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CML: Preventing chemo-induced vascular toxicity
PARIS –
Cardiologist Gabrielle Sarlon, MD, PhD, a professor at Marseille (France) University Hospital, offered her recommendations at the European Days of the French Society of Cardiology Conference 2023.
In the literature, we find many hypotheses that seek to explain why these drugs bring about the formation of atheromatous plaque. The findings of one French study led Dr. Sarlon to state, “I firmly believe that, in some patients, these treatments make LDL cholesterol go up.” This would be the main cause of the coronary and peripheral arterial diseases that are being seen.
Therefore, “LDL-C should start being monitored when the therapy starts, and a statin may have to be prescribed,” she said.
Arterial diseases
By bringing about a marked improvement in patients’ chances of survival, TKIs “have revolutionized the management of chronic myeloid leukemia,” Dr. Sarlon added. But these treatments have side effects. The most common is high blood pressure, “an effect that attests to the efficacy of targeted therapies and that must be quickly treated” with antihypertensives.
It is well known that the targeted therapies cause the rise in blood pressure. What was unexpected, though, was the vascular toxicity seen with the latest generation of TKIs. “This is a real toxicity that we need to know about, detect, and manage,” said Dr. Sarlon.
The prevalence of arterial diseases induced by nilotinib, a second-generation TKI, can be as high as 10%. Single-center studies have indicated much higher numbers. In a small study that Dr. Sarlon and her team conducted at Marseille University Hospital, atherosclerotic-type arterial injuries were observed in more than 30% of patients treated with nilotinib.
Dr. Sarlon noted that the signs of arterial toxicity occurring with this treatment have not appeared in clinical trials. Observations of the real-life use of nilotinib led French and German teams to sound the alarm. They noticed that some patients treated for CML had developed claudication and progression to critical limb ischemia of the lower extremities.
Risk factors uncovered
The first retrospective analysis to explore this risk was carried out by a German team. They included 179 patients who received nilotinib and found that 11 (6.2%) developed severe and previously unrecognized lower-extremity peripheral arterial disease (PAD) that required invasive therapy. The mean time from initiation of nilotinib to the first PAD event was 105.1 weeks (range = 16-212 weeks).
The following have emerged as major risk factors for nilotinib-induced PAD: the presence of cardiovascular risk factors, age older than 60 years, and long duration of exposure to nilotinib. Some of these factors were confirmed in the more recent study conducted at Marseille University Hospital involving patients treated with nilotinib. According to other research, there seems to be a correlation between this risk and the dose administered.
In the case of ponatinib, the side effects are even more common – so much so that, a few months after this third-generation TKI was authorized, a warning was issued about its use. A long-term follow-up study reported a 28% prevalence of cardiovascular events, while arterial diseases were observed in 20% of cases after 1-2 years on the treatment.
In terms of pathophysiology, the Marseilles University Hospital study found that arterial injuries were associated with stenosis greater than 50% in almost half of cases. “The atheromatous plaques were found where they typically are,” with the carotid bulb being the most involved territory, according to the researchers. But they’re also found in other arteries – femoral, vertebral, even renal – “sometimes in patients without cardiovascular risk factors.”
One distinctive characteristic to keep in mind is that “lipid-rich atheromatous plaques appear very dark on imaging” and thus can go unnoticed during a Doppler ultrasound. And, Dr. Sarlon added, “surprisingly, the thickening can extend to the external carotid artery.”
Ankle-brachial index
Published last year, the first European Society of Cardiology Guidelines on Cardio-Oncology present specific baseline risk-assessment and monitoring recommendations regarding patients treated with nilotinib and ponatinib. One suggests that a cardiovascular risk assessment be done every 3 months during the first year and every 6-12 months thereafter. This assessment would include such items as ECGs, blood pressure measurements, and lipid profile tests.
In addition, it is advised that every 6 months an ankle-brachial index test be performed to check for PAD. At Marseille University Hospital, a Doppler ultrasound is also done at each follow-up appointment to look for arterial plaques, “even for patients at low risk for cardiovascular disease,” said Dr. Sarlon. “It seems, above all, absolutely necessary that hematologists order an LDL-C test and, if needed, consider statin therapy,” all the while keeping in mind that “the target LDL-C level is 1 gram per liter.”
This article was translated from the Medscape French edition. A version of this article first appeared on Medscape.com.
PARIS –
Cardiologist Gabrielle Sarlon, MD, PhD, a professor at Marseille (France) University Hospital, offered her recommendations at the European Days of the French Society of Cardiology Conference 2023.
In the literature, we find many hypotheses that seek to explain why these drugs bring about the formation of atheromatous plaque. The findings of one French study led Dr. Sarlon to state, “I firmly believe that, in some patients, these treatments make LDL cholesterol go up.” This would be the main cause of the coronary and peripheral arterial diseases that are being seen.
Therefore, “LDL-C should start being monitored when the therapy starts, and a statin may have to be prescribed,” she said.
Arterial diseases
By bringing about a marked improvement in patients’ chances of survival, TKIs “have revolutionized the management of chronic myeloid leukemia,” Dr. Sarlon added. But these treatments have side effects. The most common is high blood pressure, “an effect that attests to the efficacy of targeted therapies and that must be quickly treated” with antihypertensives.
It is well known that the targeted therapies cause the rise in blood pressure. What was unexpected, though, was the vascular toxicity seen with the latest generation of TKIs. “This is a real toxicity that we need to know about, detect, and manage,” said Dr. Sarlon.
The prevalence of arterial diseases induced by nilotinib, a second-generation TKI, can be as high as 10%. Single-center studies have indicated much higher numbers. In a small study that Dr. Sarlon and her team conducted at Marseille University Hospital, atherosclerotic-type arterial injuries were observed in more than 30% of patients treated with nilotinib.
Dr. Sarlon noted that the signs of arterial toxicity occurring with this treatment have not appeared in clinical trials. Observations of the real-life use of nilotinib led French and German teams to sound the alarm. They noticed that some patients treated for CML had developed claudication and progression to critical limb ischemia of the lower extremities.
Risk factors uncovered
The first retrospective analysis to explore this risk was carried out by a German team. They included 179 patients who received nilotinib and found that 11 (6.2%) developed severe and previously unrecognized lower-extremity peripheral arterial disease (PAD) that required invasive therapy. The mean time from initiation of nilotinib to the first PAD event was 105.1 weeks (range = 16-212 weeks).
The following have emerged as major risk factors for nilotinib-induced PAD: the presence of cardiovascular risk factors, age older than 60 years, and long duration of exposure to nilotinib. Some of these factors were confirmed in the more recent study conducted at Marseille University Hospital involving patients treated with nilotinib. According to other research, there seems to be a correlation between this risk and the dose administered.
In the case of ponatinib, the side effects are even more common – so much so that, a few months after this third-generation TKI was authorized, a warning was issued about its use. A long-term follow-up study reported a 28% prevalence of cardiovascular events, while arterial diseases were observed in 20% of cases after 1-2 years on the treatment.
In terms of pathophysiology, the Marseilles University Hospital study found that arterial injuries were associated with stenosis greater than 50% in almost half of cases. “The atheromatous plaques were found where they typically are,” with the carotid bulb being the most involved territory, according to the researchers. But they’re also found in other arteries – femoral, vertebral, even renal – “sometimes in patients without cardiovascular risk factors.”
One distinctive characteristic to keep in mind is that “lipid-rich atheromatous plaques appear very dark on imaging” and thus can go unnoticed during a Doppler ultrasound. And, Dr. Sarlon added, “surprisingly, the thickening can extend to the external carotid artery.”
Ankle-brachial index
Published last year, the first European Society of Cardiology Guidelines on Cardio-Oncology present specific baseline risk-assessment and monitoring recommendations regarding patients treated with nilotinib and ponatinib. One suggests that a cardiovascular risk assessment be done every 3 months during the first year and every 6-12 months thereafter. This assessment would include such items as ECGs, blood pressure measurements, and lipid profile tests.
In addition, it is advised that every 6 months an ankle-brachial index test be performed to check for PAD. At Marseille University Hospital, a Doppler ultrasound is also done at each follow-up appointment to look for arterial plaques, “even for patients at low risk for cardiovascular disease,” said Dr. Sarlon. “It seems, above all, absolutely necessary that hematologists order an LDL-C test and, if needed, consider statin therapy,” all the while keeping in mind that “the target LDL-C level is 1 gram per liter.”
This article was translated from the Medscape French edition. A version of this article first appeared on Medscape.com.
PARIS –
Cardiologist Gabrielle Sarlon, MD, PhD, a professor at Marseille (France) University Hospital, offered her recommendations at the European Days of the French Society of Cardiology Conference 2023.
In the literature, we find many hypotheses that seek to explain why these drugs bring about the formation of atheromatous plaque. The findings of one French study led Dr. Sarlon to state, “I firmly believe that, in some patients, these treatments make LDL cholesterol go up.” This would be the main cause of the coronary and peripheral arterial diseases that are being seen.
Therefore, “LDL-C should start being monitored when the therapy starts, and a statin may have to be prescribed,” she said.
Arterial diseases
By bringing about a marked improvement in patients’ chances of survival, TKIs “have revolutionized the management of chronic myeloid leukemia,” Dr. Sarlon added. But these treatments have side effects. The most common is high blood pressure, “an effect that attests to the efficacy of targeted therapies and that must be quickly treated” with antihypertensives.
It is well known that the targeted therapies cause the rise in blood pressure. What was unexpected, though, was the vascular toxicity seen with the latest generation of TKIs. “This is a real toxicity that we need to know about, detect, and manage,” said Dr. Sarlon.
The prevalence of arterial diseases induced by nilotinib, a second-generation TKI, can be as high as 10%. Single-center studies have indicated much higher numbers. In a small study that Dr. Sarlon and her team conducted at Marseille University Hospital, atherosclerotic-type arterial injuries were observed in more than 30% of patients treated with nilotinib.
Dr. Sarlon noted that the signs of arterial toxicity occurring with this treatment have not appeared in clinical trials. Observations of the real-life use of nilotinib led French and German teams to sound the alarm. They noticed that some patients treated for CML had developed claudication and progression to critical limb ischemia of the lower extremities.
Risk factors uncovered
The first retrospective analysis to explore this risk was carried out by a German team. They included 179 patients who received nilotinib and found that 11 (6.2%) developed severe and previously unrecognized lower-extremity peripheral arterial disease (PAD) that required invasive therapy. The mean time from initiation of nilotinib to the first PAD event was 105.1 weeks (range = 16-212 weeks).
The following have emerged as major risk factors for nilotinib-induced PAD: the presence of cardiovascular risk factors, age older than 60 years, and long duration of exposure to nilotinib. Some of these factors were confirmed in the more recent study conducted at Marseille University Hospital involving patients treated with nilotinib. According to other research, there seems to be a correlation between this risk and the dose administered.
