Collaboration Is Key in MDS Research

Rami S. Komrokji, MD

When conducting research on a rare cancer such as myelodysplastic syndrome (MDS), where any one institution may be treating only a small amount of people with the disease, collaboration is key — on both national and international levels.

What new treatments are on the horizon for MDS?

CURE spoke with Rami S. Komrokji, M.D., clinical director of Hematologic Malignancies at Moffitt Cancer Center, about these collaborations as well as some exciting treatment advances that may be coming down the pipeline.In MDS there is an unmet need for treatments. We've made some progress with medications like azacytidine and decitabine. We consider transplant as a curative option for patients with high-risk disease. Those are the options we currently use.

Other than transplant, most of the treatment options are not curative. They work, and the patient can derive benefit in terms of survival and quality of life, but at one point, they stop working. So we are always in need for next treatments. What happened over the last few years is that we started understanding the biology of the disease and finding certain genetic abnormalities that hopefully we can target.

There are several trials with promising medications looking at this concept. So, for example, there is a study that just finished that tests a drug called luspatercept. It's an injection every three weeks for patients with lower-risk MDS who need transfusions on a regular basis. The drug, in the early phases, showed promising results, and now is finishing phase 3. If that study is positive, then this drug could get approved and available for patients with anemia. It seems in certain subsets of patients with MDS, they have certain gene mutations, splicing mutations, like the SF3B1 mutation.

There are other studies. For example, a mutation called IDH2 mutation. There are drugs that can target that mutation that have been tested in leukemias. They are also tested in a subset of MDS patients and are in development. There are new medications, that target somatic mutations, which are common mutations that happen in MDS, we call them splicing mutations. So, there are drugs called splicing inhibitors that are going into early phase testing in MDS.

There is also a subset of MDS patients that have a gene mutation called B53. If it is mutated, patients tend to have more aggressive disease. They are patients who respond early on to therapies but then the disease progresses after that. So, we are trying to have medications that can target that B53 mutation, or at least restore its function to control the aggressiveness of the disease.

What is the MDS Clinical Research Consortium?

There are different new modalities of treatments. Most of them are going after certain molecular targets, which is something new. In the past, most of the studies of MDS would include a heterogeneous group of patients without really knowing their biology. Nowadays the treatments could be based on the underlying biology of the disease, and we hope that some of the studies will lead to the approval of drugs in the near future. The MDS Clinical Research Consortium is a collaborative effort between the Edward P. Evans Foundation for MDS, which generously supports the efforts of the consortium through grants, and the Aplastic Anemia and MDS Foundation, that serves as the coordinator for the consortium — they are our link with the patients. The consortium is a collaboration between six large institutions that see a large volume of MDS, including Moffitt Cancer Center, where I work, the MD Anderson Cancer Center, Cleveland Clinic Taussig Cancer Institute, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, the Dana-Farber Cancer Institute and Weill Medical College of Cornell University.

The idea is to try to get clinical trials available to patients in different areas and be conducted quickly, so if the drug seems promising, we'd be able to push them through development faster. Typically, MDS studies are very difficult to do at a singular-institution level. There are similar consortiums in Europe for MDS, where they conduct studies in collaborative fashions like this.

What are some of the key accomplishments of the Consortium so far?

Through the consortium, we have a large database that are seen at those institutions, so we've been able to collaborate with data and answer some questions that could not be looked at in clinical trials. For example, the response criteria for using clinical trials — are they valid or not? What happens to patients when they stop responding? These are important questions that cannot be answered in clinical studies, but when you have a large dataset of patients, then you can basically answer those questions. We've conducted a few studies, so far, through the consortium, including a study in CML with a drug called Jakafi (ruxolitinib). We have an important study in lower-risk MDS patients, where we are looking at different dosages of azacytidine, decitabine, comparing them to the classical five days of azacytidine, and asking a very important question: if we treat patients early versus waiting in the lower-risk population, does it make a difference? We are also bringing the first study with a drug called APR-246 to target that subset of patients who have the P53 mutation.

What are some of the international collaborative efforts in MDS?

Those are all studies ongoing or planned in the MDS Consortium.With the works that had been done in the five years, the consortium had emerged to be the representative for the U.S. and we've collaborated with several colleagues in Europe and other areas in database projects, where we share patients' data. We look at predictive responses, molecular models and risk stratification models.

But the next step is really trying to conduct trials, again, in a similar fashion. For example, we are starting to collaborate with the French MDS group, with the trial I mentioned with the APR-246. It's going to be conducted as a study both through the MDS Consortium in the United States, and in France through the French MDS Consortium. Then we'll look at the data and decide how to move forward. This is a new thing that we're trying, that we may start thinking of designing those big trials, where some arms may be conducted in Europe, some in the United States, some elsewhere. The winner -- or the drug that looks more promising -- is the one that is going to move further down the line.

We also sometimes involve international groups in advisory roles. They'll give us some advice on how to guide our work. We do the same for their groups as well.