Exploring Unanswered Questions in Hematologic Malignancies

While exciting advances have led to chimeric antigen receptor (CAR) T-cell therapy and immune checkpoint inhibitors entering the treatment landscape for hematologic malignancies, there are still plenty of questions that remain unanswered, said Leo I. Gordon, M.D.

“The question is, ‘What's going to be the role of these checkpoint inhibitors when you try to combine them with more standard treatments?’” said Gordon. “How do you combine what we know works with one of these drugs that may or may not work [with another]? There are some data suggesting that there is some added toxicity if you give a checkpoint inhibitor and then follow with allogeneic stem cell transplant.”

There have been a handful of recent FDA approvals and encouraging clinical trial results across the field of hematologic cancers. What is most notable to mention?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Gordon, a professor of medicine at Feinberg School of Medicine, Northwestern University, and chair of the meeting, discussed promising advances and lingering challenges with novel treatments for patients with hematologic malignancies.In the beginning [of the conference], Dr Olga Frankfurt spoke about acute myeloid leukemia (AML). The highlight there is better understanding of the disease and better understanding of the molecular biology. The big question for AML is, “When will that translate into better outcomes?” We've been struggling with that for years, but Dr Frankfurt had some exciting data. She also spoke about novel clinical trials that are based upon some of the molecular defects that have now been uncovered. We're beginning to make progress in AML.

Myeloma is an area where there have been major advances over the years and marked improvement in outcomes in progression-free survival. There was a period of time when some of the newer drugs, newer approaches and novel treatments were thought to perhaps be a replacement for stem cell transplant. However, recent large clinical trials have shown that we're not quite there yet.

We heard from Dr Jayesh Mehta that progress has been made. There's a good look to the future, but we're still relying on at least autologous stem cell transplant and maybe allogeneic stem cell transplant for this disease.

We heard a few words about something exciting in myeloma, and we talked about this when we got to lymphoma. That is the use of CAR T cells. There are some intriguing data from China suggesting very high response rates in patients with myeloma who are treated with CAR T cells, so more work needs to be done in that area—but we're making good progress.

The second half of the sessions started with Dr Brady Stein, who is an associate professor and is in charge of myeloproliferative neoplasms (MPNs) at Northwestern University. He sees people with MPNs, such as polycythemia vera and essential thrombocythemia. There have been major advances in those areas, but also a lot of confusion and different opinions about how to manage these, and very little in the way of guidelines, which we need.

He introduced some novel guidelines that have been put forth through the National Comprehensive Cancer Network and spoke about some preclinical data—data in the laboratory on aurora kinase inhibitors that may have some clinical impact very soon. There are some novel clinical trials that are emerging in MPNs, so we need a structure around those diseases.

Dr Barbara Pro, a professor of medicine in our group interested in malignant lymphomas, has a special interest in T-cell lymphomas. Those are rarer and more difficult to treat. She put together an outline of the T-cell lymphomas that highlighted some differences among them and some novel approaches to treatment. She talked about some of the clinical trials that are ongoing in that area.

Dr Jane Winter spoke about Hodgkin lymphoma. You might say, "What's to talk about with Hodgkin lymphoma? We're doing great." We're doing great in a majority of patients, but we're not doing great in all patients. There are some interesting data that suggest that the immune system may play an important role in Hodgkin lymphoma and the use of checkpoint inhibitors. These novel agents take the brakes off our own immune system in order to let our immune system attack the disease.

She discussed some novel clinical trials in two areas. One is in patients with relapsed/refractory Hodgkin lymphoma who are on their way to transplant. She talked about a trial utilizing the standard second-line treatment prior to transplant—which is ICE [ifosfamide, carboplatin and etoposide] chemotherapy—but adding the checkpoint inhibitor Keytruda (pembrolizumab) to ICE. We just started a clinical trial with that and we discussed the rationale for that. We've also been using the ABVD [Adriamycin, bleomycin, vinblastine, dacarbazine] chemotherapy regimen for years.

We have done trials comparing that with other regimens and ABVD remains the standard. However, a thorn in the side of ABVD and patients taking it has been the drug bleomycin, which causes pulmonary toxicity, especially in patients who are a little bit older with a smoking history. The question is, “Can we eliminate bleomycin and what would be the replacement?” The replacement might be Keytruda or another checkpoint inhibitor, so now we've initiated a trial that Dr Winter is leading to use Keytruda plus AVD—eliminating the bleomycin. These are novel ideas using some of the basic science observations over the past 10 to 15 years. It's going to be interesting to hear about that.

