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Women hematologists advance MM research, give back
Inspired in childhood to study medicine, Dr. Madduri chose to specialize in oncology after losing a grandparent to cancer. After moving to the United States as a fifth grader, she went back to India every summer. While visiting as a college student, Dr. Madduri found her grandmother pale, with symptoms such as blood in the stool. Diagnosed with stage IV colon cancer, the grandmother died 6 months later.
“I realized I really wanted to be an oncologist because I wanted to see what I could have done to help my grandma,” Dr. Madduri said in an interview.
Today, as a senior medical director at Janssen Oncology, Dr. Madduri joins her colleague Lisa Kallenbach, MD, and others on a team of hematologist oncologists who are working to advance the treatment of multiple myeloma with chimeric antigen receptor (CAR) T-cell therapy. She and Dr. Kallenbach also mentor other blood cancer specialists through a company-sponsored Women in Hematology program.
Dr. Kallenbach, group medical director at the firm, had also long wanted to become a doctor. Unlike Dr. Madduri, however, Dr. Kallenbach took a “long and winding road” and didn’t start med school until age 30.
Put off by college premed requirements, Dr. Kallenbach majored in anthropology and suppressed her desire to study medicine while she got a master’s degree in public administration, worked in public health, and volunteered with the Peace Corps. Ultimately, she decided to do a postbaccalaureate program, entered Brown University in Providence, R.I., and loved it.
“No one in my family was a doctor, so it was all very mystical to me,” she said. “It wasn’t until I worked for a doctor where it was demystified, and I thought, ‘Ah, they’re not any smarter. They just work really hard, and I can work hard. I always do.’”
Time for a change
Hard work brought both Dr. Kallenbach and Dr. Madduri to Janssen at roughly the same time, for similar reasons.
Dr. Madduri had been a junior faculty member at Mount Sinai, where she followed her mentor’s advice and fought hard to become principal investigator of the CARTITUDE-1 trial, which she presented at the annual meetings of the American Society of Hematology in 2019 and 2020. This research led to the Food and Drug Administration’s approval of the CAR T therapy Carvykti for multiple myeloma. Dr. Madduri also launched the CAR T program at Mount Sinai and quickly gained prominence in her field, despite being the hospital’s youngest faculty member for myeloma. But when the pandemic hit, she decided to try something different.
“I was helping one person at a time as a physician, but [Janssen] gave me the opportunity to help people in a much broader sense,” said Dr. Madduri, who joined the firm in April 2021. “I’m now the one designing the trials and looking at what the needs are in myeloma.”
“Janssen’s CAR T product [Carvykti] revolutionized the space because after a one-time treatment, patients are in a deep and durable remission and living much longer,” she said. Furthermore, Janssen offered Dr. Madduri the chance to design the trials toward that long-held goal.
“I want to be part of the team where they’re really dedicated to curing myeloma,” Dr. Madduri said. And she continues to see patients as an adjunct assistant professor at Stanford (Calif.) University, where she did a blood & marrow transplantation fellowship.
Dr. Kallenbach was also drawn to Janssen because of her pandemic experiences – and the promise of broader opportunities, including a better work-life balance. One patient at a time, she was treating a variety of hematologic disorders and malignancies. Although she enjoyed it, she just needed a change.
“It had been 9 months of COVID, and it was just a really busy time and stressful,” Dr. Kallenbach said. When a friend shared the Janssen job posting, she took it as a sign. “I thought, I could really make an impact here. Now I’ve gone from treating one patient at a time to treating tons of patients and helping to get this drug [Carvykti] to patients who can really use it.”
A cancer field with potential
While it was Dr. Madduri’s grandmother’s illness that drew her to study oncology, she chose not to work on the colon cancer that killed her grandmother. It felt too personal, and she didn’t foresee being able to help patients in the ways she wanted. Instead of sending them to hospice when treatment options ran out, Dr. Madduri saw the myeloma landscape advancing rapidly, with more drugs becoming available.
“What really interests me is that this field is going somewhere, and we can potentially find something to cure these patients,” Dr. Madduri said. “There’s great need, but there’s rapid advancement happening as well. I wanted to go into something where I could really make a difference and help these patients that I couldn’t help before.”
She’s currently managing CARTITUDE-6, a head-to-head frontline trial testing CAR T-cell therapy (Carvykti) in patients eligible for transplant. “Right now the standard of care is transplant, so there’s a lot of excitement” with the idea of replacing transplant with CAR T in newly diagnosed patients, something that’s never been done. Dr. Madduri hopes this will move patients into deeper remission and eventually help pave the path to a cure. “We have to change the landscape. We have to push the boundaries, right?”
Similarly, Dr. Kallenbach was drawn to myeloma because of the rush of new therapies.
“From the time I was training to the time I was practicing, the treatments completely changed,” she said. “That’s always exciting when you’re making that much progress on a disease, to see these enormous changes. Now you’re actually seeing people who’ve had tons of prior therapies have responses that I’ve just never seen before.”
Dr. Kallenbach also found fulfillment through patient care. “People really connect with their oncologist, and that relationship is really special,” she said. “The other thing is that you really learn from cancer patients how to live your life, like what’s important. People’s priorities become very clear.”
Importance of mentorship
Both women credit part of their success to finding excellent mentors early on, and both are paying it forward by mentoring other women in their field.
Dr. Madduri met her mentor, Sundar Jagannath, MBBS, when he interviewed her at Icahn School of Medicine’s Tisch Cancer Institute in New York, where he’s director of the multiple myeloma program and the Myeloma Center of Excellence. Noting her enthusiasm and excellent training, Dr. Jagannath recruited Dr. Madduri and quickly discovered her organizational skills. When she expressed interest in running the CAR T program, he let her run with it, while advising her on how to ensure that she got respect and credit for her work.
“You have to do your part, but if you don’t have the right mentor telling you, it’d be really hard for someone who’s just starting out to know what to do,” Dr. Madduri said.
Dr. Jagannath’s guidance paid off. “When she made the ASH presentation, everybody was impressed,” he said. “She captured the attention of my peers who have been in the field for a long time, so she immediately made a national splash.”
Just a few years out of her own fellowship, Dr. Madduri had already begun mentoring other fellows. Through Women in Hematology, she helps gather data about the roles women play in her field and how to further their advancement. “The myeloma field is slowly starting to shift” toward more gender balance, she said – progress she feels happy to support.
Dr. Kallenbach’s mentoring is less formal, yet it makes a deep impact on those she takes under her wing. Her mentees are mostly the students she’s met on the Bryn Mawr College campus where she walks her two Labradors. That’s how she met Louise Breen, who, after a postbaccalaureate there, just graduated from University of Pennsylvania, Philadelphia, and is headed for residency at Mass General Hospital, Boston.
Dr. Breen said her mentor’s greatest gift has been “showing many of us that it’s possible to do it and what life could look like.” While fostering students’ self-confidence as they wrangle with imposter syndrome, Dr. Kallenbach has also demonstrated what a work-life balance in medicine can look like. She learned that from her own mentor, Hedy Smith, MD, PhD, now clinical director of inpatient hematology/oncology at MedStar Washington Hospital Center, and previously an associate professor at Tufts Medical Center.
Dr. Kallenbach quickly made an impression on Dr. Smith by coming to her door in tears one day.
“She was so devastated at the additions I made in her notes,” recalled Dr. Smith. “She felt that she had presented me with this less-than-adequate document. ... I told her, ‘this really says the world about who you are, who you’re going to become in oncology.’ I was struck by her character, a dedication to her work, and her desire to perfect it.”
Three years later, Dr. Smith remembers Dr. Kallenbach coming to her office with a big smile and saying: “Look at this. You didn’t make any changes.” Then Dr. Smith knew that her mentee was ready for the next chapter of her career.
They have kept in touch, with Dr. Kallenbach periodically calling to discuss a difficult case or to plan to meet up at conferences. “It always puts a smile on my face because this person who was once my student has now undergone this metamorphosis, and here we are, now truly equals and colleagues attending the meetings together,” Dr. Smith remarked.
Dr. Kallenbach feels grateful about finding a strong female mentor early in her medical career, especially given some of the everyday sexism she has encountered. A male colleague at a conference once expressed shock that she was practicing medicine full time while also being a mother. Dr. Kallenbach hasn’t encountered such attitudes while working in the pharmaceutical industry.
“I feel more valued as a doctor now than I ever did in practice,” she said. While before, she felt respected, “here, I feel like your expertise is valued, and you can actually help shape programs and inform how doctors practice.”
Dr. Madduri, too, feels like she’s where she’s supposed to be. “I went into the field because I really wanted to help people and make a difference,” she said. “I’m doing everything that I wanted to do.”
Inspired in childhood to study medicine, Dr. Madduri chose to specialize in oncology after losing a grandparent to cancer. After moving to the United States as a fifth grader, she went back to India every summer. While visiting as a college student, Dr. Madduri found her grandmother pale, with symptoms such as blood in the stool. Diagnosed with stage IV colon cancer, the grandmother died 6 months later.
“I realized I really wanted to be an oncologist because I wanted to see what I could have done to help my grandma,” Dr. Madduri said in an interview.
Today, as a senior medical director at Janssen Oncology, Dr. Madduri joins her colleague Lisa Kallenbach, MD, and others on a team of hematologist oncologists who are working to advance the treatment of multiple myeloma with chimeric antigen receptor (CAR) T-cell therapy. She and Dr. Kallenbach also mentor other blood cancer specialists through a company-sponsored Women in Hematology program.
Dr. Kallenbach, group medical director at the firm, had also long wanted to become a doctor. Unlike Dr. Madduri, however, Dr. Kallenbach took a “long and winding road” and didn’t start med school until age 30.
Put off by college premed requirements, Dr. Kallenbach majored in anthropology and suppressed her desire to study medicine while she got a master’s degree in public administration, worked in public health, and volunteered with the Peace Corps. Ultimately, she decided to do a postbaccalaureate program, entered Brown University in Providence, R.I., and loved it.
“No one in my family was a doctor, so it was all very mystical to me,” she said. “It wasn’t until I worked for a doctor where it was demystified, and I thought, ‘Ah, they’re not any smarter. They just work really hard, and I can work hard. I always do.’”
Time for a change
Hard work brought both Dr. Kallenbach and Dr. Madduri to Janssen at roughly the same time, for similar reasons.
Dr. Madduri had been a junior faculty member at Mount Sinai, where she followed her mentor’s advice and fought hard to become principal investigator of the CARTITUDE-1 trial, which she presented at the annual meetings of the American Society of Hematology in 2019 and 2020. This research led to the Food and Drug Administration’s approval of the CAR T therapy Carvykti for multiple myeloma. Dr. Madduri also launched the CAR T program at Mount Sinai and quickly gained prominence in her field, despite being the hospital’s youngest faculty member for myeloma. But when the pandemic hit, she decided to try something different.
“I was helping one person at a time as a physician, but [Janssen] gave me the opportunity to help people in a much broader sense,” said Dr. Madduri, who joined the firm in April 2021. “I’m now the one designing the trials and looking at what the needs are in myeloma.”
“Janssen’s CAR T product [Carvykti] revolutionized the space because after a one-time treatment, patients are in a deep and durable remission and living much longer,” she said. Furthermore, Janssen offered Dr. Madduri the chance to design the trials toward that long-held goal.
“I want to be part of the team where they’re really dedicated to curing myeloma,” Dr. Madduri said. And she continues to see patients as an adjunct assistant professor at Stanford (Calif.) University, where she did a blood & marrow transplantation fellowship.
Dr. Kallenbach was also drawn to Janssen because of her pandemic experiences – and the promise of broader opportunities, including a better work-life balance. One patient at a time, she was treating a variety of hematologic disorders and malignancies. Although she enjoyed it, she just needed a change.
“It had been 9 months of COVID, and it was just a really busy time and stressful,” Dr. Kallenbach said. When a friend shared the Janssen job posting, she took it as a sign. “I thought, I could really make an impact here. Now I’ve gone from treating one patient at a time to treating tons of patients and helping to get this drug [Carvykti] to patients who can really use it.”
A cancer field with potential
While it was Dr. Madduri’s grandmother’s illness that drew her to study oncology, she chose not to work on the colon cancer that killed her grandmother. It felt too personal, and she didn’t foresee being able to help patients in the ways she wanted. Instead of sending them to hospice when treatment options ran out, Dr. Madduri saw the myeloma landscape advancing rapidly, with more drugs becoming available.
“What really interests me is that this field is going somewhere, and we can potentially find something to cure these patients,” Dr. Madduri said. “There’s great need, but there’s rapid advancement happening as well. I wanted to go into something where I could really make a difference and help these patients that I couldn’t help before.”
She’s currently managing CARTITUDE-6, a head-to-head frontline trial testing CAR T-cell therapy (Carvykti) in patients eligible for transplant. “Right now the standard of care is transplant, so there’s a lot of excitement” with the idea of replacing transplant with CAR T in newly diagnosed patients, something that’s never been done. Dr. Madduri hopes this will move patients into deeper remission and eventually help pave the path to a cure. “We have to change the landscape. We have to push the boundaries, right?”
Similarly, Dr. Kallenbach was drawn to myeloma because of the rush of new therapies.
“From the time I was training to the time I was practicing, the treatments completely changed,” she said. “That’s always exciting when you’re making that much progress on a disease, to see these enormous changes. Now you’re actually seeing people who’ve had tons of prior therapies have responses that I’ve just never seen before.”
Dr. Kallenbach also found fulfillment through patient care. “People really connect with their oncologist, and that relationship is really special,” she said. “The other thing is that you really learn from cancer patients how to live your life, like what’s important. People’s priorities become very clear.”
Importance of mentorship
Both women credit part of their success to finding excellent mentors early on, and both are paying it forward by mentoring other women in their field.
Dr. Madduri met her mentor, Sundar Jagannath, MBBS, when he interviewed her at Icahn School of Medicine’s Tisch Cancer Institute in New York, where he’s director of the multiple myeloma program and the Myeloma Center of Excellence. Noting her enthusiasm and excellent training, Dr. Jagannath recruited Dr. Madduri and quickly discovered her organizational skills. When she expressed interest in running the CAR T program, he let her run with it, while advising her on how to ensure that she got respect and credit for her work.
“You have to do your part, but if you don’t have the right mentor telling you, it’d be really hard for someone who’s just starting out to know what to do,” Dr. Madduri said.
Dr. Jagannath’s guidance paid off. “When she made the ASH presentation, everybody was impressed,” he said. “She captured the attention of my peers who have been in the field for a long time, so she immediately made a national splash.”
Just a few years out of her own fellowship, Dr. Madduri had already begun mentoring other fellows. Through Women in Hematology, she helps gather data about the roles women play in her field and how to further their advancement. “The myeloma field is slowly starting to shift” toward more gender balance, she said – progress she feels happy to support.
Dr. Kallenbach’s mentoring is less formal, yet it makes a deep impact on those she takes under her wing. Her mentees are mostly the students she’s met on the Bryn Mawr College campus where she walks her two Labradors. That’s how she met Louise Breen, who, after a postbaccalaureate there, just graduated from University of Pennsylvania, Philadelphia, and is headed for residency at Mass General Hospital, Boston.
Dr. Breen said her mentor’s greatest gift has been “showing many of us that it’s possible to do it and what life could look like.” While fostering students’ self-confidence as they wrangle with imposter syndrome, Dr. Kallenbach has also demonstrated what a work-life balance in medicine can look like. She learned that from her own mentor, Hedy Smith, MD, PhD, now clinical director of inpatient hematology/oncology at MedStar Washington Hospital Center, and previously an associate professor at Tufts Medical Center.
Dr. Kallenbach quickly made an impression on Dr. Smith by coming to her door in tears one day.
“She was so devastated at the additions I made in her notes,” recalled Dr. Smith. “She felt that she had presented me with this less-than-adequate document. ... I told her, ‘this really says the world about who you are, who you’re going to become in oncology.’ I was struck by her character, a dedication to her work, and her desire to perfect it.”
Three years later, Dr. Smith remembers Dr. Kallenbach coming to her office with a big smile and saying: “Look at this. You didn’t make any changes.” Then Dr. Smith knew that her mentee was ready for the next chapter of her career.
They have kept in touch, with Dr. Kallenbach periodically calling to discuss a difficult case or to plan to meet up at conferences. “It always puts a smile on my face because this person who was once my student has now undergone this metamorphosis, and here we are, now truly equals and colleagues attending the meetings together,” Dr. Smith remarked.
Dr. Kallenbach feels grateful about finding a strong female mentor early in her medical career, especially given some of the everyday sexism she has encountered. A male colleague at a conference once expressed shock that she was practicing medicine full time while also being a mother. Dr. Kallenbach hasn’t encountered such attitudes while working in the pharmaceutical industry.
“I feel more valued as a doctor now than I ever did in practice,” she said. While before, she felt respected, “here, I feel like your expertise is valued, and you can actually help shape programs and inform how doctors practice.”
Dr. Madduri, too, feels like she’s where she’s supposed to be. “I went into the field because I really wanted to help people and make a difference,” she said. “I’m doing everything that I wanted to do.”
