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Revumenib Earns FDA Priority Review In R/R KMT2Ar Acute Leukemia
Revumenib, a first-in-class Menin inhibitor, was granted priority review from the FDA for the treatment of adult and pediatric relapsed or refractory KMT2A-rearranged acute leukemia.
The FDA granted priority review to the NDA for revumenib in adult and pediatric R/R KMT2A-rearranged acute leukemia.1
Revumenib is a first-in-class Menin inhibitor. The NDA filing for the agent is currently being reviewed under the FDA's real-time oncology review program, which allows for a more efficient review and engagement between the sponsor and the FDA throughout the submission process.
A PDUFA date for the agent has been set for September 26, 2024.
"The receipt of priority review for the revumenib NDA filing is a significant milestone as we transition to a leading commercial-stage oncology company with the planned launches of 2 first- and best-in class drugs in 2024," said Michael A. Metzger, chief executive officer of Syndax Pharmaceuticals, in a press release. "With 2 regulatory filings now under FDA priority review, our team is focused on commercial preparations to enable Syndax's continued success as we enter this next stage of growth."
a close-up of red blood cells flowing through a vein, displaying the characteristic sickle shape Generative AI: © catalin - stock.Adobe.Com
Findings from the AUGMENT-101 trial of revumenib in adult and pediatric patients with KMT2A-rearranged AML and ALL support this approval. At the protocol-defined interim analysis, the trial met its primary end point by showing a complete remission (CR) or a CR with partial hematologic recovery (CRh) rate of 23% (95% CI, 12.7%-35.8%; P =.0036).2 This was seen among the 57 patients who were in the pooled KMT2Ar acute leukemia population and were efficacy-evaluable.
In both the overall population and among patients with AML, a durable CR/CRh response was seen with a 6.4-month (95% CI, 3.4-not reached) median duration as of the data cutoff date of July 24, 2023. At this time, 46% of patients remained in response.
Ten of the 13 patients who achieved CR/CRh had minimal residual disease (MRD) status assessed, and 70% of patients were MRD-negative. In the overall cohort of 57 patients, 36 achieved an overall response, 39% (14/36) of whom underwent hematopoietic stem cell transplant. Additionally, 50% of these patients (7/14) restarted revumenib as post transplant maintenance at the time of the data cutoff.
Further findings from phase 2 AUGMENT-101 trial in this patient population were presented at the 2023 American Society of Hematology Annual Meeting. Data from the phase 1 portion of the AUGMENT-101 trial in acute leukemia were also published in Nature.1
Previously, in December 2022, the FDA granted a breakthrough therapy designation to revumenib for the treatment of adult and pediatric patients with R/R acute leukemia who harbor a KMT2A rearrangement.
REFERENCES: 1. Syndax announces FDA priority review of NDA for revumenib for the treatment of relapsed/refractory KMT2Ar acute leukemia. News release. Syndax Pharmaceuticals. March 26, 2024. Accessed March 26, 2024. Https://tinyurl.Com/27x4vena 2. Aldoss I, Issa GC, Thirman M, et al. Revumenib monotherapy in patients with relapsed/refractory acute leukemia topline efficacy and safety results from the pivotal augment-101 phase 2 study. Blood. 2023;142(supple 2): LBA-5. Doi:10.1182/blood-2023-192042Community Raises $53,000 For Bemidji Family After 3-year-old Receives Leukemia Diagnosis
BEMIDJI — Just a few weeks before his cancer diagnosis, 3-year-old Gunnar Haseltine had been laughing while wrestling with his father. He seemed happy and healthy, and any thought to the contrary was nearly unimaginable.
Then he started feeling sick. At first, it seemed like just a cold, but after a few days his skin took on a yellow hue and he became increasingly despondent. So his parents, Paul and Courtney Haseltine, took him to the doctor.
"It was like a bad cold or a really mild flu. He was complaining about his feet hurting, so we thought maybe he's just going through a growth spurt. Then his skin started to get yellow and he got more and more checked out," Paul shared. "We were advised to bring him in and we did. Then it was just a bombshell dropped on us."
Paul and Courtney Haseltine are pictured with their 3-year-old son Gunnar leaving a chemotherapy appointment. Paul says Gunnar likes to ride in wheelchairs and usually lacks energy for long walks.Contributed
They were told that it was likely Gunnar had cancer. Before they knew it Courtney was flying with him from Bemidji to Fargo, with Paul close behind.
