Novel Combo Boosts Survival in IDH1-Mutated AML
Ivosidenib combined with azacitidine extended median overall survival to 29.3 months compared with 7.9 months for placebo plus azacitidine in newly diagnosed isocitrate dehydrogenase 1 (IDH1)-mutated acute myeloid leukemia (AML). The combination therapy also improved hematologic recovery and increased transfusion independence rate to 53.8% vs 17.1% with placebo.
METHODOLOGY:
A total of 148 patients with newly diagnosed IDH1-mutated AML who were unfit for intensive chemotherapy were randomized to receive either ivosidenib-azacitidine (n = 73) or placebo-azacitidine (n = 75).
Treatment consisted of 500 mg ivosidenib or placebo administered orally once daily, combined with subcutaneous or intravenous 75 mg/m² azacitidine for 7 days in 28-day cycles, with randomization stratified by geographic region and disease status.
Analysis included a median follow-up period of 28.6 months, with overall survival as the key outcome measure, along with hematologic recovery, transfusion independence, and molecular measurable residual disease response.
TAKEAWAY:
Median overall survival was significantly longer with ivosidenib-azacitidine at 29.3 months (95% CI, 13.2-not reached) compared to 7.9 months (95% CI, 4.1-11.3) with placebo-azacitidine (hazard ratio [HR], 0.42; 95% CI, 0.27-0.65; P < .0001).
Among patients who were transfusion dependent at baseline, conversion to transfusion independence was achieved in 53.8% (21/39) of ivosidenib-azacitidine patients vs 17.1% (7/41) of placebo-azacitidine patients (P = .0004).
Of 33 ivosidenib-treated patients evaluable for molecular measurable residual disease, 10 (30.3%) achieved MRD negativity by day 1 of cycle 14, all of whom had complete remission.
The safety profile remained consistent with previous reports, with lower rates of febrile neutropenia and infections in the ivosidenib-azacitidine arm, though neutropenia and bleeding events were more common than with placebo.
IN PRACTICE:
'These long-term efficacy and safety results confirm the benefit of ivosidenib-azacitidine in this challenging-to-treat population and support its use as a standard of care with the longest reported survival benefit for intensive chemotherapy-ineligible patients with IDH1-mutated AML,' the authors of the study wrote.
SOURCE:
The study was led by Pau Montesinos, Hospital Universitari i Politécnic La Fe in Valencia, Spain, and Hartmut Döhner, Ulm University Hospital in Ulm, Germany. It was published online in Blood Advances.
LIMITATIONS:
According to the authors, molecular response analysis was limited by the small number of measurable residual disease-evaluable patients and samples, as well as the discontinuation of sample collection after study unblinding in March 2021. The limited number of variants that could be tracked with sufficient sensitivity in panel-based next-generation sequencing measurable residual disease assessment also constrained the molecular analyses.
DISCLOSURES:
Montesinos disclosed having relationships with AbbVie, Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Novartis, Pfizer, Sanofi, Servier, and Teva Pharmaceuticals. Additional disclosures are noted in the original article.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
Hashtags
Try Our AI Features
Explore what Daily8 AI can do for you:
Comments
No comments yet...
Related Articles
Yahoo
4 hours ago
- Yahoo
A wasting disease killed millions of sea stars. After years of searching, scientists just found a cause.