Inspired in childhood to study medicine, Dr. Madduri chose to specialize in oncology after losing a grandparent to cancer. After moving to the United States as a fifth grader, she went back to India every summer. While visiting as a college student, Dr. Madduri found her grandmother pale, with symptoms such as blood in the stool. Diagnosed with stage IV colon cancer, the grandmother died 6 months later.
“I realized I really wanted to be an oncologist because I wanted to see what I could have done to help my grandma,” Dr. Madduri said in an interview.
Today, as a senior medical director at Janssen Oncology, Dr. Madduri joins her colleague Lisa Kallenbach, MD, and others on a team of hematologist oncologists who are working to advance the treatment of multiple myeloma with chimeric antigen receptor (CAR) T-cell therapy. She and Dr. Kallenbach also mentor other blood cancer specialists through a company-sponsored Women in Hematology program.
Dr. Kallenbach, group medical director at the firm, had also long wanted to become a doctor. Unlike Dr. Madduri, however, Dr. Kallenbach took a “long and winding road” and didn’t start med school until age 30.
Put off by college premed requirements, Dr. Kallenbach majored in anthropology and suppressed her desire to study medicine while she got a master’s degree in public administration, worked in public health, and volunteered with the Peace Corps. Ultimately, she decided to do a postbaccalaureate program, entered Brown University in Providence, R.I., and loved it.
“No one in my family was a doctor, so it was all very mystical to me,” she said. “It wasn’t until I worked for a doctor where it was demystified, and I thought, ‘Ah, they’re not any smarter. They just work really hard, and I can work hard. I always do.’”
Time for a change
Hard work brought both Dr. Kallenbach and Dr. Madduri to Janssen at roughly the same time, for similar reasons.
Dr. Madduri had been a junior faculty member at Mount Sinai, where she followed her mentor’s advice and fought hard to become principal investigator of the CARTITUDE-1 trial, which she presented at the annual meetings of the American Society of Hematology in 2019 and 2020. This research led to the Food and Drug Administration’s approval of the CAR T therapy Carvykti for multiple myeloma. Dr. Madduri also launched the CAR T program at Mount Sinai and quickly gained prominence in her field, despite being the hospital’s youngest faculty member for myeloma. But when the pandemic hit, she decided to try something different.
“I was helping one person at a time as a physician, but [Janssen] gave me the opportunity to help people in a much broader sense,” said Dr. Madduri, who joined the firm in April 2021. “I’m now the one designing the trials and looking at what the needs are in myeloma.”
“Janssen’s CAR T product [Carvykti] revolutionized the space because after a one-time treatment, patients are in a deep and durable remission and living much longer,” she said. Furthermore, Janssen offered Dr. Madduri the chance to design the trials toward that long-held goal.
“I want to be part of the team where they’re really dedicated to curing myeloma,” Dr. Madduri said. And she continues to see patients as an adjunct assistant professor at Stanford (Calif.) University, where she did a blood & marrow transplantation fellowship.
Dr. Kallenbach was also drawn to Janssen because of her pandemic experiences – and the promise of broader opportunities, including a better work-life balance. One patient at a time, she was treating a variety of hematologic disorders and malignancies. Although she enjoyed it, she just needed a change.
“It had been 9 months of COVID, and it was just a really busy time and stressful,” Dr. Kallenbach said. When a friend shared the Janssen job posting, she took it as a sign. “I thought, I could really make an impact here. Now I’ve gone from treating one patient at a time to treating tons of patients and helping to get this drug [Carvykti] to patients who can really use it.”
A cancer field with potential
While it was Dr. Madduri’s grandmother’s illness that drew her to study oncology, she chose not to work on the colon cancer that killed her grandmother. It felt too personal, and she didn’t foresee being able to help patients in the ways she wanted. Instead of sending them to hospice when treatment options ran out, Dr. Madduri saw the myeloma landscape advancing rapidly, with more drugs becoming available.
“What really interests me is that this field is going somewhere, and we can potentially find something to cure these patients,” Dr. Madduri said. “There’s great need, but there’s rapid advancement happening as well. I wanted to go into something where I could really make a difference and help these patients that I couldn’t help before.”
She’s currently managing CARTITUDE-6, a head-to-head frontline trial testing CAR T-cell therapy (Carvykti) in patients eligible for transplant. “Right now the standard of care is transplant, so there’s a lot of excitement” with the idea of replacing transplant with CAR T in newly diagnosed patients, something that’s never been done. Dr. Madduri hopes this will move patients into deeper remission and eventually help pave the path to a cure. “We have to change the landscape. We have to push the boundaries, right?”
Similarly, Dr. Kallenbach was drawn to myeloma because of the rush of new therapies.
“From the time I was training to the time I was practicing, the treatments completely changed,” she said. “That’s always exciting when you’re making that much progress on a disease, to see these enormous changes. Now you’re actually seeing people who’ve had tons of prior therapies have responses that I’ve just never seen before.”
Dr. Kallenbach also found fulfillment through patient care. “People really connect with their oncologist, and that relationship is really special,” she said. “The other thing is that you really learn from cancer patients how to live your life, like what’s important. People’s priorities become very clear.”
Importance of mentorship
Both women credit part of their success to finding excellent mentors early on, and both are paying it forward by mentoring other women in their field.
Dr. Madduri met her mentor, Sundar Jagannath, MBBS, when he interviewed her at Icahn School of Medicine’s Tisch Cancer Institute in New York, where he’s director of the multiple myeloma program and the Myeloma Center of Excellence. Noting her enthusiasm and excellent training, Dr. Jagannath recruited Dr. Madduri and quickly discovered her organizational skills. When she expressed interest in running the CAR T program, he let her run with it, while advising her on how to ensure that she got respect and credit for her work.
“You have to do your part, but if you don’t have the right mentor telling you, it’d be really hard for someone who’s just starting out to know what to do,” Dr. Madduri said.
Dr. Jagannath’s guidance paid off. “When she made the ASH presentation, everybody was impressed,” he said. “She captured the attention of my peers who have been in the field for a long time, so she immediately made a national splash.”
Just a few years out of her own fellowship, Dr. Madduri had already begun mentoring other fellows. Through Women in Hematology, she helps gather data about the roles women play in her field and how to further their advancement. “The myeloma field is slowly starting to shift” toward more gender balance, she said – progress she feels happy to support.
Dr. Kallenbach’s mentoring is less formal, yet it makes a deep impact on those she takes under her wing. Her mentees are mostly the students she’s met on the Bryn Mawr College campus where she walks her two Labradors. That’s how she met Louise Breen, who, after a postbaccalaureate there, just graduated from University of Pennsylvania, Philadelphia, and is headed for residency at Mass General Hospital, Boston.
Dr. Breen said her mentor’s greatest gift has been “showing many of us that it’s possible to do it and what life could look like.” While fostering students’ self-confidence as they wrangle with imposter syndrome, Dr. Kallenbach has also demonstrated what a work-life balance in medicine can look like. She learned that from her own mentor, Hedy Smith, MD, PhD, now clinical director of inpatient hematology/oncology at MedStar Washington Hospital Center, and previously an associate professor at Tufts Medical Center.
Dr. Kallenbach quickly made an impression on Dr. Smith by coming to her door in tears one day.
“She was so devastated at the additions I made in her notes,” recalled Dr. Smith. “She felt that she had presented me with this less-than-adequate document. ... I told her, ‘this really says the world about who you are, who you’re going to become in oncology.’ I was struck by her character, a dedication to her work, and her desire to perfect it.”
Three years later, Dr. Smith remembers Dr. Kallenbach coming to her office with a big smile and saying: “Look at this. You didn’t make any changes.” Then Dr. Smith knew that her mentee was ready for the next chapter of her career.
They have kept in touch, with Dr. Kallenbach periodically calling to discuss a difficult case or to plan to meet up at conferences. “It always puts a smile on my face because this person who was once my student has now undergone this metamorphosis, and here we are, now truly equals and colleagues attending the meetings together,” Dr. Smith remarked.
Dr. Kallenbach feels grateful about finding a strong female mentor early in her medical career, especially given some of the everyday sexism she has encountered. A male colleague at a conference once expressed shock that she was practicing medicine full time while also being a mother. Dr. Kallenbach hasn’t encountered such attitudes while working in the pharmaceutical industry.
“I feel more valued as a doctor now than I ever did in practice,” she said. While before, she felt respected, “here, I feel like your expertise is valued, and you can actually help shape programs and inform how doctors practice.”
Dr. Madduri, too, feels like she’s where she’s supposed to be. “I went into the field because I really wanted to help people and make a difference,” she said. “I’m doing everything that I wanted to do.”
Ibrutinib + venetoclax: High-risk features don’t lessen CLL response
In the new analysis, published in Clinical Cancer Research, investigators compared outcomes in 66 adults without genetic risk factors to 129 with deletion of 17p, mutated TP53, and/or unmutated immunoglobulin heavy chain, all of which are associated with poor outcomes and poor responses to chemoimmunotherapy.
Over 95% of patients responded regardless of risk factors, with complete response in 61% of patients with and 53% of subjects without high-risk features. Progression free-survival (PFS) lasted at least 3 years in 88% of the high-risk group and 92% of low-risk patients, with over 95% of patients in both groups alive at 3 years
“Since high-risk genetic features inform treatment selection, understanding the efficacy of fixed-duration ibrutinib plus venetoclax in patients with high-risk CLL is important to determine how this regimen fits in the first-line treatment algorithm for the disease,” hematologic oncologist John Allan, MD, a CLL specialist at Weill Cornell Medical Center in New York and the lead investigator, said in a press release from American Association for Cancer Research, publisher of CCR.
Although the analysis was not powered to perform statistical comparisons between the two groups, Dr. Allan said the results “support fixed-duration ibrutinib plus venetoclax as a treatment approach for this patient population.”
The press release also noted that the outcomes “compare favorably” to other upfront targeted therapy approaches for CLL.
Experts respond
Asked for comment, Thomas LeBlanc, MD, a hematologic oncologist at Duke University in Durham, N.C., said “the advent of some fixed duration regimens with novel therapies has been an exciting thing for patients especially, recognizing that at the start of treatment one already knows the completion date, and one can also thus forgo much of the potentially cumulative physical, psychological, and financial toxicity of an indefinite oral therapy.”
As for the new findings, he said they show “that even in this high-risk population ... we can achieve remarkable remission rates and levels of [minimal residual disease] negativity by combining the two best drug classes to date in CLL: BTK inhibitors and venetoclax.”
Another expert, hematologic oncologist John Byrd, MD, a leukemia specialist at the University of Cincinnati, was more cautious.
“These findings confirm the results of many other prior studies of targeted therapies where high complete response rates with absence of detectable disease is observed,” he said.
However, while “such therapeutic combinations for sure enable treatment discontinuation,” Dr. Byrd noted, they “lack long-term follow-up. Given the added toxicities associated with these combinations and lack of long-term follow up, use of treatments such as those brought forth in the CAPTIVATE trial should be considered only in the context of a well-designed clinical trial.”
Study details
The new findings follow previous reports of CAPTIVATE, which found strong first-line response across CLL patients but did not focus as specifically on patients with high-risk genetic features.
Subjects received three 28-day cycles of ibrutinib 420 mg/day followed by twelve 28-day cycles of ibrutinib plus venetoclax, with a 5-week venetoclax ramp-up to 400 mg/day.
Side effects were similar regardless of high-risk features and included, most commonly, diarrhea, neutropenia, nausea, and arthralgia. The most common grade 3/4 treatment-emergent adverse events were neutropenia in 36% of patients in both groups and hypertension in 9% of patients with and 3% of patients without high-risk features.
The study was funded by Pharmacyclics/AbbVie, maker/marketer of both ibrutinib and venetoclax. Investigators had numerous ties to the companies, including Dr. Allan, who reported grants and/or personal fees. Dr. LeBlanc reported speaker/consulting honoraria from AbbVie as well as institutional research funding. Dr. Byrd did not have any connections to the companies.
In the new analysis, published in Clinical Cancer Research, investigators compared outcomes in 66 adults without genetic risk factors to 129 with deletion of 17p, mutated TP53, and/or unmutated immunoglobulin heavy chain, all of which are associated with poor outcomes and poor responses to chemoimmunotherapy.
Over 95% of patients responded regardless of risk factors, with complete response in 61% of patients with and 53% of subjects without high-risk features. Progression free-survival (PFS) lasted at least 3 years in 88% of the high-risk group and 92% of low-risk patients, with over 95% of patients in both groups alive at 3 years
“Since high-risk genetic features inform treatment selection, understanding the efficacy of fixed-duration ibrutinib plus venetoclax in patients with high-risk CLL is important to determine how this regimen fits in the first-line treatment algorithm for the disease,” hematologic oncologist John Allan, MD, a CLL specialist at Weill Cornell Medical Center in New York and the lead investigator, said in a press release from American Association for Cancer Research, publisher of CCR.
Although the analysis was not powered to perform statistical comparisons between the two groups, Dr. Allan said the results “support fixed-duration ibrutinib plus venetoclax as a treatment approach for this patient population.”
The press release also noted that the outcomes “compare favorably” to other upfront targeted therapy approaches for CLL.
Experts respond
Asked for comment, Thomas LeBlanc, MD, a hematologic oncologist at Duke University in Durham, N.C., said “the advent of some fixed duration regimens with novel therapies has been an exciting thing for patients especially, recognizing that at the start of treatment one already knows the completion date, and one can also thus forgo much of the potentially cumulative physical, psychological, and financial toxicity of an indefinite oral therapy.”
As for the new findings, he said they show “that even in this high-risk population ... we can achieve remarkable remission rates and levels of [minimal residual disease] negativity by combining the two best drug classes to date in CLL: BTK inhibitors and venetoclax.”
Another expert, hematologic oncologist John Byrd, MD, a leukemia specialist at the University of Cincinnati, was more cautious.
“These findings confirm the results of many other prior studies of targeted therapies where high complete response rates with absence of detectable disease is observed,” he said.
However, while “such therapeutic combinations for sure enable treatment discontinuation,” Dr. Byrd noted, they “lack long-term follow-up. Given the added toxicities associated with these combinations and lack of long-term follow up, use of treatments such as those brought forth in the CAPTIVATE trial should be considered only in the context of a well-designed clinical trial.”
Study details
The new findings follow previous reports of CAPTIVATE, which found strong first-line response across CLL patients but did not focus as specifically on patients with high-risk genetic features.
Subjects received three 28-day cycles of ibrutinib 420 mg/day followed by twelve 28-day cycles of ibrutinib plus venetoclax, with a 5-week venetoclax ramp-up to 400 mg/day.
Side effects were similar regardless of high-risk features and included, most commonly, diarrhea, neutropenia, nausea, and arthralgia. The most common grade 3/4 treatment-emergent adverse events were neutropenia in 36% of patients in both groups and hypertension in 9% of patients with and 3% of patients without high-risk features.
The study was funded by Pharmacyclics/AbbVie, maker/marketer of both ibrutinib and venetoclax. Investigators had numerous ties to the companies, including Dr. Allan, who reported grants and/or personal fees. Dr. LeBlanc reported speaker/consulting honoraria from AbbVie as well as institutional research funding. Dr. Byrd did not have any connections to the companies.
In the new analysis, published in Clinical Cancer Research, investigators compared outcomes in 66 adults without genetic risk factors to 129 with deletion of 17p, mutated TP53, and/or unmutated immunoglobulin heavy chain, all of which are associated with poor outcomes and poor responses to chemoimmunotherapy.
Over 95% of patients responded regardless of risk factors, with complete response in 61% of patients with and 53% of subjects without high-risk features. Progression free-survival (PFS) lasted at least 3 years in 88% of the high-risk group and 92% of low-risk patients, with over 95% of patients in both groups alive at 3 years
“Since high-risk genetic features inform treatment selection, understanding the efficacy of fixed-duration ibrutinib plus venetoclax in patients with high-risk CLL is important to determine how this regimen fits in the first-line treatment algorithm for the disease,” hematologic oncologist John Allan, MD, a CLL specialist at Weill Cornell Medical Center in New York and the lead investigator, said in a press release from American Association for Cancer Research, publisher of CCR.
Although the analysis was not powered to perform statistical comparisons between the two groups, Dr. Allan said the results “support fixed-duration ibrutinib plus venetoclax as a treatment approach for this patient population.”
The press release also noted that the outcomes “compare favorably” to other upfront targeted therapy approaches for CLL.
Experts respond
Asked for comment, Thomas LeBlanc, MD, a hematologic oncologist at Duke University in Durham, N.C., said “the advent of some fixed duration regimens with novel therapies has been an exciting thing for patients especially, recognizing that at the start of treatment one already knows the completion date, and one can also thus forgo much of the potentially cumulative physical, psychological, and financial toxicity of an indefinite oral therapy.”
As for the new findings, he said they show “that even in this high-risk population ... we can achieve remarkable remission rates and levels of [minimal residual disease] negativity by combining the two best drug classes to date in CLL: BTK inhibitors and venetoclax.”