In the case of ponatinib, the side effects are even more common – so much so that, a few months after this third-generation TKI was authorized, a warning was issued about its use. A long-term follow-up study reported a 28% prevalence of cardiovascular events, while arterial diseases were observed in 20% of cases after 1-2 years on the treatment.
In terms of pathophysiology, the Marseilles University Hospital study found that arterial injuries were associated with stenosis greater than 50% in almost half of cases. “The atheromatous plaques were found where they typically are,” with the carotid bulb being the most involved territory, according to the researchers. But they’re also found in other arteries – femoral, vertebral, even renal – “sometimes in patients without cardiovascular risk factors.”
One distinctive characteristic to keep in mind is that “lipid-rich atheromatous plaques appear very dark on imaging” and thus can go unnoticed during a Doppler ultrasound. And, Dr. Sarlon added, “surprisingly, the thickening can extend to the external carotid artery.”
Ankle-brachial index
Published last year, the first European Society of Cardiology Guidelines on Cardio-Oncology present specific baseline risk-assessment and monitoring recommendations regarding patients treated with nilotinib and ponatinib. One suggests that a cardiovascular risk assessment be done every 3 months during the first year and every 6-12 months thereafter. This assessment would include such items as ECGs, blood pressure measurements, and lipid profile tests.
In addition, it is advised that every 6 months an ankle-brachial index test be performed to check for PAD. At Marseille University Hospital, a Doppler ultrasound is also done at each follow-up appointment to look for arterial plaques, “even for patients at low risk for cardiovascular disease,” said Dr. Sarlon. “It seems, above all, absolutely necessary that hematologists order an LDL-C test and, if needed, consider statin therapy,” all the while keeping in mind that “the target LDL-C level is 1 gram per liter.”
This article was translated from the Medscape French edition. A version of this article first appeared on Medscape.com.
New cancer screen, same issues: Physicians confront Galleri test
In January 2022, Anthony Arenz, a 51-year-old living in Mesa, Ariz., breathed a small sigh of relief.
The Galleri blood test, which screens for 50 types of cancer, hadn’t detected any positive signs.
It would be welcome news to anyone but especially to a firefighter with a 9% greater risk of developing cancer and a 14% greater risk of dying from it than the average person. The Mesa unit had lost two servicemen to cancer in the past 3 years. Both were more than a decade younger than Mr. Arenz.
When the city of Mesa offered additional free screening – including a full-body MRI – to firefighters over 50, Mr. Arenz initially shrugged it off. With a negative Galleri test in hand, he didn’t want to spend more time dwelling on it.
Still, he began to feel a creeping guilt for skipping a test that many of his fallen colleagues hadn’t been offered. He tried to soothe his anxiety with research. A look through the company’s website didn’t set him at ease. According to Grail Bio, a test result of “no cancer signal detected” does not rule out cancer.
Mr. Arenz booked his free MRI.
The results left him heavy: stage I kidney cancer. The Galleri test had missed it.
Mr. Arenz received his free Galleri test through a cancer screening program funded by the city of Mesa. The program is housed at Vincere Cancer Center in Scottsdale, Ariz. Under the leadership of radiation oncologist and Vincere co-owner Vershalee Shukla, MD, the program currently screens first responders in more than 10 Arizona cities at no cost to them.
Vincere began using Galleri shortly after the test launched for consumers in June 2021. Since then, the first responder program has become the largest commercial user of the test in North America.
The Galleri test, which has not yet been approved by the Food and Drug Administration, is so new that few know what incorrect results look like in practice and how often they might occur.
After running the test on about 2,000 servicemen and servicewomen, Dr. Shukla can offer some insight about the test’s real-world value in a high-risk population.
“Cancer screening is a very complicated issue,” Dr. Shukla said in an interview. “Being honest, the tests are good but are not ready yet [for wider use].”
Mr. Arenz was not the only firefighter who got a surprise after taking a Galleri test.
In nearby Phoenix, 51-year-old firefighter Mike Curtis knew his risk for cancer was high, but he wasn’t that worried. Mr. Curtis had been running into fires since he was 17. His dad, also a firefighter, had died of cancer at age 58.
Mr. Curtis had taken the Vincere Cancer Center up on every free screening service since the program began in late 2018 – well before Dr. Shukla started using Galleri in 2021. His most recent lung CT was clear. But he underwent the Galleri test just to stay vigilant.
His result was a shock. The test detected signs of cancer.
Mr. Curtis decided to tell no one, not even his wife. He’d bear the bad news alone until he was certain.
Dr. Shukla, however, immediately doubted the blood test result. She expedited several follow-up tests. One week, a PET, and CT of the abdomen and pelvis later, her hunch was confirmed. The Galleri test result was wrong, Mr. Curtis did not have cancer.
The price of his peace of mind: an extensive workup with a $4,000 price tag. Fortunately, the bill was covered by the screening program.
Overall, in just over 18 months of using the blood test, Dr. Shukla has only encountered 1 other false positive out of about 2,000 Galleri results.
She also discovered two positive signals for cancer using Galleri that were confirmed with follow-up tests. One was a chordoma, a rare type of bone cancer, and the other was a squamous cell carcinoma of the head and neck. The Galleri test caught both remarkably early, in time for treatment.
For Dr. Shukla, however, false negatives were particularly “horrible.” Mr. Arenz’s was just 1 of 28 cancers that the blood test missed. And because 500 negative tests are yet to be validated, the 28 false negatives may be an underestimate.
In her experience, the binary test result – a simple positive or negative cancer signal – is an oversimplification of risk, she said. It “gives a false perception that you have cancer or you don’t,” although the test itself is not definitive.
Grail senior medical director Whitney Jones, MD, agreed that the test is not meant to be a stand-alone screening test for cancer. The purpose of the Galleri test is to “complement other screenings, not replace them,” Dr. Jones told this news organization.
According to an analysis of Galleri data and Dr. Shukla’s experience, the test’s specificity was over 99%. That means the test successfully minimizes false positives.
But the test’s sensitivity was much lower. From data from first responders, Dr. Shukla determined the sensitivity to be 6.7%. That means the test misses about 93 of every 100 cancers. According to Grail’s latest data from more than 6,300 people older than 50, the test’s sensitivity was 29%.
Specificity and sensitivity are metrics used to credential a test and establish confidence in its ability to detect the target disease. A test with high specificity can correctly identify patients who do not have the condition in question, while a test with high sensitivity can correctly identify patients who do have the disease. But there are trade-offs between sensitivity and specificity. One value is increased at the expense of the other.
It’s normal for a cancer screening test to prioritize specificity, according to Aparna Parikh, MD, an oncologist at Mass General Cancer Center in Boston. In a test like Galleri, which is meant to be an adjunct to other screening modalities, “at least we are seeing a good specificity, which is important, because we don’t want false positives, where the downstream impact on the patient can be high.”
Overall, Dr. Jones said, Grail Bio’s aim is to build a test that’s sensitive enough to catch the most dangerous cancers without inundating the healthcare system with false positives. In addition, Dr. Jones explained, sensitivity varies by cancer type. It tends to be lower for cancers for which other screening modalities are available, as well as for earlier-stage disease.
However, the Galleri sensitivity values are “a little bit scary,” said Ji-Hyun Lee, DrPH, professor of biostatistics at the University of Florida and director of the division of quantitative sciences at the University of Florida Health Cancer Center, both in Gainesville. Dr. Lee, who is not affiliated with Grail, reviewed the company’s publicly available data as well as Dr. Shukla’s data at the request of this news organization.
While there’s no definitive threshold for sensitivity, miss rates as high as 93% and 71% “provide little confidence in the [accuracy of the] test,” Dr. Lee said.
Positive and negative predictive values, however, are more clinically relevant measures of a screening test. These numbers indicate how likely it is that a patient’s results are true and therefore how worried they should be about a positive result and how much they should trust a negative result.
Galleri’s data in the over-50 population and Dr. Shukla’s in first responders suggest the test’s negative predictive value is very high – 98.6% and 98.1%, respectively – which means most people can trust a negative test result.
The positive predictive value, however, was less straightforward. In first responders, Dr. Shukla found that only half of positive Galleri tests were confirmed cases of cancer. And an analysis of Grail’s data found that only 38% of positive Galleri tests – 35 of 92 tests – represented a validated cancer diagnosis.
“In a clinical setting, positive predictive value is more usable for decision-making for the patient,” said Dr. Lee. “Positive predictive value isn’t always high, because everything doesn’t always transfer perfectly to the clinic.” But in the general population, if only 38% of patients with positive Galleri results truly have cancer, the test is “not quite useful to make a decision for the patient or the providers.”
Galleri may also be a costly prospect for patients, no matter the result, cautioned Electra Paskett, PhD, an epidemiologist and cancer screening expert at Ohio State University, Columbus. A positive Galleri test leads to a cascade of follow-up diagnostic tests, which payers may not cover. For a negative result, Galleri recommends that the patient undergo screening again in a year, at an annual cost of $950 plus the cost of any follow-up testing when Galleri does pick something up.
“If a provider wants to offer the Galleri test, all those things need to be made abundantly clear, in my opinion,” Dr. Paskett said.
Following the negative Galleri test, Mr. Arenz’s cancer didn’t slip through the cracks because he received other advanced imaging free of charge. But whether all doctors will go to such lengths to back up Galleri results, even for patients with negative results, is unknown.
A negative result can give patients “a huge false sense of security,” said Dr. Shukla. And if a test is positive, the workup isn’t simple. Chasing cancer, especially one that’s not really there, can be nerve-wracking and expensive.
The question, then, is why perform the Galleri test at all if results require so much validation?
Dr. Parikh explained that a high-risk group such as firefighters represents an ideal-use case for Galleri and other liquid biopsy tests. But she noted that she would be “wary of the ability of the system to manage this test en masse” were the test to be used more widely in the general population.
Dr. Shukla said it’s less about the results she’s getting today and more about making the test more effective for her patients in the future. First responders need a test such as this that can quickly identify multiple cancers. However, to improve the test, Grail needs more data from this high-risk population. That’s what she’s after.
Mr. Curtis doesn’t regret taking the Galleri test. The emotional toll of thinking he had cancer for a few days wasn’t too high a price, in his opinion. It’s part of cancer screening. But he acknowledged that it would have been a much more burdensome experience had he’d been financially responsible for the workup or if he hadn’t had Dr. Shukla to manage his case from start to finish.
Because it was free, Mr. Arenz doesn’t regret undergoing the Galleri test either. But he tells his coworkers to check the site, do their research, and get more screening.
“Any medical center that’s just doing this one test, you just have to be careful,” Dr. Shukla said. “It’s not that easy.”
A version of this article first appeared on Medscape.com.
