Meeri Kim

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.”

Jim Helminski received a diagnosis of myelodysplastic syndrome, which quickly progressed into AML, after he retired following almost 30 years with the Secret Service.

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.

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
of treatment.”

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%.

Irma Smith was treated with induction chemotherapy followed by consolidation chemotherapy.

“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.

After going into remission in 2017, Smith enrolled in a clinical trial for oral azacitidine as maintenance therapy to prevent disease recurrence.

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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An abundance of clinical trials is giving patients with acute myeloid leukemia (AML) hope for a better future.

Better Days Ahead for Patients With AML

In the fall of 2017, Deborah Barker noticed a strange pain developing on the left side of her body, around waist level. An avid scuba diver and underwater photographer, she thought it might be related to a back injury and requested an MRI from her primary care doctor.

The scan identified a lesion close to her spine, which was concerning. But she was floored after her biopsy when the pathology results came back with a diagnosis of stage 4 non-small cell lung cancer (NSCLC).

“It was really shocking. You think, ‘Oh, God, this is it.’ And my dad died of lung cancer in 2000,” says Barker, 69, who lives in St. Petersburg, Florida. “I went through the normal, scary feelings for about a week, and then I remember being real anxious to start treatment.”

Her local oncologist recommended radiation therapy right off the bat since the lesion was so close to the spine. But her tumor didn’t have any of the gene mutations that would make her eligible for the newer targeted therapy drugs. Barker wasn’t satisfied with receiving only the standard treatment regimen of chemotherapy and asked him about clinical trials for metastatic lung cancer.

“I had gone through a clinical trial with my sister back in 2007. She had severe aplastic anemia and I was the donor for her stem cell transplant,” she says. “That went real well for her, and it was kind of neat going through it all.”

After being disqualified for a study based in her hometown because the researchers were unable to get a large enough biopsy sample, Barker headed to the much larger Moffitt Cancer Center in neighboring Tampa. There, she learned about a clinical trial for tumor-infiltrating lymphocyte (TIL) therapy, a type of cellular immunotherapy being newly tested in patients with NSCLC. It extracts immune cells present inside and presumably attacking the tumor, grows billions of them in a lab and then infuses them back into the patient.

Such approaches to immunotherapy, which involve modifying the patient’s own immune cells to more successfully attack the cancer cells, were first used to treat melanoma or blood cancers such as lymphoma and leukemia. Recently, clinical trials have explored the efficacy of TIL therapy and another type called chimeric antigen receptor (CAR)-T cell therapy in other cancer types, including lung cancer. Early results appear promising and give hope to patients with metastatic disease, like Barker, who lack options.

“We have a long track record of a percentage of patients with metastatic melanoma getting durable, complete responses from TIL therapy dating back to the 1980s,” says Dr. Ben Creelan, medical oncologist and principal investigator of the TIL therapy clinical trial at Moffitt. “Based on that positive experience, we wanted to take that into lung cancer and see if we could achieve similar results. Of the lung cancer patients we treated, a proportion of them have had durable responses lasting four years now, in some cases.”

Cell-based therapy encompasses a broad range of techniques that all include the injection or transplantation of cellular material into a patient. For example, bone marrow trans- plants infuse healthy, blood-forming stem cells into the body to replace damaged or diseased bone marrow. They could be cells from a donor or the patient’s own cells.

Cellular immunotherapy — which includes TIL therapy, CAR-T cell therapy and others —specifically focuses on immune cells. TIL therapy extracts a patient’s own TILs or immune cells that have moved from the blood into a tumor and stimulates their growth in tissue culture. CAR-T cell therapy, on the other hand, collects a type of white blood cell, called T cells, from a patient and genetically alters them to better identify cancer cells.

Both therapies then inject the modified immune cells back into the patient so they can go to work, newly empowered to attack the cancer cells. Patients usually need to receive chemotherapy before the infusion to wipe their immune system clean of other immune cells.

“The main side effects of cell-based therapies are due to this conditioning chemotherapy that can be a little bit rough,” explains Dr. Erminia Massarelli, co-director of the lung cancer and thoracic oncology program and an associate clinical professor of medical oncology and therapeutics research at City of Hope in Duarte, California. “So the patient will need to be at a good stage of their well-being — we call it ‘performance status’ — to tolerate this type of chemo- therapy. We cannot treat patients who are in a wheelchair, for example, or oxygen dependent.”