Another expert, hematologic oncologist John Byrd, MD, a leukemia specialist at the University of Cincinnati, was more cautious.
“These findings confirm the results of many other prior studies of targeted therapies where high complete response rates with absence of detectable disease is observed,” he said.
However, while “such therapeutic combinations for sure enable treatment discontinuation,” Dr. Byrd noted, they “lack long-term follow-up. Given the added toxicities associated with these combinations and lack of long-term follow up, use of treatments such as those brought forth in the CAPTIVATE trial should be considered only in the context of a well-designed clinical trial.”
Study details
The new findings follow previous reports of CAPTIVATE, which found strong first-line response across CLL patients but did not focus as specifically on patients with high-risk genetic features.
Subjects received three 28-day cycles of ibrutinib 420 mg/day followed by twelve 28-day cycles of ibrutinib plus venetoclax, with a 5-week venetoclax ramp-up to 400 mg/day.
Side effects were similar regardless of high-risk features and included, most commonly, diarrhea, neutropenia, nausea, and arthralgia. The most common grade 3/4 treatment-emergent adverse events were neutropenia in 36% of patients in both groups and hypertension in 9% of patients with and 3% of patients without high-risk features.
The study was funded by Pharmacyclics/AbbVie, maker/marketer of both ibrutinib and venetoclax. Investigators had numerous ties to the companies, including Dr. Allan, who reported grants and/or personal fees. Dr. LeBlanc reported speaker/consulting honoraria from AbbVie as well as institutional research funding. Dr. Byrd did not have any connections to the companies.
FROM CLINICAL CANCER RESEARCH
The road to weight loss is paved with collusion and sabotage
Three big bumps on the weight-loss journey
The search for the Holy Grail. The destruction of the One Ring. The never-ending struggle to Lose Weight.
Like most legendary quests, weight loss is a journey, and we need support to help us achieve our goal. Maybe it’s gaining a new workout partner or finding a similarly-goaled Facebook Group. For a lot of people, it’s as simple as your friends and family. A recent study, however, suggests that the people closest to you may be your worst weight-loss enemies, and they might not even know it.
Researchers at the University of Surrey reviewed the literature on the positives and negatives of social support when it comes to weight loss and identified three types of negative effects: acts of sabotage, feeding behavior, and collusion.
Let’s start with the softest of intentions and work our way up. Collusion is the least negative. Friends and family may just go with the flow, even if it doesn’t agree with the goals of the person who’s trying to lose weight. It can even happen when health care professionals try to help their patients navigate or avoid obesity, ultimately killing with kindness, so to speak.
Next up, feeding behavior. Maybe you know someone whose love language is cooking. There are also people who share food because they don’t want to waste it or because they’re trying to be polite. They act out of the goodness of their hearts, but they’re putting up roadblocks to someone’s goals. These types of acts are usually one-sided, the researchers found. Remember, it’s okay to say, “No thanks.”
The last method, sabotage, is the most sinister. The saboteur may discourage others from eating healthy, undermine their efforts to be physically active, or take jabs at their confidence or self-esteem. Something as simple as criticizing someone for eating a salad or refusing to go on a walk with them can cause a setback.
“We need to explore this area further to develop interventions which could target family and friends and help them be more supportive in helping those they are close to lose weight,” said lead author Jane Odgen, PhD, of the University of Surrey, Guildford, England.
Like we said before, weight loss is a journey. The right support can only improve the odds of success.
Robots vs. mosquitoes
If there’s one thing robots are bad at, it’s giving solid mental health advice to people in crisis. If there’s one thing robots are very, very good at, it’s causing apocalypses. And joyous day for humanity, this time we’re not the ones being apocalypsed.
Yet.
Taiwan has a big mosquito problem. Not only do the mosquitoes in Taiwan carry dengue – among other dangerous diseases – but they’ve urbanized. Not urbanized in the sense that they’ve acquired a taste for organic coffee and avocado toast (that would be the millennial mosquito, a separate but even more terrifying creature), but more that they’ve adapted to reproduce literally anywhere and everywhere. Taiwanese mosquitoes like to breed in roadside sewer ditches, and this is where our genocidal robot comes in.
To combat the new, dangerous form of street-savvy mosquito, researchers built a robot armed with both insecticide and high-temperature, high-pressure water jets and sent it into the sewers of Kaohsiung City. The robot’s goal was simple: Whenever it came across signs of heavy mosquito breeding – eggs, larvae, pupae, and so on – the robot went to work. Utilizing both its primary weapons, the robot scrubbed numerous breeding sites across the city clean.
The researchers could just sit back and wait to see how effective their robot was. In the immediate aftermath, at various monitoring sites placed alongside the ditches, adult mosquito density fell by two-thirds in areas targeted by the robot. That’s nothing to sniff at, and it does make sense. After all, mosquitoes are quite difficult to kill in their adult stage, why not target them when they’re young and basically immobile?
The researchers saw promise with their mosquito-killing robot, but we’ve noticed a rather large issue. Killing two-thirds of mosquitoes is fine, but the third that’s left will be very angry. Very angry indeed. After all, we’re targeting the mosquito equivalent of children. Let’s hope our mosquito Terminator managed to kill mosquito Sarah Connor, or we’re going to have a big problem on our hands a bit later down the line.
This is knot what you were expecting
Physicians who aren’t surgeons probably don’t realize it, but the big thing that’s been getting between the knot-tying specialists and perfect suturing technique all these years is a lack of physics. Don’t believe us? Well, maybe you’ll believe plastic surgeon Samia Guerid, MD, of Lausanne, Switzerland: “The lack of physics-based analysis has been a limitation.” Nuff said.
That’s not enough for you, is it? Fine, we were warned.
Any surgical knot, Dr. Guerid and associates explained in a written statement, involves the “complex interplay” between six key factors: topology, geometry, elasticity, contact, friction, and polymer plasticity of the suturing filament. The strength of a suture “depends on the tension applied during the tying of the knot, [which] permanently deforms, or stretches the filament, creating a holding force.” Not enough tension and the knot comes undone, while too much snaps the filament.
For the experiment, Dr. Guerid tied a few dozen surgical knots, which were then scanned using x-ray micro–computed tomography to facilitate finite element modeling with a “3D continuum-level constitutive model for elastic-viscoplastic mechanical behavior” – no, we have no idea what that means, either – developed by the research team.
That model, and a great deal of math – so much math – allowed the researchers to define a threshold between loose and tight knots and uncover “relationships between knot strength and pretension, friction, and number of throws,” they said.
But what about the big question? The one about the ideal amount of tension? You may want to sit down. The answer to the ultimate question of the relationship between knot pretension and strength is … Did we mention that the team had its own mathematician? Their predictive model for safe knot-tying is … You’re not going to like this. The best way to teach safe knot-tying to both trainees and robots is … not ready yet.
The secret to targeting the knot tension sweet spot, for now, anyway, is still intuition gained from years of experience. Nobody ever said science was perfect … or easy … or quick.
Three big bumps on the weight-loss journey
The search for the Holy Grail. The destruction of the One Ring. The never-ending struggle to Lose Weight.
Like most legendary quests, weight loss is a journey, and we need support to help us achieve our goal. Maybe it’s gaining a new workout partner or finding a similarly-goaled Facebook Group. For a lot of people, it’s as simple as your friends and family. A recent study, however, suggests that the people closest to you may be your worst weight-loss enemies, and they might not even know it.
Researchers at the University of Surrey reviewed the literature on the positives and negatives of social support when it comes to weight loss and identified three types of negative effects: acts of sabotage, feeding behavior, and collusion.
Let’s start with the softest of intentions and work our way up. Collusion is the least negative. Friends and family may just go with the flow, even if it doesn’t agree with the goals of the person who’s trying to lose weight. It can even happen when health care professionals try to help their patients navigate or avoid obesity, ultimately killing with kindness, so to speak.
Next up, feeding behavior. Maybe you know someone whose love language is cooking. There are also people who share food because they don’t want to waste it or because they’re trying to be polite. They act out of the goodness of their hearts, but they’re putting up roadblocks to someone’s goals. These types of acts are usually one-sided, the researchers found. Remember, it’s okay to say, “No thanks.”
The last method, sabotage, is the most sinister. The saboteur may discourage others from eating healthy, undermine their efforts to be physically active, or take jabs at their confidence or self-esteem. Something as simple as criticizing someone for eating a salad or refusing to go on a walk with them can cause a setback.
“We need to explore this area further to develop interventions which could target family and friends and help them be more supportive in helping those they are close to lose weight,” said lead author Jane Odgen, PhD, of the University of Surrey, Guildford, England.
Like we said before, weight loss is a journey. The right support can only improve the odds of success.
Robots vs. mosquitoes
If there’s one thing robots are bad at, it’s giving solid mental health advice to people in crisis. If there’s one thing robots are very, very good at, it’s causing apocalypses. And joyous day for humanity, this time we’re not the ones being apocalypsed.
Yet.
Taiwan has a big mosquito problem. Not only do the mosquitoes in Taiwan carry dengue – among other dangerous diseases – but they’ve urbanized. Not urbanized in the sense that they’ve acquired a taste for organic coffee and avocado toast (that would be the millennial mosquito, a separate but even more terrifying creature), but more that they’ve adapted to reproduce literally anywhere and everywhere. Taiwanese mosquitoes like to breed in roadside sewer ditches, and this is where our genocidal robot comes in.
To combat the new, dangerous form of street-savvy mosquito, researchers built a robot armed with both insecticide and high-temperature, high-pressure water jets and sent it into the sewers of Kaohsiung City. The robot’s goal was simple: Whenever it came across signs of heavy mosquito breeding – eggs, larvae, pupae, and so on – the robot went to work. Utilizing both its primary weapons, the robot scrubbed numerous breeding sites across the city clean.
The researchers could just sit back and wait to see how effective their robot was. In the immediate aftermath, at various monitoring sites placed alongside the ditches, adult mosquito density fell by two-thirds in areas targeted by the robot. That’s nothing to sniff at, and it does make sense. After all, mosquitoes are quite difficult to kill in their adult stage, why not target them when they’re young and basically immobile?
The researchers saw promise with their mosquito-killing robot, but we’ve noticed a rather large issue. Killing two-thirds of mosquitoes is fine, but the third that’s left will be very angry. Very angry indeed. After all, we’re targeting the mosquito equivalent of children. Let’s hope our mosquito Terminator managed to kill mosquito Sarah Connor, or we’re going to have a big problem on our hands a bit later down the line.
This is knot what you were expecting
Physicians who aren’t surgeons probably don’t realize it, but the big thing that’s been getting between the knot-tying specialists and perfect suturing technique all these years is a lack of physics. Don’t believe us? Well, maybe you’ll believe plastic surgeon Samia Guerid, MD, of Lausanne, Switzerland: “The lack of physics-based analysis has been a limitation.” Nuff said.
That’s not enough for you, is it? Fine, we were warned.
Any surgical knot, Dr. Guerid and associates explained in a written statement, involves the “complex interplay” between six key factors: topology, geometry, elasticity, contact, friction, and polymer plasticity of the suturing filament. The strength of a suture “depends on the tension applied during the tying of the knot, [which] permanently deforms, or stretches the filament, creating a holding force.” Not enough tension and the knot comes undone, while too much snaps the filament.
For the experiment, Dr. Guerid tied a few dozen surgical knots, which were then scanned using x-ray micro–computed tomography to facilitate finite element modeling with a “3D continuum-level constitutive model for elastic-viscoplastic mechanical behavior” – no, we have no idea what that means, either – developed by the research team.
That model, and a great deal of math – so much math – allowed the researchers to define a threshold between loose and tight knots and uncover “relationships between knot strength and pretension, friction, and number of throws,” they said.
But what about the big question? The one about the ideal amount of tension? You may want to sit down. The answer to the ultimate question of the relationship between knot pretension and strength is … Did we mention that the team had its own mathematician? Their predictive model for safe knot-tying is … You’re not going to like this. The best way to teach safe knot-tying to both trainees and robots is … not ready yet.
The secret to targeting the knot tension sweet spot, for now, anyway, is still intuition gained from years of experience. Nobody ever said science was perfect … or easy … or quick.
Three big bumps on the weight-loss journey
The search for the Holy Grail. The destruction of the One Ring. The never-ending struggle to Lose Weight.
Like most legendary quests, weight loss is a journey, and we need support to help us achieve our goal. Maybe it’s gaining a new workout partner or finding a similarly-goaled Facebook Group. For a lot of people, it’s as simple as your friends and family. A recent study, however, suggests that the people closest to you may be your worst weight-loss enemies, and they might not even know it.
Researchers at the University of Surrey reviewed the literature on the positives and negatives of social support when it comes to weight loss and identified three types of negative effects: acts of sabotage, feeding behavior, and collusion.
Let’s start with the softest of intentions and work our way up. Collusion is the least negative. Friends and family may just go with the flow, even if it doesn’t agree with the goals of the person who’s trying to lose weight. It can even happen when health care professionals try to help their patients navigate or avoid obesity, ultimately killing with kindness, so to speak.
Next up, feeding behavior. Maybe you know someone whose love language is cooking. There are also people who share food because they don’t want to waste it or because they’re trying to be polite. They act out of the goodness of their hearts, but they’re putting up roadblocks to someone’s goals. These types of acts are usually one-sided, the researchers found. Remember, it’s okay to say, “No thanks.”
The last method, sabotage, is the most sinister. The saboteur may discourage others from eating healthy, undermine their efforts to be physically active, or take jabs at their confidence or self-esteem. Something as simple as criticizing someone for eating a salad or refusing to go on a walk with them can cause a setback.
“We need to explore this area further to develop interventions which could target family and friends and help them be more supportive in helping those they are close to lose weight,” said lead author Jane Odgen, PhD, of the University of Surrey, Guildford, England.
Like we said before, weight loss is a journey. The right support can only improve the odds of success.
Robots vs. mosquitoes
If there’s one thing robots are bad at, it’s giving solid mental health advice to people in crisis. If there’s one thing robots are very, very good at, it’s causing apocalypses. And joyous day for humanity, this time we’re not the ones being apocalypsed.
Yet.
Taiwan has a big mosquito problem. Not only do the mosquitoes in Taiwan carry dengue – among other dangerous diseases – but they’ve urbanized. Not urbanized in the sense that they’ve acquired a taste for organic coffee and avocado toast (that would be the millennial mosquito, a separate but even more terrifying creature), but more that they’ve adapted to reproduce literally anywhere and everywhere. Taiwanese mosquitoes like to breed in roadside sewer ditches, and this is where our genocidal robot comes in.
To combat the new, dangerous form of street-savvy mosquito, researchers built a robot armed with both insecticide and high-temperature, high-pressure water jets and sent it into the sewers of Kaohsiung City. The robot’s goal was simple: Whenever it came across signs of heavy mosquito breeding – eggs, larvae, pupae, and so on – the robot went to work. Utilizing both its primary weapons, the robot scrubbed numerous breeding sites across the city clean.
The researchers could just sit back and wait to see how effective their robot was. In the immediate aftermath, at various monitoring sites placed alongside the ditches, adult mosquito density fell by two-thirds in areas targeted by the robot. That’s nothing to sniff at, and it does make sense. After all, mosquitoes are quite difficult to kill in their adult stage, why not target them when they’re young and basically immobile?
The researchers saw promise with their mosquito-killing robot, but we’ve noticed a rather large issue. Killing two-thirds of mosquitoes is fine, but the third that’s left will be very angry. Very angry indeed. After all, we’re targeting the mosquito equivalent of children. Let’s hope our mosquito Terminator managed to kill mosquito Sarah Connor, or we’re going to have a big problem on our hands a bit later down the line.
This is knot what you were expecting
Physicians who aren’t surgeons probably don’t realize it, but the big thing that’s been getting between the knot-tying specialists and perfect suturing technique all these years is a lack of physics. Don’t believe us? Well, maybe you’ll believe plastic surgeon Samia Guerid, MD, of Lausanne, Switzerland: “The lack of physics-based analysis has been a limitation.” Nuff said.
That’s not enough for you, is it? Fine, we were warned.
Any surgical knot, Dr. Guerid and associates explained in a written statement, involves the “complex interplay” between six key factors: topology, geometry, elasticity, contact, friction, and polymer plasticity of the suturing filament. The strength of a suture “depends on the tension applied during the tying of the knot, [which] permanently deforms, or stretches the filament, creating a holding force.” Not enough tension and the knot comes undone, while too much snaps the filament.
For the experiment, Dr. Guerid tied a few dozen surgical knots, which were then scanned using x-ray micro–computed tomography to facilitate finite element modeling with a “3D continuum-level constitutive model for elastic-viscoplastic mechanical behavior” – no, we have no idea what that means, either – developed by the research team.
That model, and a great deal of math – so much math – allowed the researchers to define a threshold between loose and tight knots and uncover “relationships between knot strength and pretension, friction, and number of throws,” they said.
