Allie Casey

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?

, 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.

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 

 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.

Articles

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.

Making Progress for Myelodysplastic Syndrome

It is difficult for advances to be made in rare cancers because there are fewer patients. This makes it more challenging to conduct clinical trials for these diseases. Rare ovarian cancers are no exception to this.

Can you tell me a little about the rare types of ovarian cancer and what is important to know about them?

, professor of Gynecologic Oncology at the University of Texas MD Anderson Cancer Center discusses the treatments available for some of these rare types, as well as what the future could look like.

There are several types of ovarian cancer: malignant ovarian germ cell tumors, sex cord stromal tumors and then the rare types of epithelial tumors: ovarian clear cell carcinoma, low-grade serous carcinoma and mucinous epithelial ovarian cancer.

There are challenges and barriers to studying rare ovarian cancer. It's very difficult to conduct clinical trials because there are fewer patients. It sometimes can take a long time to accrue patients on a clinical trial. There is also not a lot of federal funding for trials of rare cancers in general. The pharmaceutical companies are not that interested, for obvious reasons related to revenue. So, there are many challenges in trying to make advances in the study of ovarian cancers that are rare.

What are the current treatment options for a patient with one of these rare ovarian cancers?

Also, some of these rare ovarian cancers have a number of genetic or genomic abnormalities. Unlike high-grade serous carcinoma which is the most common type, rare cancers have many abnormalities that are difficult to treat. These types have fairly specific genomic aberrations that can be, in some cases, treated with targeted agents. I think that the emphasis over the past few years has been, and in the next decade, will be on targeted agents, combinations of targeted agents, and, in some of these rare tumors, hormonal therapies. For instance, for granulosa cell tumors, a type of sex cord stromal tumor, as well as low-grade serous cancers, these are relevant. There are many different targeted treatments and new treatments that we'd like to study, but again it gets back to the challenges that we have in conducting clinical trials.

It varies. For low-grade serous carcinoma, there have been first generation trials of MEK inhibitors. MEK is a gene that occurs in the MAP kinase pathway and we know that there are mutations of KRAS and BRAF that occur in that pathway. There have been a number of trials of these targeted agents, these MEK inhibitors. One has been completed, three have been done in the second-generation, the last of them is finishing accrual later this year. That's one major area of research.

Another treatment option for low-grade serous carcinoma is hormonal therapies. We know that low-grade serous carcinoma has many features in common with ER+ breast cancer. We are studying aromatase inhibitors in upcoming trials in the neoadjuvant setting, in the recurrent setting, as well as in the frontline setting for maintenance therapy.

Clear cell cancer is another area where there are a number of aberrations in the pathways. There's a great opportunity to study targeted agents in that area. There have been some trials and there will be future trials as well.

Do these rare types of ovarian cancers have symptoms or effects on the body that differ from the most common type?

The other thing I would mention for clear cell cancer is immune checkpoint-inhibitor treatments. There have been some very interesting responses in clear cell cancers with immune checkpoint drugs. And there will be future trials, which are currently in development, focused on the checkpoint inhibitors.

No. Most of these rare ovarian cancers have symptoms that are not really differentiated from those of women who have the most common type, which is high-grade serous. Abdominal pain, bloating, those kinds of symptoms occur at the time of diagnosis.

Some of the patients with certain types live a very long time, because the diseases are indolent. That would be true for granulosa cell tumors as well as low-grade serous carcinomas. These patients may experience side-effects from treatment. It is all related to the quality of life that they may have. Not only from cancer, but from the many treatments. 

Sixteen is a very young age to encounter cancer. Can you discuss some of the specific concerns for those patients?

One of the areas where we're really reducing the amount of treatment is a success story with malignant ovarian germ cell tumors. The average age at diagnosis is about 16 and up. Until the 1970s, most girls and women who had this type died of their disease. We had no good therapy. The introduction of Platinol (cisplatin) in the late 1970s completely transformed that area. Now the cure rate is 95 percent. However, these girls and women experience some of the side-effects of chemotherapy. Now, there's a big move, and a recent clinical trial, that focuses on reduction in the surgical treatment of germ cell tumors, as well as trying to completely get rid of chemotherapy in some patients who have early-stage disease.

Late-effects and fertility are the two major concerns. Fortunately, for instance with germ-cell tumors and granulosa cell tumors, they are almost always unilateral, they only affect one ovary. In almost all of these patients, you can preserve a normal contralateral ovary and uterus, so you preserve their fertility. However, if the patients does receive chemotherapy, there's about a 15 percent rate, or frequency, of acute ovarian failure, making them infertile.

A big concern for many patients with ovarian cancer is the high rate of recurrence. Does that apply to these rare types?

Most young patients are able to preserve their fertility. We’ve conducted studies to show that many of these young patients can go on to have normal pregnancies and normal offspring. That's good news. Once we start to reduce the amount of chemotherapy we're using in these patients, that will be even better, because then we won't have to face that 15 percent frequency of acute ovarian failure.