Massarelli and her colleagues are currently recruiting participants for a phase 2 clinical trial investigating TIL therapy for patients with metastatic NSCLC. They are part of a recent wave of researchers hoping to transfer the success of cellular immunotherapy in hematological malignancies to lung cancer. At this point, the Food and Drug Administration has approved four types of cellular immunotherapy — all CAR-T cell therapies — for patients with different kinds of blood cancers.

These strategies have had limited efficacy in patients with solid tumors, mainly because solid tumor cells lack an easy target for immune cells to latch onto. Normally, T cells use receptors to attach to proteins called antigens on the surface of invading cells. This lock-and-key mechanism allows T cells to recognize and destroy the invading cells. CAR-T cell therapy adds a man-made receptor — the chimeric antigen receptor, or CAR — specific to a cancer-specific antigen to the patient’s harvested T cells.

However, there isn’t a widely expressed antigen in solid tumors that doesn’t also appear on normal cells. So the infusion of modified cells might kill a patient’s cancer cells but end up hurting healthy tissue in the process. In addition, solid tumors and their antigens mutate so frequently that using traditional CAR-T cell therapy on them becomes like shooting a moving target.

“The problem with lung cancer is that the cancer cells are constantly evolving, and they’re all very different. It’s very challenging to pick a specific target,” says Dr. Adam Schoenfeld, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City. “Our therapies continue to evolve with new techniques, but we still face the challenge of a multitude of targets and potential resistance.”

In this sense, TIL therapy has the advantage for treating lung cancer since the immune cells infiltrating a tumor are already trained against a patient’s specific tumor antigens. The lymphocytes, after being extracted from the patient, go through testing in the lab to determine which ones best recognize the tumor cells. The front-runners are then chosen and allowed to multiply before going back into the patient.

TIL therapy remains in early stages for solid tumors other than melanoma, although recent studies have reported some success in head and neck cancer and cervical cancer. Last year, Moffitt’s phase 1 clinical trial in lung cancer demonstrated the safety and efficacy of TIL therapy for this patient population. Creelan and his colleagues recruited 20 patients with metastatic NSCLC, including Barker, and two have achieved complete responses with no evidence of disease on their scans.

“Stage 4 lung cancer traditionally has a lot of room to go when it comes to getting durable remission for patients,” Creelan notes. “I would say that a good number of the patients we treated were never smokers and historically bereft of immunotherapy options, and now it seems like (TIL therapy) could level the playing field.”

Overall, the clinical trial went smoothly for Barker, although things didn’t happen exactly as planned. To collect the lymphocytes, a surgeon removed part of the tumor from her right upper lung with minimally invasive robotic surgery. While waiting for the immune cells to multiply in the lab, she received an immunotherapy drug called Opdivo (nivolumab) for about a month. To everyone’s surprise, she fared very well on Opdivo — so much so that she didn’t require TIL therapy after all.

“I was getting a good response, and then I was told, ‘Well, we’re not going to give you your cells,’” says Barker. “That was really interesting because I had a combination of being happy that I was responding but disappointed that I wasn’t getting my cells.”

Barker ended up receiving her cells almost a year later, when an imaging scan spotted a recurrence. Thankfully, Moffitt had frozen her billions of lymphocytes, and Creelan assured her they were still viable. She went through a grueling week of chemotherapy to flush her immune system clean, which left her fatigued and bedridden, and then received the infusion of cells over several hours.

Although the cell infusion itself doesn’t have any notable side effects, other aspects of TIL therapy can take a toll on patients. Because of low blood cell counts, Barker needed blood transfusions after chemotherapy, and most patients in the study experienced low levels of albumin, phosphate and sodium in the blood. Other reported side effects included nausea and diarrhea. However, most of these side effects resolved after roughly 10 days.

In addition, all patients were put on interleukin 2, an immunotherapy drug that increases the growth and activity of T cells, for five days after infusion. Common side effects related to interleukin 2 use include fever, chills and other flu-like symptoms.

Although the initial results of this phase 1 trial seem promising, a much clearer picture should emerge within the next few years regarding the role of cell-based therapies in treating lung cancer. Investigators with phase 2 clinical trials by Massarelli, Schoenfeld and other research groups hope to publish their results by 2024 or earlier.

