Today we are discussing immunotherapy approaches for patients with acute myeloid leukemia (AML) with Dr. Naval Daver, MD, associate professor of leukemia at the MD Anderson Cancer Center in Houston. Daver leads several trials for patients with AML that are investigating the potential role of various immunotherapy approaches to better the outcomes of patients with this hematological malignancy.
—Interviewed by Anna Azvolinsky
Cancer Network: First, can you talk about the rationale for using immunotherapy to treat AML? Are there specific characteristics of AML that make it amenable to immunotherapy approaches?
Dr. Daver: Thank you for having me. AML is one of the diseases that is one of the first conditions for which we used immunotherapy in the form of allogeneic stem cell transplant. For almost four decades we have been using this as a modality to replace the patient’s immune system with a donor immune system, and we have seen that it is quite an effective approach for treating AML.
In addition, in the last 4 to 5 years, myself along with colleagues in the immunotherapy group at MD Anderson including Dr. Padmee Sharma and Jim Allison, have been interrogating acute myeloid leukemia patients’ blood and bone marrow samples to try to understand the nature of T-cells in AML. Our data will be published very shortly in an upcoming paper in the journal Cancer, and what we found when we looked at more than 100 patients with AML is that in fact, the T-cell population, both in the absolute numbers and the percentage, was quite preserved compared to healthy donors who had no disease. We did see that there was an upregulation of multiple different immune checkpoint co-receptors, the most striking being PD-1 and OX40.
Upregulation was highest in patients with relapsed AML compared to patients with new AML, but both sets of patients had a higher expression of PD1 and OX40 compared to healthy donors. This suggested that there is a favorable T-cell profile as well as expression of what we call inhibitory immune checkpoint receptors in the setting of AML, which may be one of the ways that AML tries to escape from being killed by the host defense immune system. We could potentially activate these T-cells by blocking the inhibitory immune checkpoint receptors allowing them to fight the leukemia.
This form of immunotherapy, what we call T-cell-specific immunotherapy, such as immune checkpoint antibodies, bi-specific antibodies, CAR T-cells, enhance the patient’s own immune system.
There is another type of immunotherapy that is frequently used in patients with AML and that is called antibody-drug conjugates. This is an approach where we target leukemia-specific antigens and the most common ones have been CD33, CD133 and we now have newer ones like CLL1 (CLEC12a). We usually develop an antibody that also carries a toxic payload that is bacterial or chemical and these are delivered directly to the leukemia cells. It is important to know that there is a difference, when we talk about immunotherapy, namely T-cell based and the antibody-based immunotherapy. But both types seem to have efficacy, pre-clinical and clinical in AML.
Cancer Network: On the T-cell based immunotherapy, you and your colleagues recently published positive results of a study at MD Anderson that tested the combination of azacitidine and nivolumab in patients with relapsed or refractory AML. Can you tell us about this trial and the results? Is this among the first positive immunotherapy clinical trials in AML?
Dr. Daver: We developed this trial a few years ago in a large collaboration that we had with BMS [Bristol Myers Squibb] to evaluate immunotherapies in different types of leukemia. The conception of this trial actually came from some pre-clinical data that our colleagues at MD Anderson had generated that showed that azacitidine, which we have used for many years both in frontline AML and in relapsed AML and in MDS [myelodysplastic syndromes], upregulated the expression of PD1 and PDL1 on the surface of T-cells in patients with MDS and in those with AML. It was thought that we could use azacitidine as an immune-modulator in this situation and combine it with the anti-PD1 antibody and the one we used in this study is nivolumab.
The study was designed as most initial, first-in-human trials in any given malignancy are designed, to look at relapsed, AML patients and the idea is that if we found that the combination was safe and effective, giving us better efficacy than other contemporary azacitidine-based combination therapies or azacitidine single agent, then we would move it to the frontline.
