Immunotherapy May Be Next Frontier for AML, Says Daver

Naval G. Daver, MD

Immunotherapy offers promise in acute myeloid leukemia (AML), a disease type which has not seen significant progress in many years, said Naval G. Daver, MD, assistant professor, Department of Leukemia, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center.

“AML has been probably one of the most difficult types of leukemia historically to treat. In the last 40 years, no drugs have been approved for AML,” he said. “I think there is a huge need for new treatments. What we are seeing in many hematological malignancies is that there is a role for immunotherapies, just like in solid tumors.”

Nivolumab (Opdivo) is currently being investigated in combination with azacitidine in patients with relapsed AML in a single-center phase IB/II study. To date, 30 patients have received treatment and 22 were evaluable for response. After a median follow-up of 3.6 months, 4 (18%) achieved complete remission (CR)/ complete remission with insufficient count recovery (CRi), 2 (9%) had hematologic improvement (HI) with blast reduction, 5 (23%) had HI only, and 5 (23%) had greater than 50% BM blast reduction only. Six patients had stable disease (n=2) or progression (n=4). Grade III/IV and grade II immune toxicities were observed in 6 (20%) and 5 (17%) patients, respectively.¹

In an interview withTargeted Oncology, Daver, the lead author on the nivolumab/azacitidine study, discusses its findings as well as other promising immunotherapy studies in AML. He also discusses studies specifically looking at immunotherapies in MDS.

TARGETED ONCOLOGY:Where do you see potential for the use of immunotherapies in AML?

Daver:

In hematology, CAR-T cells as well as other immune agents such as lenalidomide (Revlimid) have shown activity. What our effort has been is to identify other checkpoint targetable pathways. As we know, in the immune system there have been a number of activating and inhibiting checkpoints. We have been working to identify which of these play a role in AML. We have found that PD-1 and OX40 seem to be important checkpoints that are upregulated in the AML bone marrow compared to healthy human controls. Now we have a number of trials targeting these immune checkpoints with the idea that if we can unsuppress the T-cells in the bone marrow microenvironment, we’d have a better chance of fighting against leukemia. Some of these trials are showing encouraging results.

TARGETED ONCOLOGY:What trials are currently ongoing looking at immunotherapies in AML?

Daver:

We have a number of trials in AML ongoing right now and these are mainly combinations with a PD-1 inhibitor. Azacytidine with nivolumab is one of the trials where we have accrued a number of patients and we are seeing very encouraging response rates. We presented our initial data at the European Hematology Association meeting in May. What is more interesting is that the responses seem to be much more durable in salvage AML. In salvage AML, the response rate with azacytidine alone is usually 10 to 15% and usually last 4 to 8 months.

We are seeing response rate of 30% or higher and a number of these are durable with a median response duration of greater than 9 to 10 months. This is very exciting, and gives us a hint that these agents have some activity when used in combination.

We are also doing a study with high-dose chemotherapy plus nivolumab in frontline, younger patients with AML. This is to see if we can improve the relapsed-free survival and prevent a relapse in patients who acquire a remission in standard therapy. This is ongoing, and it is too early to know if this going to be beneficial or not. We will need to follow for 2 to 3 years. We also have a study looking at nivolumab maintenance in patients who have completed their AML therapy, whether its high-dose chemotherapy or azacytidine-based therapy.

TARGETED ONCOLOGY:Are there studies looking at the use of immunotherapies in MDS?

Daver:

In MDS we have a number of combination studies using nivolumab plus ipilimumab (Yervoy). We also have a single-agent study of pembrolizumab (Keytruda) in MDS and we are seeing some activity with that, usually with people that failed hypomethylating therapy with MDS. With hypomethylating therapy, the median survival is about 6 to 10 months. We now have a subset of patients due to pembrolizumab who are alive beyond 2 years, which is quite better than the expected outcomes.

In addition to this, we are working closely with the immune platform with James Allison, MD, and Padmanee Sharma, MD, at MD Anderson Cancer Center to do detailed immune assessment by flow cytometry and immunohistochemistry on patients that are going on these trials. So not only do we see good responses, but we are also working to identify certain biomarkers that can help pick out the patients with highest chance of response. We know that this is not working for all of our patients, but it seems to work for about one-third. We need to determine how to select these patients with the highest chance of response so we don’t expose patients that little chance of responding to these therapies.

TARGETED ONCOLOGY:Is there an understanding as to how immunogenic AML is?

Daver:

AML is not considered as immunogenic as melanoma or lung cancer for example, but data has shown that there is actually a good amount of T-cell infiltrate in the AML bone marrow. We did a study in about 80 AML patients; 40 new AML, 40 relapsed AML. What we found is that the T-cells were actually well preserved. In the median total bone marrow cellularity about 15 to 20% were made up of different types of T-cells.

What is more interesting is that the T-cells seem to be activated. If you look at markers like CD25 or CD8, those are actually increased in an AML bone marrow environment as compared to a healthy person, indicating that there is some degree of immune infiltrate. When we looked for specific immune inhibitory markers, we did see that PD-1 was expressed at a higher level on CD4 effectors, CD8, and the Tregs in the ALM patients, as compared to a control group of healthy patients. I think it does have an immune modulation, maybe not as robust as some solid tumors, but for sure one that can be exploited. ​

Reference:

Daver N, Cortes J, Ravandi F, “Phase Ib/Ii Study Of Nivolumab In Combination With 5-Azacytidine (Aza) In Patients (Pts) With Relapsed Acute Myeloid Leukemia (AML)” Abstract release date: May 19, 2016, EHA Learning Center. Daver N. Jun 10, 2016; 133177, Abstracts 2016.