“I’m very curious to see the results of our current efforts with TIL-based therapies. I think the early data are encouraging, so this could be a potential option in the next few years if we have results similar to what we’re seeing in melanoma translate over to lung cancer,” Schoenfeld says. “One of the things we’re exploring with these studies is looking at them in earlier settings and if that is potentially helpful.”

Experts believe cellular immunotherapy could be more effective if given to patients before their immune system becomes suppressed by chemotherapy and other forms of treatment. About half of the participants in Creelan’s study, for instance, had not received any prior treatment.

“I wouldn’t say that it’s something that you would reserve for the very last line, because usually patients aren’t healthy enough to go through with it if they’ve been through five or six different previous treatments,” says Creelan. “Reserving a trial for the very end rarely works, because usually by that point, patients are too sick to be eligible for these kinds of studies.”

Researchers are also exploring whether cell-based therapies could work better in combination with immunotherapy drugs like Keytruda (pembrolizumab). Early data suggest that pairing the two types of treatment may help reduce drug resistance and increase long-term response. Other studies focus on tweaking aspects of CAR-T cell therapy to make it more suitable for lung cancer, by evaluating new antigen targets that won’t harm as much healthy tissue. And still others are testing less-established cellular immunotherapies for lung cancer like T-cell-receptor-engineered cells, double-negative T cells and clonal neoantigen T cells.

Regardless of the approach, one thing remains clear: Patients with NSCLC still need more treatment options, even with all the recent advances in targeted therapy and immunotherapy drugs. Not everyone responds to immune checkpoint inhibitors such as Opdivo and Keytruda or is eligible for targeted therapy drugs.

“The majority of non-small cell lung cancer patients actually don’t have targetable mutations — I would say about 60% to 70% of non-small cell lung cancer patients don’t have specific targets — so they are mainly treated with chemotherapy and immunotherapy,” Massarelli says. “So cell-based therapies are very good options for these kinds of patients.”

After receiving TIL therapy through the clinical trial at Moffitt, Barker has been in remission since June and celebrated her three-year survival in October. She looks forward to getting back into the water with her scuba gear as soon as the weather warms up.

Although she normally travels to exotic destinations like the Galapagos Islands, the Philippines and Indonesia for her dives, the COVID-19 pandemic has thrown a wrench into Barker’s international travel plans. But there are plenty of local options in her home state of Florida, and she feels an overwhelming sense of gratitude to have her life and health back.

“My quality of life has been great, and I feel completely blessed,” Barker notes. “When you’re faced with stage 4 lung cancer, there’s not much out there for people like me, so I didn’t have one moment of hesitation about doing the clinical trial.”

Even with all the recent advances in targeted therapies and immunotherapy drugs, patients with non-small cell lung cancer still need more treatment options. Although it’s early, cell-based therapies have shown some promise, with more research underway.

Cell-Based Therapies May ‘Level the Playing Field’ in Non-Small Cell Lung Cancer

Over Mother’s Day weekend 2011, Kimberly Schuetz took her 2-year-old son on a road trip from their hometown of Fall River, Wisconsin, to visit family in Illinois. Leading up to the journey, Austin had been his normal, energetic self.

“He was eating like a horse and being very active, very playful. No sicknesses, fevers, or anything like that,” Schuetz says.

On Saturday, Schuetz’s father-in-law noticed something alarming while tickling his grandson. One of Austin’s lymph nodes on his neck had swollen to the size of a golf ball. As an oncology nurse, Schuetz immediately had a sick feeling in her stomach. Her mind went straight to thoughts of cancer.

While her gut reaction told her to take Austin to the emergency department, Schuetz decided to wait until Monday to visit his pediatrician back home. After all, her son was acting fine.

A week later, after visits to two pediatricians, the emergency department at their local hospital and pediatric hematologists at a children’s hospital, a bone marrow biopsy confirmed that Austin had acute lymphoblastic leukemia (ALL). A cancer of the blood and bone marrow, ALL is the most common type of cancer that occurs in children.

“I literally felt like I was living somebody else’s life, like I was watching a movie. I remember sitting there and listening to the doctor, but I also felt like I was floating above myself,” Schuetz says. “I was numb and couldn’t cry. Your brain just goes into this state of shock.”