'It was like a battleground,' Drew Harvell remembers. 'It was really horrible.' She's reflecting on a time in December 2013, on the coast of Washington state, when she went out at low tide and saw hundreds of sick, dying sea stars. 'There were arms that had just fallen off the stars,' she says. 'It was really like a bomb had gone off.' The stars were suffering from something known as sea star wasting disease. It's a sickness that sounds like something out of a horror movie: Stars can develop lesions in their bodies. Eventually, their arms can detach and crawl away from them before the stars disintegrate completely. Harvell is a longtime marine ecologist whose specialty is marine diseases. And she was out for this low tide in 2013 because a massive outbreak of this seastar wasting had started spreading up and down the West Coast — from Mexico to Alaska — ultimately affecting around 20 distinct species of sea stars and wiping out entire populations in droves. In the decade since, some species have been able to bounce back, but others, like the sunflower sea star, continue to struggle. In California, for example, sunflower stars have almost completely died out. The question in 2013 was: What, exactly, was killing all these stars? While marine ecologists like Harvell could recognize the symptoms of seastar wasting, they weren't actually sure what was causing the disease. From the very beginning, though, it was something they wanted to figure out. And so, soon after the outbreak started, they collected sea stars to see if they could find a pathogen or other cause responsible for the wasting. The hunt for the culprit of this terrible, mysterious disease was on. Unfortunately, it was not straightforward. ' When this disease outbreak happened, we knew quite little about what was normal [in sea stars],' says Alyssa Gehman, who is also a marine disease ecologist. She says that when researchers are trying to do similar work to chase down a pathogen in, say, humans, they have an enormous trove of information to draw on about what bacteria and viruses are common to the human body, and what might be unusual. Not so for sea stars. ' We maybe had a little bit of information, but absolutely not enough to be able to really tease that out easily.' Also, Gehman says, there can be a lag before the disease expresses itself, so some stars have the pathogen that caused the disease, but don't present with symptoms yet, making it harder for scientists to even distinguish between sick stars and healthy ones as they run their tests. So even though a research team identified a virus that they thought might be associated with the wasting disease as early as 2014, over time, it became clear that it was most likely not the culprit, but rather just a virus present in many sea stars. 'The results were always confusing,' Harvell remembers. In the decade since the initial mass outbreak, other researchers have proposed other theories, but none have brought them to a definitive answer either. And yet, it became increasingly clear that an answer was needed, because people started to realize just how important the sunflower stars they had lost really were. ' We actually learned a lot from losing so many of these animals at once,' Gehman says. Before the outbreak, she says, they'd known that sunflower stars — giant sea stars that can be the size of dinner plates, or even bike tires — were skillful hunters and voracious eaters. They even knew that many things on the seafloor would run away from them. Gehman remembers taking a class on invertebrates back in college, where she learned that if you put even just the arm of a sunflower star in a tank with scallops, 'the tank would explode with scallops swimming everywhere trying to get away.' But all that fearsome hunting was, it seems, pretty key to ecosystem health. In many places, she says, ' after the sea sunflower stars were lost, the urchin populations exploded.' And so the die-off of the sunflower star and the explosion of urchins has been connected to the collapse of the Northern California kelp forests, a marine ecosystem that provides a home for a rich diversity of species. A cross-state, cross-organizational partnership between the Nature Conservancy and a variety of research institutions is working hard to breed sunflower seastars in captivity in the hopes that they can be reintroduced to the coast and reassume their role in their ecosystems. But as Harvell remembers, she and Gehman knew that no recovery project would be successful if they couldn't find the cause of sea star wasting disease. 'You're not gonna be able to get these stars back in nature if you don't know what's killing them,' she says. So in 2021, as part of the larger partnership, Harvell and Gehman, along with a number of their colleagues, launched into an epidemiological detective project. Their quest: to finally pin down the cause of seastar wasting disease. 'Really the work over the four years was done in the trenches by Dr. Melanie Prentice and Dr. Alyssa Gehman,' Harvell says, 'and then one of my students, Grace Crandall.' It was an emotionally difficult project because it required Gehman and her colleagues to deliberately infect many stars with the disease. 'It feels bad,' she admits, and they would be open about that in the lab, 'but we also can remember that we're doing this for the good of the whole species.' That work has paid off, though, and now, after four years of research, they've nailed their culprit in a paper out in Nature Ecology & Evolution today. What follows is a conversation with Drew Harvell, edited for clarity and length, about what she and her collaborators found, how marine ecologists do this kind of detective work, and what identifying the culprit could mean for the future health of seastars. How did you start the journey to figure out what actually had happened? Well, we chose to work with the sunflower star because we knew it was the most susceptible and therefore was going to give us the most clear-cut results. So we set up at Marrowstone Point, which was the USGS Fisheries virus lab [in Washington state], because that would give us the proper quarantine conditions and lots of running seawater. The proper quarantine conditions — what does that mean? All of the outflow water has to be cleansed of any potential virus or bacterium, and so all of the water has to be run through virus filters and also actually bleached in the end, so that we're sure that nothing could get out. We did not want to do this work at our lab, Friday Harbor Labs, or at any