AML, which was a subgroup of the study. Most importantly, it could be shown that patients undergoing induction chemotherapy with CPX351 had a better chance to get into an ASCT⁠—was about a 10% versus 45% chance to subsequently move on to an ASCT.

That is key in order to consolidate the response and have the opportunity then to provide a longer progression-free survival (PFS) of these patients with high risk AML.

This is combined with the FLT3 inhibitor. The standard is the midostaurin that has been studied in the RATIFY study, 7+3 plus midostaurin now here after clinical trial, where I can test CPX351 plus midostaurin followed by ASCT with the intent to show an improved outcome of patients with this high risk AML.

The second study has to do with post ASCT immunotherapeutic approaches. My center here at Miami Cancer Institute, as a few others in the country, Memorial Sloan Kettering Cancer Center and Dana-Farber Cancer Institute, often perform ASCTs after depleting the T-cells.

This is performed by selecting the stem cells that are CD34 positive. With that, you have an indirect depletion of the donor T-cells and other cells.

That has an advantage, from my perspective, that you do reduce the development of graft-versus-host disease (GVHD), following stem cell transplantation (SCT) significantly. In addition, you can potentially perform a transplant that allows mismatch, 1 or 2 mismatches.

Most importantly, these patients do not require post-transplantation immunosuppressive therapy, which is needed to prevent GVHD in all so-called conventional stem cell transplants.

Now, the platform here is CD34 selected ASCT. Then, you have cells from the donor that are the T-cells, which are known to be the ones inducing GVHD. However, not all the T-cells are created equal. We have 2 subcategories of T lymphocytes. One are called a T-cell receptor alpha/beta T-cells, and the other ones are T-cell receptor gamma/delta T-cells.

Now, we know that the T-cell receptor alpha/beta are the cells that have the capacity to induce GVHD. Whereas the T-cell receptor gamma/delta positive T-cells don't have the capacity to induce GVHD because they react in a HLA unrestricted fashion, which is the reason why they cannot induce GVHD, but they have strong antiviral activity and they may also exert an anti-tumor effect post transplantation.

What this clinical trial that got FDA approved on December 24th last year (2021) now does is that we take the T-cells from the donor and we deplete the T-cell Receptor alpha/beta positive cells and maintain the gamma/delta positive cells, infuse them post transplantation at several time points and at several doses in order to demonstrate that we can reduce viral complications following ASCT, which is one of the biggest hurdles and complications affecting the outcome of allo-transplants.

I'm very excited about this trial, and looking forward to demonstrate that this is feasible, which will likely then provide us with an additional tool to improve the outcome of CD34-selected transplantations.