Omar Durani, a family physician in Dallas, Texas, went through similar feelings when his 9-month-old daughter Kenza received an acute myeloid leukemia (AML) diagnosis. In 2016, her swollen lymph nodes signaled to Durani and his wife that something wasn’t right.

“As a physician and dad, it’s kind of difficult to figure out what hat to wear when, and how much to worry about things like that,” he says. “When the swelling worsened, we started advocating for blood work, but all the doctors we visited only kept giving her antibiotics.”

Finally, an emergency department physician who Durani knew personally listened to their concerns and performed blood testing. The results came back with white cell counts through the roof, confirming the family’s worst fears: Kenza had cancer.

Both ALL and AML are treated initially with chemotherapy, and for the vast majority of children, it works. More than 95% of children with ALL and about 85% to 90% of those with AML enter remission after the first phase of chemotherapy. However, remission does not necessarily mean a cure.

Austin relapsed in October 2012 after two phases of chemotherapy, and despite receiving a bone marrow transplant, his ALL came back a third time in May 2013. About 10% to 20% of children with ALL have a disease that relapses or is resistant to treatment. At that point, with no treatment options left, Austin’s parents were told he had three to six months to live.

“We live 45 minutes away from the hospital, and our doctor ended up driving to our house, not to offer any solutions, because we didn’t have a plan, but just to sit and cry with us, because she was so heartbroken and, in such disbelief,” Schuetz says.

Some cancer in children does not respond to chemotherapy. After three rounds of chemotherapy, doctors told Durani that his daughter’s only hope would be a bone marrow transplant. But as a child of Asian descent and mixed ethnic background, Kenza had a less than 2% chance of finding a bone marrow donor match.

While research in adult blood cancers has led to an explosion of new targeted therapies and immunotherapies, such progress has been slower for younger patients. This can leave children such as Austin and Kenza without a path forward. Even for patients who do achieve long-term survival, the lingering toxicity of chemotherapy can lower their quality of life as adults.

“Only four cancer treatments have been approved for first use in children in the last 40 years, compared with hundreds approved for treating adults during this same time frame,” said Dr. Gwen Nichols, chief medical officer of the 

“Out of all the federal funding that goes into cancer research, only 4% goes toward pediatric cancer research,” said Dr. Deepa Bhojwani, director of the Leukemia and Lymphoma Program

at Children’s Hospital Los Angeles in California. “That being said, I would say within the last five to 10 years, there has been a lot more progress in terms of targeted treatment and immunotherapy than there was in the past.”

But the tide may be turning for this young, vulnerable population with new research initiatives dedicated to applying precision medicine to pediatric blood cancers. Much of today’s research in pediatric blood cancers aims to find tailored alternatives to chemotherapy that could prove just as or more effective with fewer harmful side effects.

Cancer is still the leading cause of death from disease among children and adolescents in the United States. From 2012 to 2016, leukemia and lymphoma accounted for 38.7% of all cancer types for patients under age 20. Approximately 40% of children with AML and 20% of those with ALL experience a relapse of their disease. Non-Hodgkin lymphoma, the most common type of lymphoma in children under age 14, that is resistant to first-line therapy has a very poor prognosis.

Before joining LLS, Nichols worked for a pharmaceutical company. She says that getting pediatric drugs tested and approved may be difficult because they typically do not bring in as much revenue as adult therapies.

As a result, upon arriving at LLS she was determined to figure out a faster, more efficient way to bring new agents and therapies to children with blood cancers.

In 2016, LLS launched the Beat AML Master Trial for adults with AML. It represented a paradigm shift in the format of clinical trials by testing several different targeted therapies in individual study arms instead of only one drug or combination of drugs at a time. Patients had a genomic screening to determine whether they had one of the genetic mutations that would make them eligible for one of the study arms to test a particular targeted therapy.

“It’s about 50% less expensive to do a master trial than it is to do one drug at a time. So, we needed to do something similar in pediatrics to make it more cost-efficient. But even more than that, if you want to get targeted therapies to kids, you have to have the right kids to test the drug,” Nichols said. “If you’re doing one drug at a time, you have to screen thousands of kids to find the five that fit your drug, which costs time and money.”