of the Hakai labs in Canada because we were really worried that if we were holding animals with an infectious agent in our tanks without really stringent quarantine protocols, that we could be contributing to the outbreak. So you have these sea stars. They're in this quarantined environment. What is the methodology here? What are you doing to them or with them? So the question is: Is there something in a diseased star that's making a healthy star sick? And that's like the most important thing to demonstrate right from the beginning — that it is somehow transmissible. And so Melanie and Alyssa early on showed that even water that washed over a sick star would make healthy stars sick, and if you co-house them in the same aquarium, the healthy ones would always get sick when they were anywhere near or exposed to the water from a diseased star. There's something in the water. That's right. There's something in the water. But they wanted to refine it a little bit more and know that it was something directly from the diseased star. And so they created a slurry from the tissues of the disease star and injected that into the healthy star to be able to show that there really was something infectious from the disease star that was making the healthy star sick and then die. And then you control those kinds of what we call 'challenge experiments' by inactivating in some way that slurry of infected disease stuff. And in this case, what they were able to do was to 'heat-kill' [any pathogens in this slurry] by heating it up. And so the thing that was very successful right from the beginning was that the stars that were infected with a presumptive disease got sick and died, and the controls essentially stayed healthy. You do that control to make sure that it's not like…injecting a slurry into a star is what makes them sick? That's right. And you're also having animals come in sick, right? So you want to know that they weren't just gonna get sick anyway. You want to be sure that it was what you did that actually affected their health status. So you have a slurry — like a milkshake of sea star — and you know that within it is a problematic agent of some kind. How do you figure out what is in that milkshake that is the problem? The real breakthrough came when Alyssa had the idea that maybe we should try a cleaner infection source and decided to test the coelomic fluid, which is basically the blood of the star. With a syringe, you can extract the coelomic fluid of the sick star and you can also heat-kill it, and you can do the same experiment challenging with that. And it was a really exciting moment because she and Melanie confirmed that that was a really effective way of transmitting the disease because it's cleaner. It's cleaner, like there's less stuff than in the tissue? Like blood is just like a simpler material? Right. So, that was really the beginning of being able to figure out what it was that was in the coelomic fluid that was causing the disease. So basically it's like: … So it seems like it might be ingredient B that's causing the problem here because it's consistent across all samples? Yeah, that's exactly it. And so then that was very, very incredibly exciting. Wow. There's this one bacterium — Vibrio pectenicida — that's showing up in all of the diseased material samples. Could it be that? We weren't sure. We sort of thought, after 12 years, this is gonna be something so strange! So weird! You know, something alien that we've never seen before. And so to have a Vibrio — something that we think of as a little bit more common — turn up was really surprising. Then one of our colleagues at the University of British Columbia, Amy Chan, was able to culture that particular bacterium from the disease star. And so now she had a pure culture of the presumptive killer. And then last summer, Melanie and Alyssa were able to test that again under quarantine conditions and find that it immediately killed the stars that were tested. How did you all feel? Oh, we were definitely dancing around the room. It was — just such a happy moment of fulfillment. I really do like to say that at the beginning of the task that Nature Conservancy handed us — to figure out the causative agent — we told them again and again that this is a very risky project. We can't guarantee we're going to be successful. So yeah, we were incredibly elated when we really felt confident in the answer. It was just hundreds and hundreds of hours of tests and challenge experiments that came out so beautifully. What does it mean to finally have an answer here? What are the next steps? This was the part of it that really kept me awake at night because I just felt so worried early on at the idea that we were working on a roadmap to recovery of a species without knowing what was killing it, and I just felt like we couldn't do it if we were flying blind like that. We wouldn't know what season the pathogenic agent came around. We wouldn't know what its environmental reservoirs were. We didn't know what was making stars susceptible. It was going to be really hard, and it wasn't going to feel right to just put animals out in the wild without knowing more. And so knowing that this is one of the primary causative agents — maybe the only causative agent — allows us to test for it in the water. It allows us to find out if there are some bays where this is being concentrated, to find out if there are some foods the stars are eating that are concentrating this bacterium and delivering a lethal dose to a star. Now we'll be able to answer those questions, and I think that's going to give us a really good opportunity to design better strategies for saving them. It feels like you now have a key to use to sort of unlock various pieces of this. We totally do. And it's so exciting and so gratifying because that's what we're supposed to do, right? As scientists and as disease ecologists, we're supposed to solve these mysteries. And it feels really great to have solved this one. And I don't think there's a day in the last 12 years that I haven't thought about it and been really frustrated we didn't know what it was. So it's particularly gratifying to me to have to have reached this point. Drew Harvell is the author of many popular science books about marine biology and ecology, including her latest, The Ocean's Menagerie. She also wrote a book about marine disease called Ocean Outbreak. Solve the daily Crossword
CBS News
12 hours ago
- CBS News
Billions of starfish have died in a decade-long epidemic. Scientists say they now know why.