It is, unfortunately. All three of the rare epithelial types: clear cell, mucinous and low-grade serous are not very sensitive to the standard chemotherapy, which is typically Abraxane (paclitaxel) and Paraplatin (carboplatin). The recurrence rate in all three of those tumors are high, in the 70 percent range.

Fortunately, low-grade serous carcinoma, despite its insensitive to chemotherapy, is an indolent disease, as is granulosa cell. Patients can still live for many years. Clear cell and mucinous are fairly aggressive types. When they recur, they're very difficult to treat.

What would you consider to be key to advancing research on rare types of ovarian cancer?

We need a grass-roots advocacy movement to lobby not only Congress but the National Cancer Institute to put more emphasis on rare cancers, specifically rare ovarian cancers. The only way we're going to advance treatments is to conduct clinical trials that prove that one treatment is better than the other. We really need the help of our advocates in that fight.

CURE spoke with an expert on what is getting in the way of advancing treatment for rare types of ovarian cancer.

Roadblocks to Advancing Treatment of Rare Ovarian Cancers

While covering softball these past months, it was hard for Holly Rowe, ESPN sports reporter, to keep quiet. “I just want to run through the stands and shake everyone by the shoulders,” she said in an interview with CURE®. “They're out there just baking their skin.” This urge is personal for Rowe, who was diagnosed with desmoplastic melanoma, a rare, invasive form of the disease. It all started with what Rowe called “an ugly-looking mole” she hoped to get removed. When the doctor called to tell her it was cancer, Rowe wasn’t devastated. “You hear the ‘C-word’ and you freak. But I just thought it was something they'll cut off my skin,” she explains. “I didn't think it was that big of a deal.” Her opinion has since changed.

Since the initial surgery in 2016, Rowe has had two separate recurrences. “Melanoma is a traveler,” she says. “Once it goes inside your body, it’s not just something on your skin.” Rowe considers this a big misconception about the disease she has found it difficult to come to terms with.

“It's very frightening and very upsetting, because you really feel powerless, like you have no control over where it goes,” Rowe says. “I try to be positive. I try to do all these healthy things, and this pesky cancer does not obey you. And that's what I'm learning and why I’m wanting to get the word out.”

Rowe knows that some people need to be told about the risks, because she herself didn’t know them. “If somebody had told me 20 years ago, ‘Holly, if you cover up now, you won’t have to go through this,’ I would have listened,” she says. Now, Rowe tries to be that voice for others. “I’ve become that crazy lady,” she says, “that is going to go up to strangers to say, 'Please cover your skin.'” Being considered “crazy” doesn’t bother her, though. “If there's one person that won't get cancer because they listened to me and learned from this experience, that's worth everything to me,” she says.

Rowe doesn’t limit herself to just pleading with strangers to protect their skin. On April 26, she was mistress of ceremonies for the Melanoma Research Foundation’s (MRF) Sixth Annual Wings of Hope for Melanoma Gala, in Denver, Colorado. Upon learning about the MRF, she reached out and asked what she could do to help. “It was one volunteer opportunity I could do to give back,” Rowe says. “I want to feel helpful in this battle, because you feel very helpless as a patient. Things are happening to you that you have no control over. Giving back, and helping to spread the word and fundraise, empowers me and makes me feel I’m doing something in this fight.”  

For Rowe, fundraising for research is a vital issue. “The immunotherapy that I’m currently on,” she says, “didn’t exist four or five years ago. The research and the development for melanoma treatment is on the cutting edge right now. Organizations like MRF are crucial.”

Moving forward, Rowe is hopeful that the issue of prevention will take a more prominent role. “My eyes were closed to it until I was a patient in this community. Our efforts have got to be stronger on prevention,” she suggests.

She also cited clinical trials — including the one she’s enrolled in &mdash; as a path to the future. “I hope whatever we find from my treatment is going to help others,” she says. Finally, Rowe is focused on promoting early detection, because it can be easy for people to dismiss a melanoma on their skin as nothing. “My new mantra,” she says, “is ‘When in doubt, get it checked out.’ If I had gone sooner, I think I would be in a better situation.”

Staying busy has helped Rowe through her own cancer. “Keep living. That sounds so trite, like a T-shirt slogan,” she admits. “But it’s really an everyday thing. I wake up and I think: What can I do today that I’m going to enjoy?”

Finding happiness and being positive can be its own battle. Rowe recognizes this, saying, “There are some down days. And it’s OK to need help. It doesn’t make you weak to ask for help, or to tell people that you’re tired. I want people to feel loved and supported no matter what their mindset is.”

Rowe said she has felt incredibly loved and supported through every step of her diagnosis and treatment, but knows that it can be very difficult for some. “When you go through a diagnosis like this, you can feel very alone,” she says.

Her advice is to reach out and see what resources are available; organizations like the MRF and plenty of others are there to provide support. “There are a lot of loving people,” she says, “who want to help us.”

For more information on the Melanoma Research Foundation, visit the organization’s website at melanoma.org.

Diagnosed with desmoplastic melanoma, sportscaster Holly Rowe is working with the Melanoma Research Foundation to teach about the disease.