We enrolled a total of 70 relapsed, AML patients and we allowed for both de novo and secondary AML and patients with different types of cytogenetics. The median age was 69. This is because we usually favor hypomethylating-based treatment approaches, whether in the frontline or relapsed setting, in elderly patients.
The study allowed patients of any age, but with younger patients we tend to try more intensive therapies both in the frontline and in relapse settings. We had one-third of patients who had adverse cytogenetics and about 22% of them had TP53 mutations. The primary endpoint of this study was to assess the response rate, which was defined by the European Leukemia Net (ELN) criteria to include complete remission (CR), complete remission with incomplete blood count recovery (CRi), as well as partial responses and hematological improvement.
The overall response that we saw was 34% in all relapsed AML patients. What was interesting was that the CR/CRi rate was 23%, but we had a number of non-traditional CR/CRi responses including hematological improvements and stable disease. These are not typically responses that we consider when we use high-dose, intensive cytotoxic therapies in AML, but these are responses that we are seeing can be quite important for quality of life, survival, transfusion-independence in elderly AML patients treated with azacitidine or with neither treatments such as IDH inhibitors.
With immunotherapy for solid tumors, we know that a number of responses could occur in the form of stable disease and that partial responses can last for many years. We are collecting these data and we showed that we had about 10%–12% additional stable disease responses in patients lasting for more than one year, in addition to the 34% response rate.
This is one of the first, larger studies using an immune checkpoint specific approach in AML showing that you can get an encouraging response rate in relapsed AML. To assess how these study results compared to what we were doing at MD Anderson with other azacitidine-based regimens, we developed a rigorous historical control that looked a 10 different trials of azacitidine or azacitidine combinations that we have done in the last 10 years.
We saw that this new combination regimen had better response rates and in fact, better survival, than all of those other combinations that we had done previously, suggesting that there is something specifically beneficial with this combination.
At the end of the day, the most important thing that we found was that it was specific subsets that seemed to have what we would consider the most clinically important benefit. Thirty-three percent is a reasonable response rate and the overall survival was 6 to 7 months, but that is not really a home run. What we also saw was that in salvage-1 patients who made up half of the study, we had an overall survival of almost 11 months, which is double the overall survival that we see with azacitidine combinations or azacitidine alone in salvage-1.
When we assessed biomarkers, we found clear biomarkers in the bone marrow or blood that could help select patients. For example, we found that pre-treatment CD3 levels in the bone marrow could predict for a higher response rate. Those patients who had more than 13% infiltrating CD3 in their bone marrow had a response rate of almost 56%, compared to those who had lower CD3 in their bone marrow initially, where the response rate was 23%.
We are thinking that the way these drugs need to be developed, which is already what is being done for solid tumors, is to use biomarkers to select the patients who are most likely to respond to these agents rather than exposing larger number of patients to see a benefit in only a small proportion. We think that if we use CD3 as a selection biomarker, which is a relatively simple assay that can be done using flow cytometry or immunohistochemistry, then we could actually have response rates of 50%–60%. So, we are basically trying to develop this combination therapy just like FLT3-mutation inhibitors and IDH inhibitors.
Cancer Network: You’re also leading and taking part in several other immunotherapy AML trials, can you tell us about one or two of those?
Dr. Daver: We are conducting a number of different immune checkpoint based trials. In MDS we have a parallel study to the AML trial that was published in Cancer Discovery going on, looking at combination of azacitidine plus nivolumab. We're also looking at azacitidine with the anti-CTLA-4 antibody immune checkpoint inhibitor, ipilimumab in both frontline, high-risk MDS patients with high blasts and in MDS patients who have failed hypomethylating agents, azacitidine and decitabine. We presented this data last year as an oral abstract at the American Society of Hematology (ASH).
What we are seeing overall is that in the frontline setting, the combination of azacitidine with ipilimumab showed very encouraging response rates and survival, so we are expanding that cohort. Even in patients who have failed azacitidine, decitabine, which are the most difficult group of hematological malignancy patients who have dismal survival, we see that azacitidine with ipilimumab is showing us some interesting activity with high response rates of about 30%–40% as well as improved survival.