But what about the big question? The one about the ideal amount of tension? You may want to sit down. The answer to the ultimate question of the relationship between knot pretension and strength is … Did we mention that the team had its own mathematician? Their predictive model for safe knot-tying is … You’re not going to like this. The best way to teach safe knot-tying to both trainees and robots is … not ready yet.
The secret to targeting the knot tension sweet spot, for now, anyway, is still intuition gained from years of experience. Nobody ever said science was perfect … or easy … or quick.
Protecting your practice data
While data protection is important in any industry, it is particularly critical in health care because in addition to the usual financial records, trade secrets, and other valuable data, confidential patient information is also at risk.
You may think that your computer vendor is responsible for safeguarding your data, but third parties can only do so much. And if your data is compromised, the ultimate responsibility is yours – not to mention the financial loss, and the damage to your practice’s reputation.
In addition to the security vulnerabilities inherent in any system, there are external vulnerabilities, such as weak passwords, viruses, and hacking (either externally or internally). And as hardware becomes more and more portable, there is the increasing risk of theft of platforms and storage media containing confidential data.
A close and ongoing relationship with your hardware and software vendors is essential to good data protection. Your office should have a permanent contact at each company, and you should talk to them regularly. Ask them what sort of firewalls, antivirus software, and other safeguards are in place to protect your system. Whenever they identify a bug or other vulnerability, you should know about it. They should tell you about each software update, what improvements it makes, and what defects it fixes. You should also know about any changes to your data encryption.
Encryption has become an essential component of data protection. It is especially important if you use portable devices such as laptops, pads, or smart phones to store and transport patient information. If you lose one of these devices, or a thumb drive or other storage media, HIPAA will probably not consider it a breach if the data it contains is encrypted.
Encryption isn’t perfect, of course. Log-in credentials can be stolen; and data that is stored in house is can be hacked with malware and phishing techniques, especially if the key to decryption is located on that server. And make sure that employees are not putting any medical data on their own private (unencrypted) devices.
Each employee should have his or her own password, and sharing should be strictly prohibited. Multifactor authentication is becoming increasingly popular for an extra level of security.
Your vendor should require you to change your passwords every few months. If it doesn’t, you need to establish a timetable to do it yourself. All passwords should be strong (no birthdays, pet names, etc.), and they shouldn’t be the same or similar to old passwords.
In some offices, I’ve been surprised to see that every employee has unrestricted access to all practice data. The vulnerabilities of such an arrangement are obvious. There is no reason why receptionists, for example, should have access to medical histories, and insurance people don’t need to know what medications a patient is on. Your vendor can help you design partitions that restrict each employee to only the information they need access to.
Ask if your vendor provides security training for employees. If not, look into hiring a security firm to do it. Regular security training can help employees to recognize data security attacks like phishing, and instills a heightened sense of security awareness and vigilance among staff. They will also gain a better understanding of the role they play in maintaining the overall security of your office.
It goes without saying that third parties, such as business vendors, payers, and managed care providers, should never have access to patient records or other personal health information.
Backing up data
I have written many times about the importance of regularly backing up your data. Industry statistics show that fully 10% of hard drives fail in any given year, and 43% of computer users lose one or more files every year in the form of clinical data, financial records, photos, email, documents, and other important information. Recovery of lost data, when it’s possible at all, can be very expensive.
Even if your EHR vendor backs up your data, you should consider making a separate backup of your own. Backup drives have been known to fail too; and if you decide to switch computer vendors, you don’t want to be at the mercy of the old company that might be reluctant to transfer your data without a hefty payment.
The first rule of backing up is to store your backup drives in a different location from your computers. Unfortunately, that’s a pain; and external drives can be lost or stolen, creating a HIPAA nightmare. So an increasingly popular alternative is automatic remote backup. Several companies offer that service, and the cost is very reasonable for individual computers. Backing up an entire office costs more, depending on how many computers and/or servers you have, but it’s still very reasonable and includes other services, such as operating system and network share support.
The procedure is simple: You create an account and tell the service which files you want copied. Your first backup can take a long time, often days, depending on how much data you are sending and how fast your Internet connection runs. After that the program runs in the background, copying only those files that have changed since the previous backup. Files are encrypted before leaving your computer, and they remain encrypted at the service’s data center, making them HIPAA compliant and, theoretically, only accessible by you.
Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at dermnews@mdedge.com.
While data protection is important in any industry, it is particularly critical in health care because in addition to the usual financial records, trade secrets, and other valuable data, confidential patient information is also at risk.
You may think that your computer vendor is responsible for safeguarding your data, but third parties can only do so much. And if your data is compromised, the ultimate responsibility is yours – not to mention the financial loss, and the damage to your practice’s reputation.
In addition to the security vulnerabilities inherent in any system, there are external vulnerabilities, such as weak passwords, viruses, and hacking (either externally or internally). And as hardware becomes more and more portable, there is the increasing risk of theft of platforms and storage media containing confidential data.
A close and ongoing relationship with your hardware and software vendors is essential to good data protection. Your office should have a permanent contact at each company, and you should talk to them regularly. Ask them what sort of firewalls, antivirus software, and other safeguards are in place to protect your system. Whenever they identify a bug or other vulnerability, you should know about it. They should tell you about each software update, what improvements it makes, and what defects it fixes. You should also know about any changes to your data encryption.
Encryption has become an essential component of data protection. It is especially important if you use portable devices such as laptops, pads, or smart phones to store and transport patient information. If you lose one of these devices, or a thumb drive or other storage media, HIPAA will probably not consider it a breach if the data it contains is encrypted.
Encryption isn’t perfect, of course. Log-in credentials can be stolen; and data that is stored in house is can be hacked with malware and phishing techniques, especially if the key to decryption is located on that server. And make sure that employees are not putting any medical data on their own private (unencrypted) devices.
Each employee should have his or her own password, and sharing should be strictly prohibited. Multifactor authentication is becoming increasingly popular for an extra level of security.
Your vendor should require you to change your passwords every few months. If it doesn’t, you need to establish a timetable to do it yourself. All passwords should be strong (no birthdays, pet names, etc.), and they shouldn’t be the same or similar to old passwords.
In some offices, I’ve been surprised to see that every employee has unrestricted access to all practice data. The vulnerabilities of such an arrangement are obvious. There is no reason why receptionists, for example, should have access to medical histories, and insurance people don’t need to know what medications a patient is on. Your vendor can help you design partitions that restrict each employee to only the information they need access to.
Ask if your vendor provides security training for employees. If not, look into hiring a security firm to do it. Regular security training can help employees to recognize data security attacks like phishing, and instills a heightened sense of security awareness and vigilance among staff. They will also gain a better understanding of the role they play in maintaining the overall security of your office.
It goes without saying that third parties, such as business vendors, payers, and managed care providers, should never have access to patient records or other personal health information.
Backing up data
I have written many times about the importance of regularly backing up your data. Industry statistics show that fully 10% of hard drives fail in any given year, and 43% of computer users lose one or more files every year in the form of clinical data, financial records, photos, email, documents, and other important information. Recovery of lost data, when it’s possible at all, can be very expensive.
Even if your EHR vendor backs up your data, you should consider making a separate backup of your own. Backup drives have been known to fail too; and if you decide to switch computer vendors, you don’t want to be at the mercy of the old company that might be reluctant to transfer your data without a hefty payment.
The first rule of backing up is to store your backup drives in a different location from your computers. Unfortunately, that’s a pain; and external drives can be lost or stolen, creating a HIPAA nightmare. So an increasingly popular alternative is automatic remote backup. Several companies offer that service, and the cost is very reasonable for individual computers. Backing up an entire office costs more, depending on how many computers and/or servers you have, but it’s still very reasonable and includes other services, such as operating system and network share support.
The procedure is simple: You create an account and tell the service which files you want copied. Your first backup can take a long time, often days, depending on how much data you are sending and how fast your Internet connection runs. After that the program runs in the background, copying only those files that have changed since the previous backup. Files are encrypted before leaving your computer, and they remain encrypted at the service’s data center, making them HIPAA compliant and, theoretically, only accessible by you.
Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at dermnews@mdedge.com.
While data protection is important in any industry, it is particularly critical in health care because in addition to the usual financial records, trade secrets, and other valuable data, confidential patient information is also at risk.
You may think that your computer vendor is responsible for safeguarding your data, but third parties can only do so much. And if your data is compromised, the ultimate responsibility is yours – not to mention the financial loss, and the damage to your practice’s reputation.
In addition to the security vulnerabilities inherent in any system, there are external vulnerabilities, such as weak passwords, viruses, and hacking (either externally or internally). And as hardware becomes more and more portable, there is the increasing risk of theft of platforms and storage media containing confidential data.
A close and ongoing relationship with your hardware and software vendors is essential to good data protection. Your office should have a permanent contact at each company, and you should talk to them regularly. Ask them what sort of firewalls, antivirus software, and other safeguards are in place to protect your system. Whenever they identify a bug or other vulnerability, you should know about it. They should tell you about each software update, what improvements it makes, and what defects it fixes. You should also know about any changes to your data encryption.
Encryption has become an essential component of data protection. It is especially important if you use portable devices such as laptops, pads, or smart phones to store and transport patient information. If you lose one of these devices, or a thumb drive or other storage media, HIPAA will probably not consider it a breach if the data it contains is encrypted.
Encryption isn’t perfect, of course. Log-in credentials can be stolen; and data that is stored in house is can be hacked with malware and phishing techniques, especially if the key to decryption is located on that server. And make sure that employees are not putting any medical data on their own private (unencrypted) devices.
Each employee should have his or her own password, and sharing should be strictly prohibited. Multifactor authentication is becoming increasingly popular for an extra level of security.
Your vendor should require you to change your passwords every few months. If it doesn’t, you need to establish a timetable to do it yourself. All passwords should be strong (no birthdays, pet names, etc.), and they shouldn’t be the same or similar to old passwords.
In some offices, I’ve been surprised to see that every employee has unrestricted access to all practice data. The vulnerabilities of such an arrangement are obvious. There is no reason why receptionists, for example, should have access to medical histories, and insurance people don’t need to know what medications a patient is on. Your vendor can help you design partitions that restrict each employee to only the information they need access to.
Ask if your vendor provides security training for employees. If not, look into hiring a security firm to do it. Regular security training can help employees to recognize data security attacks like phishing, and instills a heightened sense of security awareness and vigilance among staff. They will also gain a better understanding of the role they play in maintaining the overall security of your office.
It goes without saying that third parties, such as business vendors, payers, and managed care providers, should never have access to patient records or other personal health information.
Backing up data
I have written many times about the importance of regularly backing up your data. Industry statistics show that fully 10% of hard drives fail in any given year, and 43% of computer users lose one or more files every year in the form of clinical data, financial records, photos, email, documents, and other important information. Recovery of lost data, when it’s possible at all, can be very expensive.
Even if your EHR vendor backs up your data, you should consider making a separate backup of your own. Backup drives have been known to fail too; and if you decide to switch computer vendors, you don’t want to be at the mercy of the old company that might be reluctant to transfer your data without a hefty payment.
The first rule of backing up is to store your backup drives in a different location from your computers. Unfortunately, that’s a pain; and external drives can be lost or stolen, creating a HIPAA nightmare. So an increasingly popular alternative is automatic remote backup. Several companies offer that service, and the cost is very reasonable for individual computers. Backing up an entire office costs more, depending on how many computers and/or servers you have, but it’s still very reasonable and includes other services, such as operating system and network share support.
The procedure is simple: You create an account and tell the service which files you want copied. Your first backup can take a long time, often days, depending on how much data you are sending and how fast your Internet connection runs. After that the program runs in the background, copying only those files that have changed since the previous backup. Files are encrypted before leaving your computer, and they remain encrypted at the service’s data center, making them HIPAA compliant and, theoretically, only accessible by you.
Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at dermnews@mdedge.com.
‘Best’ for most APL patients: Chemo-free regimen
“In a large cohort of patients with APL, the chemo-free combination of ATRA/ATO is confirmed as the best treatment option, prolonging overall and event-free survival and reducing the relapse rate compared with ATRA/chemotherapy,” said first author Maria Teresa Voso, MD, of Tor Vergata University, in Rome, in presenting the findings at the 2023 annual meeting of the European Hematology Association.
APL, though rare, makes up about 10% of new AML cases, and the advent of the chemo-free ATRA-ATO regimen in recent years has transformed the disease, significantly improving survival.
However, with ongoing questions regarding factors associated with treatment benefits based on issues including the level of risk, Dr. Voso and colleagues turned to data from the large European Union–funded HARMONY registry, a big data project that uniquely provides real-world as well as clinical trial findings from diverse APL patient populations.
They identified 937 patients in the registry with newly diagnosed APL between 2007 and 2020 who met the study’s data quality criteria, including 536 (57.2%) patients from two clinical trials, the UK AML-17 and GIMEMA APL0406 trials, and 401 (42.8%) patients from national registries in 6 countries, representing real-world data.
The median duration of follow-up was 5.66 years, with a range of 0-14 years.
The patients had an average age of about 50, which is consistent with the lower age of diagnosis typical of APL, compared with other forms of AML.
Among them, 380 (40.6%) were treated with the ATRA-ATO regimen while 509 (54.3%) received the chemotherapy combination of ATRA-Idarubicin (AIDA).
Overall, 37.8% were determined to be low risk, as assessed by the Sanz risk-score; 42.3% were intermediate risk, and 18.7% were considered high risk. The rate of complete remission among the patients was 87.5%, and 9% had relapsed.
The results showed the 10-year overall survival (OS) rate to be 92% among the chemo-free ATRA-ATO-treated patients versus 75% in the AIDA-treated patients (P = .001).
Likewise, those treated with the chemo-free regimen had a higher event-free survival and a lower cumulative incidence of relapse (CIR) versus chemotherapy over 10 years (P < .001 for both).
In further stratifying by risk, patients who were low risk also had greater improvements with the chemo-free regimen in overall survival (P = .004), event-free survival, and CIR versus AIDA treatment (P < .001).
Among high-risk patients, however, only event-free survival was significantly improved in the chemo-free treated patients (P = .046).
Older age stood out as a significant determinant of survival, with patients in the age 50-69 and 70 or over age groups having a significantly lower rate of overall survival and event-free survival, compared with those under 50 years of age (P < .001), with those risks observed regardless of treatment type.
Age was not a significant factor in terms of the incidence of relapse (P = .159).
Clinical trial versus real-world outcomes
Of note, improved outcomes were reported in clinical trials versus real-world data, with overall survival higher in clinical trials among patients receiving the ATRA/ATO chemo-free treatment (P = .025), as well as in those receiving the AIDA chemotherapy (P < .001).
Early death, an uncommon but key concern with APL, usually due to bleeding complications and defined as death occurring within 30 days from APL diagnosis, occurred among 56 patients, or 5.9%, overall, and was significantly higher in the age 50-69 and over 70 groups versus those under 50 (P < .001).
Early death was more common among those with a Sanz high-risk score (15.4%), compared with low or intermediate risk (3.9%; P < .001); however, the risk was no different between the chemo-free (3.4%) and chemotherapy (5.7%) groups, regardless of whether patients had a low or high risk.
The rates of early death were significantly higher in the real-world population (10.2%), compared with patients in clinical trials (2.8%; P < .001), which Dr. Voso noted may be expected, as early deaths in some cases can occur even before a diagnosis is made.
“These patients sometimes come to the ER and if a diagnosis is not made, they may die before even receiving treatment,” she said in a press briefing.
“Indeed, the median time to death among those who had early death in the study was only 10 days, and there were even some patients dying at day 0,” she explained.
“So, it’s very important that not only hematologists but emergency doctors recognize this disease and try to reduce the early death rate.”
Overall, the results all remained consistent after adjustment in a multivariate analysis, Dr. Voso said.
“The multivariate analysis confirmed that increasing age, high Sanz risk score, the real-life treatment scenario, and the chemotherapy-based approach are independently associated with decreased survival,” she said.
The findings underscore that “elderly age and high Sanz risk score significantly impact on the rate of early deaths, irrespective of treatment,” Dr. Voso said.
ATRA/ATO ‘gold standard’ for low/intermediate risk
Commenting on the study, Alessandro Isidori, MD, PhD, a hematologist at AORMN Hospital, in Pesaro, Italy, who moderated the session, noted that the study underscores the greater challenges with higher-risk patients.
“The study did not show a statistical benefit for high-risk patients receiving ATRA/ATO versus AIDA,” he told this news organization, noting that “currently, there are many countries where ATRA/ATO is not approved for use in high-risk APL.”
“In high-risk APL, the AIDA combination should still be preferred to ATRA/ATO,” he said.
Dr. Isidori recommended careful efforts to stratify higher-risk patients who still may benefit from ATRA/ATO.
“The analysis of high-risk patients with white blood cell count as a continuous variable instead of a fixed variable (more or less than 10,000/mmc) may help to discriminate some high-risk patients who could benefit from ATRA/ATO,” he noted.
Overall, however, “ATRA/ATO is the gold standard for low and intermediate risk APL,” he said.