In January 2022, Anthony Arenz, a 51-year-old living in Mesa, Ariz., breathed a small sigh of relief.
The Galleri blood test, which screens for 50 types of cancer, hadn’t detected any positive signs.
It would be welcome news to anyone but especially to a firefighter with a 9% greater risk of developing cancer and a 14% greater risk of dying from it than the average person. The Mesa unit had lost two servicemen to cancer in the past 3 years. Both were more than a decade younger than Mr. Arenz.
When the city of Mesa offered additional free screening – including a full-body MRI – to firefighters over 50, Mr. Arenz initially shrugged it off. With a negative Galleri test in hand, he didn’t want to spend more time dwelling on it.
Still, he began to feel a creeping guilt for skipping a test that many of his fallen colleagues hadn’t been offered. He tried to soothe his anxiety with research. A look through the company’s website didn’t set him at ease. According to Grail Bio, a test result of “no cancer signal detected” does not rule out cancer.
Mr. Arenz booked his free MRI.
The results left him heavy: stage I kidney cancer. The Galleri test had missed it.
Mr. Arenz received his free Galleri test through a cancer screening program funded by the city of Mesa. The program is housed at Vincere Cancer Center in Scottsdale, Ariz. Under the leadership of radiation oncologist and Vincere co-owner Vershalee Shukla, MD, the program currently screens first responders in more than 10 Arizona cities at no cost to them.
Vincere began using Galleri shortly after the test launched for consumers in June 2021. Since then, the first responder program has become the largest commercial user of the test in North America.
The Galleri test, which has not yet been approved by the Food and Drug Administration, is so new that few know what incorrect results look like in practice and how often they might occur.
After running the test on about 2,000 servicemen and servicewomen, Dr. Shukla can offer some insight about the test’s real-world value in a high-risk population.
“Cancer screening is a very complicated issue,” Dr. Shukla said in an interview. “Being honest, the tests are good but are not ready yet [for wider use].”
Mr. Arenz was not the only firefighter who got a surprise after taking a Galleri test.
In nearby Phoenix, 51-year-old firefighter Mike Curtis knew his risk for cancer was high, but he wasn’t that worried. Mr. Curtis had been running into fires since he was 17. His dad, also a firefighter, had died of cancer at age 58.
Mr. Curtis had taken the Vincere Cancer Center up on every free screening service since the program began in late 2018 – well before Dr. Shukla started using Galleri in 2021. His most recent lung CT was clear. But he underwent the Galleri test just to stay vigilant.
His result was a shock. The test detected signs of cancer.
Mr. Curtis decided to tell no one, not even his wife. He’d bear the bad news alone until he was certain.
Dr. Shukla, however, immediately doubted the blood test result. She expedited several follow-up tests. One week, a PET, and CT of the abdomen and pelvis later, her hunch was confirmed. The Galleri test result was wrong, Mr. Curtis did not have cancer.
The price of his peace of mind: an extensive workup with a $4,000 price tag. Fortunately, the bill was covered by the screening program.
Overall, in just over 18 months of using the blood test, Dr. Shukla has only encountered 1 other false positive out of about 2,000 Galleri results.
She also discovered two positive signals for cancer using Galleri that were confirmed with follow-up tests. One was a chordoma, a rare type of bone cancer, and the other was a squamous cell carcinoma of the head and neck. The Galleri test caught both remarkably early, in time for treatment.
For Dr. Shukla, however, false negatives were particularly “horrible.” Mr. Arenz’s was just 1 of 28 cancers that the blood test missed. And because 500 negative tests are yet to be validated, the 28 false negatives may be an underestimate.
In her experience, the binary test result – a simple positive or negative cancer signal – is an oversimplification of risk, she said. It “gives a false perception that you have cancer or you don’t,” although the test itself is not definitive.
Grail senior medical director Whitney Jones, MD, agreed that the test is not meant to be a stand-alone screening test for cancer. The purpose of the Galleri test is to “complement other screenings, not replace them,” Dr. Jones told this news organization.
According to an analysis of Galleri data and Dr. Shukla’s experience, the test’s specificity was over 99%. That means the test successfully minimizes false positives.
But the test’s sensitivity was much lower. From data from first responders, Dr. Shukla determined the sensitivity to be 6.7%. That means the test misses about 93 of every 100 cancers. According to Grail’s latest data from more than 6,300 people older than 50, the test’s sensitivity was 29%.
Specificity and sensitivity are metrics used to credential a test and establish confidence in its ability to detect the target disease. A test with high specificity can correctly identify patients who do not have the condition in question, while a test with high sensitivity can correctly identify patients who do have the disease. But there are trade-offs between sensitivity and specificity. One value is increased at the expense of the other.
It’s normal for a cancer screening test to prioritize specificity, according to Aparna Parikh, MD, an oncologist at Mass General Cancer Center in Boston. In a test like Galleri, which is meant to be an adjunct to other screening modalities, “at least we are seeing a good specificity, which is important, because we don’t want false positives, where the downstream impact on the patient can be high.”
Overall, Dr. Jones said, Grail Bio’s aim is to build a test that’s sensitive enough to catch the most dangerous cancers without inundating the healthcare system with false positives. In addition, Dr. Jones explained, sensitivity varies by cancer type. It tends to be lower for cancers for which other screening modalities are available, as well as for earlier-stage disease.
However, the Galleri sensitivity values are “a little bit scary,” said Ji-Hyun Lee, DrPH, professor of biostatistics at the University of Florida and director of the division of quantitative sciences at the University of Florida Health Cancer Center, both in Gainesville. Dr. Lee, who is not affiliated with Grail, reviewed the company’s publicly available data as well as Dr. Shukla’s data at the request of this news organization.
While there’s no definitive threshold for sensitivity, miss rates as high as 93% and 71% “provide little confidence in the [accuracy of the] test,” Dr. Lee said.
Positive and negative predictive values, however, are more clinically relevant measures of a screening test. These numbers indicate how likely it is that a patient’s results are true and therefore how worried they should be about a positive result and how much they should trust a negative result.
Galleri’s data in the over-50 population and Dr. Shukla’s in first responders suggest the test’s negative predictive value is very high – 98.6% and 98.1%, respectively – which means most people can trust a negative test result.
The positive predictive value, however, was less straightforward. In first responders, Dr. Shukla found that only half of positive Galleri tests were confirmed cases of cancer. And an analysis of Grail’s data found that only 38% of positive Galleri tests – 35 of 92 tests – represented a validated cancer diagnosis.
“In a clinical setting, positive predictive value is more usable for decision-making for the patient,” said Dr. Lee. “Positive predictive value isn’t always high, because everything doesn’t always transfer perfectly to the clinic.” But in the general population, if only 38% of patients with positive Galleri results truly have cancer, the test is “not quite useful to make a decision for the patient or the providers.”
Galleri may also be a costly prospect for patients, no matter the result, cautioned Electra Paskett, PhD, an epidemiologist and cancer screening expert at Ohio State University, Columbus. A positive Galleri test leads to a cascade of follow-up diagnostic tests, which payers may not cover. For a negative result, Galleri recommends that the patient undergo screening again in a year, at an annual cost of $950 plus the cost of any follow-up testing when Galleri does pick something up.
“If a provider wants to offer the Galleri test, all those things need to be made abundantly clear, in my opinion,” Dr. Paskett said.
Following the negative Galleri test, Mr. Arenz’s cancer didn’t slip through the cracks because he received other advanced imaging free of charge. But whether all doctors will go to such lengths to back up Galleri results, even for patients with negative results, is unknown.
A negative result can give patients “a huge false sense of security,” said Dr. Shukla. And if a test is positive, the workup isn’t simple. Chasing cancer, especially one that’s not really there, can be nerve-wracking and expensive.
The question, then, is why perform the Galleri test at all if results require so much validation?
Dr. Parikh explained that a high-risk group such as firefighters represents an ideal-use case for Galleri and other liquid biopsy tests. But she noted that she would be “wary of the ability of the system to manage this test en masse” were the test to be used more widely in the general population.
Dr. Shukla said it’s less about the results she’s getting today and more about making the test more effective for her patients in the future. First responders need a test such as this that can quickly identify multiple cancers. However, to improve the test, Grail needs more data from this high-risk population. That’s what she’s after.
Mr. Curtis doesn’t regret taking the Galleri test. The emotional toll of thinking he had cancer for a few days wasn’t too high a price, in his opinion. It’s part of cancer screening. But he acknowledged that it would have been a much more burdensome experience had he’d been financially responsible for the workup or if he hadn’t had Dr. Shukla to manage his case from start to finish.
Because it was free, Mr. Arenz doesn’t regret undergoing the Galleri test either. But he tells his coworkers to check the site, do their research, and get more screening.
“Any medical center that’s just doing this one test, you just have to be careful,” Dr. Shukla said. “It’s not that easy.”
A version of this article first appeared on Medscape.com.
In January 2022, Anthony Arenz, a 51-year-old living in Mesa, Ariz., breathed a small sigh of relief.
The Galleri blood test, which screens for 50 types of cancer, hadn’t detected any positive signs.
It would be welcome news to anyone but especially to a firefighter with a 9% greater risk of developing cancer and a 14% greater risk of dying from it than the average person. The Mesa unit had lost two servicemen to cancer in the past 3 years. Both were more than a decade younger than Mr. Arenz.
When the city of Mesa offered additional free screening – including a full-body MRI – to firefighters over 50, Mr. Arenz initially shrugged it off. With a negative Galleri test in hand, he didn’t want to spend more time dwelling on it.
Still, he began to feel a creeping guilt for skipping a test that many of his fallen colleagues hadn’t been offered. He tried to soothe his anxiety with research. A look through the company’s website didn’t set him at ease. According to Grail Bio, a test result of “no cancer signal detected” does not rule out cancer.
Mr. Arenz booked his free MRI.
The results left him heavy: stage I kidney cancer. The Galleri test had missed it.
Mr. Arenz received his free Galleri test through a cancer screening program funded by the city of Mesa. The program is housed at Vincere Cancer Center in Scottsdale, Ariz. Under the leadership of radiation oncologist and Vincere co-owner Vershalee Shukla, MD, the program currently screens first responders in more than 10 Arizona cities at no cost to them.
Vincere began using Galleri shortly after the test launched for consumers in June 2021. Since then, the first responder program has become the largest commercial user of the test in North America.
The Galleri test, which has not yet been approved by the Food and Drug Administration, is so new that few know what incorrect results look like in practice and how often they might occur.
After running the test on about 2,000 servicemen and servicewomen, Dr. Shukla can offer some insight about the test’s real-world value in a high-risk population.
“Cancer screening is a very complicated issue,” Dr. Shukla said in an interview. “Being honest, the tests are good but are not ready yet [for wider use].”