"My wife and son were in the helicopter flying to Fargo, and I was following behind in the car. I was crying so hard that I developed a headache, and that's what forced me to stop crying," Paul said. "It's my son, it's my boy. It's so overwhelming."
The doctors in Fargo confirmed the diagnosis, informing the couple that their son had an acute form of leukemia.
"My first reaction was anger. How dare they even speak such evil thoughts into existence," Paul recalled. "Then it went from anger to extreme sorrow. I don't even know if it's fully set in yet."
Gunnar Haseltine's parents describe him as a fun and playful child prior to his cancer diagnosis in February, they hope he is able to return to that energetic little boy soon.Contributed
Gunnar was diagnosed on Feb. 22, and since then he's been receiving treatment in Fargo. The reality has been devastating to his parents, who have watched the little boy they love so much struggle with pain, a lack of energy and unfamiliar environments.
"It's been absolute hell," Paul said. "He's 3 years old, and even though he's small, he's a warrior. But it's been hell on everybody."
Community support
But the Haseltines haven't been alone in their struggle. Throughout the last month, they've been grateful to the friends and family who have shown them their support during such a difficult time.
"Our faith, our friends and our family have just been so pivotal," Courtney shared. "(They've) come to see us and check in on us."
A part of that support has been through a GoFundMe campaign, which so far has raised $53,000 to help the family through this crisis. Some of the 278 donors, as of Tuesday morning, are people the Haseltines know, while many others they've never met.
Courtney Haseltine and her son Gunnar pose in matching shirts as they are being released from the hospital into hospital housing, unable to return home yet.Contributed
"We've had (so many) people donate, and we don't even know who some of them are — just a connection through a friend of the family or a friend of a friend, even people we've met in passing," Courtney said. "That's been shocking, wonderfully shocking, and it makes us feel seen in such a horrible season of our life."
Paul and Courtney moved to Bemidji shortly before Gunnar was born, to be closer to family. Since their son's diagnosis, they've been staying in Fargo.
Following the move to Bemidji, Courtney has been working as an online personal trainer and health coach, and Paul has been working in contracting and as a handyman for his father's company. But neither have been able to focus on work since this health crisis took over their lives.
"I couldn't even imagine working, I feel like I'd be betraying my son and myself," Courtney shared. "I feel like 100% of my focus needs to be on him right now, and I'm very, very grateful that I don't have to work right now."
Courtney Haseltine and her son Gunnar pose for a picture in front of the Christmas tree in December 2023.Contributed
Both Paul and Courtney are spending all of their time caring for their son and advocating for him.
"Now it's just about finding the best treatment plan for him and making sure we're being good advocates. We're really trying to be in tune with his wants and needs and navigating his emotions as a child," Courtney explained. "(We want to) make sure he has the best chance of health, not just in the short term, but for his long term health."
Looking toward healing
Gunnar is currently undergoing chemotherapy, and while it's helping treat his leukemia it's also been difficult on his body and energy levels.
"Sometimes he doesn't want to walk or move, because his body just hurts," Paul said. "He's kind of checked out because of the pain he's in, and he's lost some of his confidence."
Gunnar Haseltine is pictured with some of the health care staff who have been helping his family since his diagnosis with an acute form of leukemia in February.Contributed
When he's well, his parents describe Gunnar as confident, kind and someone who loves to make others laugh.
"He's one of the most confident little boys I've ever met, and he's so friendly," Courtney said. "He makes it a point to be a friend to everybody, he's really silly and he loves to make jokes and make people laugh."
Gunnar's also adventurous, loves the outdoors and monsters, and playing with the family dog. With time and treatment, his parents know that he'll make it back to that.
"We have a very strong faith as a family, and I already believe Gunnar's healed," Courtney shared. "Acute (leukemia) means it's happening very suddenly, but the reversal can also be fast and sudden. So his chances of remission and full healing are very promising."
Courtney and Paul Haseltine hold their son Gunnar as they celebrate his third birthday party in August 2023.Contributed
For now, the family is focusing on one thing at a time — making it through the next hour, the next treatment, the next day.