“Although promising, more data are needed to confirm the efficacy of ATRA/ATO in high-risk APL.”
Dr. Voso disclosed ties with companies including Celgene/Bristol Myers Squibb, Astellas, Jazz Pharmaceuticals, Abbvie, Novartis, and AstraZeneca. Dr. Isidori reported no disclosures.
“In a large cohort of patients with APL, the chemo-free combination of ATRA/ATO is confirmed as the best treatment option, prolonging overall and event-free survival and reducing the relapse rate compared with ATRA/chemotherapy,” said first author Maria Teresa Voso, MD, of Tor Vergata University, in Rome, in presenting the findings at the 2023 annual meeting of the European Hematology Association.
APL, though rare, makes up about 10% of new AML cases, and the advent of the chemo-free ATRA-ATO regimen in recent years has transformed the disease, significantly improving survival.
However, with ongoing questions regarding factors associated with treatment benefits based on issues including the level of risk, Dr. Voso and colleagues turned to data from the large European Union–funded HARMONY registry, a big data project that uniquely provides real-world as well as clinical trial findings from diverse APL patient populations.
They identified 937 patients in the registry with newly diagnosed APL between 2007 and 2020 who met the study’s data quality criteria, including 536 (57.2%) patients from two clinical trials, the UK AML-17 and GIMEMA APL0406 trials, and 401 (42.8%) patients from national registries in 6 countries, representing real-world data.
The median duration of follow-up was 5.66 years, with a range of 0-14 years.
The patients had an average age of about 50, which is consistent with the lower age of diagnosis typical of APL, compared with other forms of AML.
Among them, 380 (40.6%) were treated with the ATRA-ATO regimen while 509 (54.3%) received the chemotherapy combination of ATRA-Idarubicin (AIDA).
Overall, 37.8% were determined to be low risk, as assessed by the Sanz risk-score; 42.3% were intermediate risk, and 18.7% were considered high risk. The rate of complete remission among the patients was 87.5%, and 9% had relapsed.
The results showed the 10-year overall survival (OS) rate to be 92% among the chemo-free ATRA-ATO-treated patients versus 75% in the AIDA-treated patients (P = .001).
Likewise, those treated with the chemo-free regimen had a higher event-free survival and a lower cumulative incidence of relapse (CIR) versus chemotherapy over 10 years (P < .001 for both).
In further stratifying by risk, patients who were low risk also had greater improvements with the chemo-free regimen in overall survival (P = .004), event-free survival, and CIR versus AIDA treatment (P < .001).
Among high-risk patients, however, only event-free survival was significantly improved in the chemo-free treated patients (P = .046).
Older age stood out as a significant determinant of survival, with patients in the age 50-69 and 70 or over age groups having a significantly lower rate of overall survival and event-free survival, compared with those under 50 years of age (P < .001), with those risks observed regardless of treatment type.
Age was not a significant factor in terms of the incidence of relapse (P = .159).
Clinical trial versus real-world outcomes
Of note, improved outcomes were reported in clinical trials versus real-world data, with overall survival higher in clinical trials among patients receiving the ATRA/ATO chemo-free treatment (P = .025), as well as in those receiving the AIDA chemotherapy (P < .001).
Early death, an uncommon but key concern with APL, usually due to bleeding complications and defined as death occurring within 30 days from APL diagnosis, occurred among 56 patients, or 5.9%, overall, and was significantly higher in the age 50-69 and over 70 groups versus those under 50 (P < .001).
Early death was more common among those with a Sanz high-risk score (15.4%), compared with low or intermediate risk (3.9%; P < .001); however, the risk was no different between the chemo-free (3.4%) and chemotherapy (5.7%) groups, regardless of whether patients had a low or high risk.
The rates of early death were significantly higher in the real-world population (10.2%), compared with patients in clinical trials (2.8%; P < .001), which Dr. Voso noted may be expected, as early deaths in some cases can occur even before a diagnosis is made.
“These patients sometimes come to the ER and if a diagnosis is not made, they may die before even receiving treatment,” she said in a press briefing.
“Indeed, the median time to death among those who had early death in the study was only 10 days, and there were even some patients dying at day 0,” she explained.
“So, it’s very important that not only hematologists but emergency doctors recognize this disease and try to reduce the early death rate.”
Overall, the results all remained consistent after adjustment in a multivariate analysis, Dr. Voso said.
“The multivariate analysis confirmed that increasing age, high Sanz risk score, the real-life treatment scenario, and the chemotherapy-based approach are independently associated with decreased survival,” she said.
The findings underscore that “elderly age and high Sanz risk score significantly impact on the rate of early deaths, irrespective of treatment,” Dr. Voso said.
ATRA/ATO ‘gold standard’ for low/intermediate risk
Commenting on the study, Alessandro Isidori, MD, PhD, a hematologist at AORMN Hospital, in Pesaro, Italy, who moderated the session, noted that the study underscores the greater challenges with higher-risk patients.
“The study did not show a statistical benefit for high-risk patients receiving ATRA/ATO versus AIDA,” he told this news organization, noting that “currently, there are many countries where ATRA/ATO is not approved for use in high-risk APL.”
“In high-risk APL, the AIDA combination should still be preferred to ATRA/ATO,” he said.
Dr. Isidori recommended careful efforts to stratify higher-risk patients who still may benefit from ATRA/ATO.
“The analysis of high-risk patients with white blood cell count as a continuous variable instead of a fixed variable (more or less than 10,000/mmc) may help to discriminate some high-risk patients who could benefit from ATRA/ATO,” he noted.
Overall, however, “ATRA/ATO is the gold standard for low and intermediate risk APL,” he said.
“Although promising, more data are needed to confirm the efficacy of ATRA/ATO in high-risk APL.”
Dr. Voso disclosed ties with companies including Celgene/Bristol Myers Squibb, Astellas, Jazz Pharmaceuticals, Abbvie, Novartis, and AstraZeneca. Dr. Isidori reported no disclosures.
“In a large cohort of patients with APL, the chemo-free combination of ATRA/ATO is confirmed as the best treatment option, prolonging overall and event-free survival and reducing the relapse rate compared with ATRA/chemotherapy,” said first author Maria Teresa Voso, MD, of Tor Vergata University, in Rome, in presenting the findings at the 2023 annual meeting of the European Hematology Association.
APL, though rare, makes up about 10% of new AML cases, and the advent of the chemo-free ATRA-ATO regimen in recent years has transformed the disease, significantly improving survival.
However, with ongoing questions regarding factors associated with treatment benefits based on issues including the level of risk, Dr. Voso and colleagues turned to data from the large European Union–funded HARMONY registry, a big data project that uniquely provides real-world as well as clinical trial findings from diverse APL patient populations.
They identified 937 patients in the registry with newly diagnosed APL between 2007 and 2020 who met the study’s data quality criteria, including 536 (57.2%) patients from two clinical trials, the UK AML-17 and GIMEMA APL0406 trials, and 401 (42.8%) patients from national registries in 6 countries, representing real-world data.
The median duration of follow-up was 5.66 years, with a range of 0-14 years.
The patients had an average age of about 50, which is consistent with the lower age of diagnosis typical of APL, compared with other forms of AML.
Among them, 380 (40.6%) were treated with the ATRA-ATO regimen while 509 (54.3%) received the chemotherapy combination of ATRA-Idarubicin (AIDA).
Overall, 37.8% were determined to be low risk, as assessed by the Sanz risk-score; 42.3% were intermediate risk, and 18.7% were considered high risk. The rate of complete remission among the patients was 87.5%, and 9% had relapsed.
The results showed the 10-year overall survival (OS) rate to be 92% among the chemo-free ATRA-ATO-treated patients versus 75% in the AIDA-treated patients (P = .001).
Likewise, those treated with the chemo-free regimen had a higher event-free survival and a lower cumulative incidence of relapse (CIR) versus chemotherapy over 10 years (P < .001 for both).
In further stratifying by risk, patients who were low risk also had greater improvements with the chemo-free regimen in overall survival (P = .004), event-free survival, and CIR versus AIDA treatment (P < .001).
Among high-risk patients, however, only event-free survival was significantly improved in the chemo-free treated patients (P = .046).
Older age stood out as a significant determinant of survival, with patients in the age 50-69 and 70 or over age groups having a significantly lower rate of overall survival and event-free survival, compared with those under 50 years of age (P < .001), with those risks observed regardless of treatment type.
Age was not a significant factor in terms of the incidence of relapse (P = .159).
Clinical trial versus real-world outcomes
Of note, improved outcomes were reported in clinical trials versus real-world data, with overall survival higher in clinical trials among patients receiving the ATRA/ATO chemo-free treatment (P = .025), as well as in those receiving the AIDA chemotherapy (P < .001).
Early death, an uncommon but key concern with APL, usually due to bleeding complications and defined as death occurring within 30 days from APL diagnosis, occurred among 56 patients, or 5.9%, overall, and was significantly higher in the age 50-69 and over 70 groups versus those under 50 (P < .001).
Early death was more common among those with a Sanz high-risk score (15.4%), compared with low or intermediate risk (3.9%; P < .001); however, the risk was no different between the chemo-free (3.4%) and chemotherapy (5.7%) groups, regardless of whether patients had a low or high risk.
The rates of early death were significantly higher in the real-world population (10.2%), compared with patients in clinical trials (2.8%; P < .001), which Dr. Voso noted may be expected, as early deaths in some cases can occur even before a diagnosis is made.
“These patients sometimes come to the ER and if a diagnosis is not made, they may die before even receiving treatment,” she said in a press briefing.
“Indeed, the median time to death among those who had early death in the study was only 10 days, and there were even some patients dying at day 0,” she explained.
“So, it’s very important that not only hematologists but emergency doctors recognize this disease and try to reduce the early death rate.”
Overall, the results all remained consistent after adjustment in a multivariate analysis, Dr. Voso said.
“The multivariate analysis confirmed that increasing age, high Sanz risk score, the real-life treatment scenario, and the chemotherapy-based approach are independently associated with decreased survival,” she said.
The findings underscore that “elderly age and high Sanz risk score significantly impact on the rate of early deaths, irrespective of treatment,” Dr. Voso said.
ATRA/ATO ‘gold standard’ for low/intermediate risk
Commenting on the study, Alessandro Isidori, MD, PhD, a hematologist at AORMN Hospital, in Pesaro, Italy, who moderated the session, noted that the study underscores the greater challenges with higher-risk patients.
“The study did not show a statistical benefit for high-risk patients receiving ATRA/ATO versus AIDA,” he told this news organization, noting that “currently, there are many countries where ATRA/ATO is not approved for use in high-risk APL.”
“In high-risk APL, the AIDA combination should still be preferred to ATRA/ATO,” he said.
Dr. Isidori recommended careful efforts to stratify higher-risk patients who still may benefit from ATRA/ATO.
“The analysis of high-risk patients with white blood cell count as a continuous variable instead of a fixed variable (more or less than 10,000/mmc) may help to discriminate some high-risk patients who could benefit from ATRA/ATO,” he noted.
Overall, however, “ATRA/ATO is the gold standard for low and intermediate risk APL,” he said.
“Although promising, more data are needed to confirm the efficacy of ATRA/ATO in high-risk APL.”
Dr. Voso disclosed ties with companies including Celgene/Bristol Myers Squibb, Astellas, Jazz Pharmaceuticals, Abbvie, Novartis, and AstraZeneca. Dr. Isidori reported no disclosures.
FROM EHA 2023
CAR-T hikes overall survival in relapsed/refractory LBCL
.
The anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy was approved for second-line treatment in 2022 based on better event-free survival, but standard second-line treatment – chemoimmunotherapy followed by high-dose chemotherapy and autologous stem-cell transplant in responders – still remains the prevailing approach, explained Jason Westin, MD, director of lymphoma research at MD Anderson Cancer Center, Houston. Dr. Westin, lead investigator, presented the trial, dubbed ZUMA-7, at the ASCO meeting.
The new findings might change that. ZUMA-7 “conclusively demonstrates that trying chemotherapy in the second line and saving cell therapy for the third line is an inferior approach ... ZUMA-7 confirms axi-cel is a second-line standard of care for patients with refractory or early relapsed large B cell lymphoma based on superior overall survival,” said Dr. Westin.
Study discussant Asher A. Chanan-Khan, MD, a CAR-T specialist at the Mayo Clinic in Jacksonville, Fla., agreed.
“This data must alter the current standard of care making CAR-T or axi-cel, based on the data we heard, a preferred second-line treatment ... Moving CAR-T earlier in the treatment paradigm is likely a better choice for our patients,” he said.
The study was published in the New England Journal of Medicine to coincide with the presentations.
Dr. Westin noted that axi-cel is now under investigation in ZUMA-23 for first-line treatment of high-risk large B-cell lymphoma (LBCL).
Study details
Zuma-7 randomized 180 LBCL patients to a one-time axi-cel infusion and 179 to standard care. Patients were refractory to first line chemoimmunotherapy or had relapsed within 12 months; just 36% of patients in the standard care group did well enough on treatment to go on to stem-cell transplant.
Median progression-free survival (PFS) was 14.7 months with axi-cel versus 3.7 months with standard care.
Significantly, the better PFS appears to have translated into better overall survival (OS).
At a median of almost 4 years, 82 patients in the axi-cel group had died, compared with 95 patients with standard care who had died. Estimated 4-year OS was 54.6% with axi-cel versus 46% with standard care (HR 0.73, P = .03).
The OS benefit held in high-risk subgroups, including patients over 64 years old, those refractory to first-line treatment, and patients with high-grade disease.
Adverse events were in keeping with labeling. Cytokine release syndrome was more common in the axi-cel arm, including grade 3 or worse CRS in 6% of axi-cel patients versus none on standard care. Grade 3 or worse infections were also more common at 16.5% versus 11.9% with standard care. Over 11% of axi-cel patients developed hypogammaglobulinemia versus 0.6% in the standard care group.
Overall, there were no new serious or fatal adverse events since the initial PFS results were reported in 2022, when eight fatal adverse events were reported with axi-cel versus two with standard care.
The work was funded by axi-cel maker Kite Pharma, a subsidiary of Gilead. Investigators included Kite/Gilead employees and others who reported financial relationships with the companies, including Dr. Westin, a Kite/Gilead researcher and adviser. Dr. Chanan-Khan disclosed ties with Cellectar, Starton Therapeutics, Ascentage Pharma, and others.
.
The anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy was approved for second-line treatment in 2022 based on better event-free survival, but standard second-line treatment – chemoimmunotherapy followed by high-dose chemotherapy and autologous stem-cell transplant in responders – still remains the prevailing approach, explained Jason Westin, MD, director of lymphoma research at MD Anderson Cancer Center, Houston. Dr. Westin, lead investigator, presented the trial, dubbed ZUMA-7, at the ASCO meeting.
The new findings might change that. ZUMA-7 “conclusively demonstrates that trying chemotherapy in the second line and saving cell therapy for the third line is an inferior approach ... ZUMA-7 confirms axi-cel is a second-line standard of care for patients with refractory or early relapsed large B cell lymphoma based on superior overall survival,” said Dr. Westin.
Study discussant Asher A. Chanan-Khan, MD, a CAR-T specialist at the Mayo Clinic in Jacksonville, Fla., agreed.
“This data must alter the current standard of care making CAR-T or axi-cel, based on the data we heard, a preferred second-line treatment ... Moving CAR-T earlier in the treatment paradigm is likely a better choice for our patients,” he said.
The study was published in the New England Journal of Medicine to coincide with the presentations.
Dr. Westin noted that axi-cel is now under investigation in ZUMA-23 for first-line treatment of high-risk large B-cell lymphoma (LBCL).
Study details
Zuma-7 randomized 180 LBCL patients to a one-time axi-cel infusion and 179 to standard care. Patients were refractory to first line chemoimmunotherapy or had relapsed within 12 months; just 36% of patients in the standard care group did well enough on treatment to go on to stem-cell transplant.
Median progression-free survival (PFS) was 14.7 months with axi-cel versus 3.7 months with standard care.
Significantly, the better PFS appears to have translated into better overall survival (OS).
At a median of almost 4 years, 82 patients in the axi-cel group had died, compared with 95 patients with standard care who had died. Estimated 4-year OS was 54.6% with axi-cel versus 46% with standard care (HR 0.73, P = .03).
The OS benefit held in high-risk subgroups, including patients over 64 years old, those refractory to first-line treatment, and patients with high-grade disease.
Adverse events were in keeping with labeling. Cytokine release syndrome was more common in the axi-cel arm, including grade 3 or worse CRS in 6% of axi-cel patients versus none on standard care. Grade 3 or worse infections were also more common at 16.5% versus 11.9% with standard care. Over 11% of axi-cel patients developed hypogammaglobulinemia versus 0.6% in the standard care group.
Overall, there were no new serious or fatal adverse events since the initial PFS results were reported in 2022, when eight fatal adverse events were reported with axi-cel versus two with standard care.
