An abundance of clinical trials is giving patients with acute myeloid leukemia (AML) hope for a better future.
As an almost 30-year veteran of the Secret Service, Jim Helminski took pride in maintaining his physical health — both for his own sake and to be better fit to protect others. His demanding career placed the safety of Presidents Bill Clinton and George W. Bush and then-Vice President Joe Biden in his hands.
In late 2015, he retired as deputy assistant director to live a more tranquil life on Orcas Island, Washington, with his wife, Teresa Patrick, a former Department of Justice attorney. Not one to sit still, Helminski started a security consulting business on the side while running, weightlifting and practicing karate. He even earned his private pilot’s license and began flying a vintage Cessna.
During a routine yearly checkup in 2019, his primary care doctor remarked that Helminski was in better shape at 61 than most 30-year-olds who came into the office. But later, that changed.
“I went for a jog one day that week after my exam, and my cell phone rings. It was my doctor, and he said, ‘Jim, there’s something wrong with your blood. Your white blood cell count is dangerously low,’” Helminski, now 63, recalls. “I had no symptoms. I felt nothing.”
The direness of the situation hit him when he arrived at a Seattle-based health facility for a consultation with a hematologist that ended with a bone marrow biopsy. A few days later, he received a diagnosis of myelodysplastic syndrome (MDS), a type of cancer in which immature blood cells in the bone marrow do not mature or become healthy blood cells. MDS can be a precursor to different types of leukemia. His myelodysplastic syndrome progressed rapidly to acute myeloid leukemia (AML).
AML, which starts in the bone marrow, usually moves quickly into the blood. From there it can spread to other parts of the body, including the lymph nodes, liver, spleen, brain and spinal cord. Typically, AML develops from the malignant transformation of cells that would turn into white blood cells, but it also may start in very immature forms of red blood cells or cells that make platelets. Approximately 19,940 new cases of AML were diagnosed last year in the U.S., with most occurring in adults.
“It was a huge shock,” Helminski says. “I scheduled an appointment at the (regional) cancer center to see one of their top leukemia doctors, and it became the lowest point in my life.”
The reviewing oncologist advised him that standard treatment gave him only a 10% to 20% chance of remission and provided little guidance about which therapy to pursue. Instead, he simply recommended that, rather than attempting standard chemotherapy, Helminski and his wife look online to find a list of clinical trials for AML and pick one.
Understandably, they left the appointment dissatisfied and began looking elsewhere for guidance. Meanwhile, Helminski broke the bad news to family and friends, including his flight instructor, whose daughter happened to be an oncologist at the University of California, San Diego. She shared his patient profile with a colleague at Johns Hopkins Medicine in Baltimore, who in turn recommended that Helminski consider a clinical trial helmed by her friend, Dr. Courtney DiNardo, an associate professor of leukemia in the division of cancer medicine at The University of Texas MD Anderson Cancer Center in Houston.
Less than two weeks later, Helminski had an appointment and jumped on a plane to Houston to meet DiNardo in person. The study was planning to test a novel three-drug therapy: Tibsovo (ivosidenib tablets), a targeted therapy for patients with the IDH1 gene mutation; Venclexta (venetoclax), an oral medication approved for adults 75 years and older or adults who cannot tolerate chemotherapy; and azacitidine. After an extensive new-patient visit, he was accepted into the clinical trial as one of 48 participants.
Similarly, Irma Smith saw her doctor for isolated pain in her toe and received a diagnosis of AML in 2016. The 75-year-old lived in Fort Wayne, Indiana, with no major health problems and had worked as a real estate agent for the past 29 years.
“I didn’t have a clue. I felt great. I went into shock when I heard the diagnosis because I thought, ‘How can somebody feel so good and then get hit with AML?’” Smith, now 80, says. “The doctor gave me two weeks to two months to live.”
Smith and her daughter decided to seek a second opinion from Dr. Hamid Sayar, a professor of clinical medicine at Indiana University School of Medicine in Indianapolis. Instead of painting a bleak picture, he went straight to work by putting Smith on induction chemo- therapy followed by consolidation chemotherapy. After successfully achieving remission in early 2017, Smith was entered into a clinical trial for oral azacitidine as maintenance therapy to prevent relapse.
In September 2020, oral azacitidine was approved by the Food and Drug Administration (FDA) for patients aged 55 years and older with AML who achieve remission after chemotherapy and are not able to complete intensive curative therapy with a stem cell transplant.
PAVING THE WAY
After decades of stagnation, progress in AML treatments has experienced a resurgence in recent years due to rapid advances in genetics, understanding of molecular mechanisms and development of novel therapeutics. Since 2017, nine new drug approvals by the FDA have significantly changed the treatment landscape of the disease. As a next step, clinical trials such as DiNardo’s aim to find which combinations of therapies will offer patients the best outcomes.