Mr. Arenz was not the only firefighter who got a surprise after taking a Galleri test.
In nearby Phoenix, 51-year-old firefighter Mike Curtis knew his risk for cancer was high, but he wasn’t that worried. Mr. Curtis had been running into fires since he was 17. His dad, also a firefighter, had died of cancer at age 58.
Mr. Curtis had taken the Vincere Cancer Center up on every free screening service since the program began in late 2018 – well before Dr. Shukla started using Galleri in 2021. His most recent lung CT was clear. But he underwent the Galleri test just to stay vigilant.
His result was a shock. The test detected signs of cancer.
Mr. Curtis decided to tell no one, not even his wife. He’d bear the bad news alone until he was certain.
Dr. Shukla, however, immediately doubted the blood test result. She expedited several follow-up tests. One week, a PET, and CT of the abdomen and pelvis later, her hunch was confirmed. The Galleri test result was wrong, Mr. Curtis did not have cancer.
The price of his peace of mind: an extensive workup with a $4,000 price tag. Fortunately, the bill was covered by the screening program.
Overall, in just over 18 months of using the blood test, Dr. Shukla has only encountered 1 other false positive out of about 2,000 Galleri results.
She also discovered two positive signals for cancer using Galleri that were confirmed with follow-up tests. One was a chordoma, a rare type of bone cancer, and the other was a squamous cell carcinoma of the head and neck. The Galleri test caught both remarkably early, in time for treatment.
For Dr. Shukla, however, false negatives were particularly “horrible.” Mr. Arenz’s was just 1 of 28 cancers that the blood test missed. And because 500 negative tests are yet to be validated, the 28 false negatives may be an underestimate.
In her experience, the binary test result – a simple positive or negative cancer signal – is an oversimplification of risk, she said. It “gives a false perception that you have cancer or you don’t,” although the test itself is not definitive.
Grail senior medical director Whitney Jones, MD, agreed that the test is not meant to be a stand-alone screening test for cancer. The purpose of the Galleri test is to “complement other screenings, not replace them,” Dr. Jones told this news organization.
According to an analysis of Galleri data and Dr. Shukla’s experience, the test’s specificity was over 99%. That means the test successfully minimizes false positives.
But the test’s sensitivity was much lower. From data from first responders, Dr. Shukla determined the sensitivity to be 6.7%. That means the test misses about 93 of every 100 cancers. According to Grail’s latest data from more than 6,300 people older than 50, the test’s sensitivity was 29%.
Specificity and sensitivity are metrics used to credential a test and establish confidence in its ability to detect the target disease. A test with high specificity can correctly identify patients who do not have the condition in question, while a test with high sensitivity can correctly identify patients who do have the disease. But there are trade-offs between sensitivity and specificity. One value is increased at the expense of the other.
It’s normal for a cancer screening test to prioritize specificity, according to Aparna Parikh, MD, an oncologist at Mass General Cancer Center in Boston. In a test like Galleri, which is meant to be an adjunct to other screening modalities, “at least we are seeing a good specificity, which is important, because we don’t want false positives, where the downstream impact on the patient can be high.”
Overall, Dr. Jones said, Grail Bio’s aim is to build a test that’s sensitive enough to catch the most dangerous cancers without inundating the healthcare system with false positives. In addition, Dr. Jones explained, sensitivity varies by cancer type. It tends to be lower for cancers for which other screening modalities are available, as well as for earlier-stage disease.
However, the Galleri sensitivity values are “a little bit scary,” said Ji-Hyun Lee, DrPH, professor of biostatistics at the University of Florida and director of the division of quantitative sciences at the University of Florida Health Cancer Center, both in Gainesville. Dr. Lee, who is not affiliated with Grail, reviewed the company’s publicly available data as well as Dr. Shukla’s data at the request of this news organization.
While there’s no definitive threshold for sensitivity, miss rates as high as 93% and 71% “provide little confidence in the [accuracy of the] test,” Dr. Lee said.
Positive and negative predictive values, however, are more clinically relevant measures of a screening test. These numbers indicate how likely it is that a patient’s results are true and therefore how worried they should be about a positive result and how much they should trust a negative result.
Galleri’s data in the over-50 population and Dr. Shukla’s in first responders suggest the test’s negative predictive value is very high – 98.6% and 98.1%, respectively – which means most people can trust a negative test result.
The positive predictive value, however, was less straightforward. In first responders, Dr. Shukla found that only half of positive Galleri tests were confirmed cases of cancer. And an analysis of Grail’s data found that only 38% of positive Galleri tests – 35 of 92 tests – represented a validated cancer diagnosis.
“In a clinical setting, positive predictive value is more usable for decision-making for the patient,” said Dr. Lee. “Positive predictive value isn’t always high, because everything doesn’t always transfer perfectly to the clinic.” But in the general population, if only 38% of patients with positive Galleri results truly have cancer, the test is “not quite useful to make a decision for the patient or the providers.”
Galleri may also be a costly prospect for patients, no matter the result, cautioned Electra Paskett, PhD, an epidemiologist and cancer screening expert at Ohio State University, Columbus. A positive Galleri test leads to a cascade of follow-up diagnostic tests, which payers may not cover. For a negative result, Galleri recommends that the patient undergo screening again in a year, at an annual cost of $950 plus the cost of any follow-up testing when Galleri does pick something up.
“If a provider wants to offer the Galleri test, all those things need to be made abundantly clear, in my opinion,” Dr. Paskett said.
Following the negative Galleri test, Mr. Arenz’s cancer didn’t slip through the cracks because he received other advanced imaging free of charge. But whether all doctors will go to such lengths to back up Galleri results, even for patients with negative results, is unknown.
A negative result can give patients “a huge false sense of security,” said Dr. Shukla. And if a test is positive, the workup isn’t simple. Chasing cancer, especially one that’s not really there, can be nerve-wracking and expensive.
The question, then, is why perform the Galleri test at all if results require so much validation?
Dr. Parikh explained that a high-risk group such as firefighters represents an ideal-use case for Galleri and other liquid biopsy tests. But she noted that she would be “wary of the ability of the system to manage this test en masse” were the test to be used more widely in the general population.
Dr. Shukla said it’s less about the results she’s getting today and more about making the test more effective for her patients in the future. First responders need a test such as this that can quickly identify multiple cancers. However, to improve the test, Grail needs more data from this high-risk population. That’s what she’s after.
Mr. Curtis doesn’t regret taking the Galleri test. The emotional toll of thinking he had cancer for a few days wasn’t too high a price, in his opinion. It’s part of cancer screening. But he acknowledged that it would have been a much more burdensome experience had he’d been financially responsible for the workup or if he hadn’t had Dr. Shukla to manage his case from start to finish.
Because it was free, Mr. Arenz doesn’t regret undergoing the Galleri test either. But he tells his coworkers to check the site, do their research, and get more screening.
“Any medical center that’s just doing this one test, you just have to be careful,” Dr. Shukla said. “It’s not that easy.”
A version of this article first appeared on Medscape.com.
Transplant vs. chemo: Similar AML survival rates
Notably, all patients who relapsed after consolidation chemotherapy were able to receive allogeneic HCT, suggesting that transplantation may be safely delayed in some patients until their first relapse.
“The results of this randomized clinical trial indicate that the probability of survival after [allogeneic] HCT is not superior to that of conventional consolidation chemotherapy” among patients 60 years or younger with intermediate-risk AML, the authors concluded.
However, two experts highlighted several caveats to the study, which suggest the results may not translate to current clinical practice.
The study was published online in JAMA Oncology.
Approximately 50%-70% of patients with AML who receive intensive induction chemotherapy for AML and achieve a first complete remission are referred for post-remission therapy.
While consolidation chemotherapy with high-dose cytarabine has shown a benefit for those with a favorable risk profile, patients considered high-risk with adequate performance status may be candidates for allogeneic HCT.
However, determining the optimal post-remission treatment option for patients who fall into the intermediate-risk category can be more challenging.
To compare outcomes among intermediate-risk patients, researchers from Germany conducted a multicenter trial, enrolling 143 adults aged 60 or younger with intermediate-risk AML who had achieved first complete remission or complete remission with incomplete blood cell count recovery following conventional induction therapy.
The patients, who had a mean age of 48.2 years, were randomly assigned to consolidation treatment with allogeneic HCT (n = 76) or chemotherapy with high-dose cytarabine (n = 67), with the option for salvage HCT in the case of relapse. Overall, 12 patients in the HCT group received one consolidation course of high-dose cytarabine after achieving complete remission to bridge until allogeneic HCT, while all other patients in this group received allogeneic HCT directly after induction therapy.
Overall, disease-free survival at 2 years was significantly higher in the allogeneic HCT group (69%), compared with the consolidation therapy group (40%; P = .001). And the cumulative incidence of relapse at 2 years in the allogeneic HCT group was also lower, at 20%, compared with 58% in the consolidation therapy group (P < .001).
The overall survival data, however, painted a slightly more complex picture. In the intention-to-treat analysis, the probability of survival at 2 years was similar between the allogeneic HCT group (74%, or 56 of 76 patients), compared with consolidation chemotherapy (84%, or 56 of 67 patients; P = .22).
In addition, the rates of nonrelapse mortality at 2 years were higher in the allogeneic HCT group (9%) versus chemotherapy (2%; P = .005).
Although the rate of nonrelapse mortality was higher with allogeneic HCT, the relatively low rate with each treatment strategies was “an important and rewarding finding,” the authors noted. “This achievement is clearly due to the availability of less toxic but still effective conditioning therapies and modern antiviral and antifungal prophylaxis.”
In addition, among the 41 patients who relapsed after consolidation chemotherapy, all received allogeneic HCT, and the authors observed no significant differences between the groups in terms of health-related quality of life measures.
Results ‘may not translate to real-life clinical practice’
An important caveat is that the findings do not reflect some key updated strategies currently used in clinical practice, said Diego Adrianzen Herrera, MD, from the University of Vermont’s Larner College of Medicine, Burlington, who was not involved in the study.
“A charitable interpretation of the results is that a clear, large survival benefit of transplant in first complete remission is not apparent, which in turn can inform decision-making in certain circumstances for patients meeting the trial criteria, [including] younger patients with a readily available donor,” he told this news organization.
“However, risk stratification strategies currently used were not followed,” he said.
For instance, molecular risk stratification was not universally used, which may have led the researchers to overrepresent the number of patients considered to have favorable risk disease and “could have skewed the results in favor of the chemotherapy arm,” he explained.
In addition, minimal residual disease surveillance by flow cytometry was not used. Plus, Dr. Herrera added, in practice, not all patients can be salvaged and taken to HCT when in their second complete remission, or even achieve complete remission again.
“Unfortunately, these issues make the clinical significance of these results limited,” he concluded.