The work was funded by axi-cel maker Kite Pharma, a subsidiary of Gilead. Investigators included Kite/Gilead employees and others who reported financial relationships with the companies, including Dr. Westin, a Kite/Gilead researcher and adviser. Dr. Chanan-Khan disclosed ties with Cellectar, Starton Therapeutics, Ascentage Pharma, and others.
.
The anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy was approved for second-line treatment in 2022 based on better event-free survival, but standard second-line treatment – chemoimmunotherapy followed by high-dose chemotherapy and autologous stem-cell transplant in responders – still remains the prevailing approach, explained Jason Westin, MD, director of lymphoma research at MD Anderson Cancer Center, Houston. Dr. Westin, lead investigator, presented the trial, dubbed ZUMA-7, at the ASCO meeting.
The new findings might change that. ZUMA-7 “conclusively demonstrates that trying chemotherapy in the second line and saving cell therapy for the third line is an inferior approach ... ZUMA-7 confirms axi-cel is a second-line standard of care for patients with refractory or early relapsed large B cell lymphoma based on superior overall survival,” said Dr. Westin.
Study discussant Asher A. Chanan-Khan, MD, a CAR-T specialist at the Mayo Clinic in Jacksonville, Fla., agreed.
“This data must alter the current standard of care making CAR-T or axi-cel, based on the data we heard, a preferred second-line treatment ... Moving CAR-T earlier in the treatment paradigm is likely a better choice for our patients,” he said.
The study was published in the New England Journal of Medicine to coincide with the presentations.
Dr. Westin noted that axi-cel is now under investigation in ZUMA-23 for first-line treatment of high-risk large B-cell lymphoma (LBCL).
Study details
Zuma-7 randomized 180 LBCL patients to a one-time axi-cel infusion and 179 to standard care. Patients were refractory to first line chemoimmunotherapy or had relapsed within 12 months; just 36% of patients in the standard care group did well enough on treatment to go on to stem-cell transplant.
Median progression-free survival (PFS) was 14.7 months with axi-cel versus 3.7 months with standard care.
Significantly, the better PFS appears to have translated into better overall survival (OS).
At a median of almost 4 years, 82 patients in the axi-cel group had died, compared with 95 patients with standard care who had died. Estimated 4-year OS was 54.6% with axi-cel versus 46% with standard care (HR 0.73, P = .03).
The OS benefit held in high-risk subgroups, including patients over 64 years old, those refractory to first-line treatment, and patients with high-grade disease.
Adverse events were in keeping with labeling. Cytokine release syndrome was more common in the axi-cel arm, including grade 3 or worse CRS in 6% of axi-cel patients versus none on standard care. Grade 3 or worse infections were also more common at 16.5% versus 11.9% with standard care. Over 11% of axi-cel patients developed hypogammaglobulinemia versus 0.6% in the standard care group.
Overall, there were no new serious or fatal adverse events since the initial PFS results were reported in 2022, when eight fatal adverse events were reported with axi-cel versus two with standard care.
The work was funded by axi-cel maker Kite Pharma, a subsidiary of Gilead. Investigators included Kite/Gilead employees and others who reported financial relationships with the companies, including Dr. Westin, a Kite/Gilead researcher and adviser. Dr. Chanan-Khan disclosed ties with Cellectar, Starton Therapeutics, Ascentage Pharma, and others.
FROM ASCO 2023
Widespread carboplatin, cisplatin shortages: NCCN survey
The survey, which included responses from 27 NCCN member institutions, revealed that 93% are experiencing a shortage of carboplatin and that 70% have reported a shortage of cisplatin.
“This is an unacceptable situation,” Robert W. Carlson, MD, NCCN’s chief executive offer, said in the statement released by the network.
“We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now,” Dr. Carlson said. And while the survey results show patients are still able to get lifesaving care, “it comes at a burden to our overtaxed medical facilities.”
The NCCN called on the federal government, the pharmaceutical industry, providers, and payers to take steps to “help mitigate any impacts” from this cancer drug shortage.
“We need to work together to improve the current situation and prevent it from happening again in the future,” Dr. Carlson stressed.
Carboplatin and cisplatin, which are frequently used together for systemic treatment, are highly effective therapies prescribed to treat many cancer types, including lung, breast, and prostate cancers, as well as leukemias and lymphomas. An estimated 500,000 new patients with cancer receive these agents each year.
The current survey, conducted over the last week of May, found that 100% of responding centers are able to continue to treat patients who need cisplatin without delays.
The same cannot be said for carboplatin: only 64% of centers said they are still able to continue treating all current patients receiving the platinum-based therapy. Among 19 responding centers, 20% reported that they were continuing carboplatin regimens for some but not all patients. And 16% reported treatment delays from having to obtain prior authorization for modified treatment plans, though none reported denials.
“Carboplatin has been in short supply for months but in the last 4 weeks has reached a critical stage,” according to one survey comment. “Without additional inventory many of our sites will be out of drug by early next week.”
In response to the survey question, “Is your center experiencing a shortage of carboplatin,” others made similar comments:
- “Current shipments from established manufacturers have been paused.”
- “The supply of carboplatin available is not meeting our demands.”
- “Without additional supply in early June, we will have to implement several shortage mitigation strategies.”
Survey respondents also addressed whether manufacturers or suppliers have provided any indication of when these drugs will become readily available again. For both drugs, about 60% of respondents said no. And for those who do receive updates, many noted that the “information is tentative and variable.”
Respondents indicated that other cancer agents, including methotrexate (67%) and 5FU (26%), are also in short supply at their centers.
The shortage and the uncertainty as to when it will end are forcing some centers to develop conservation and mitigation strategies.
The NCCN has broadly outlined how the federal government, the pharmaceutical industry, providers, and payers can help with prevention and mitigation. The NCCN has called on the federal government and the pharmaceutical industry to work to secure a steady supply of core anticancer drugs and has asked payers to “put patients first and provide flexible and efficient systems of providing coverage for alternative therapies replacing anti-cancer drugs that are unavailable or in shortage.”
Overall, the survey results “demonstrate the widespread impact of the chemotherapy shortage,” said Alyssa Schatz, MSW, senior director of policy and advocacy for NCCN. “We hope that by sharing this survey and calling for united action across the oncology community, we can come together to prevent future drug shortages and ensure quality, effective, equitable, and accessible cancer care for all.”
A version of this article first appeared on Medscape.com.
The survey, which included responses from 27 NCCN member institutions, revealed that 93% are experiencing a shortage of carboplatin and that 70% have reported a shortage of cisplatin.
“This is an unacceptable situation,” Robert W. Carlson, MD, NCCN’s chief executive offer, said in the statement released by the network.
“We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now,” Dr. Carlson said. And while the survey results show patients are still able to get lifesaving care, “it comes at a burden to our overtaxed medical facilities.”
The NCCN called on the federal government, the pharmaceutical industry, providers, and payers to take steps to “help mitigate any impacts” from this cancer drug shortage.
“We need to work together to improve the current situation and prevent it from happening again in the future,” Dr. Carlson stressed.
Carboplatin and cisplatin, which are frequently used together for systemic treatment, are highly effective therapies prescribed to treat many cancer types, including lung, breast, and prostate cancers, as well as leukemias and lymphomas. An estimated 500,000 new patients with cancer receive these agents each year.
The current survey, conducted over the last week of May, found that 100% of responding centers are able to continue to treat patients who need cisplatin without delays.
The same cannot be said for carboplatin: only 64% of centers said they are still able to continue treating all current patients receiving the platinum-based therapy. Among 19 responding centers, 20% reported that they were continuing carboplatin regimens for some but not all patients. And 16% reported treatment delays from having to obtain prior authorization for modified treatment plans, though none reported denials.
“Carboplatin has been in short supply for months but in the last 4 weeks has reached a critical stage,” according to one survey comment. “Without additional inventory many of our sites will be out of drug by early next week.”
In response to the survey question, “Is your center experiencing a shortage of carboplatin,” others made similar comments:
- “Current shipments from established manufacturers have been paused.”
- “The supply of carboplatin available is not meeting our demands.”
- “Without additional supply in early June, we will have to implement several shortage mitigation strategies.”
Survey respondents also addressed whether manufacturers or suppliers have provided any indication of when these drugs will become readily available again. For both drugs, about 60% of respondents said no. And for those who do receive updates, many noted that the “information is tentative and variable.”
Respondents indicated that other cancer agents, including methotrexate (67%) and 5FU (26%), are also in short supply at their centers.
The shortage and the uncertainty as to when it will end are forcing some centers to develop conservation and mitigation strategies.
The NCCN has broadly outlined how the federal government, the pharmaceutical industry, providers, and payers can help with prevention and mitigation. The NCCN has called on the federal government and the pharmaceutical industry to work to secure a steady supply of core anticancer drugs and has asked payers to “put patients first and provide flexible and efficient systems of providing coverage for alternative therapies replacing anti-cancer drugs that are unavailable or in shortage.”
Overall, the survey results “demonstrate the widespread impact of the chemotherapy shortage,” said Alyssa Schatz, MSW, senior director of policy and advocacy for NCCN. “We hope that by sharing this survey and calling for united action across the oncology community, we can come together to prevent future drug shortages and ensure quality, effective, equitable, and accessible cancer care for all.”
A version of this article first appeared on Medscape.com.
The survey, which included responses from 27 NCCN member institutions, revealed that 93% are experiencing a shortage of carboplatin and that 70% have reported a shortage of cisplatin.
“This is an unacceptable situation,” Robert W. Carlson, MD, NCCN’s chief executive offer, said in the statement released by the network.
“We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now,” Dr. Carlson said. And while the survey results show patients are still able to get lifesaving care, “it comes at a burden to our overtaxed medical facilities.”
The NCCN called on the federal government, the pharmaceutical industry, providers, and payers to take steps to “help mitigate any impacts” from this cancer drug shortage.
“We need to work together to improve the current situation and prevent it from happening again in the future,” Dr. Carlson stressed.
Carboplatin and cisplatin, which are frequently used together for systemic treatment, are highly effective therapies prescribed to treat many cancer types, including lung, breast, and prostate cancers, as well as leukemias and lymphomas. An estimated 500,000 new patients with cancer receive these agents each year.
The current survey, conducted over the last week of May, found that 100% of responding centers are able to continue to treat patients who need cisplatin without delays.
The same cannot be said for carboplatin: only 64% of centers said they are still able to continue treating all current patients receiving the platinum-based therapy. Among 19 responding centers, 20% reported that they were continuing carboplatin regimens for some but not all patients. And 16% reported treatment delays from having to obtain prior authorization for modified treatment plans, though none reported denials.
“Carboplatin has been in short supply for months but in the last 4 weeks has reached a critical stage,” according to one survey comment. “Without additional inventory many of our sites will be out of drug by early next week.”
In response to the survey question, “Is your center experiencing a shortage of carboplatin,” others made similar comments:
- “Current shipments from established manufacturers have been paused.”
- “The supply of carboplatin available is not meeting our demands.”
- “Without additional supply in early June, we will have to implement several shortage mitigation strategies.”
Survey respondents also addressed whether manufacturers or suppliers have provided any indication of when these drugs will become readily available again. For both drugs, about 60% of respondents said no. And for those who do receive updates, many noted that the “information is tentative and variable.”
Respondents indicated that other cancer agents, including methotrexate (67%) and 5FU (26%), are also in short supply at their centers.
The shortage and the uncertainty as to when it will end are forcing some centers to develop conservation and mitigation strategies.
The NCCN has broadly outlined how the federal government, the pharmaceutical industry, providers, and payers can help with prevention and mitigation. The NCCN has called on the federal government and the pharmaceutical industry to work to secure a steady supply of core anticancer drugs and has asked payers to “put patients first and provide flexible and efficient systems of providing coverage for alternative therapies replacing anti-cancer drugs that are unavailable or in shortage.”
Overall, the survey results “demonstrate the widespread impact of the chemotherapy shortage,” said Alyssa Schatz, MSW, senior director of policy and advocacy for NCCN. “We hope that by sharing this survey and calling for united action across the oncology community, we can come together to prevent future drug shortages and ensure quality, effective, equitable, and accessible cancer care for all.”
A version of this article first appeared on Medscape.com.
Is ChatGPT a friend or foe of medical publishing?
. These tools should not be listed as authors, and researchers must denote how AI-assisted technologies were used, the committee said.
These new guidelines are the latest effort for medical journals to define policies for using these large-scale language models (LLMs) in scientific publication. While these AI-assisted tools can help with tasks such as writing, analyzing data, catching mistakes, and much more, they are also prone to errors, noted Casey Greene, PhD, a professor of biomedical informatics at the University of Colorado at Denver, Aurora. It is also not totally clear how information is stored and processed in these kinds of tools, and who has access to that information, he noted.
At the same time, experts argue that these AI tools could have a positive impact on the field by limiting some of the linguistic disparities in scientific publishing as well as alleviating the burden of some monotonous or mechanical tasks that come along with manuscript writing.
What experts can agree on, though, is that the use of AI tools is here to stay. “This is going to become a common tool,” Dr. Greene said. “I don’t think there’s a way out of that at this point.”
A change in medical publishing
OpenAI released ChatGPT in November 2022. In its own words, ChatGPT is “a deep learning model that has been trained on a massive amount of text data to understand and generate humanlike text.” Enter a question or a prompt, and it will respond. For example, when asked how the AI tool can be used in scientific publishing, ChatGPT responded:
“ChatGPT can aid scientific publishing by generating ideas, clarifying concepts, conducting preliminary literature reviews, providing proofreading and editing suggestions, and assisting with outlining and organizing scientific papers. However, it should be used as a supportive tool alongside domain expertise and validation from trusted scientific sources.”
Just a few months after ChatGPT became available, researchers began using this tool in their own work. One individual, Som Biswas, MD, a radiologist at the University of Tennessee Health Science Center in Memphis, reportedly used ChatGPT to author 16 scientific articles in just 4 months, according to the Daily Beast. Five of these articles have been published in four different journals. Dr. Biswas declined to be interviewed for this article.
There were also reports of papers with ChatGPT as one of the listed authors, which sparked backlash. In response, JAMA, Nature, and Science all published editorials in January outlining their policies for using ChatGPT and other large language models in the scientific authoring process. Editors from the journals of the American College of Cardiology and the American College of Rheumatology also updated their policies to reflect the influence of AI authoring tools.
The consensus is that AI has no place on the author byline.
“We think that’s not appropriate, because coauthorship means that you are taking responsibility for the analysis and the generation of data that are included in a manuscript. A machine that is dictated by AI can’t take responsibility,” said Daniel Solomon, MD, MPH, a rheumatologist at Brigham and Women’s Hospital, Boston, and the editor in chief of the ACR journal Arthritis & Rheumatology.
Issues with AI
One of the big concerns around using AI in writing is that it can generate text that seems plausible but is untrue or not supported by data. For example, Dr. Greene and colleague Milton Pividori, PhD, also of the University of Colorado, were writing a journal article about new software they developed that uses a large language model to revise scientific manuscripts.
“We used the same software to revise that article and at one point, it added a line that noted that the large language model had been fine-tuned on a data set of manuscripts from within the same field. This makes a lot of sense, and is absolutely something you could do, but was not something that we did,” Dr. Greene said. “Without a really careful review of the content, it becomes possible to invent things that were not actually done.”
In another case, ChatGPT falsely stated that a prominent law professor had been accused of sexual assault, citing a Washington Post article that did not exist.
“We live in a society where we are extremely concerned about fake news,” Dr. Pividori added, “and [these kinds of errors] could certainly exacerbate that in the scientific community, which is very concerning because science informs public policy.”
Another issue is the lack of transparency around how large language models like ChatGPT process and store data used to make queries.
“We have no idea how they are recording all the prompts and things that we input into ChatGPT and their systems,” Dr. Pividori said.
OpenAI recently addressed some privacy concerns by allowing users to turn off their chat history with the AI chatbot, so conversations cannot be used to train or improve the company’s models. But Dr. Greene noted that the terms of service “still remain pretty nebulous.”
Dr. Solomon is also concerned with researchers using these AI tools in authoring without knowing how they work. “The thing we are really concerned about is that fact that [LLMs] are a bit of a black box – people don’t really understand the methodologies,” he said.
A positive tool?
But despite these concerns, many think that these types of AI-assisted tools could have a positive impact on medical publishing, particularly for researchers for whom English is not their first language, noted Catherine Gao, MD, a pulmonary and critical care instructor at Northwestern University, Chicago. She recently led research comparing scientific abstracts written by ChatGPT and real abstracts and discovered that reviewers found it “surprisingly difficult” to differentiate the two.
“The majority of research is published in English,” she said in an email. “Responsible use of LLMs can potentially reduce the burden of writing for busy scientists and improve equity for those who are not native English speakers.”
Dr. Pividori agreed, adding that as a non-native English speaker, he spends much more time working on the structure and grammar of sentences when authoring a manuscript, compared with people who speak English as a first language. He noted that these tools can also be used to automate some of the more monotonous tasks that come along with writing manuscripts and allow researchers to focus on the more creative aspects.
In the future, “I want to focus more on the things that only a human can do and let these tools do all the rest of it,” he said.
