Making Progress for Myelodysplastic Syndrome

Myelodysplastic syndromes (MDS) are rare, which can make them difficult to study. The biggest challenge is finding enough patients to enroll in clinical trials that could help to advance treatment. But the Aplastic Anemia and Myelodysplastic Syndrome International Foundation (AAMDSIF), a nonprofit organization, wants to change this by providing patients and patient data to support research. One of its efforts in this area is the MDS Clinical Research Consortium.

What progress has been made in the field of MDS in the last few years?

In an interview with CURE, Rami Komrokji, M.D., a hematologist at Moffitt Cancer Center in Tampa, Florida, discusses the advances that have been made in MDS in the past few years, as well as the MDS Clinical Research Consortium and its importance.There have been several discoveries that led to better understanding of the disease and its biology. Hopefully this can translate into improving patient care and finding new treatments.

The use of molecular testing can help us in deciding, or tailoring, the treatment. There are also some new treatments on the horizon based on some of the molecular targets of testing that are being conducted.

Advances have also been made in the biology of the disease and our understanding of MDS. We've made huge progress in understanding what occurs in MDS, what are the gene mutations that are acquired in this disease, the role of the bone marrow microenvironment and inflammation in developing MDS.

What new treatments are in this area?

Also, risk stratification for patients with MDS is a crucial step for patient management. How do we risk stratify the disease? Once we establish a diagnosis for patients, we try to gauge the risk of the disease because we tailor therapy based on that, such as recommending allogeneic stem cell transplant for patients. An accurate risk assessment for the disease or certification is important for the patient and their families. It gives them prognostic information. It's also important for the physicians because we decide on our therapies based on the disease risk.In MDS, there is an unmet need for patient treatments. We've made some progress with current medications like Vidaza (azacitidine), Dacogen (decitabine), Revlimid (lenalidomide). 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 patients can derive benefit in terms of survival and quality of life, but at some point they stop working. We always are in a need for next treatments.

Over the last few years, we started to understand more about the biology of the disease and found certain genetic abnormalities that hopefully we can target. There are several trials with promising medications looking at this concept.

For example, there is a study that just finished, called the MEDALIST study, which tests a drug called luspatercept, which is injected every three weeks for patients with lower-risk MDS, but need transfusions on a regular basis. In the early phases, phase 1 and 2, this drug showed promising results and is now finishing the phase 3 study. If that study is positive, then this drug could be approved and available for patients. Luspatercept works in certain subsets of patients with MDS, particularly those who have ring sideroblasts or a certain gene splicing mutations, SF3B1 mutation.

Other studies are testing drugs that can target the IDH2 mutation. They have been tested in leukemias and in subsets of patients with MDS.

A lot of the new medications have the same theme, targeting those somatic mutations that are common in MDS. We call them splicing mutations. There are drugs that are known as splicing inhibitors that are going into the early phases of testing in MDS.

There is also a subset of patients with MDS who have a gene mutation called p53. This is a protein or the brake on the cycle. If it's abnormal or mutated, patients tend to have more aggressive disease. With this mutation patients usually respond to available therapies early on, but then the disease progresses after that. We are trying to also develop medications that target that p53 mutation or at least restore its function to control the aggressiveness of the disease.

Can you talk about the MDS Clinical Research Consortium?

There are different, new modalities of treatment. Most of them have the theme that they 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. Now, the treatments could be based on that underlying biology for the disease and we hope that some of those studies will lead to approvals of drugs in the near future.The MDS Clinical Research Consortium is supported by the Evans Foundation for MDS with a generous grant. The AAMDSIF serves as the coordinator for the consortium. The foundation is our link with patients.

The consortium is a collaboration between six large institutions that see a high volume of MDS cases, including Moffitt Cancer Center, MD Anderson Cancer Center, Cleveland Clinic Cancer Institute, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Dana-Farber Cancer Institute and Weill Medical College of Cornell University.

The idea is to try to get clinical trials available for patients in different areas and get the trials conducted quickly. That way, if the drug seems promising, we'll be able to push them through development in a faster way.

Typically, MDS studies are very difficult to do at the single-institution level. There are similar consortiums in Europe for MDS where they conduct studies in collaborative fashions like this. This is really the main idea of the consortium, to try to conduct clinical trials of agents that are promising early on, during phase 1/2 development, to be able to get the drugs for patients in phase 3 in a faster way.

Also, through the consortium, we have large datasets of patients, databases that are seen at those institutions so we've been able to collaborate on those data and answer some questions that could not be looked at in clinical trials. For example, the response criteria we're using for clinical trials, are they valid? What happens to patients when they stop responding to Vidaza? Some important questions that cannot be answered in clinical studies, but when you have large datasets of patients, then you can answer those questions.

We've conducted a few studies so far through the consortium, including the first study in chronic myelomonocytic leukemia (CMML) with the drug called Jakafi (ruxolitinib). Jakafi is a drug approved for myelofibrosis, however, through some work in the consortium, we identified that patients with CMML may be sensitive to the treatment because in CMML they have oversensitivity to a growth factor called GM-CSF, where Jakafi will target. We conducted the first phase of the first study particularly in CMML and the first round of results looked promising. We finished a phase 1/2 study in less than two years, which typically would have taken a single institution six or seven years to finish in this subset of the disease.

We have an important study looking at early treatment versus waiting in patients with lower-risk MDS, looking at different dosing of Vidaza and then randomizing them to Dacogen for three days or Vidaza for five days, which is the standard for lower risk. That study will answer two important questions: Is there benefit of early treatment? And, which is the best schedule for high-proliferating agents?

Why is it important to collaborate among institutions, both nationally and internationally?

We are also bringing the first study with a drug called APR-246 to target that subset of patients that have the p53 mutation.The most important thing is being able to conduct clinical trials in a fast way that can lead to patients getting these medications sooner. Typically, the drug approval process takes many years. The first step of conducting phase 1/2 studies is slow and a single institution, no matter how large the volume of patients they see is, may take two years to run the first phase 1 or phase 2 of the study. A collaboration like this can get some of those studies done in six months, so we know if the drug is promising and we can move it further. We hope with this collaboration we'll be able to shorten the time it takes to get a drug from the early testing to the benefit of patients.

Also, sharing the patient information data gives us the power. Let's say we see 1,000 patients. But, if we collaborate with five or six centers, we'll have data on 6,000 or 7,000 patients, which becomes much more powerful in answering certain questions that we cannot answer in clinical trials.