Scientists say they have at last solved the mystery of what killed more than 5 billion sea stars – often known as starfish – off the Pacific coast of North America in a decade-long epidemic. Starting in 2013, a mysterious sea star wasting disease sparked a mass die-off from Mexico to Alaska. The epidemic has devastated more than 20 species and continues today. Worst hit was a species called the sunflower sea star, which lost around 90% of its population in the outbreak's first five years. "It's really quite gruesome," said marine disease ecologist Alyssa Gehman at the Hakai Institute in British Columbia, Canada, who helped pinpoint the cause. Healthy sea stars have "puffy arms sticking straight out," she said. But the wasting disease causes them to grow lesions and "then their arms actually fall off." The culprit? Bacteria that has also infected shellfish, according to a study published Monday in the journal Nature Ecology and Evolution. The findings "solve a long-standing question about a very serious disease in the ocean," said Rebecca Vega Thurber, a marine microbiologist at University of California, Santa Barbara, who was not involved in the study. Sea stars typically have five arms and some species sport up to 24 arms. They range in color from solid orange to tapestries of orange, purple, brown and green. "Symptoms of sea star wasting syndrome include abnormally twisted arms, white lesions, deflation of arms and body, arm loss, and body disintegration," the National Park Service says. "They die over the course of days or weeks." It took more than a decade for researchers to identify the cause of the disease, with many false leads and twists and turns along the way. Early research hinted the cause might be a virus, but it turned out the densovirus that scientists initially focused on was actually a normal resident inside healthy sea stars and not associated with disease, said Melanie Prentice of the Hakai Institute, co-author of the new study. Other efforts missed the real killer because researchers studied tissue samples of dead sea stars that no longer contained the bodily fluid that surrounds the organs. But the latest study includes detailed analysis of this fluid, called coelomic fluid, where the bacteria Vibrio pectenicida were found. "It's incredibly difficult to trace the source of so many environmental diseases, especially underwater," said microbiologist Blake Ushijima of the University of North Carolina, Wilmington, who was not involved in the research. He said the detective work by this team was "really smart and significant." Now that scientists know the cause, they have a better shot at intervening to help sea stars. The International Union for Conservation of Nature has listed the sunflower sea star as critically endangered. Prentice said that scientists could potentially now test which of the remaining sea stars are still healthy — and consider whether to relocate them, or breed them in captivity to later transplant them to areas that have lost almost all their sunflower sea stars. Scientists may also test if some populations have natural immunity, and if treatments like probiotics may help boost immunity to the disease. Such recovery work is not only important for sea stars, but for entire Pacific ecosystems because healthy starfish gobble up excess sea urchins, researchers say. Sunflower sea stars "look sort of innocent when you see them, but they eat almost everything that lives on the bottom of the ocean," said Gehman. "They're voracious eaters." With many fewer sea stars, the sea urchins that they usually munch on exploded in population — and in turn gobbled up around 95% of the kelp forest s in Northern California within a decade. These kelp forests provide food and habitat for a wide variety of animals including fish, sea otters and seals. Researchers hope the new findings will allow them to restore sea star populations — and regrow the kelp forests that Thurber compares to "the rainforests of the ocean."