New rules
But despite how individual researchers feel about LLMs, they agree that these AI tools are here to stay.
“I think that we should anticipate that they will become part of the medical research establishment over time, when we figure out how to use them appropriately,” Dr. Solomon said.
While the debate of how to best use AI in medical publications will continue, journal editors agree that all authors of a manuscript are solely responsible for content in articles that used AI-assisted technology.
“Authors should carefully review and edit the result because AI can generate authoritative-sounding output that can be incorrect, incomplete, or biased,” the ICMJE guidelines state. “Authors should be able to assert that there is no plagiarism in their paper, including in text and images produced by the AI.” This includes appropriate attribution of all cited materials.
The committee also recommends that authors write in both the cover letter and submitted work how AI was used in the manuscript writing process. Recently updated guidelines from the World Association of Medical Editors recommend that all prompts used to generate new text or analytical work should be provided in submitted work. Dr. Greene also noted that if authors used an AI tool to revise their work, they can include a version of the manuscript untouched by LLMs.
It is similar to a preprint, he said, but rather than publishing a version of a paper prior to peer review, someone is showing a version of a manuscript before it was reviewed and revised by AI. “This type of practice could be a path that lets us benefit from these models,” he said, “without having the drawbacks that many are concerned about.”
Dr. Solomon has financial relationships with AbbVie, Amgen, Janssen, CorEvitas, and Moderna. Both Dr. Greene and Dr. Pividori are inventors in the U.S. Provisional Patent Application No. 63/486,706 that the University of Colorado has filed for the “Publishing Infrastructure For AI-Assisted Academic Authoring” invention with the U.S. Patent and Trademark Office. Dr. Greene and Dr. Pividori also received a grant from the Alfred P. Sloan Foundation to improve their AI-based manuscript revision tool. Dr. Gao reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
. These tools should not be listed as authors, and researchers must denote how AI-assisted technologies were used, the committee said.
These new guidelines are the latest effort for medical journals to define policies for using these large-scale language models (LLMs) in scientific publication. While these AI-assisted tools can help with tasks such as writing, analyzing data, catching mistakes, and much more, they are also prone to errors, noted Casey Greene, PhD, a professor of biomedical informatics at the University of Colorado at Denver, Aurora. It is also not totally clear how information is stored and processed in these kinds of tools, and who has access to that information, he noted.
At the same time, experts argue that these AI tools could have a positive impact on the field by limiting some of the linguistic disparities in scientific publishing as well as alleviating the burden of some monotonous or mechanical tasks that come along with manuscript writing.
What experts can agree on, though, is that the use of AI tools is here to stay. “This is going to become a common tool,” Dr. Greene said. “I don’t think there’s a way out of that at this point.”
A change in medical publishing
OpenAI released ChatGPT in November 2022. In its own words, ChatGPT is “a deep learning model that has been trained on a massive amount of text data to understand and generate humanlike text.” Enter a question or a prompt, and it will respond. For example, when asked how the AI tool can be used in scientific publishing, ChatGPT responded:
“ChatGPT can aid scientific publishing by generating ideas, clarifying concepts, conducting preliminary literature reviews, providing proofreading and editing suggestions, and assisting with outlining and organizing scientific papers. However, it should be used as a supportive tool alongside domain expertise and validation from trusted scientific sources.”
Just a few months after ChatGPT became available, researchers began using this tool in their own work. One individual, Som Biswas, MD, a radiologist at the University of Tennessee Health Science Center in Memphis, reportedly used ChatGPT to author 16 scientific articles in just 4 months, according to the Daily Beast. Five of these articles have been published in four different journals. Dr. Biswas declined to be interviewed for this article.
There were also reports of papers with ChatGPT as one of the listed authors, which sparked backlash. In response, JAMA, Nature, and Science all published editorials in January outlining their policies for using ChatGPT and other large language models in the scientific authoring process. Editors from the journals of the American College of Cardiology and the American College of Rheumatology also updated their policies to reflect the influence of AI authoring tools.
The consensus is that AI has no place on the author byline.
“We think that’s not appropriate, because coauthorship means that you are taking responsibility for the analysis and the generation of data that are included in a manuscript. A machine that is dictated by AI can’t take responsibility,” said Daniel Solomon, MD, MPH, a rheumatologist at Brigham and Women’s Hospital, Boston, and the editor in chief of the ACR journal Arthritis & Rheumatology.
Issues with AI
One of the big concerns around using AI in writing is that it can generate text that seems plausible but is untrue or not supported by data. For example, Dr. Greene and colleague Milton Pividori, PhD, also of the University of Colorado, were writing a journal article about new software they developed that uses a large language model to revise scientific manuscripts.
“We used the same software to revise that article and at one point, it added a line that noted that the large language model had been fine-tuned on a data set of manuscripts from within the same field. This makes a lot of sense, and is absolutely something you could do, but was not something that we did,” Dr. Greene said. “Without a really careful review of the content, it becomes possible to invent things that were not actually done.”
In another case, ChatGPT falsely stated that a prominent law professor had been accused of sexual assault, citing a Washington Post article that did not exist.
“We live in a society where we are extremely concerned about fake news,” Dr. Pividori added, “and [these kinds of errors] could certainly exacerbate that in the scientific community, which is very concerning because science informs public policy.”
Another issue is the lack of transparency around how large language models like ChatGPT process and store data used to make queries.
“We have no idea how they are recording all the prompts and things that we input into ChatGPT and their systems,” Dr. Pividori said.
OpenAI recently addressed some privacy concerns by allowing users to turn off their chat history with the AI chatbot, so conversations cannot be used to train or improve the company’s models. But Dr. Greene noted that the terms of service “still remain pretty nebulous.”
Dr. Solomon is also concerned with researchers using these AI tools in authoring without knowing how they work. “The thing we are really concerned about is that fact that [LLMs] are a bit of a black box – people don’t really understand the methodologies,” he said.
A positive tool?
But despite these concerns, many think that these types of AI-assisted tools could have a positive impact on medical publishing, particularly for researchers for whom English is not their first language, noted Catherine Gao, MD, a pulmonary and critical care instructor at Northwestern University, Chicago. She recently led research comparing scientific abstracts written by ChatGPT and real abstracts and discovered that reviewers found it “surprisingly difficult” to differentiate the two.
“The majority of research is published in English,” she said in an email. “Responsible use of LLMs can potentially reduce the burden of writing for busy scientists and improve equity for those who are not native English speakers.”
Dr. Pividori agreed, adding that as a non-native English speaker, he spends much more time working on the structure and grammar of sentences when authoring a manuscript, compared with people who speak English as a first language. He noted that these tools can also be used to automate some of the more monotonous tasks that come along with writing manuscripts and allow researchers to focus on the more creative aspects.
In the future, “I want to focus more on the things that only a human can do and let these tools do all the rest of it,” he said.
New rules
But despite how individual researchers feel about LLMs, they agree that these AI tools are here to stay.
“I think that we should anticipate that they will become part of the medical research establishment over time, when we figure out how to use them appropriately,” Dr. Solomon said.
While the debate of how to best use AI in medical publications will continue, journal editors agree that all authors of a manuscript are solely responsible for content in articles that used AI-assisted technology.
“Authors should carefully review and edit the result because AI can generate authoritative-sounding output that can be incorrect, incomplete, or biased,” the ICMJE guidelines state. “Authors should be able to assert that there is no plagiarism in their paper, including in text and images produced by the AI.” This includes appropriate attribution of all cited materials.
The committee also recommends that authors write in both the cover letter and submitted work how AI was used in the manuscript writing process. Recently updated guidelines from the World Association of Medical Editors recommend that all prompts used to generate new text or analytical work should be provided in submitted work. Dr. Greene also noted that if authors used an AI tool to revise their work, they can include a version of the manuscript untouched by LLMs.
It is similar to a preprint, he said, but rather than publishing a version of a paper prior to peer review, someone is showing a version of a manuscript before it was reviewed and revised by AI. “This type of practice could be a path that lets us benefit from these models,” he said, “without having the drawbacks that many are concerned about.”
Dr. Solomon has financial relationships with AbbVie, Amgen, Janssen, CorEvitas, and Moderna. Both Dr. Greene and Dr. Pividori are inventors in the U.S. Provisional Patent Application No. 63/486,706 that the University of Colorado has filed for the “Publishing Infrastructure For AI-Assisted Academic Authoring” invention with the U.S. Patent and Trademark Office. Dr. Greene and Dr. Pividori also received a grant from the Alfred P. Sloan Foundation to improve their AI-based manuscript revision tool. Dr. Gao reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
. These tools should not be listed as authors, and researchers must denote how AI-assisted technologies were used, the committee said.
These new guidelines are the latest effort for medical journals to define policies for using these large-scale language models (LLMs) in scientific publication. While these AI-assisted tools can help with tasks such as writing, analyzing data, catching mistakes, and much more, they are also prone to errors, noted Casey Greene, PhD, a professor of biomedical informatics at the University of Colorado at Denver, Aurora. It is also not totally clear how information is stored and processed in these kinds of tools, and who has access to that information, he noted.
At the same time, experts argue that these AI tools could have a positive impact on the field by limiting some of the linguistic disparities in scientific publishing as well as alleviating the burden of some monotonous or mechanical tasks that come along with manuscript writing.
What experts can agree on, though, is that the use of AI tools is here to stay. “This is going to become a common tool,” Dr. Greene said. “I don’t think there’s a way out of that at this point.”
A change in medical publishing
OpenAI released ChatGPT in November 2022. In its own words, ChatGPT is “a deep learning model that has been trained on a massive amount of text data to understand and generate humanlike text.” Enter a question or a prompt, and it will respond. For example, when asked how the AI tool can be used in scientific publishing, ChatGPT responded:
“ChatGPT can aid scientific publishing by generating ideas, clarifying concepts, conducting preliminary literature reviews, providing proofreading and editing suggestions, and assisting with outlining and organizing scientific papers. However, it should be used as a supportive tool alongside domain expertise and validation from trusted scientific sources.”
Just a few months after ChatGPT became available, researchers began using this tool in their own work. One individual, Som Biswas, MD, a radiologist at the University of Tennessee Health Science Center in Memphis, reportedly used ChatGPT to author 16 scientific articles in just 4 months, according to the Daily Beast. Five of these articles have been published in four different journals. Dr. Biswas declined to be interviewed for this article.
There were also reports of papers with ChatGPT as one of the listed authors, which sparked backlash. In response, JAMA, Nature, and Science all published editorials in January outlining their policies for using ChatGPT and other large language models in the scientific authoring process. Editors from the journals of the American College of Cardiology and the American College of Rheumatology also updated their policies to reflect the influence of AI authoring tools.
The consensus is that AI has no place on the author byline.
“We think that’s not appropriate, because coauthorship means that you are taking responsibility for the analysis and the generation of data that are included in a manuscript. A machine that is dictated by AI can’t take responsibility,” said Daniel Solomon, MD, MPH, a rheumatologist at Brigham and Women’s Hospital, Boston, and the editor in chief of the ACR journal Arthritis & Rheumatology.
Issues with AI
One of the big concerns around using AI in writing is that it can generate text that seems plausible but is untrue or not supported by data. For example, Dr. Greene and colleague Milton Pividori, PhD, also of the University of Colorado, were writing a journal article about new software they developed that uses a large language model to revise scientific manuscripts.
“We used the same software to revise that article and at one point, it added a line that noted that the large language model had been fine-tuned on a data set of manuscripts from within the same field. This makes a lot of sense, and is absolutely something you could do, but was not something that we did,” Dr. Greene said. “Without a really careful review of the content, it becomes possible to invent things that were not actually done.”
In another case, ChatGPT falsely stated that a prominent law professor had been accused of sexual assault, citing a Washington Post article that did not exist.
“We live in a society where we are extremely concerned about fake news,” Dr. Pividori added, “and [these kinds of errors] could certainly exacerbate that in the scientific community, which is very concerning because science informs public policy.”
Another issue is the lack of transparency around how large language models like ChatGPT process and store data used to make queries.
“We have no idea how they are recording all the prompts and things that we input into ChatGPT and their systems,” Dr. Pividori said.
OpenAI recently addressed some privacy concerns by allowing users to turn off their chat history with the AI chatbot, so conversations cannot be used to train or improve the company’s models. But Dr. Greene noted that the terms of service “still remain pretty nebulous.”
Dr. Solomon is also concerned with researchers using these AI tools in authoring without knowing how they work. “The thing we are really concerned about is that fact that [LLMs] are a bit of a black box – people don’t really understand the methodologies,” he said.
A positive tool?
But despite these concerns, many think that these types of AI-assisted tools could have a positive impact on medical publishing, particularly for researchers for whom English is not their first language, noted Catherine Gao, MD, a pulmonary and critical care instructor at Northwestern University, Chicago. She recently led research comparing scientific abstracts written by ChatGPT and real abstracts and discovered that reviewers found it “surprisingly difficult” to differentiate the two.
“The majority of research is published in English,” she said in an email. “Responsible use of LLMs can potentially reduce the burden of writing for busy scientists and improve equity for those who are not native English speakers.”
Dr. Pividori agreed, adding that as a non-native English speaker, he spends much more time working on the structure and grammar of sentences when authoring a manuscript, compared with people who speak English as a first language. He noted that these tools can also be used to automate some of the more monotonous tasks that come along with writing manuscripts and allow researchers to focus on the more creative aspects.
In the future, “I want to focus more on the things that only a human can do and let these tools do all the rest of it,” he said.
New rules
But despite how individual researchers feel about LLMs, they agree that these AI tools are here to stay.
“I think that we should anticipate that they will become part of the medical research establishment over time, when we figure out how to use them appropriately,” Dr. Solomon said.
While the debate of how to best use AI in medical publications will continue, journal editors agree that all authors of a manuscript are solely responsible for content in articles that used AI-assisted technology.
“Authors should carefully review and edit the result because AI can generate authoritative-sounding output that can be incorrect, incomplete, or biased,” the ICMJE guidelines state. “Authors should be able to assert that there is no plagiarism in their paper, including in text and images produced by the AI.” This includes appropriate attribution of all cited materials.
The committee also recommends that authors write in both the cover letter and submitted work how AI was used in the manuscript writing process. Recently updated guidelines from the World Association of Medical Editors recommend that all prompts used to generate new text or analytical work should be provided in submitted work. Dr. Greene also noted that if authors used an AI tool to revise their work, they can include a version of the manuscript untouched by LLMs.
It is similar to a preprint, he said, but rather than publishing a version of a paper prior to peer review, someone is showing a version of a manuscript before it was reviewed and revised by AI. “This type of practice could be a path that lets us benefit from these models,” he said, “without having the drawbacks that many are concerned about.”
Dr. Solomon has financial relationships with AbbVie, Amgen, Janssen, CorEvitas, and Moderna. Both Dr. Greene and Dr. Pividori are inventors in the U.S. Provisional Patent Application No. 63/486,706 that the University of Colorado has filed for the “Publishing Infrastructure For AI-Assisted Academic Authoring” invention with the U.S. Patent and Trademark Office. Dr. Greene and Dr. Pividori also received a grant from the Alfred P. Sloan Foundation to improve their AI-based manuscript revision tool. Dr. Gao reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Guide explains nonsurgical management of major hemorrhage
A new guide offers recommendations for the nonsurgical management of major hemorrhage, which is a challenging clinical problem.
Major hemorrhage is a significant cause of death and can occur in a myriad of clinical settings.
“In Ontario, we’ve been collecting quality metrics on major hemorrhages to try and make sure that a higher percentage of patients gets the best possible care when they are experiencing significant bleeding,” author Jeannie Callum, MD, professor and director of transfusion medicine at Kingston (Ont.) Health Sciences Centre and Queen’s University, also in Kingston, said in an interview. “There were some gaps, so this is our effort to get open, clear information out to the emergency doctors, intensive care unit doctors, the surgeons, and everyone else involved in managing major hemorrhage, to help close these gaps.”
The guide was published in the Canadian Medical Association Journal.
Fast care essential
The guide aims to provide answers, based on the latest research, to questions such as when to activate a massive hemorrhage protocol (MHP), which patients should receive tranexamic acid (TXA), which blood products should be transfused before laboratory results are available, how to monitor the effects of blood transfusion, and when fibrinogen concentrate or prothrombin complex concentrate should be given.
Not all recommendations will be followed, Dr. Callum said, especially in rural hospitals with limited resources. But the guide is adaptable, and rural hospitals can create protocols that are customized to their unique circumstances.
Care must be “perfect and fast” in the first hour of major injury, said Dr. Callum. “You need to get a proclotting drug in that first hour if you have a traumatic or postpartum bleed. You have to make sure your clotting factors never fail you throughout your resuscitation. You have to be fast with the transfusion. You have to monitor for the complications of the transfusion, electrolyte disturbances, and the patient’s temperature dropping. It’s a complicated situation that needs a multidisciplinary team.”
Bleeding affects everybody in medicine, from family doctors in smaller institutions who work in emergency departments to obstetricians and surgeons, she added.