In 2019, LLS announced a collaboration with the National Cancer Institute and the Children’s Oncology Group called LLS PedAL (Pediatric Acute Leukemia), a global precision medicine master clinical trial in the same vein as the Beat AML trial. Children with relapsed acute leukemia will undergo genomic screening to match the specific abnormalities driving their cancer with one of several targeted therapies.

As part of The LLS Children’s Initiative: Cures and Care for Children, a $100 million, multiyear effort to take on pediatric blood cancers, LLS PedAL will test multiple agents simultaneously at up to 200 sites worldwide. Trials will follow the same format so that data from multiple institutions can be shared and consolidated.

Nichols and her colleagues hoped to begin the trial this year, but with the coronavirus disease 2019 pandemic, LLS PedAL’s start date has been pushed back to early 2021.

Another inspiring research project is the Pediatric Cancer Genome Project (PCGP), a joint initiative from St. Jude Children’s Research Hospital and Washington University School of Medicine. Since 2010, the two insti- tutions have pioneered efforts to define the genomic landscape of pediatric cancer by sequencing the genomes of normal and cancer cells from 800 patients.

“That work really filled in much of the landscape of mutations that drive ALL, AML and many of the other kinds of pediatric cancer,” says Dr. James R. Downing, president and CEO of St. Jude, who was instrumental in launching the PCGP. “In particular, important fundamental discoveries came out for ALL in terms of new understandings related to the identification of new genetic subtypes, amplifications, fusions and chromosomal translocations of the disease.”

For instance, the PCGP pinpointed genes linked to an ALL subtype with a poor prognosis known as Philadelphia chromosome-like ALL (Ph-like ALL). In 2009, St. Jude scientists were among the first to describe Ph-like ALL in children. Five years later, next-generation sequencing revealed the genetic alterations that give rise to Ph-like ALL, which could be targeted with drugs widely used to treat other types of leukemia more common in adults.

A 2017 study from the PCGP identified potential targets for immunotherapies in pediatric cancers, finding that 88% of leukemias have at least one that could be exploited. A 2018 pan-cancer analysis that examined commonalities and differences among various cancer types, including ALL and AML, suggest that half of the cancers studied may have a targeted treatment available or under development.

“The second phase of the genome project is moving all that technology into frontline diagnostics,” Downing says. “So now we’re getting the whole genome, whole exome and RNA sequencing of every patient, and we gain insight that can be funneled into a protocol that allows them to be treated.”

St. Jude’s frontline ALL protocol includes an unparalleled level of genomic sequencing on the patient, on both cancer and normal cells, which allows physicians to make personalized therapeutic decisions. Downing hopes that collecting such a wealth of data will help usher in new therapies and lead to a further improvement in outcomes.

“So the momentum is there, the studies are ongoing, and hopefully five years from now, we will have a huge variety of therapies to offer our kids instead of just one,” Bhojwani says.

Bhojwani participates in the Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) consortium, which has its headquarters at Children’s Hospital Los Angeles. TACL brings together children’s hospitals and universities to accelerate the progress of new therapies for pediatric leukemia and lymphoma. The consortium includes 31 institutions in the United States and Australia that collaborate on clinical trials of new drugs and novel therapy combinations in the hopes of expanding the number of treatments available.

Both Kenza and Austin were saved by an experimental treatment called chimeric antigen receptor (CAR)-T cell therapy administered in a clinical trial. It involves engineering the body’s T cells, a type of white blood cell, to produce receptors on their surface called chimeric antigen receptors (CARs). The engineered cells are infused back into the patient, where they can recognize and kill cancer cells.

The Duranis couldn’t find a bone marrow donor match for Kenza, despite having more than 60 donor drives inspired by her diagnosis that registered more than 5,000 new potential bone marrow donors around the country. At that point, they decided to move forward with CAR-T cell therapy coupled with a haploidentical, or partially matched, stem cell transplant in August 2016.

“It was a no-brainer for us since there were no other therapies available besides a standard bone marrow transplant,” Durani says. “Now Kenza’s been in remission for four years, and she’s doing fantastic. She’s a thriving, spunky 5-year-old.”

After his third relapse, Austin’s parents enrolled him in a clinical trial to receive CAR-T cell therapy as a last- ditch effort to save their son. He received the treatment at the beginning of October, and on Halloween – which also happens to be his mother’s birthday – they received the good news that his biopsy showed no traces of cancer.