Margaret Kasner, MD, who was not associated with the research, agreed that aspects of the study design may not translate to real-life clinical practice, particularly in terms of quality-of-life outcomes.
“Although the [study] showed no difference in quality of life in the patient groups, this is likely due to the patient selection,” Dr. Kasner, of the Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, said in an interview. “Most patients do not allow themselves to be randomized between these two very different strategies, so those who are willing to be randomized may be a different population in terms how their quality of life is affected by relapse.”
The authors acknowledged some of these limitations, adding that the routine use of minimal residual disease monitoring in some patients was only established once the trial was underway, and the number of patients with complete minimal residual disease was therefore limited.
In addition, Dr. Herrera explained that because HCT involves significant disruptions to daily life and extensive follow-up and monitoring, decisions to use the strategy are not taken lightly by clinicians or patients.
“This is a major issue,” he said. “HCT remains a therapeutic option which causes significant apprehension to patients.”
Nevertheless, “in my experience most patients would prefer an upfront strategy if there is a definitive need for transplant,” he added. “I think the main question patients have is whether they absolutely need an HCT and how can we better identify up front who will be in the relapse-free group at 2 years.”
The study received grant funding from the Deutsche Forschungsgemeinschaft. The authors’ disclosures are detailed in the original article. Dr. Herrera and Dr. Kasner report no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Notably, all patients who relapsed after consolidation chemotherapy were able to receive allogeneic HCT, suggesting that transplantation may be safely delayed in some patients until their first relapse.
“The results of this randomized clinical trial indicate that the probability of survival after [allogeneic] HCT is not superior to that of conventional consolidation chemotherapy” among patients 60 years or younger with intermediate-risk AML, the authors concluded.
However, two experts highlighted several caveats to the study, which suggest the results may not translate to current clinical practice.
The study was published online in JAMA Oncology.
Approximately 50%-70% of patients with AML who receive intensive induction chemotherapy for AML and achieve a first complete remission are referred for post-remission therapy.
While consolidation chemotherapy with high-dose cytarabine has shown a benefit for those with a favorable risk profile, patients considered high-risk with adequate performance status may be candidates for allogeneic HCT.
However, determining the optimal post-remission treatment option for patients who fall into the intermediate-risk category can be more challenging.
To compare outcomes among intermediate-risk patients, researchers from Germany conducted a multicenter trial, enrolling 143 adults aged 60 or younger with intermediate-risk AML who had achieved first complete remission or complete remission with incomplete blood cell count recovery following conventional induction therapy.
The patients, who had a mean age of 48.2 years, were randomly assigned to consolidation treatment with allogeneic HCT (n = 76) or chemotherapy with high-dose cytarabine (n = 67), with the option for salvage HCT in the case of relapse. Overall, 12 patients in the HCT group received one consolidation course of high-dose cytarabine after achieving complete remission to bridge until allogeneic HCT, while all other patients in this group received allogeneic HCT directly after induction therapy.
Overall, disease-free survival at 2 years was significantly higher in the allogeneic HCT group (69%), compared with the consolidation therapy group (40%; P = .001). And the cumulative incidence of relapse at 2 years in the allogeneic HCT group was also lower, at 20%, compared with 58% in the consolidation therapy group (P < .001).
The overall survival data, however, painted a slightly more complex picture. In the intention-to-treat analysis, the probability of survival at 2 years was similar between the allogeneic HCT group (74%, or 56 of 76 patients), compared with consolidation chemotherapy (84%, or 56 of 67 patients; P = .22).
In addition, the rates of nonrelapse mortality at 2 years were higher in the allogeneic HCT group (9%) versus chemotherapy (2%; P = .005).
Although the rate of nonrelapse mortality was higher with allogeneic HCT, the relatively low rate with each treatment strategies was “an important and rewarding finding,” the authors noted. “This achievement is clearly due to the availability of less toxic but still effective conditioning therapies and modern antiviral and antifungal prophylaxis.”
In addition, among the 41 patients who relapsed after consolidation chemotherapy, all received allogeneic HCT, and the authors observed no significant differences between the groups in terms of health-related quality of life measures.
Results ‘may not translate to real-life clinical practice’
An important caveat is that the findings do not reflect some key updated strategies currently used in clinical practice, said Diego Adrianzen Herrera, MD, from the University of Vermont’s Larner College of Medicine, Burlington, who was not involved in the study.
“A charitable interpretation of the results is that a clear, large survival benefit of transplant in first complete remission is not apparent, which in turn can inform decision-making in certain circumstances for patients meeting the trial criteria, [including] younger patients with a readily available donor,” he told this news organization.
“However, risk stratification strategies currently used were not followed,” he said.
For instance, molecular risk stratification was not universally used, which may have led the researchers to overrepresent the number of patients considered to have favorable risk disease and “could have skewed the results in favor of the chemotherapy arm,” he explained.
In addition, minimal residual disease surveillance by flow cytometry was not used. Plus, Dr. Herrera added, in practice, not all patients can be salvaged and taken to HCT when in their second complete remission, or even achieve complete remission again.
“Unfortunately, these issues make the clinical significance of these results limited,” he concluded.
Margaret Kasner, MD, who was not associated with the research, agreed that aspects of the study design may not translate to real-life clinical practice, particularly in terms of quality-of-life outcomes.
“Although the [study] showed no difference in quality of life in the patient groups, this is likely due to the patient selection,” Dr. Kasner, of the Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, said in an interview. “Most patients do not allow themselves to be randomized between these two very different strategies, so those who are willing to be randomized may be a different population in terms how their quality of life is affected by relapse.”
The authors acknowledged some of these limitations, adding that the routine use of minimal residual disease monitoring in some patients was only established once the trial was underway, and the number of patients with complete minimal residual disease was therefore limited.
In addition, Dr. Herrera explained that because HCT involves significant disruptions to daily life and extensive follow-up and monitoring, decisions to use the strategy are not taken lightly by clinicians or patients.
“This is a major issue,” he said. “HCT remains a therapeutic option which causes significant apprehension to patients.”
Nevertheless, “in my experience most patients would prefer an upfront strategy if there is a definitive need for transplant,” he added. “I think the main question patients have is whether they absolutely need an HCT and how can we better identify up front who will be in the relapse-free group at 2 years.”
The study received grant funding from the Deutsche Forschungsgemeinschaft. The authors’ disclosures are detailed in the original article. Dr. Herrera and Dr. Kasner report no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Notably, all patients who relapsed after consolidation chemotherapy were able to receive allogeneic HCT, suggesting that transplantation may be safely delayed in some patients until their first relapse.
“The results of this randomized clinical trial indicate that the probability of survival after [allogeneic] HCT is not superior to that of conventional consolidation chemotherapy” among patients 60 years or younger with intermediate-risk AML, the authors concluded.
However, two experts highlighted several caveats to the study, which suggest the results may not translate to current clinical practice.
The study was published online in JAMA Oncology.
Approximately 50%-70% of patients with AML who receive intensive induction chemotherapy for AML and achieve a first complete remission are referred for post-remission therapy.
While consolidation chemotherapy with high-dose cytarabine has shown a benefit for those with a favorable risk profile, patients considered high-risk with adequate performance status may be candidates for allogeneic HCT.
However, determining the optimal post-remission treatment option for patients who fall into the intermediate-risk category can be more challenging.
To compare outcomes among intermediate-risk patients, researchers from Germany conducted a multicenter trial, enrolling 143 adults aged 60 or younger with intermediate-risk AML who had achieved first complete remission or complete remission with incomplete blood cell count recovery following conventional induction therapy.
The patients, who had a mean age of 48.2 years, were randomly assigned to consolidation treatment with allogeneic HCT (n = 76) or chemotherapy with high-dose cytarabine (n = 67), with the option for salvage HCT in the case of relapse. Overall, 12 patients in the HCT group received one consolidation course of high-dose cytarabine after achieving complete remission to bridge until allogeneic HCT, while all other patients in this group received allogeneic HCT directly after induction therapy.
Overall, disease-free survival at 2 years was significantly higher in the allogeneic HCT group (69%), compared with the consolidation therapy group (40%; P = .001). And the cumulative incidence of relapse at 2 years in the allogeneic HCT group was also lower, at 20%, compared with 58% in the consolidation therapy group (P < .001).
The overall survival data, however, painted a slightly more complex picture. In the intention-to-treat analysis, the probability of survival at 2 years was similar between the allogeneic HCT group (74%, or 56 of 76 patients), compared with consolidation chemotherapy (84%, or 56 of 67 patients; P = .22).
In addition, the rates of nonrelapse mortality at 2 years were higher in the allogeneic HCT group (9%) versus chemotherapy (2%; P = .005).
Although the rate of nonrelapse mortality was higher with allogeneic HCT, the relatively low rate with each treatment strategies was “an important and rewarding finding,” the authors noted. “This achievement is clearly due to the availability of less toxic but still effective conditioning therapies and modern antiviral and antifungal prophylaxis.”
In addition, among the 41 patients who relapsed after consolidation chemotherapy, all received allogeneic HCT, and the authors observed no significant differences between the groups in terms of health-related quality of life measures.
Results ‘may not translate to real-life clinical practice’
An important caveat is that the findings do not reflect some key updated strategies currently used in clinical practice, said Diego Adrianzen Herrera, MD, from the University of Vermont’s Larner College of Medicine, Burlington, who was not involved in the study.
“A charitable interpretation of the results is that a clear, large survival benefit of transplant in first complete remission is not apparent, which in turn can inform decision-making in certain circumstances for patients meeting the trial criteria, [including] younger patients with a readily available donor,” he told this news organization.
“However, risk stratification strategies currently used were not followed,” he said.
For instance, molecular risk stratification was not universally used, which may have led the researchers to overrepresent the number of patients considered to have favorable risk disease and “could have skewed the results in favor of the chemotherapy arm,” he explained.
In addition, minimal residual disease surveillance by flow cytometry was not used. Plus, Dr. Herrera added, in practice, not all patients can be salvaged and taken to HCT when in their second complete remission, or even achieve complete remission again.
“Unfortunately, these issues make the clinical significance of these results limited,” he concluded.
Margaret Kasner, MD, who was not associated with the research, agreed that aspects of the study design may not translate to real-life clinical practice, particularly in terms of quality-of-life outcomes.
“Although the [study] showed no difference in quality of life in the patient groups, this is likely due to the patient selection,” Dr. Kasner, of the Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, said in an interview. “Most patients do not allow themselves to be randomized between these two very different strategies, so those who are willing to be randomized may be a different population in terms how their quality of life is affected by relapse.”
The authors acknowledged some of these limitations, adding that the routine use of minimal residual disease monitoring in some patients was only established once the trial was underway, and the number of patients with complete minimal residual disease was therefore limited.
In addition, Dr. Herrera explained that because HCT involves significant disruptions to daily life and extensive follow-up and monitoring, decisions to use the strategy are not taken lightly by clinicians or patients.
