A hematologist at NYU Langone Health’s Perlmutter Cancer Center, Mohammad Maher Abdul Hay, MD, treats people with leukemia. His research focuses on creating more effective targeted novel therapies for patients with myeloid malignancies and, ultimately, obtaining regulatory approval for these agents. Dr. Abdul Hay, an associate professor in the Department of Medicine at NYU Grossman School of Medicine, also directs Perlmutter Cancer Center’s Clinical Leukemia Program, where he oversees the care of people with both chronic and acute leukemia as well as early-phase clinical trials. The trials—designed primarily for people with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndromes (MDS)—range from studies of potential first-line treatments to therapies for refractory and relapsed disease.
He discusses innovative clinical trials for leukemia, advances in treatment for older people with leukemia, and more.
You conduct your own clinical trials as well as oversee clinical trials for the Clinical Leukemia Program. What trials do you find to be particularly exciting?
In leukemia, and in AML in particular, when patients relapse or they are refractory to conventional standard of care treatment, they have poor outcomes and very limited options. In these cases, clinical trials for targeted therapy are really the future.
One of the most common mutations in AML is called the FLT3 mutation, which is found in 30 percent of all AML cases. We have some targeted therapies for FLT3, but if people don’t respond, the outcomes can be horrible. We have a trial using a new technology called BITE, which stands for bi-specific T-cell engager. This technology, which is considered “off-the-shelf,” takes T cells from the patient, which are good white blood cells, to attack the leukemic cells that express FLT3. I think it is very exciting that we have BITE studies now for people with AML because BITE first showed efficacy in ALL, and it is now approved for use in these patients.
We also have a trial for a targeted therapy against two other mutations in AML, NPM and KMT2A. NPM is associated with about 20 percent of all cases of AML. KMT2A, which is an abnormality on chromosome 11 called the 11q23 rearrangement or translocation, is a predictor of poor outcomes in patients. We have a targeted therapy for both NPM and KMT2A, an inhibitor of the menin protein in pill form, that can differentiate the white blood cells and eradicate the leukemia. This is exciting because people with these mutations do worse when they relapse, and they have very limited options. And now we have a targeted therapy, a pill, that can fix this problem.
For MDS, the only approved upfront therapy for intermediate- to high-risk patients is a hypomethylating agent, either azacitidine or decitabine, which inhibits an enzyme called DNA methyltransferase and prevents cancer cells in the bone marrow from growing and dividing. As an addition to using a hypomethylating agent, which is the standard of care, we can use an inhibitor of the TIM-3 receptor as an immunotherapy, and we are seeing much better results than by using a hypomethylating agent by itself.
For refractory and relapsed patients, we have a very interesting study that uses kidney embryonic stem cells that have been manufactured and manipulated to be able to target the Wilms’ tumor-1 (WT1) protein, which is expressed about 95 percent of the time on leukemic blast cells. These progenitor cells are targeting WT1 directly and the blast cells indirectly. This is another off-the-shelf treatment. It is given as one infusion every four weeks and looks promising.
For a long time MDS as a disease has been orphaned because there has been so much attention on developing therapies for AML. I think now, since we have seen the approval of novel therapies for AML, the focus is shifting. It’s an exciting time for MDS.
What changes have you seen in the treatment of leukemias since you have been treating people with these conditions?
If you go back just five years ago, there were very few treatment options. Now we have targeted therapies. We have inhibitors of the IDH1 and IDH2 gene mutations, which help drive leukemia. We have the FLT3 inhibitors that I mentioned earlier. We also have venetoclax, which I think revolutionized our ability to treat people because it is not as toxic as high-intensity chemotherapy. Venetoclax is a BCL-2 inhibitor, and you can combine it with a hypomethylating agent to treat patients with AML.
I think the main breakthrough that happened in AML was understanding the disease better, understanding what drives the disease and targeting that driver and not just giving chemotherapy.
There was a study looking at all the different chemotherapies used in patients with refractory and relapsed AML, and the median overall survival was three months. And then FLT3 ITD inhibitors—the pill that targets FLT3—were approved and increased the median overall survival to more than nine months. Overall survival was more than tripled with just a pill. I think that’s really what changed the whole algorithm in leukemia: understanding the disease and developing a targeted therapy. Now we are trying to combine this targeted therapy with chemotherapy; maybe we’ll have two targeted therapies instead of one in the near future. I think this is where we are heading, and it’s a very exciting time.
What treatments do you see coming for people with leukemia in the next five years?
I think more novel technologies like BITE are going to become available. Chimeric antigen receptor (CAR) T-cell therapy is now a treatment for ALL, and people are having great responses, and I think this treatment will become available for AML as well.
Toxicity of transplants, meaning rejection and complications, is becoming less frequent, and I think more people will be able to have transplants for cures. Donors are becoming much easier to find because we are doing haploidentical transplants with half-matched related donors. I think we definitely will have better outcomes with stem cell transplants over the coming five years.
Can you talk more about your work on stem cell transplants?
As a member of Perlmutter Cancer Center’s Blood and Marrow Transplant Program, I perform autologous stem cell transplants and different types of allogeneic stem cell transplants as well as CAR T-cell therapy for ALL and lymphomas. I also serve as medical director of the unit at Kimmel Pavilion that provides blood and marrow transplants as well as hematology and oncology services.
The beauty of my work is that I am able to see patients from A to Z. I treat them, get them into remission, take them for transplants, and see them after transplant when they are cured. It’s both amazing and fascinating for me.
Are there any stories about people you have treated that stand out for you?
Some of our patients are in their early 70s, and they are not candidates for induction chemotherapy, which involves very toxic chemotherapy for 7 days and then for 3 days. For these patients, we enrolled them in an upfront trial, which was a lower-intensity chemotherapy regimen. And we had such a great response. A few of these patients in their 70s went into remission and then they went for a transplant because they were in such good shape and not beaten by so much toxic chemotherapy. They completed their transplants, and they are now being monitored.
That would never have been thought about a few years ago, but now we can do a lower-intensity upfront regimen, get them into remission based on that trial, and then take them for a transplant. And they are cured.
Another patient of mine, also in her 70s, had clots in her leg and was in very poor performance status, which is a score that estimates the patient’s ability to perform certain activities of daily living without help. A few years ago, she would never have made it. Now, I was able to put her on the study with low-intensity chemotherapy and get her into remission. She also had severe aortic valve impairment, and because she was in remission, she was able to have open heart surgery to repair that valve. We gave her a stem cell transplant afterward, and she’s doing well.
What should someone with leukemia expect when they come to see you for care?
I think what people can expect when they come to see us is that we are going to do our best to get them into a specific treatment, tailored to get them into remission, and then, hopefully, ultimately cured by a stem cell transplant if they need it. I truly believe that we should aim for a cure for every patient who comes in.
I tell my patients upfront that, whether it’s AML, MDS, or ALL, they have an aggressive disease, but it’s not the end of the world. It is the start of a new world where things will change and they will face many challenges, but there is hope we can get them back to where life was before their diagnosis.
Obviously, no one ever wants to have leukemia or a blood cancer, but our treatments have evolved. We now understand the diseases better. We have better equipment and better, novel therapies. We have more clinical trials available, and we can do transplants with less toxicity. If anyone gets this disease, there is hope. That’s something very important that I always try to relate to our patients.