Dr Koehne Highlights New Treatment Advancements for Hematologic Malignancies

In honor of Blood Cancer Awareness month in September, Guenther Koehne, MD, PhD, Deputy Director and Chief of Blood & Marrow Transplant and Hematologic Oncology at Miami Cancer Institute, part of Baptist Health South Florida, highlights new immunotherapy advancements in the treatment of hematologic malignancies.

Transcript

Hello, my name is Dr Guenther Koehne. I'm the deputy director of Miami Cancer Institute. I'm the chief of blood and marrow transplantation, immunotherapies, and hematologic malignancies of Miami Cancer Institute. In addition, I'm a professor of medicine and the chairman of the department of translational medicine at Herbert Wertheim College of Medicine of Florida International University.

Thank you for giving me the chance to talk about updates in hematologic malignancies, or blood cancers, particularly in the time of the upcoming Blood Cancer Awareness Month in September.

Let me start off with a few general remarks because there are a lot of exciting and interesting updates that are developing very rapidly right now in the field of hematologic malignancies.

Particularly of interest because most of the updates are clearly focused on immunotherapeutic approaches for non-Hodgkin's lymphoma, for multiple myeloma, and for acute lymphoblastic leukemia, as well as, down the road to acute myeloid leukemia.

That means there is a trend toward more immunotherapy and a trend toward less chemotherapy. That is of big excitement because that will also likely have an effect on the quality of life of the patients.

If you have to make a choice, I can get immunotherapy or chemotherapy or side effects, I would predict that most patients would say, “Let's try the immunotherapy.” That's very exciting, but it's complex.

There are 3 different immunotherapeutic approaches that I'd like to go into for a minute so that I can, later on, go into more detail with respect to the particular disease.

You all heard about chimeric antigen receptor T cells, in short, CAR-T cells, that have been approved for non-Hodgkin's lymphoma , for acute lymphoblastic leukemia, now recently, also for multiple myeloma, that certainly are a very exciting development and progress that we've made.

The principle of CAR-T cells, T-cells from the patient that get into the laboratory and they are ex vivo, that means in the laboratory, modified to express an antibody so that they can then specifically target a tumor cell.

CD19 CARs are known for ALL, for non-Hodgkin's lymphoma—CD22 CARs are also known already now that it's the second generation of CARs. Then, there is the B cell maturation antigens, BCMA, for multiple myeloma.

The alternative approach would be a bispecific antibody, which is an antibody that consists of an antigen targeting agents specifically bringing a CD3 component to the tumor. It's an antibody plus CD3, and with that, the endogenous T cells from the patient can be attracted to the tumor cell by binding to CD3. That is the bi-specific antibody approach, or in short, BiTES, that exists for the same indications.

There, we are already in trouble because now we have CAR-T cells and BiTES for myeloma, for non-Hodgkin's lymphoma, for acute lymphoblastic leukemia, and the question is, is there a difference? Is one better or less toxic and so on? We don't know at this point.

Thirdly, there are monoclonal antibody conjugates. That is a monoclonal antibody linked to a drug. With that, it binds to CD19 or BCMA and gets the drug to the tumor cell. Once there, it can be internalized within the tumor cell, and then, of course, induce cell death.

Those are the 3 things that we have and that's exciting.

More exciting is, we don't really know what's the best sequence, and is one better over the other at this point? The reason why I think it's exciting is because we have a lot more work to come.

Now, in more detail, for example, in non-Hodgkin's lymphoma, diffuse large B cell lymphoma, the standard of care is still treated with chemotherapy—R-CHOP, R-EPOCH, and so on—has in the relapsed setting, a completely new approach now. That would then be either the CAR-T cells, or the BiTES, or antibody conjugates. Loncastuximab, for example, is an antibody that brings a drug to the non-Hodgkin's lymphoma cell, can be internalized, and induce cell death.

The sequence is unknown. There are certain possibilities to give these drugs but what we also don't know, how does this affect, for example, autologous stem cell transplantation, which has been the standard of care for relapsed refractory (R/R) diffuse large B cell lymphoma?

Should the CARs be given before the transplant? Can they be held off until after transplant? Those are questions that we are asking right now as the next generation of clinical trials.

With respect to acute lymphoblastic leukemia, in adults, ALL is a very aggressive disease at a very poor outcome with standard chemotherapy until investigators implemented the administration of even more chemotherapy, which is the pediatric regimen. Which, in the beginning, investigators thought that the adults would not be able to tolerate that high amount of chemotherapy, but they did and the outcome was better.

Now, we have blinatumomab. Blinatumomab is another BiTES, a CD19 conjugate with CD3. We can get this blinatumomab through CD19 to the tumor cell, the CD3 gets attached by the T cell and we have tumor cell lysis specifically targeting the leukemic cell population.