“AML is still, unfortunately, a very life-threatening cancer. Cancer is clever — it’s going to figure out a resistance mechanism to evade a single agent,” DiNardo says. “Putting agents together, if you don’t have overlapping toxicity, is just a smarter way of giving cancer therapy. So we’re trying to move these drug combinations into the frontline setting where they have the best chance of eradicating all disease and preventing relapses.”
Other studies focus on improving treatment for elderly individuals with AML, given that the average age at receiving a diagnosis is 68. Researchers are also testing new targeted therapies, immunotherapies and different ways of delivering drugs that are more convenient for patients.
“AML is more a disease of older populations. Historically, one challenge in the treatment of older adults has been exposing them to intense therapies, which we can do for the younger patients,” Sayar explains. “But treatment of AML at any age, at any phase of the disease, is a challenge. There is an unmet need at every aspect
REFINING AND PERSONALIZING THERAPY
The approval of more therapies has certainly helped many patients, and researchers such as DiNardo are looking to optimize their administration even more by finding the most effective combinations and timings. The clinical trial that Helminski participated in brought together three approved agents for the first time in the frontline setting for patients who have AML with an IDH1 mutation.
Helminski underwent a 28-day isolation in his hospital room at MD Anderson while receiving the three medications due to his immunocompromised state from the leukemia and the treatment. It kept him as infection-free as possible until his immune system recovered. He remained as active as he could — using an exercise bike daily, strength training with resistance bands and meditating with the help of a smartphone app — but did experience some setbacks, such as pneumonia and minor liver inflammation attributed to an antifungal drug.
On the 28th day, the results of Helminski’s follow-up bone marrow biopsy showed that he went from 40% leukemic myeloblasts — immature blood cells that serve as a marker of AML progression — to just 1%.
“He’s a great example of someone who went into a really deep remission. He’s been leukemia-free and doing great for over a year now,” DiNardo says. “We have all of these new approvals now, and they were approved in the single-agent setting. But that’s probably not the best way to actually use them in the real world.”
Two years after going into remission, Smith’s disease returned in 2019 while she was still participating in the clinical trial for oral azacytidine. When the randomized trial was unblinded, it was revealed that she was administered a placebo as part of the control group instead of the maintenance therapy. She is currently being treated indefinitely with Venclexta (venetoclax) and decitabine, a chemotherapy drug, every six weeks — which temporarily takes a toll on her body.
“I don’t want to go out or see anybody. I’m pretty miserable, but I know it’s not going to last,” Smith says. She still enjoys maintaining her house, going on long walks with her dog and spending quality time with family: “The side effects stop in a week and a half, and the rest of the time, I’m just fine. I have a lot of energy.”
Other studies aim to help patients like Smith who relapse after undergoing therapy. Sometimes another round of chemotherapy can put the leukemia into remission again, but it is not likely to be long-lasting. A stem cell transplant or newer targeted therapy for a specific genetic mutation could be better options, but with much more toxicities, and patients must be eligible for these therapies.
“Unfortunately, AML still is a disease where the leukemia does recur or come back, so a lot of research is focused on treating patients who have relapsed after upfront therapy,” Dr. Sangmin Lee, an assistant professor of medicine at Weill Cornell Medicine in New York City, says.
“Several ongoing clinical trials are geared toward relapsed and refractory settings, such as those investigating cell-based therapies, targeted therapies and drugs that overcome resistance.”
For example, a number of clinical trials are exploring the use of chimeric antigen receptor (CAR)-T cell therapy, a novel treatment that involves engineering a patient’s own immune cells, for AML. CAR-T cell therapy has shown promise in other blood cancers. Research is still in the early stages for AML, with initial studies looking at the safety and feasibility of the therapy in adults and children.
Overall, experts agree that several avenues are being explored by researchers to help patients with AML, who are recommended to look into clinical trials as soon as they receive their diagnosis. Helminski, for example, emphasized that he would not have been eligible for DiNardo’s study if he had undergone standard therapy first.
“There is a lot of research trying to see if novel therapies provide benefit, so patients should be on the lookout for clinical trials — both in an upfront setting and also in the relapsed or refractory setting — when they (receive a diagnosis of ) leukemia,” Lee says.
Since the trio of medications Helminski received worked well enough to induce a deep remission, he was able to undergo a curative stem cell transplant in February 2020 from an unrelated donor.
After the stem cell transplant, he gradually regained his strength over the course of 100 days. Today, at more than 500 days post-transplant, Helminski shows no signs of measurable residual disease. He is back to having a full life on Orcas Island with his wife, exercising regularly, flying his airplane and building furniture.
“I initially believed that I was terminally ill, and there was no hope for me. And there’s always the monster of a possibility of a recurrence,” Helminski says. “But I take life one day at a time, and I’m very appreciative of every day that I have.”
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