“I immediately started screaming and crying. I was just elated. It was the best birthday present that I could ever, ever have. Nothing will ever top that,” Schuetz says.

Today, Austin is a typical 12-year-old boy who enjoys video games, swimming with his friends and complaining about household chores. He and Kenza are living proof that innovations such as CAR-T cell therapy give children who have run out of options another chance at life.

For years, childhood blood cancers were understudied forcing patients’ treatments into a one size-fits-all approach. But new efforts are changing that.

Coming of Age: New Research Efforts are Improving Treatment of Childhood Blood Cancers

KATHLEEN PACKARD and her daughter, AMY, took this picture on the seventh day of chemotherapy to show unity during her cancer battle. - PHOTO BY KIM SMITH

The biggest battle of Kathleen Packard’s life began in late 2016 with sudden severe pain in her abdomen. The 59-year-old resident of Amherst, New York, couldn’t remember the last time she had been sick, but this kind of stomachache warranted a trip to the hospital.

The doctors discovered that Packard had pancolitis, a severe form of ulcerative colitis that had spread throughout her large intestine, and ordered a blood test. From there, her life took an unexpected and tumultuous turn.

“My white blood cell count was 86,000, whereas normal is 4,500 to 11,000. They sent me to Roswell Park Comprehensive Cancer Center immediately, where I met the phenomenal Dr. Eunice Wang,” Packard recalls. “She made sense out of madness.”

Wang, M.D., chief of the Leukemia Service at Roswell Park in Buffalo, New York, diagnosed Packard with acute myeloid leukemia (AML) and started her on treatment the very next day. In patients with AML, the bone marrow makes abnormal malignant blood cells such as myeloblasts (a type of white blood cell), red blood cells or platelets. It is one of the four main types of leukemia.

The American Cancer Society estimates that in 2017, there were 21,380 new cases and 10,590 deaths from AML. Although AML can occur in children, adults aged 45 years and older are generally most susceptible. The disease is slightly more common in men than in women, but the average lifetime risk for both sexes is less than half of 1 percent.

A bone marrow sample at diagnosis confirmed that Packard had a subtype of AML characterized by a mutation in the FMS-like tyrosine kinase 3 (FLT3) gene, which plays an important role in blood-forming stem cell survival and proliferation. About 1 in 3 patients with AML has this mutation, which may be associated with a particularly poor prognosis. But Wang offered Packard hope through participation in a clinical trial for a new drug specifically targeting FLT3-mutated AML.

Patients with AML are typically treated with two phases of chemotherapy: induction and consolidation. Induction involves treatment with the chemotherapy drugs cytarabine and daunorubicin. Consolidation chemotherapy occurs after remission — clearance of malignant leukemia cells in the marrow followed by regeneration of normal marrow blood-forming cells &mdash; to help prevent a relapse and usually includes high doses of cytarabine, often followed by an allogeneic stem cell transplant.

At Roswell Park, Packard took the two induction drugs in combination with crenolanib, an experimental FLT3 tyrosine kinase inhibitor. “I was on heavy chemotherapy for 13 days, and I was very sick,” she says. “I had every side effect they had to offer. It was a horrific time.”

In January 2017, Packard had an allogeneic bone marrow transplant from an unrelated donor. Today, she remains in remission and recently restarted maintenance therapy with crenolanib as part of another clinical trial.

“My blood went from 99.9 percent filled with leukemia to 99.9 percent cancer-free. I got over that hump,” Packard says. “It was a horrible situation, but when you’re going through it, you learn very quickly that you’re a strong person.”

Packard represents one of countless patients who have benefited from a growing number of treatment options for AML. After 40 years of little to no improvement in higher remission or cure rates since the advent of cytarabine and daunorubicin, four new agents were approved for AML by the Food and Drug Administration (FDA) in 2017 alone: Rydapt (midostaurin), Vyxeos (CPX-351), Mylotarg (gemtuzumab ozogamacin) and Idhifa (enasidenib). Several other promising drugs, such as crenolanib, are still in the pipeline but expected to gain approval in the near future. More treatment options will translate into better outcomes for patients, because oncologists can figure out which of several agents will work best for a given individual. For instance, through a bone marrow sample, Wang found out at diagnosis about Packard’s FLT3 mutation and gave her a targeted drug.