"When you're faced with overwhelming obstacles and situations, you've got to just focus on one tiny step in front of you at a time," Paul explained. "Your first step, your next step, and as you go you can look back and see you've made it through the jungle."
They're also working to protect Gunnar and make the experience and treatment as comfortable and positive as it can be.
"I just want our spirits to stay bright, especially Gunnar's," Courtney said, "so that his childhood and the magic behind that can be protected through this process."
To support Gunnar and his family, visit gofundme.Com/f/gunnars-fight-against-leukemia-fund.
Paul and Courtney Haseltine are pictured with their son Gunnar on a sleigh ride this last winter celebrating Christmas before he was diagnosed with an acute form of leukemia in February.Contributed
Research Into Reactive Oxygen Species Could Help Address AML Treatment Resistance
Treatment resistance remains a major challenge in the treatment of acute myeloid leukemia (AML), and leveraging actionable therapeutic targets is far from straightforward.
Reactive oxygen species (ROS) appear to play a key role in treatment resistance among patients with acute myeloid leukemia (AML). Yet, a new review explains that the precise role ROS plays is complex, and leveraging ROS into actionable therapeutic targets is far from straightforward. The findings were published in the journal Cancer Drug Resistance.
The investigators began by outlining the challenge of treatment resistance in AML. The complete remission rate for patients with AML undergoing standard induction therapy varies from about 40% to more than 90%, depending on characteristics such as patient age and genetic characteristics, they explained.
"However, at least 50% of younger patients and 80% of those older than 60 years will experience relapse within 5 years," they noted, adding that even with additional chemotherapy or hematopoietic stem cell transplant, most patients will not survive 5 years. "In most cases, it has been shown that the founder leukemic clone persisted following chemotherapy and established the basis of relapse years later."
Thus, much of the recent research into AML has been focused on investigating leukemic stem cells (LCS) as the source of relapse, the authors said. Those cells rely on oxidative phosphorylation (OXPHOS) for energy. Venetoclax (Venclexta; Abbvie/Genentech), a selective BCL-2 inhibitor, suppresses OXPHOS, the authors noted, adding to the drug's antileukemic activity. Yet, they said, the effect has its limits.
AML representationImage credti: Andrey - stock.Adobe.Com.
"Despite promising responses in various studies, resistance to VEN-based combinations can emerge in AML patients," the authors said. Previous research has indicated that the majority of patients who initially responded to venetoclax-combination therapy relapsed within about a year, Tonks and colleagues said.
The understanding of the role of OXPHOS has led to increased investigation of ROS, which are byproducts of OXPHOS. However, the investigators said ROS appears to affect AML resistance in multiple ways.
"The contribution of ROS to drug resistance is thought to be influenced by its concentration, the underlying source of production, or the type of treatment, and therefore, it is complex," they wrote. In terms of concentration, both high and low levels of ROS can play a role in therapy resistance and relapse.
"Lower levels of ROS are associated with the maintenance of leukemia stemness, reduced sensitivity to chemotherapy, and a higher risk of future relapse," the authors explained. "In contrast, NOX2-mediated ROS generation may enhance AML cell survival by providing an additional source of energy. This occurs through mediating the transfer of mitochondria and essential metabolites from stromal cells in the microenvironment to AML cells."
NOX2-generated ROS may induce metabolic alterations in AML cells, lending protection against chemotherapy and potentially altering the microenvironment to suppress immune components.
As the contribution of ROS to AML treatment resistance is complex, so too is the challenge of directly targeting ROS. On the other hand, targeting NOX2 shows promise.
"Recent increasing evidence highlights the significance of NOX2 in therapy resistance," the authors wrote. "Preliminary data even suggest a predictive role for NOX2 expression in resistance to therapy."
The authors said there are a number of NOX2 inhibitors already available, which ought to be the subject of future investigation as potential therapeutic options.
"Alternatively, conducting a detailed analysis of the signaling pathways altered by ROS and exploring them as potential therapeutic targets, rather than directly targeting ROS or their substrates, offers alternative avenues for research in the development of additional therapeutic targets in AML," they concluded.
Reference
Khorashad JS, Rizzo S, Tonks A. Reactive oxygen species and its role in pathogenesis and resistance to therapy in acute myeloid leukemia. Cancer Drug Resist. 2024;7:5. Published 2024 Feb 22. Doi:10.20517/cdr.2023.125
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