Gizmodo
13 hours ago
- Gizmodo
A Mystery Killer Wiped Out Billions of Sea Stars. Biologists Just Solved the Case.
Columbo, eat your heart out: A team of scientists has just solved a massive marine murder mystery, nabbing the culprit behind the deaths of billions of sea stars over the past decade. In a new study, researchers in the U.S. and Canada argue that the bacterial cousin of cholera is behind the epidemic. Through a series of experiments involving both wild and captive sea stars, they found evidence that Vibrio pectenicida is the likely cause of sea star wasting disease—a devastating condition that causes the invertebrates to decay and essentially 'melt.' The team's findings appear to be well supported with evidence, Zak Swartz, a biologist specializing in sea stars at the Marine Biological Laboratory who was not involved with the study, told Gizmodo. 'This study definitely passes the sniff test for me. It seems quite convincing that V. pectenicida bacteria are at least one causative agent of SSWS,' Swartz said. Sea stars started disappearing in 2013, when a massive outbreak of SSWD struck the North American Pacific coast. The disease swept the seas from Alaska to Mexico, decimating more than 20 different species of sea stars, which are also known as starfish. Afflicted creatures first develop visible lesions on their skin, and then their tissue starts to decay. Death by SSWD is often swift, killing the sea star within days. There have been other mass sea star die-offs in recent decades, but the sheer scale and spread of this outbreak makes it possibly the largest marine disease epidemic ever recorded in the wild. Researchers estimate that one particular sea star species, Pycnopodia helianthoides, has lost 90% of its population to SSWD. The destruction has also dramatically changed the environments where the sea stars once thrived. In the aftermath of SSWD outbreaks, some areas have also lost kelp forests, as sea urchins—once kept in check by sea stars—decimated the underwater forests. Marine scientists have been looking for the cause of SSWD ever since its emergence. And like any great mystery, there have been some twists. In 2014, a research team published a paper that argued a sea star-associated densovirus caused SSWD. But subsequent studies showed that this virus—or any potentially pathogenic virus for that matter—could only be found in a minority of affected species, ruling it out as the likeliest suspect. Swartz noted that some Vibrio bacteria, however, were already known to cause disease in echinoderms—the broad group of marine invertebrates that includes sea stars. 'So in a sense, it feels like the answer was hiding right under our noses. It makes total sense,' he said. Several species of Vibrio can also sicken humans, including cholera (Vibrio cholerae). The researchers didn't set out on this study with V. pectenicida in mind from the get-go. They exhaustively studied samples of sea stars with SSWD and healthy specimens, eventually finding that only the diseased sea stars carried high levels of the bacteria in their coelomic fluid (the invertebrate version of blood). The researchers were then able to isolate and grow new populations of the bacteria collected from the sick sea stars. And when they exposed healthy sea stars to these bacteria, the creatures rapidly developed and died from SSWD. These experiments are the same sort used to identify and conclusively show a particular germ causes a specific disease in humans, strengthening the team's case. Further analysis also revealed that SSWD is caused by a specific strain of the bacteria, called FHCF-3. 'Here we use controlled exposure experiments, genetic datasets, and field observations to demonstrate that the bacterium, Vibrio pectenicida strain FHCF-3, is a causative agent of SSWD,' the authors wrote in their paper, published Monday in Nature Ecology and Evolution. Though the mystery of what causes SSWD appears solved, Swartz and the study authors note that there are still several important unanswered questions. For example, scientists aren't sure exactly how the outbreaks start. It's possible the bacteria could spread via sea stars' shared food, or through physical contact with other sea stars. Low levels of the bacteria may also always be circulating in the environment, but only become a major problem under specific conditions, like at a certain temperature (Vibrio bacteria in general thrive in warmer water). Still, given that SSWD remains a threat to sea stars, simply knowing its cause could boost sea star recovery efforts, the researchers said. It might be possible to find genetic mutations that help sea stars fend off these infections, for instance, enabling scientists to breed sea stars carrying these mutations in captivity with the aim of reintroducing them into the wild to bolster the population's resilience.