“I think it will change the work that we do upfront to better stratify patients in order to offer the benefits of these targeted therapies,” Wang says. “We have an abundance of riches, and it’s up to physicians to understand that it will take a little time to identify the particular individuals who will benefit.”

The sudden bounty is the culmination of AML research and knowledge that built up for decades — patient genome sequencing, identifying new mutations and understanding their consequences, performing clinical trials, and so on. The discovery of mutations that characterize subtypes of AML led to more personalized treatment options that could outperform the standard regimen.

“We’re reaping the benefits of major innovations in basic science which are sometimes not immediately cancer related, like sequencing the human genome,” says Akil Merchant, M.D., assistant professor of medicine at the University of Southern California in Los Angeles. “These aren’t directly studies of cancer, but they ultimately lay the foundation for these kinds of rapid approvals.”

Typically, about a quarter of adults with AML can be expected to survive three or more years and may be cured. But a number of factors, such as advanced age, systemic infection at diagnosis, elevated white blood cell count, central nervous system involvement with leukemia and certain genetic mutations, lead to poorer outcomes.

Factors that increase a person’s risk of AML include advanced age, being male, previous cancer treatment with certain chemotherapy drugs, exposure to radiation, smoking, toxins (some solvents, for example), other blood disorders, genetic syndromes and family history. Signs and symptoms in the early stages of AML, such as fever, bone pain, fatigue, shortness of breath and pale skin, can mimic the flu or other common diseases.

Because it doesn’t usually form tumors, AML is not staged the same way other cancers are. Instead, lab tests determine subtypes and a patient’s outlook. The French- American-British classification divides AML into subtypes, M0 to M7, based on the type of cell from which the leukemia develops and how mature the cells are. An updated classification by the World Health Organization separates AML into several groups by considerations such as the presence of certain genetic abnormalities, disease related to previous chemotherapy or radiation, and disease related to blood disorders.

“AML is not one disease. What it will come down to one day is that if you have a disease like AML, it will be as unique as you are,” Merchant says. “That’s where we’re heading with precision medicine and really tailoring the therapy to that individual.”

To that end, two of the new agents target subtypes of AML characterized by specific genetic abnormalities. In April 2017, the FDA approved Rydapt for the treatment of adults with newly diagnosed FLT3-positive AML in combination with standard two-phase chemotherapy. The phase 3 RATIFY trial randomized 717 patients with AML who had the FLT3 mutation to standard induction and consolidation chemotherapy plus Rydapt (360 patients) or placebo (357 patients).

Median overall survival was 74.7 months with Rydapt versus 25.6 months with chemotherapy alone.

Four months later, Idhifa was approved for treating patients who have relapsed or refractory isocitrate dehydrogenase 2 (IDH2)-mutated AML based on the promising results of a phase 1/2 study.

The IDH2 gene encodes for metabolic enzymes found in mitochondria, the energy- producing centers within cells. The single- arm, multicenter clinical trial included 199 adults with relapsed or refractory AML who had an IDH2 mutation. They took the oral drug daily, and 19.3 percent experienced complete remission with a median duration of 8.2 months.

Both Rydapt and Idhifa were approved along with companion diagnostic tests, the LeukoStrat CDx FLT3 Mutation Assay and the RealTime IDH2 Assay, respectively. As a result, the diagnostic workup for patients will change to identify those who would benefit from the new drugs. “With these new agents in our arsenal, we’ll be able to translate the positive results in clinical trials to improving the outcome of patients with these mutations,” says Bruno Medeiros, M.D., associate professor of hematology at Stanford Cancer Center in California. “Information about the patient which used to be prognostic is now relevant and critical for treatment. It changes the potential outcome for patients, but it also changes how physicians and patients should expect the initial workup to take place.”

Common side effects of Rydapt include low levels of white blood cells with fever (febrile neutropenia), nausea, inflammation of the mucous membranes (mucositis), vomiting and headache. Idhifa’s side effects include nausea, vomiting, diarrhea, increased levels of bilirubin (a substance found in bile) and decreased appetite.