That is very interesting because, now, we have for the first time, a chemotherapy induction therapy regimen that consists of blinatumomab plus a TK inhibitor—such as dasatinib, ponatinib—and we can get patients in a complete remission with a very high rate of minimal residual disease (MRD)-negative situation complete remission. That is completely exciting because the side effects are a lot less. The complete remission rate MRD-negative is even higher than with chemotherapy only. More importantly, if you then follow up with an allogeneic stem cell transplantation, after that you have improved outcome of the allo transplant because the toxicity of this chemotherapy-free regimen is improving the infectious complications rate after transplant. Thus, you have improved outcome of allogeneic transplant.

With respect to acute myeloid leukemia, it is very difficult to treat because the marker that's specific for AML—called CD33, expressed on the leukemic blasts—is also expressed on the normal hematopoietic stem cell.

Therefore, the theory would be if you administer a CAR-T cell against myeloid leukemia, you will not only destroy the leukemic cells but potentially also the healthy hematopoietic stem cell. That's not what you want to do.

It turns out if you eliminate the expression of CD33 on the normal hematopoietic stem cell, the biologic activity is unchanged. That means CD33 is not necessarily needed for the survival of the healthy stem cell. Therefore, if you could silence the expression of CD33 on the myeloid cell, all that's left that's CD33-positive is the leukemic population. Complicated, but possible because now we have what's called CRISPR technology.

This trial has now been FDA approved. What we can do—and I am leading this trial here at Miami Cancer Institute for patients with acute myeloid leukemia—you can select out the healthy stem cell from the donor, send this to the laboratory, silence the CD33 expression, and infuse the CD33-negative stem cells.

Now, they go into the bone marrow, start producing the normal cells, and with that, you have options to treat those cells that are CD33-positive after transplant that are left. What is that? Leukemia cells.

What that means is now you provide a platform to specifically target leukemic cells with gemtuzumab, which is an anti-CD33 antibody, or with a donor-derived CAR-T cell.

Let's move to multiple myeloma, which is also very fast expanding in the approaches. The standard of care and the categorization of MM is very different. You have newly diagnosed myeloma you treat with the standard of care. There are also changes, but then you have relapsed disease. You have options to treat with that. Then, patients relapse again.

All the drugs that are available for the treatment of MM, a standard proteasome inhibitor—such as bortezomib, carfilzomib. Immunomodulators—such as lenalidomide, pomalidomide, and/or daratumumab.

At some point, patients were treated with all of it. They relapsed. All these 3 drug possibilities have been administered and the patient is refractory to treatment. This is then called triple-class refractory MM.

There was nothing a short time ago to treat these patients. The median overall survival (OS) of triple refractory MM is 3.5 months. That's it, 3.5 months. Now, we have the immunoconjugates. Now, we have the CAR-T cells. Now, we have new drugs that were just FDA-approved for the treatment of triple refractory MM.

That goes back to the same principle. We have CAR-T cells for targeting BCMA. We have drug conjugates, and we also have the BiTES that are very close to come out for clinical trials for MM.

All of that, in summary, is exciting.

Obviously, COVID complicated the timely approach of treatment. On the other hand, it should not really because you cannot wait to treat some of the diseases because you are concerned that the patient may be exposed to COVID.

The challenges are there, but with those diseases that are rapidly progressing, there was a very limited time for us to bring the patients in for treatment. We have here very stringent screening criteria for every patient before he or she enters the hospital.

We have visitor restrictions to minimize exposure, but all with the goal to not prevent the individual that needs appropriate treatment to undergo the appropriate treatment.

The answer on the other one you may be interested in is, what's the vaccination status? Does it help to vaccinate patients? The answer is yes. If there is enough time for them prior to treatment, but once they undergo treatment— immunosuppressive therapy, or chemotherapy— they would not necessarily respond appropriately to the vaccination at that time. So, we have to have all the precautions until the patient is through with the treatment and has a normal immune function.

I just came back from my first in-person meeting after 18 months of not being able to travel to international meetings. It was a pan pacific lymphoma conference, which was, by the way, well attended and we were all hungry to get together again and talk to each other.

All of the treatment approaches that I summarized, CAR-T cells, monoclonal antibody conjugates, called the BiTES, bispecific antibodies, are administered in relatively specialized centers.

These treatments are complex and they have side effects that need to be managed by experts that know about how to treat these side effects.

My point is that, therefore, these novel treatment approaches for these diseases are not available equally throughout the nation. More focused in specialized centers that are able to provide this treatment.

If there are providers that are not able to administer these treatments, they should really look for collaborators in their environment or nearby that can help to exchange and help to treat the patients appropriately and then, send back for follow-up care.

That complexity of treatment will increase, particularly if you now have 1 or 2 subsequent treatment approaches after the first completed. Then, you go to move to another monoclonal antibody. That would help if all of the treating physicians have collaborated that provides that care.

I'm excited to announce that our third Miami Cancer Institute symposium of the Americas on immunotherapies for hematologic malignancies will be an in-person meeting in Miami, Florida, Coconut Grove, Ritz Carlton, with specifics covering all of the issues that I just described.

It's always a very exciting event. It will be January 21-22, 2022. I hope that, by then, we will be cleared again and we can have in-person meetings.