Finally, staying with the theme of the immune system, Dr Reem Karmali, who is a new assistant professor in our group, spoke about CAR T cells once again—but this time for diffuse large B-cell lymphoma (DLBCL). There are very exciting data that we're seeing at our institution, [which has treated about] 15 patients so far in a clinical trial.

There are waiting lists for this treatment that, at least at our institution, extending out into January or February. We know that in patients with relapsed or refractory DLBCL, the standard of care has been either an autologous stem cell transplant using patients' own cells or an allogeneic stem cell transplant using a donor’s cell. We know that the results are always a little bit better if we use the donor’s. If we use an allogeneic transplant, we are limited by the toxicity. The question that arises here is, “Can we find a way to make our own T cells attack the lymphoma and spare ourselves the risk, consequences, and toxicity of graft-versus-host disease?”

There have been two recent FDA approvals with CAR T-cell therapy. What are the biggest questions we have right now with these treatments?

Based on work that started in Israel many years ago, carried on by Dr Carl H. June and many other investigators around the world, we now have the ability to take our own T cells and, using a lentivirus gene, insert it into those T cells and give it back to the patient. These cells are now revitalized, active, killer T cells, which now recognize the lymphoma as a foreign entity. The concept is a good one. We're still working out the details of the toxicity. There are still concerns, but the clinical trials that are ongoing around the country are exciting.There are probably three things that are of concern. I'll start with the most important one. Does it work? Are we going to turn around the way we treat DLBCL? Ultimately, once we identify the target, you can theoretically treat almost any malignancy if the target is there. As it always is in cancer research, the [non-Hodgkin] lymphomas and Hodgkin lymphoma tend to be the leaders because we can study the biology a little bit better and we can gain some ground there.

Does it work? Can we replace aggressive chemotherapy, autologous or allogeneic stem cell transplant with CAR T cells? Certainly, the preliminary data suggest that it works in a significant proportion of patients, maybe more than a 50 percent complete remission rate and maybe around 40 percent to 50 percent of responses that are lasting six months or longer. This is in a very heavily treated group of patients.

If it does work, is the toxicity manageable? Is it worth it? Is there mortality? We know that in the acute lymphoblastic leukemia (ALL) study in children — one of the early ALL studies, which was closed — there were four fatal brain edema deaths that were related to the treatment. There are neurologic toxicity and blood pressure issues that occur as a result of CAR T-cell therapy. We have to learn how to manipulate the cells to make them safer and what kind of pre-infusion or lymphodepleting therapy we should give to balance the rate of growth of the CAR T cells and the suppression of our own immune system. That has got to be worked out.

Then, if we find that it works and it is not too toxic, great. Then, the big question is, “What does it cost?” At the moment, we are hearing that it's going to be somewhere between $400,000 and $600,000, which is probably legitimate in terms of the right number. Whether it's legitimate in terms of the cost I don’t know. How are we going to afford this in our healthcare system? How are payers going to respond? Will the cost eventually go down?

Will we see more checkpoint inhibitors, such as Keytruda and Opdivo (nivolumab), playing big roles across malignancies?

A lot of the initial cost is related to recouping some of the investment that's been made. We know that Gilead Sciences bought Kite Pharma, which is one of the leaders in this, for almost $12 billion. There's certainly a partnership between Celgene and Juno Therapeutics and the investors want to make back their money. There's a high cost initially, but this is not sustainable—especially if this technology is used across a wider frame. If it's used in myeloma, chronic lymphocytic leukemia, and in some solid tumors, how are we going to afford this? We should answer the first two questions first and the third question then becomes, perhaps, a stumbling block. I hope not.Well, I think so. We did one of the first trials in DLBCL in patients who already had a transplant. We had an international trial of 72 patients who received pidilizumab, which is probably one of the first checkpoint inhibitors. It turns out it may not work like a checkpoint inhibitor, so it's in the background now. However, we certainly saw very little toxicity with that drug.

There's a trial coming up…called the PLATFORM study, which is going to be combining the…checkpoint inhibitor Imfinzi (durvalumab) with CAR T cells in patients with DLBCL. It certainly makes sense that you begin to combine the checkpoint inhibitors with CAR T cells; however, the safety issues, how to work it, what the dose is, and what the sequencing should be still needs to be worked out. That's going to be the future of some of those trials. There's a place [for it], but we must be careful about integrating it into existing therapies.