A Team Effort to Fight Melanoma

After getting through her treatment for breast cancer, Ms. K* looked at the experience as an opportunity to get back into shape. She knew that she would have trouble motivating herself and needed a kick-start. It was an advertisement in her state newspaper that gave her just what she needed.

The ad was for Moving Forward Together 3, a study aiming to evaluate how to get breast cancer survivors to start and maintain an exercise routine.

There’s no question that exercise is good for patients and survivors of cancer. It’s an easy answer to the question of what survivors can do for themselves, once they’ve been declared “cancer-free.” However, getting started on exercising, and keeping up with it, can be difficult, and this is especially true for cancer survivors who have gone through physically taxing and exhausting treatment regimens.

Bernardine Pinto, Ph.D., associate dean for research and professor at the College of Nursing at the University of South Carolina, is the lead researcher on this study. “We know that exercise, becoming physically active, helps to improve patients’ recovery, in the sense that it improves their physical functioning, their mood, quality of life, and in some cases even fatigue,” Pinto said in an interview with 

. “And then we have the issue of cancer patients being at increased risk for cardiovascular disease, diabetes, obesity and so on.”

The Moving Forward Together study will be open to women who are 21 years of age or older, have been diagnosed with stage 0-3 breast cancer in the past five years, are not participating in regular physical activity, can read and speak English, and have access to a telephone. Survivors must be able to walk without assistance and must live within the Eastern timezone.

Each of these survivors will receive a pedometer and then be paired with a fellow breast cancer survivor who has been trained through the American Cancer Society’s Reach to Recovery (RTR) program. “RTR is a peer-based program,” Pinto explained. “These are breast cancer survivors who have survived their treatment, and the ACS trained these individuals to help them to provide emotional and other kinds of support to patients at different times in diagnosis. They already know how to work with patients.”

Via weekly phone calls over 12 weeks, the RTR volunteers offer their survivor partners a home-based exercise program (mostly brisk walking) to help them gradually progress to exercise at least 150 minutes/week (this goal is consistent with the American College of Sports Medicine’s recommendation for cancer survivors). 

Investigators plan to enroll 150 women in the study that launched in April 2015 and will be completed in March 2020.

, Ms. K said that having a survivor for an exercise coach “was a big help,” because it allowed her to “not only talk to the professionals, but to talk to someone who had been through it as well, someone who truly understands what the obstacles may be, but was still telling me, ‘I know you're going to do well.’”

 For Ms. L, a coach with Moving Forward Together 3, physical fitness was always a part of her recovery. “Establishing a regular walking routine was a part of getting back to something like normal,” she said. “And that was on three levels — not just physical, but also part of the mental and spiritual recovery.”

All three of those components are important to Ms. L, and to her counseling. She explained that patients in this program “have to be prepared to understand that there are going to be setbacks.” She went on, “I counsel thoughtful goal-setting and a lot of forgiveness and patience with yourself.”

Ms. K also stressed the importance of starting slowly. “The key is just to do it incrementally,” she said, “a little bit at a time.” She went on to explain that her coach was sympathetic. “If I was only able to get in two sessions in a week, she would ask how I felt and tell me, ‘I had times when it was tough, but I did as much as I possibly could.’ It helped, since I knew she had gone through it herself.”

Before Moving Forward Together 3 in South Carolina, Pinto led two similar studies in 2015. These studies also evaluated the effects of survivors receiving exercise-related telephone mentorship from fellow survivors. Early results show that the intervention was successful in getting cancer survivors to engage in exercise routines. Pinto said, “We found that [the participants’] physical activity had improved significantly from their baseline. Their vigor had improved. Their quality of life had improved. Their fatigue had gone down.”

After the initial 12-week program in the study enrolling now, there will also be a follow-up at the six month, nine month and twelve month marks to determine whether survivors were able to maintain their exercise routines.

The focus of Moving Forward Together 3 is on helping survivors adopt and 

exercise. After the initial 12-week program has been completed, the study will examine three types of communication as maintenance strategies, including monthly phone calls, exercise logs and text messages/emails, to determine which is the most effective.

“The research shows how exercise can help cancer survivors with fitness, physical functioning and quality of life,” Pinto said. “In this partnership with the American Cancer Society, we hope to show how community-based organizations will be able to implement our home-based exercise program and help survivors become and stay physically active.”

If the study’s goals are met, researchers plan to conduct a larger trial of the program that will allow cancer care organizations that have been peer-based programs an opportunity to expand the scope of the services they offer to survivors of breast cancer.

Those interested in learning more about, or participating in, Moving Forward Together 3 may contact Kimberly Bowyer, University of South Carolina research assistant, at 803-777-3909, 888-829-1916 or 

. Participants do not have to live in South Carolina, but they must live in the Eastern time zone to participate.

A study is helping to motivate breast cancer survivors to be physically fit.

Author | Allie Casey

Making Progress for Myelodysplastic Syndrome

Roadblocks to Advancing Treatment of Rare Ovarian Cancers

A Team Effort to Fight Melanoma

Moving Forward Together: Breast Cancer Survivors Are Helping Each Other to Get and Stay Physically Active