In August 2017, the FDA approved Vyxeos, a repackaged formulation of induction chemotherapy drugs cytarabine and daunorubicin, for two subtypes of AML with typically poor prognoses. Therapy-relatedAML occurs as a result of specific types of chemotherapy or radiation, and AML with myelodysplasia-related changes is characterized by a history of certain blood disorders and other mutations within cancer cells.

Vyxeos combines the two drugs into a single formulation encapsulated in liposomes. In a clinical trial, 309 patients newly diagnosed with one of the two AML subtypes received either Vyxeos or separately administered treatments of daunorubicin and cytarabine. Those who received Vyxeos had a median overall survival of 9.56 months versus 5.95 months for patients who received the two drugs separately. Side effects of Vyxeos include hemorrhage, febrile neutropenia, rash, swelling of tissues, nausea, mucositis and fatigue.

Lastly, anti-CD33 antibody drug conjugate Mylotarg received approval in September 2017 for adults with newly diagnosed AML whose tumors express the CD33 antigen. The drug combines an antibody with chemotherapy to attack tumor cells with CD33. It was originally approved in 2000 but voluntarily withdrawn from the market after several early deaths and lack of evidence of efficacy.

“Mylotarg was previously approved and now has been reapproved,” Wang says. “It was taken off the market for several years because of questions by the FDA that required additional analysis based on patients who developed liver issues. Liver problems with Mylotarg are still an issue, but the incidence has decreased.”

The agent has a new dosing regimen that has been shown to be more safe and efficient. A randomized phase 3 trial, ALFA-0701, compared daunorubicin and cytarabine with or without the addition of Mylotarg in 271 patients with CD33-positive AML. Those who received Mylotarg had a median event-free survival of 17.3 months compared with the control group’s 9.5 months. However, no significant improvement in overall survival was seen with Mylotarg.

Severe side effects of Mylotarg include low blood counts, infections, liver damage, blockage of veins in the liver, infusion-related reactions, and severe bleeding. In the clinical trial, patients who took Mylotarg were seven times more likely to experience side effects compared with those in the control group.

“These are exciting times, but with that excitement comes questions,” Medeiros says. “All of these agents were tested in isolation of one another, so it’s going to be a challenge for us to learn how to use and combine these agents.

But there are more opportunities for treatment, which will, hopefully, lead to improvements in the survival of a disease that is very hard to treat.”

Last year brought many new possibilities in the treatment of AML, and it appears 2018 does likewise. Specifically, Medeiros says ivosidenib, an IDH1 inhibitor that targets IDH1-mutated disease, has a good chance of hitting the market early this year. It was submitted to the FDA in December following phase 1 trial results that showed a complete response or complete response with partial hematologic recovery rate of 30.4 percent, which lasted for a median duration of 8.2 months.

Another potential target is B-cell lymphoma 2 (BCL-2), the protein that makes cancer cells resistant to therapy. BCL-2 inhibitors have shown promise for patients who aren’t good fits for induction chemotherapy, such as older adults. Venclexta (venetoclax), previously approved for patients with chronic lymphocytic leukemia, recently demonstrated a complete remission in up to 50 percent of patients aged 60 years or older with relapsed or refractory AML.

Although Rydapt is already on the market, Merchant expects other FLT3 inhibitors to follow suit: “Rydapt is the first but not the best FLT3 inhibitor. There is a whole crop of FLT3 inhibitors that are more targeted, more specific, and have fewer side effects and greater activity than Rydapt. I think the three or four agents on the horizon are even more exciting.”

In a recent study conducted by Wang, crenolanib combined with chemotherapy saw very high response rates of over 80 percent complete remission or complete remission with incomplete hematologic recovery. While most FLT3 inhibitors bind only to the receptor in its inactive configuration, crenolanib can bind for FLT3 in both active and inactive configurations.

Packard says she owes her survival to Wang and other members of her care team at Roswell Park who are willing to take a chance with new therapies. She takes crenolanib in pill form three times a day, every eight hours, which disrupts her sleep schedule and normal routine. But her main objective is survival, and although the treatment has been tough, she feels grateful to be alive.

“The most important thing to believe in is your doctor,” says Packard. “Have a strong bond with your doctor and realize that you matter. It’s your journey, and you have the right to have a bad day, but you need to get back up. You have to reach the top of that mountain and have a strong will to live.”

New drugs bring advancements to acute myeloid leukemia after 40 years.

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