Leonard Highlights Agents, Approaches in Pipeline for Hematologic Malignancies

John P. Leonard, MD

There is an abundance of emerging developments for the treatment of patients with various hematologic malignancies, with a strong focus on precision medicine, says John P. Leonard, MD.

“I think that we have always been ahead of the curve—as far as moving new treatments forward—and with respect to immunotherapy, we are also at the cutting edge,” said Leonard, a professor of medicine at Weill Cornell Medicine/NewYork-Presbyterian Hospital.

OncLive: What are some of the exciting developments across the board in hematology?

How could some of the more modern immunotherapies have a role in hematologic malignancies?

During an interview at the 2017 OncLive^® State of the Science Summit on Hematologic Malignancies, Leonard, who chaired the event, discussed advancements across hematologic malignancies and pivotal trial data he is anticipating at the 2017 ASCO Annual Meeting.Leonard: Like much in oncology, the theme that is coming through in hematologic malignancies is precision medicine and precision science. We are focused on setting disease subcategories, whether that be for targeted therapies and identifying molecular targets within subsets of patients, or identifying minimal residual disease so that we can figure out who needs more or less therapy, a different therapy, or understanding relapse. Those are the big areas across hematologic malignancies, and that is the theme in cancer care in general.I would say hematologic malignancies led the way for immunotherapy in cancer. The first real immunotherapy included interferon, which was approved long ago in lymphomas, and rituximab (Rituxan), a passive antibody-immunotherapy approved [by the FDA] in 1997, over 20 years ago. They have been mainstay therapies.

Please expand on CAR T-cell therapies.

Certainly for lymphoma, we have antibody-drug conjugates and you see them in clinical trials for other lymphomas. We have also seen data for [antibody-drug conjugates] in leukemias. There have also been FDA approvals for checkpoint inhibitors, particularly in Hodgkin lymphoma, but they are being studied in clinical trials in other hematologic malignancies. We have had epigenetic treatments like azacitidine, which is in some ways an immunotherapy. Clearly, chimeric antigen receptor (CAR) T cells and bispecific antibodies have made and will continue to make an impact in the coming years in hematologic malignancies.CAR T cells have been most well established, in my mind, in acute lymphoblastic leukemia. We have a lot of data coming along, particularly in the hardest-to-treat lymphomas, such as resistant large B-cell lymphoma. There is no doubt that there are patients who have had excellent responses that seem to be durable.

The challenge, really, is [understanding] where this therapy fits in and how many patients will benefit. If you start with 100 patients, there are patients who are not going to be candidates due to age or comorbidities. There are also patients who fall off these trials because their disease is too aggressive to wait for CAR T cells to be generated. There are some selection biases as you look at these data.

It seems that even as all of these therapies are coming out, chemotherapy and stem cell transplantation are still backbone treatments. As more agents get approved, will the roles of these standard therapies change or evolve?

Ultimately, it will come down to how many patients this will benefit and how durable [the responses are]. If you go through this whole process for a 2-, 3-, or 6-month remission in a minority of patients, it is hard to say. On the other hand, if we start seeing 1- to 3-year remissions in patients who don’t have any other options, then it will certainly be there. There is no doubt that there will be some patients who benefit, but ultimately—at least in the near term—it will be a small percentage of patients who will get CAR T cells for their lymphoma treatment.Like in solid tumors, chemotherapy works better in liquid tumors and hematologic malignancies. It is hard to replace a therapy that cures people. I don’t think chemotherapy will totally go away for patients with Hodgkin lymphoma or large cell lymphoma. It is easier to replace chemotherapy when it doesn’t work well and when a new therapy can be dramatically better. When we see big differences in the currently incurable diseases, it will be relatively easier. But, we will be using chemotherapy for a while.

What data are you anticipating at the 2017 ASCO Annual Meeting?

There were exciting data at ASH about rituximab maintenance therapy in mantle cell lymphoma (MCL). Is that a viable strategy for treating those patients?

Obviously, patients don’t like the idea of chemotherapy or the toxicities; those are meaningful for patients. On the other hand, when you can cure a substantial fraction of patients as we do in large cell lymphoma, it is hard to “throw the baby out with the bathwater,” so to speak.In hematologic malignancies, the data that have been most exciting and we will follow up with is treatment with ibrutinib (Imbruvica) for [patients with] chronic lymphocytic leukemia. We will see more targeted therapies in leukemia, and more follow-up data with bendamustine studies in indolent lymphoma. Because there are so many meetings these days, we get to see the incremental advancements.Maintenance therapy with rituximab has shown benefit in MCL after CHOP or R-CHOP therapy. It has also shown benefit after an autologous stem cell transplant, where it’s provided not only a progression-free survival benefit but also an overall survival benefit. It has not been quite as well established after bendamustine-based therapy, which is the most common therapy, at least for older patients.

What do you find to be some of the exciting developments in MCL lately?

We have an ECOG intergroup 4-arm study that is looking at bendamustine and rituximab with a variation on that, which includes adding bortezomib (Velcade) as an induction therapy, and adding rituximab or rituximab and lenalidomide as 1 of the maintenance therapies. It may be a while until we have that data, since patients tend to do well on that. Ultimately, I do think rituximab maintenance has a clear value in treating MCL, and it wouldn’t surprise me if adding lenalidomide or some other novel agents over time also makes a difference.In MCL, ibrutinib has made a big difference for patients. We are learning more about sub-classifying the MCL population, and the future is going to have more combinations with ibrutinib, whether it’s venetoclax (Venclexta), or cell cycle inhibitors, or other novel compounds to try to minimize or treat resistance as well as extend the duration of remission.