“This is a major issue,” he said. “HCT remains a therapeutic option which causes significant apprehension to patients.”
Nevertheless, “in my experience most patients would prefer an upfront strategy if there is a definitive need for transplant,” he added. “I think the main question patients have is whether they absolutely need an HCT and how can we better identify up front who will be in the relapse-free group at 2 years.”
The study received grant funding from the Deutsche Forschungsgemeinschaft. The authors’ disclosures are detailed in the original article. Dr. Herrera and Dr. Kasner report no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Surviving CLL: Higher risk of other cancer DXs
The report, which appeared in January in Blood Cancer Journal, found that patients diagnosed with CLL between 1989 and 2019 were 63% more likely to were diagnosed with SPM than a matched population: standardized incidence ratio = 1.63, 95% confidence interval (CI), 1.59-1.68.
“Our results provide patients and their treating physicians with an overview of the risk of SPM development. This information can be used in treatment decision-making and for planning appropriate surveillance activities and interventions,” study lead author Lina van der Straten, MD, PhD, of the Albert Schweitzer Hospital and Erasmus University Medical Center in the Netherlands, said in an interview.
Ohio State University hematologist David Bond, MD, who’s familiar with the findings, said in an interview that “it’s been well-established that patients with CLL are at increased risk for second primary malignancies. This is thought to be due to impaired immune surveillance and possibly carcinogenic effects of CLL treatments.” It’s not clear, he said, “whether the rate of second cancers differs between chemoimmunotherapy-treated patients and those receiving newer oral kinase inhibitors.”
Previous research into CLL and SPM has been sparse, Dr. van der Straten said, and most studies haven’t looked at SPM over time and taken into account the widespread use of chemoimmunotherapy and agents such as ibrutinib and venetoclax.
It’s important to study this topic, she said, since “cancers diagnosed after the CLL diagnosis can outweigh the improved longevity and contribute to excess morbidity and mortality in long-term CLL survivors.”
With the help of the Netherlands Cancer Registry, researchers tracked 24,815 patients with CLL who were diagnosed over the 20-year period; 4,369 developed SPM. “We demonstrated that the risk of SPM development was higher than in the general population with an excess of 125 malignancies per 10,000 person-years in the CLL cohort,” Dr. van der Straten said. “The risk of SPM development was found to be heightened in solid and hematological cancers. Patients with CLL had an increased risk of developing cancers at the following sites or types: skin, acute myeloid leukemia, soft-tissue sarcomas, thyroid, kidney, unknown primary localization, non-Hodgkin lymphomas, lung and bronchus, and colon and rectum.”
Specifically, the study reports that “elevated risk was observed for solid (SIR = 1.67; 95% CI, 1.65-1.75) and hematological SPMs (SIR = 1.42; 95% CI, 1.24-1.62). The highest risk for SPMs was noted beyond 5 years post diagnosis (SIR = 1.70; 95% CI, 1.62-1.77), for male individuals (SIR = 1.70; 95% CI, 1.64-1.77), and patients aged 18-69 years (SR = 1.92; 95% CI, 1.79-2.05).
“Patients with CLL exposed to treatment have a higher risk of SPM development than patients who will never receive therapy,” Dr. van der Straten said. Research has shown that “treatment with fludarabine, cyclophosphamide, and rituximab has been associated with a 2.38 increased risk for SPM development, particularly acute myeloid leukemia. Indeed, we found an increased risk for hematological malignancies in patients diagnosed between 2003-2009 and 2010-2019, which might be explained by the broader administration of fludarabine-based strategies in these calendar periods.”
Multiple factors could explain the higher risk of SPM in patients with CLL, including “a dysregulated immune system, treatment-related effects, and surveillance bias,” Dr. van der Straten said. “In addition, it is proposed that the immune dysfunctional nature of CLL might enhance the effect of common carcinogens, such as UV exposure and smoking, in increasing the probability of skin and respiratory cancers.”
She added that “the risk and the spectrum of SPMs were comparable for the 2003-2009 and 2010-2019 periods, suggesting that both the introduction of chemoimmunotherapy and, in part, targeted therapies did not dramatically alter the SPM landscape. However, due to the short follow-up period for the small cohort of patients receiving targeted therapies, further research is warranted.”
Dr. Bond said the findings “are largely in line with prior studies and strengthen their conclusions. Immune surveillance appears to be critical to reducing the risk for some but not all malignancies including lung cancer and melanoma, and the treatments given for CLL can cause immune suppression and thus may increase the risk.”
Moving forward, he said, “this research highlights the importance of second cancers to patients with CLL. It also highlights the need for secondary cancer screening for CLL patients, patient education to avoid known cancer risk factors including smoking and excess UV light exposure, and the need as a field to continue to invest in research into characteristics of second cancers and mitigation strategies.”
Study funding was not reported. The authors and Dr. Bond report no disclosures.
The report, which appeared in January in Blood Cancer Journal, found that patients diagnosed with CLL between 1989 and 2019 were 63% more likely to were diagnosed with SPM than a matched population: standardized incidence ratio = 1.63, 95% confidence interval (CI), 1.59-1.68.
“Our results provide patients and their treating physicians with an overview of the risk of SPM development. This information can be used in treatment decision-making and for planning appropriate surveillance activities and interventions,” study lead author Lina van der Straten, MD, PhD, of the Albert Schweitzer Hospital and Erasmus University Medical Center in the Netherlands, said in an interview.
Ohio State University hematologist David Bond, MD, who’s familiar with the findings, said in an interview that “it’s been well-established that patients with CLL are at increased risk for second primary malignancies. This is thought to be due to impaired immune surveillance and possibly carcinogenic effects of CLL treatments.” It’s not clear, he said, “whether the rate of second cancers differs between chemoimmunotherapy-treated patients and those receiving newer oral kinase inhibitors.”
Previous research into CLL and SPM has been sparse, Dr. van der Straten said, and most studies haven’t looked at SPM over time and taken into account the widespread use of chemoimmunotherapy and agents such as ibrutinib and venetoclax.
It’s important to study this topic, she said, since “cancers diagnosed after the CLL diagnosis can outweigh the improved longevity and contribute to excess morbidity and mortality in long-term CLL survivors.”
With the help of the Netherlands Cancer Registry, researchers tracked 24,815 patients with CLL who were diagnosed over the 20-year period; 4,369 developed SPM. “We demonstrated that the risk of SPM development was higher than in the general population with an excess of 125 malignancies per 10,000 person-years in the CLL cohort,” Dr. van der Straten said. “The risk of SPM development was found to be heightened in solid and hematological cancers. Patients with CLL had an increased risk of developing cancers at the following sites or types: skin, acute myeloid leukemia, soft-tissue sarcomas, thyroid, kidney, unknown primary localization, non-Hodgkin lymphomas, lung and bronchus, and colon and rectum.”
Specifically, the study reports that “elevated risk was observed for solid (SIR = 1.67; 95% CI, 1.65-1.75) and hematological SPMs (SIR = 1.42; 95% CI, 1.24-1.62). The highest risk for SPMs was noted beyond 5 years post diagnosis (SIR = 1.70; 95% CI, 1.62-1.77), for male individuals (SIR = 1.70; 95% CI, 1.64-1.77), and patients aged 18-69 years (SR = 1.92; 95% CI, 1.79-2.05).
“Patients with CLL exposed to treatment have a higher risk of SPM development than patients who will never receive therapy,” Dr. van der Straten said. Research has shown that “treatment with fludarabine, cyclophosphamide, and rituximab has been associated with a 2.38 increased risk for SPM development, particularly acute myeloid leukemia. Indeed, we found an increased risk for hematological malignancies in patients diagnosed between 2003-2009 and 2010-2019, which might be explained by the broader administration of fludarabine-based strategies in these calendar periods.”
Multiple factors could explain the higher risk of SPM in patients with CLL, including “a dysregulated immune system, treatment-related effects, and surveillance bias,” Dr. van der Straten said. “In addition, it is proposed that the immune dysfunctional nature of CLL might enhance the effect of common carcinogens, such as UV exposure and smoking, in increasing the probability of skin and respiratory cancers.”
She added that “the risk and the spectrum of SPMs were comparable for the 2003-2009 and 2010-2019 periods, suggesting that both the introduction of chemoimmunotherapy and, in part, targeted therapies did not dramatically alter the SPM landscape. However, due to the short follow-up period for the small cohort of patients receiving targeted therapies, further research is warranted.”
Dr. Bond said the findings “are largely in line with prior studies and strengthen their conclusions. Immune surveillance appears to be critical to reducing the risk for some but not all malignancies including lung cancer and melanoma, and the treatments given for CLL can cause immune suppression and thus may increase the risk.”
Moving forward, he said, “this research highlights the importance of second cancers to patients with CLL. It also highlights the need for secondary cancer screening for CLL patients, patient education to avoid known cancer risk factors including smoking and excess UV light exposure, and the need as a field to continue to invest in research into characteristics of second cancers and mitigation strategies.”
Study funding was not reported. The authors and Dr. Bond report no disclosures.
The report, which appeared in January in Blood Cancer Journal, found that patients diagnosed with CLL between 1989 and 2019 were 63% more likely to were diagnosed with SPM than a matched population: standardized incidence ratio = 1.63, 95% confidence interval (CI), 1.59-1.68.
“Our results provide patients and their treating physicians with an overview of the risk of SPM development. This information can be used in treatment decision-making and for planning appropriate surveillance activities and interventions,” study lead author Lina van der Straten, MD, PhD, of the Albert Schweitzer Hospital and Erasmus University Medical Center in the Netherlands, said in an interview.
Ohio State University hematologist David Bond, MD, who’s familiar with the findings, said in an interview that “it’s been well-established that patients with CLL are at increased risk for second primary malignancies. This is thought to be due to impaired immune surveillance and possibly carcinogenic effects of CLL treatments.” It’s not clear, he said, “whether the rate of second cancers differs between chemoimmunotherapy-treated patients and those receiving newer oral kinase inhibitors.”
Previous research into CLL and SPM has been sparse, Dr. van der Straten said, and most studies haven’t looked at SPM over time and taken into account the widespread use of chemoimmunotherapy and agents such as ibrutinib and venetoclax.
It’s important to study this topic, she said, since “cancers diagnosed after the CLL diagnosis can outweigh the improved longevity and contribute to excess morbidity and mortality in long-term CLL survivors.”
With the help of the Netherlands Cancer Registry, researchers tracked 24,815 patients with CLL who were diagnosed over the 20-year period; 4,369 developed SPM. “We demonstrated that the risk of SPM development was higher than in the general population with an excess of 125 malignancies per 10,000 person-years in the CLL cohort,” Dr. van der Straten said. “The risk of SPM development was found to be heightened in solid and hematological cancers. Patients with CLL had an increased risk of developing cancers at the following sites or types: skin, acute myeloid leukemia, soft-tissue sarcomas, thyroid, kidney, unknown primary localization, non-Hodgkin lymphomas, lung and bronchus, and colon and rectum.”