“For people under the age of 45, trauma is the most common cause of death. When people die of trauma, they die of bleeding. So many people experience these extreme bleeds. We believe that some of them might be preventable with faster, more standardized, more aggressive care. That’s why we wrote this review,” said Dr. Callum.
Administer TXA quickly
The first recommendation is to ensure that every hospital has a massive hemorrhage protocol. Such a protocol is vital for the emergency department, operating room, and obstetric unit. “Making sure you’ve got a protocol that is updated every 3 years and adjusted to the local hospital context is essential,” said Dr. Callum.
Smaller hospitals will have to adjust their protocols according to the capabilities of their sites. “Some smaller hospitals do not have platelets in stock and get their platelets from another hospital, so you need to adjust your protocol to what you are able to do. Not every hospital can control bleeding in a trauma patient, so your protocol would be to stabilize and call a helicopter. Make sure all of this is detailed so that implementing it becomes automatic,” said Dr. Callum.
An MHP should be activated for patients with uncontrolled hemorrhage who meet the clinical criteria of the local hospital and are expected to need blood product support and red blood cells.
“Lots of people bleed, but not everybody is bleeding enough that they need a code transfusion,” said Dr. Callum. Most patients with gastrointestinal bleeds caused by NSAID use can be managed with uncrossed matched blood from the local blood bank. “But in patients who need the full code transfusion because they are going to need plasma, clotting factor replacement, and many other drugs, that is when the MHP should be activated. Don’t activate it when you don’t need it, because doing so activates the whole hospital and diverts care away from other patients.”
TXA should be administered as soon as possible after onset of hemorrhage in most patients, with the exception of gastrointestinal hemorrhage, where a benefit has not been shown.
TXA has been a major advance in treating massive bleeding, Dr. Callum said. “TXA was invented by a Japanese husband-and-wife research team. We know that it reduces the death rate in trauma and in postpartum hemorrhage, and it reduces the chance of major bleeding with major surgical procedures. We give it routinely in surgical procedures. If a patient gets TXA within 60 minutes of injury, it dramatically reduces the death rate. And it costs $10 per patient. It’s cheap, it’s easy, it has no side effects. It’s just amazing.”
Future research must address several unanswered questions, said Dr. Callum. These questions include whether prehospital transfusion improves patient outcomes, whether whole blood has a role in the early management of major hemorrhage, and what role factor concentrates play in patients with major bleeding.
‘Optimal recommendations’
Commenting on the document, Bourke Tillmann, MD, PhD, trauma team leader at Sunnybrook Health Sciences Centre and the Ross Tilley Burn Center in Toronto, said: “Overall, I think it is a good overview of MHPs as an approach to major hemorrhage.”
The review also is timely, since Ontario released its MHP guidelines in 2021, he added. “I would have liked to see more about the treatment aspects than just an overview of an MHP. But if you are the person overseeing the emergency department or running the blood bank, these protocols are incredibly useful and incredibly important.”
“This report is a nice and thoughtful overview of best practices in many areas, especially trauma, and makes recommendations that are optimal, although they are not necessarily practical in all centers,” Eric L. Legome, MD, professor and chair of emergency medicine at Mount Sinai West and Mount Sinai Morningside, New York, said in an interview.
“If you’re in a small rural hospital with one lab technician, trying to do all of these things, it will not be possible. These are optimal recommendations that people can use to the best of their ability, but they are not standard of care, because some places will not be able to provide this level of care,” he added. “This paper provides practical, reasonable advice that should be looked at as you are trying to implement transfusion policies and processes, with the understanding that it is not necessarily applicable or practical for very small hospitals in very rural centers that might not have access to these types of products and tools, but it’s a reasonable and nicely written paper.”
No outside funding for the guideline was reported. Dr. Callum has received research funding from Canadian Blood Services and Octapharma. She sits on the nominating committee with the Association for the Advancement of Blood & Biotherapies and on the data safety monitoring boards for the Tranexamic Acid for Subdural Hematoma trial and the Fibrinogen Replacement in Trauma trial. Dr. Tillmann and Dr. Legome reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
A new guide offers recommendations for the nonsurgical management of major hemorrhage, which is a challenging clinical problem.
Major hemorrhage is a significant cause of death and can occur in a myriad of clinical settings.
“In Ontario, we’ve been collecting quality metrics on major hemorrhages to try and make sure that a higher percentage of patients gets the best possible care when they are experiencing significant bleeding,” author Jeannie Callum, MD, professor and director of transfusion medicine at Kingston (Ont.) Health Sciences Centre and Queen’s University, also in Kingston, said in an interview. “There were some gaps, so this is our effort to get open, clear information out to the emergency doctors, intensive care unit doctors, the surgeons, and everyone else involved in managing major hemorrhage, to help close these gaps.”
The guide was published in the Canadian Medical Association Journal.
Fast care essential
The guide aims to provide answers, based on the latest research, to questions such as when to activate a massive hemorrhage protocol (MHP), which patients should receive tranexamic acid (TXA), which blood products should be transfused before laboratory results are available, how to monitor the effects of blood transfusion, and when fibrinogen concentrate or prothrombin complex concentrate should be given.
Not all recommendations will be followed, Dr. Callum said, especially in rural hospitals with limited resources. But the guide is adaptable, and rural hospitals can create protocols that are customized to their unique circumstances.
Care must be “perfect and fast” in the first hour of major injury, said Dr. Callum. “You need to get a proclotting drug in that first hour if you have a traumatic or postpartum bleed. You have to make sure your clotting factors never fail you throughout your resuscitation. You have to be fast with the transfusion. You have to monitor for the complications of the transfusion, electrolyte disturbances, and the patient’s temperature dropping. It’s a complicated situation that needs a multidisciplinary team.”
Bleeding affects everybody in medicine, from family doctors in smaller institutions who work in emergency departments to obstetricians and surgeons, she added.
“For people under the age of 45, trauma is the most common cause of death. When people die of trauma, they die of bleeding. So many people experience these extreme bleeds. We believe that some of them might be preventable with faster, more standardized, more aggressive care. That’s why we wrote this review,” said Dr. Callum.
Administer TXA quickly
The first recommendation is to ensure that every hospital has a massive hemorrhage protocol. Such a protocol is vital for the emergency department, operating room, and obstetric unit. “Making sure you’ve got a protocol that is updated every 3 years and adjusted to the local hospital context is essential,” said Dr. Callum.
Smaller hospitals will have to adjust their protocols according to the capabilities of their sites. “Some smaller hospitals do not have platelets in stock and get their platelets from another hospital, so you need to adjust your protocol to what you are able to do. Not every hospital can control bleeding in a trauma patient, so your protocol would be to stabilize and call a helicopter. Make sure all of this is detailed so that implementing it becomes automatic,” said Dr. Callum.
An MHP should be activated for patients with uncontrolled hemorrhage who meet the clinical criteria of the local hospital and are expected to need blood product support and red blood cells.
“Lots of people bleed, but not everybody is bleeding enough that they need a code transfusion,” said Dr. Callum. Most patients with gastrointestinal bleeds caused by NSAID use can be managed with uncrossed matched blood from the local blood bank. “But in patients who need the full code transfusion because they are going to need plasma, clotting factor replacement, and many other drugs, that is when the MHP should be activated. Don’t activate it when you don’t need it, because doing so activates the whole hospital and diverts care away from other patients.”
TXA should be administered as soon as possible after onset of hemorrhage in most patients, with the exception of gastrointestinal hemorrhage, where a benefit has not been shown.
TXA has been a major advance in treating massive bleeding, Dr. Callum said. “TXA was invented by a Japanese husband-and-wife research team. We know that it reduces the death rate in trauma and in postpartum hemorrhage, and it reduces the chance of major bleeding with major surgical procedures. We give it routinely in surgical procedures. If a patient gets TXA within 60 minutes of injury, it dramatically reduces the death rate. And it costs $10 per patient. It’s cheap, it’s easy, it has no side effects. It’s just amazing.”
Future research must address several unanswered questions, said Dr. Callum. These questions include whether prehospital transfusion improves patient outcomes, whether whole blood has a role in the early management of major hemorrhage, and what role factor concentrates play in patients with major bleeding.
‘Optimal recommendations’
Commenting on the document, Bourke Tillmann, MD, PhD, trauma team leader at Sunnybrook Health Sciences Centre and the Ross Tilley Burn Center in Toronto, said: “Overall, I think it is a good overview of MHPs as an approach to major hemorrhage.”
The review also is timely, since Ontario released its MHP guidelines in 2021, he added. “I would have liked to see more about the treatment aspects than just an overview of an MHP. But if you are the person overseeing the emergency department or running the blood bank, these protocols are incredibly useful and incredibly important.”
“This report is a nice and thoughtful overview of best practices in many areas, especially trauma, and makes recommendations that are optimal, although they are not necessarily practical in all centers,” Eric L. Legome, MD, professor and chair of emergency medicine at Mount Sinai West and Mount Sinai Morningside, New York, said in an interview.
“If you’re in a small rural hospital with one lab technician, trying to do all of these things, it will not be possible. These are optimal recommendations that people can use to the best of their ability, but they are not standard of care, because some places will not be able to provide this level of care,” he added. “This paper provides practical, reasonable advice that should be looked at as you are trying to implement transfusion policies and processes, with the understanding that it is not necessarily applicable or practical for very small hospitals in very rural centers that might not have access to these types of products and tools, but it’s a reasonable and nicely written paper.”
No outside funding for the guideline was reported. Dr. Callum has received research funding from Canadian Blood Services and Octapharma. She sits on the nominating committee with the Association for the Advancement of Blood & Biotherapies and on the data safety monitoring boards for the Tranexamic Acid for Subdural Hematoma trial and the Fibrinogen Replacement in Trauma trial. Dr. Tillmann and Dr. Legome reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
A new guide offers recommendations for the nonsurgical management of major hemorrhage, which is a challenging clinical problem.
Major hemorrhage is a significant cause of death and can occur in a myriad of clinical settings.
“In Ontario, we’ve been collecting quality metrics on major hemorrhages to try and make sure that a higher percentage of patients gets the best possible care when they are experiencing significant bleeding,” author Jeannie Callum, MD, professor and director of transfusion medicine at Kingston (Ont.) Health Sciences Centre and Queen’s University, also in Kingston, said in an interview. “There were some gaps, so this is our effort to get open, clear information out to the emergency doctors, intensive care unit doctors, the surgeons, and everyone else involved in managing major hemorrhage, to help close these gaps.”
The guide was published in the Canadian Medical Association Journal.
Fast care essential
The guide aims to provide answers, based on the latest research, to questions such as when to activate a massive hemorrhage protocol (MHP), which patients should receive tranexamic acid (TXA), which blood products should be transfused before laboratory results are available, how to monitor the effects of blood transfusion, and when fibrinogen concentrate or prothrombin complex concentrate should be given.
Not all recommendations will be followed, Dr. Callum said, especially in rural hospitals with limited resources. But the guide is adaptable, and rural hospitals can create protocols that are customized to their unique circumstances.
Care must be “perfect and fast” in the first hour of major injury, said Dr. Callum. “You need to get a proclotting drug in that first hour if you have a traumatic or postpartum bleed. You have to make sure your clotting factors never fail you throughout your resuscitation. You have to be fast with the transfusion. You have to monitor for the complications of the transfusion, electrolyte disturbances, and the patient’s temperature dropping. It’s a complicated situation that needs a multidisciplinary team.”
Bleeding affects everybody in medicine, from family doctors in smaller institutions who work in emergency departments to obstetricians and surgeons, she added.
“For people under the age of 45, trauma is the most common cause of death. When people die of trauma, they die of bleeding. So many people experience these extreme bleeds. We believe that some of them might be preventable with faster, more standardized, more aggressive care. That’s why we wrote this review,” said Dr. Callum.
Administer TXA quickly
The first recommendation is to ensure that every hospital has a massive hemorrhage protocol. Such a protocol is vital for the emergency department, operating room, and obstetric unit. “Making sure you’ve got a protocol that is updated every 3 years and adjusted to the local hospital context is essential,” said Dr. Callum.
Smaller hospitals will have to adjust their protocols according to the capabilities of their sites. “Some smaller hospitals do not have platelets in stock and get their platelets from another hospital, so you need to adjust your protocol to what you are able to do. Not every hospital can control bleeding in a trauma patient, so your protocol would be to stabilize and call a helicopter. Make sure all of this is detailed so that implementing it becomes automatic,” said Dr. Callum.
An MHP should be activated for patients with uncontrolled hemorrhage who meet the clinical criteria of the local hospital and are expected to need blood product support and red blood cells.
“Lots of people bleed, but not everybody is bleeding enough that they need a code transfusion,” said Dr. Callum. Most patients with gastrointestinal bleeds caused by NSAID use can be managed with uncrossed matched blood from the local blood bank. “But in patients who need the full code transfusion because they are going to need plasma, clotting factor replacement, and many other drugs, that is when the MHP should be activated. Don’t activate it when you don’t need it, because doing so activates the whole hospital and diverts care away from other patients.”
TXA should be administered as soon as possible after onset of hemorrhage in most patients, with the exception of gastrointestinal hemorrhage, where a benefit has not been shown.
TXA has been a major advance in treating massive bleeding, Dr. Callum said. “TXA was invented by a Japanese husband-and-wife research team. We know that it reduces the death rate in trauma and in postpartum hemorrhage, and it reduces the chance of major bleeding with major surgical procedures. We give it routinely in surgical procedures. If a patient gets TXA within 60 minutes of injury, it dramatically reduces the death rate. And it costs $10 per patient. It’s cheap, it’s easy, it has no side effects. It’s just amazing.”
Future research must address several unanswered questions, said Dr. Callum. These questions include whether prehospital transfusion improves patient outcomes, whether whole blood has a role in the early management of major hemorrhage, and what role factor concentrates play in patients with major bleeding.
‘Optimal recommendations’
Commenting on the document, Bourke Tillmann, MD, PhD, trauma team leader at Sunnybrook Health Sciences Centre and the Ross Tilley Burn Center in Toronto, said: “Overall, I think it is a good overview of MHPs as an approach to major hemorrhage.”
The review also is timely, since Ontario released its MHP guidelines in 2021, he added. “I would have liked to see more about the treatment aspects than just an overview of an MHP. But if you are the person overseeing the emergency department or running the blood bank, these protocols are incredibly useful and incredibly important.”
“This report is a nice and thoughtful overview of best practices in many areas, especially trauma, and makes recommendations that are optimal, although they are not necessarily practical in all centers,” Eric L. Legome, MD, professor and chair of emergency medicine at Mount Sinai West and Mount Sinai Morningside, New York, said in an interview.
“If you’re in a small rural hospital with one lab technician, trying to do all of these things, it will not be possible. These are optimal recommendations that people can use to the best of their ability, but they are not standard of care, because some places will not be able to provide this level of care,” he added. “This paper provides practical, reasonable advice that should be looked at as you are trying to implement transfusion policies and processes, with the understanding that it is not necessarily applicable or practical for very small hospitals in very rural centers that might not have access to these types of products and tools, but it’s a reasonable and nicely written paper.”
No outside funding for the guideline was reported. Dr. Callum has received research funding from Canadian Blood Services and Octapharma. She sits on the nominating committee with the Association for the Advancement of Blood & Biotherapies and on the data safety monitoring boards for the Tranexamic Acid for Subdural Hematoma trial and the Fibrinogen Replacement in Trauma trial. Dr. Tillmann and Dr. Legome reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM THE CANADIAN MEDICAL ASSOCIATION JOURNAL
`Remarkable’: CAR T therapy for CLL/SLL
The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.
“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.
Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.
“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.
With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.
In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.
The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 106 CAR-positive viable T cells of liso-cel.
With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).
Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.
The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.
The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).
The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.
The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.
In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.
Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.
Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.
For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.
Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.
One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.
“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.
She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.
“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.
For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”
Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.
“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
Largest data set to date
Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.
“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.
“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”
Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.
Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.
In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”
Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.
“The results of this study are very exciting,” she said during her discussion in the session.
“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”
Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”
The results were also published in The Lancet.
The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.
The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.
“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.
Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.
“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.
With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.
In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.
The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 106 CAR-positive viable T cells of liso-cel.
With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).
Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.
The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.
The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).
The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.
The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.
In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.
Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.
Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.
For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.
Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.
One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.
“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.
She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.
“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.
For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”
Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.
“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
Largest data set to date
Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.
“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.
“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”
Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.
Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.
In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”
Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.
“The results of this study are very exciting,” she said during her discussion in the session.
“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”
Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”
The results were also published in The Lancet.
The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.
The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.
“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.
Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.
“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.
With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.
In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.
The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 106 CAR-positive viable T cells of liso-cel.
With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).
Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.
The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.
The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).
The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.
The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.
In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.
Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.
Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.
For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.
Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.
One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.
“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.
She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.
“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.
For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”
Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.
“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
Largest data set to date
Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.
“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.
“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”
Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.
Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.
In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”
Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.
“The results of this study are very exciting,” she said during her discussion in the session.
“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”
Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”
The results were also published in The Lancet.
The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.
FROM ASCO 2023