We think that in MDS, there may be a role for ipilimumab, which seems to have both single agent as well as combination activity with azacitidine. Learning from this experience, we are also going to be evaluating ipilimumab in AML. We have an ongoing study that is combining azacitidine with nivolumab and now adding to that ipilimumab at a low dose of 1 mg/kg, which is one-third of the standard dose and given every 6 weeks.
Just as has been seen in solid tumors where the combination of these two immune checkpoint inhibitors usually doubled or tripled response rates, we are hoping that this combination will further improve response rates and may even work in patients who have lower bone marrow CD3 infiltration and overcome what we consider the negative biomarker.
There are also a number of other phase II studies with other immune checkpoint inhibitors such as pembrolizumab, an anti-PD1 inhibitor, pidilizumab, and durvalumab, most in combination with azacitidine that we are also studying. One approach that I think will be very interesting, [which was] first shown by our colleagues at the Dana Farber Cancer Institute, is using an immune checkpoint inhibitor after a stem cell transplant. It was shown that this is quite an efficacious approach in patients who have relapsed AML post-transplant where single agent ipilimumab showed complete remission in 5 of 12 patients, including skin and lymph node clearance of disease.
So, we are looking at this combination of ipilimumab plus nivolumab in patients who have either relapsed or have high-risk features before or after transplant including adverse cytogenetics, TP53 mutation, MRD [minimal residual disease] positivity and we believe that in the setting of a transplant, enhancing immune surveillance with these drugs would potentially improve the relapse-free and overall survival of these high-risk patients who often do poorly even with transplant if you give some form of maintenance therapy.
Cancer Network: Are there other important immunotherapy modalities that are now being tested for AML patients that we haven’t discussed yet?
Dr. Daver: There are a number of other immunotherapy modalities that have been gaining traction in the last 3 to 4 years. I think we are seeing what was seen with solid tumors a few years ago, where initially the targeted approaches took precedence and these were developed and became mainstream but then quickly, there was a large onslaught of immunotherapy approaches that became a major part of therapy.
The other approaches that I think that are going to be important in hematological malignancies are the monoclonal antibodies. There will be updates on trials of monoclonal antibodies targeting CD33, as well as a CD123 antibody that we are working on at MD Anderson. Both of these are antibody drug conjugates so they carry a potent toxin on the antibody and both of these have been shown single agent complete responses in patients with AML who are relapsed after failing standard therapy. We believe that when we combine these antibodies with azacitidine or with venetoclax or with other therapies, we could enhance their activity even more.
In ALL, we have the FDA-approved one, blinatumomab, which links to CD3 on T-cells and the CD19 antigen on the blast cell, and by doing that, brings the T cell in close proximity to the ALL blast cell resulting in T-cell mediated death of the blasts. Based on this concept, many companies, 2 to 3 years ago, started developing bispecific antibodies, including Amgen with AMG330 and Xmab with Xmab CD3-CD133 and MacroGenics also with a CD3-CD133 antibody. We are seeing with these agents, that they do have single agent activity in the relapsed AML setting.
The response rates have been lower than what we have seen with blinatumomab in ALL patients, and the responses do seem to be best in patients with low burden disease so we believe that these bispecific antibodies may actually play a role in low burden disease or minimal residual disease, which is also where they happen to work best in ALL patients.
Lastly, there is early development but not yet clear or large datasets of CAR T-cells in AML. In ALL and lymphoma, we have good data with CAR T-cells with high response rates. There are some early signals including a City of Hope study that showed that you could get responses in multiply relapsed AML with CD123 CAR T-cell and there are updates at this past ASH meeting, but I think the CAR T-cell therapy is about 4 to 5 years away from being mainstream and it’s more likely that the immune checkpoint inhibitors and the bispecific antibodies and monoclonals could be and commercialized in the early future for AML.
Cancer Network: Thank you so much for joining us today Dr. Daver.