Specifically, the study reports that “elevated risk was observed for solid (SIR = 1.67; 95% CI, 1.65-1.75) and hematological SPMs (SIR = 1.42; 95% CI, 1.24-1.62). The highest risk for SPMs was noted beyond 5 years post diagnosis (SIR = 1.70; 95% CI, 1.62-1.77), for male individuals (SIR = 1.70; 95% CI, 1.64-1.77), and patients aged 18-69 years (SR = 1.92; 95% CI, 1.79-2.05).
“Patients with CLL exposed to treatment have a higher risk of SPM development than patients who will never receive therapy,” Dr. van der Straten said. Research has shown that “treatment with fludarabine, cyclophosphamide, and rituximab has been associated with a 2.38 increased risk for SPM development, particularly acute myeloid leukemia. Indeed, we found an increased risk for hematological malignancies in patients diagnosed between 2003-2009 and 2010-2019, which might be explained by the broader administration of fludarabine-based strategies in these calendar periods.”
Multiple factors could explain the higher risk of SPM in patients with CLL, including “a dysregulated immune system, treatment-related effects, and surveillance bias,” Dr. van der Straten said. “In addition, it is proposed that the immune dysfunctional nature of CLL might enhance the effect of common carcinogens, such as UV exposure and smoking, in increasing the probability of skin and respiratory cancers.”
She added that “the risk and the spectrum of SPMs were comparable for the 2003-2009 and 2010-2019 periods, suggesting that both the introduction of chemoimmunotherapy and, in part, targeted therapies did not dramatically alter the SPM landscape. However, due to the short follow-up period for the small cohort of patients receiving targeted therapies, further research is warranted.”
Dr. Bond said the findings “are largely in line with prior studies and strengthen their conclusions. Immune surveillance appears to be critical to reducing the risk for some but not all malignancies including lung cancer and melanoma, and the treatments given for CLL can cause immune suppression and thus may increase the risk.”
Moving forward, he said, “this research highlights the importance of second cancers to patients with CLL. It also highlights the need for secondary cancer screening for CLL patients, patient education to avoid known cancer risk factors including smoking and excess UV light exposure, and the need as a field to continue to invest in research into characteristics of second cancers and mitigation strategies.”
Study funding was not reported. The authors and Dr. Bond report no disclosures.
FROM BLOOD CANCER JOURNAL
Despite limits, COVID vaccines protect CLL patients
These findings don’t reveal whether the T-cell boost actually provides extra protection against COVID-19. Still, the study suggests that patients with CLL should be vaccinated no matter which medications they’re taking, coauthor and hematologist/oncologist Clemens-Martin Wendtner, MD, of the Munich (Germany) Clinic, said in an interview.
“Do not defer or pause treatment,” said Dr. Wendtner, whose study was published in Blood Advances.
Patients with CLL appear to have among the weakest responses to the COVID-19 vaccine among people with various types of blood cancer. A meta-analysis published in 2022 found that seropositivity rates following vaccination were just 51% in patients with CLL, compared with 80%-90% in those with acute leukemia and 76%-80% of those with myeloma.
“Usually, the response rate to vaccination among the nonimmunocompromised would be 95%,” Dr. Wendtner said.
Research has also suggested that patients treated with B-cell pathway inhibitors and anti-CD20 antibodies are especially likely to have poorer responses to COVID-19 vaccines, no surprise considering that their job is to dampen the immune system. But there’s an unanswered question, according to Dr. Wendtner: Does “just measuring B-cell response tell us everything about the immune response?”
The new prospective, single-institution study aims to answer that question in patients who each received two types of vaccines. Researchers compared peripheral blood mononuclear cell transcriptional response with antibody and T-cell response rates in 15 patients with CLL/small lymphocytic lymphoma following vaccination with both the Pfizer-BioNTech and AstraZeneca vaccines.
The average antibody response was limited. “Overall, 7/15 of patients failed to mount a humoral response even after three-dose vaccination,” the researchers reported. All of the patients were “heavily pretreated” with CLL medications such as venetoclax, an anti-CD20 monoclonal antibody.
By contrast, the T-cell response was much stronger: 80% of patients (12/15) had a robust response, a number that grew to 90% (14/15) after a booster. This response is “almost ideal” considering that the response in a nonimmunocompromised person would be about 99%, Dr. Wendtner said.
The study also revealed that vaccine responses were weaker in patients who took a combination of a Bruton tyrosine kinase inhibitor and venetoclax within a year.
Four patients developed COVID-19 infections with the Omicron variant about 6 months after vaccination. All had mild symptoms. A lone patient had a history of COVID-19 infection prior to vaccination.
The researchers noted that the study had several limitations, including its small size, its reliance on a single institution, and the differences in treatments and vaccination protocols among the patient population.
Broadly speaking, the study showed that “a vaccine is not in vain” in patients with CLL, “although the doctor might not detect an antibody response,” Dr. Wendtner said. He added that mixing vaccine types should provide more protection. Start with a viral vector vaccine followed by an mRNA vaccine or vice versa, he suggested.
In an interview, infectious disease physician Joshua A. Hill, MD, from Fred Hutchinson Cancer Center, Seattle, who wasn’t involved with the study, said it makes “important and interesting observations to reinforce other studies with similar findings.”
Specifically, Dr. Hill said, “despite the absence of a robust antibody response some of these patients who are on active treatment, patients can still generate robust cellular immune responses in the form of T-cell immunity. Our understanding is that having T cell immunity will provide important additional protection for developing severe disease, although is less easily tested.”
As for the best vaccination strategies, Dr. Hill said “patients should get vaccinated as soon as they are eligible, according to standard guidelines. If patients have not yet started therapy, they should get their indicated vaccines before starting treatment whenever possible.”
The German study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Bavarian State Ministry of Science and Art. Dr. Wendtner disclosed consultant fees from AstraZeneca and BioNTech, and another author disclosed consultant fees from AstraZeneca. The other authors reported no disclosures. Dr. Hill disclosed consultant fees from Moderna, Pfizer, and Gilead.
These findings don’t reveal whether the T-cell boost actually provides extra protection against COVID-19. Still, the study suggests that patients with CLL should be vaccinated no matter which medications they’re taking, coauthor and hematologist/oncologist Clemens-Martin Wendtner, MD, of the Munich (Germany) Clinic, said in an interview.
“Do not defer or pause treatment,” said Dr. Wendtner, whose study was published in Blood Advances.
Patients with CLL appear to have among the weakest responses to the COVID-19 vaccine among people with various types of blood cancer. A meta-analysis published in 2022 found that seropositivity rates following vaccination were just 51% in patients with CLL, compared with 80%-90% in those with acute leukemia and 76%-80% of those with myeloma.
“Usually, the response rate to vaccination among the nonimmunocompromised would be 95%,” Dr. Wendtner said.
Research has also suggested that patients treated with B-cell pathway inhibitors and anti-CD20 antibodies are especially likely to have poorer responses to COVID-19 vaccines, no surprise considering that their job is to dampen the immune system. But there’s an unanswered question, according to Dr. Wendtner: Does “just measuring B-cell response tell us everything about the immune response?”
The new prospective, single-institution study aims to answer that question in patients who each received two types of vaccines. Researchers compared peripheral blood mononuclear cell transcriptional response with antibody and T-cell response rates in 15 patients with CLL/small lymphocytic lymphoma following vaccination with both the Pfizer-BioNTech and AstraZeneca vaccines.
The average antibody response was limited. “Overall, 7/15 of patients failed to mount a humoral response even after three-dose vaccination,” the researchers reported. All of the patients were “heavily pretreated” with CLL medications such as venetoclax, an anti-CD20 monoclonal antibody.
By contrast, the T-cell response was much stronger: 80% of patients (12/15) had a robust response, a number that grew to 90% (14/15) after a booster. This response is “almost ideal” considering that the response in a nonimmunocompromised person would be about 99%, Dr. Wendtner said.
The study also revealed that vaccine responses were weaker in patients who took a combination of a Bruton tyrosine kinase inhibitor and venetoclax within a year.
Four patients developed COVID-19 infections with the Omicron variant about 6 months after vaccination. All had mild symptoms. A lone patient had a history of COVID-19 infection prior to vaccination.
The researchers noted that the study had several limitations, including its small size, its reliance on a single institution, and the differences in treatments and vaccination protocols among the patient population.
Broadly speaking, the study showed that “a vaccine is not in vain” in patients with CLL, “although the doctor might not detect an antibody response,” Dr. Wendtner said. He added that mixing vaccine types should provide more protection. Start with a viral vector vaccine followed by an mRNA vaccine or vice versa, he suggested.
In an interview, infectious disease physician Joshua A. Hill, MD, from Fred Hutchinson Cancer Center, Seattle, who wasn’t involved with the study, said it makes “important and interesting observations to reinforce other studies with similar findings.”
Specifically, Dr. Hill said, “despite the absence of a robust antibody response some of these patients who are on active treatment, patients can still generate robust cellular immune responses in the form of T-cell immunity. Our understanding is that having T cell immunity will provide important additional protection for developing severe disease, although is less easily tested.”
As for the best vaccination strategies, Dr. Hill said “patients should get vaccinated as soon as they are eligible, according to standard guidelines. If patients have not yet started therapy, they should get their indicated vaccines before starting treatment whenever possible.”
The German study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Bavarian State Ministry of Science and Art. Dr. Wendtner disclosed consultant fees from AstraZeneca and BioNTech, and another author disclosed consultant fees from AstraZeneca. The other authors reported no disclosures. Dr. Hill disclosed consultant fees from Moderna, Pfizer, and Gilead.
These findings don’t reveal whether the T-cell boost actually provides extra protection against COVID-19. Still, the study suggests that patients with CLL should be vaccinated no matter which medications they’re taking, coauthor and hematologist/oncologist Clemens-Martin Wendtner, MD, of the Munich (Germany) Clinic, said in an interview.
“Do not defer or pause treatment,” said Dr. Wendtner, whose study was published in Blood Advances.
Patients with CLL appear to have among the weakest responses to the COVID-19 vaccine among people with various types of blood cancer. A meta-analysis published in 2022 found that seropositivity rates following vaccination were just 51% in patients with CLL, compared with 80%-90% in those with acute leukemia and 76%-80% of those with myeloma.
“Usually, the response rate to vaccination among the nonimmunocompromised would be 95%,” Dr. Wendtner said.
Research has also suggested that patients treated with B-cell pathway inhibitors and anti-CD20 antibodies are especially likely to have poorer responses to COVID-19 vaccines, no surprise considering that their job is to dampen the immune system. But there’s an unanswered question, according to Dr. Wendtner: Does “just measuring B-cell response tell us everything about the immune response?”
The new prospective, single-institution study aims to answer that question in patients who each received two types of vaccines. Researchers compared peripheral blood mononuclear cell transcriptional response with antibody and T-cell response rates in 15 patients with CLL/small lymphocytic lymphoma following vaccination with both the Pfizer-BioNTech and AstraZeneca vaccines.
The average antibody response was limited. “Overall, 7/15 of patients failed to mount a humoral response even after three-dose vaccination,” the researchers reported. All of the patients were “heavily pretreated” with CLL medications such as venetoclax, an anti-CD20 monoclonal antibody.
By contrast, the T-cell response was much stronger: 80% of patients (12/15) had a robust response, a number that grew to 90% (14/15) after a booster. This response is “almost ideal” considering that the response in a nonimmunocompromised person would be about 99%, Dr. Wendtner said.
The study also revealed that vaccine responses were weaker in patients who took a combination of a Bruton tyrosine kinase inhibitor and venetoclax within a year.
Four patients developed COVID-19 infections with the Omicron variant about 6 months after vaccination. All had mild symptoms. A lone patient had a history of COVID-19 infection prior to vaccination.
The researchers noted that the study had several limitations, including its small size, its reliance on a single institution, and the differences in treatments and vaccination protocols among the patient population.
Broadly speaking, the study showed that “a vaccine is not in vain” in patients with CLL, “although the doctor might not detect an antibody response,” Dr. Wendtner said. He added that mixing vaccine types should provide more protection. Start with a viral vector vaccine followed by an mRNA vaccine or vice versa, he suggested.
In an interview, infectious disease physician Joshua A. Hill, MD, from Fred Hutchinson Cancer Center, Seattle, who wasn’t involved with the study, said it makes “important and interesting observations to reinforce other studies with similar findings.”
Specifically, Dr. Hill said, “despite the absence of a robust antibody response some of these patients who are on active treatment, patients can still generate robust cellular immune responses in the form of T-cell immunity. Our understanding is that having T cell immunity will provide important additional protection for developing severe disease, although is less easily tested.”
As for the best vaccination strategies, Dr. Hill said “patients should get vaccinated as soon as they are eligible, according to standard guidelines. If patients have not yet started therapy, they should get their indicated vaccines before starting treatment whenever possible.”
The German study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Bavarian State Ministry of Science and Art. Dr. Wendtner disclosed consultant fees from AstraZeneca and BioNTech, and another author disclosed consultant fees from AstraZeneca. The other authors reported no disclosures. Dr. Hill disclosed consultant fees from Moderna, Pfizer, and Gilead.
FROM BLOOD ADVANCES
FDA approves pirtobrutinib for r/r mantle cell lymphoma
Pirtobrutinib is the first and only noncovalent Bruton’s tyrosine kinase inhibitor approved for use in this MCL setting, manufacturer Eli Lilly noted in a press release.
“The approval of Jaypirca represents an important advance for patients with relapsed or refractory MCL, who currently have limited options and historically have had a poor prognosis following discontinuation of treatment with a covalent Bruton’s tyrosine kinase inhibitor,” senior author Michael Wang, MD, University of Texas MD Anderson Cancer Center, Houston, said in the release.
The approval was based on efficacy demonstrated in the open-label, single-arm, phase 1/2 BRUIN trial – a multicenter study assessing 200 mg once-daily oral pirtobrutinib monotherapy in 120 patients with MCL who had previously received a Bruton’s tyrosine kinase inhibitor, most often ibrutinib (Imbruvica, 67%) acalabrutinib (Calquence, 30%) and zanubrutinib (Brukinsa, 8%). Pirtobrutinib was continued until disease progression or unacceptable toxicity.
Study participants had a median of three prior lines of therapy, and 83% discontinued their last Bruton’s tyrosine kinase inhibitor because of refractory or progressive disease.
The overall response rate in pirtobrutinib-treated patients was 50% with a complete response rate of 13%. Estimated median duration of response was 8.3 months, and the estimated duration of response at 6 months occurred in nearly two-thirds of patients.
Adverse reactions that occurred in at least 15% of patients included fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Grade 3 or 4 laboratory abnormalities occurring in at least 10% of patients included decreased neutrophil counts, lymphocyte counts, and platelet counts.
Prescribing information for pirtobrutinib includes warnings and precautions for infections, hemorrhage, cytopenias, atrial fibrillation and flutter, and second primary malignancies, noted the FDA, which granted priority review, fast track designation, and orphan drug designation for the application submitted by Eli Lilly.
“Jaypirca can reestablish Bruton’s tyrosine kinase inhibition in MCL patients previously treated with a covalent Bruton’s tyrosine kinase inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) and extend the benefit of targeting the Bruton’s tyrosine kinase pathway,” according to Eli Lilly’s release.
Dr. Wang added that the agent “has the potential to meaningfully impact the treatment paradigm for relapsed and refractory MCL patients.”
Meghan Gutierrez, CEO at the Lymphoma Research Foundation, also noted that “the approval of Jaypirca brings a new treatment option and, along with that, new hope for people with relapsed or refractory MCL.”
The drug is expected to be available in the United States in the coming weeks, and the confirmatory phase 3 BRUIN trial is currently enrolling patients, Eli Lilly announced. The company also indicated the list price would be $21,000 for a 30-day supply of the 200-mg dose.
Serious adverse events believed to be associated with the use of pirtobrutinib or any medicine or device should be reported to the FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.
A version of this article first appeared on Medscape.com.
Pirtobrutinib is the first and only noncovalent Bruton’s tyrosine kinase inhibitor approved for use in this MCL setting, manufacturer Eli Lilly noted in a press release.
“The approval of Jaypirca represents an important advance for patients with relapsed or refractory MCL, who currently have limited options and historically have had a poor prognosis following discontinuation of treatment with a covalent Bruton’s tyrosine kinase inhibitor,” senior author Michael Wang, MD, University of Texas MD Anderson Cancer Center, Houston, said in the release.
The approval was based on efficacy demonstrated in the open-label, single-arm, phase 1/2 BRUIN trial – a multicenter study assessing 200 mg once-daily oral pirtobrutinib monotherapy in 120 patients with MCL who had previously received a Bruton’s tyrosine kinase inhibitor, most often ibrutinib (Imbruvica, 67%) acalabrutinib (Calquence, 30%) and zanubrutinib (Brukinsa, 8%). Pirtobrutinib was continued until disease progression or unacceptable toxicity.
Study participants had a median of three prior lines of therapy, and 83% discontinued their last Bruton’s tyrosine kinase inhibitor because of refractory or progressive disease.
The overall response rate in pirtobrutinib-treated patients was 50% with a complete response rate of 13%. Estimated median duration of response was 8.3 months, and the estimated duration of response at 6 months occurred in nearly two-thirds of patients.
Adverse reactions that occurred in at least 15% of patients included fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Grade 3 or 4 laboratory abnormalities occurring in at least 10% of patients included decreased neutrophil counts, lymphocyte counts, and platelet counts.
Prescribing information for pirtobrutinib includes warnings and precautions for infections, hemorrhage, cytopenias, atrial fibrillation and flutter, and second primary malignancies, noted the FDA, which granted priority review, fast track designation, and orphan drug designation for the application submitted by Eli Lilly.
“Jaypirca can reestablish Bruton’s tyrosine kinase inhibition in MCL patients previously treated with a covalent Bruton’s tyrosine kinase inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) and extend the benefit of targeting the Bruton’s tyrosine kinase pathway,” according to Eli Lilly’s release.
Dr. Wang added that the agent “has the potential to meaningfully impact the treatment paradigm for relapsed and refractory MCL patients.”
Meghan Gutierrez, CEO at the Lymphoma Research Foundation, also noted that “the approval of Jaypirca brings a new treatment option and, along with that, new hope for people with relapsed or refractory MCL.”
The drug is expected to be available in the United States in the coming weeks, and the confirmatory phase 3 BRUIN trial is currently enrolling patients, Eli Lilly announced. The company also indicated the list price would be $21,000 for a 30-day supply of the 200-mg dose.
Serious adverse events believed to be associated with the use of pirtobrutinib or any medicine or device should be reported to the FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.
A version of this article first appeared on Medscape.com.
Pirtobrutinib is the first and only noncovalent Bruton’s tyrosine kinase inhibitor approved for use in this MCL setting, manufacturer Eli Lilly noted in a press release.
“The approval of Jaypirca represents an important advance for patients with relapsed or refractory MCL, who currently have limited options and historically have had a poor prognosis following discontinuation of treatment with a covalent Bruton’s tyrosine kinase inhibitor,” senior author Michael Wang, MD, University of Texas MD Anderson Cancer Center, Houston, said in the release.
The approval was based on efficacy demonstrated in the open-label, single-arm, phase 1/2 BRUIN trial – a multicenter study assessing 200 mg once-daily oral pirtobrutinib monotherapy in 120 patients with MCL who had previously received a Bruton’s tyrosine kinase inhibitor, most often ibrutinib (Imbruvica, 67%) acalabrutinib (Calquence, 30%) and zanubrutinib (Brukinsa, 8%). Pirtobrutinib was continued until disease progression or unacceptable toxicity.
Study participants had a median of three prior lines of therapy, and 83% discontinued their last Bruton’s tyrosine kinase inhibitor because of refractory or progressive disease.
The overall response rate in pirtobrutinib-treated patients was 50% with a complete response rate of 13%. Estimated median duration of response was 8.3 months, and the estimated duration of response at 6 months occurred in nearly two-thirds of patients.
Adverse reactions that occurred in at least 15% of patients included fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Grade 3 or 4 laboratory abnormalities occurring in at least 10% of patients included decreased neutrophil counts, lymphocyte counts, and platelet counts.
Prescribing information for pirtobrutinib includes warnings and precautions for infections, hemorrhage, cytopenias, atrial fibrillation and flutter, and second primary malignancies, noted the FDA, which granted priority review, fast track designation, and orphan drug designation for the application submitted by Eli Lilly.
“Jaypirca can reestablish Bruton’s tyrosine kinase inhibition in MCL patients previously treated with a covalent Bruton’s tyrosine kinase inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) and extend the benefit of targeting the Bruton’s tyrosine kinase pathway,” according to Eli Lilly’s release.
Dr. Wang added that the agent “has the potential to meaningfully impact the treatment paradigm for relapsed and refractory MCL patients.”
Meghan Gutierrez, CEO at the Lymphoma Research Foundation, also noted that “the approval of Jaypirca brings a new treatment option and, along with that, new hope for people with relapsed or refractory MCL.”
The drug is expected to be available in the United States in the coming weeks, and the confirmatory phase 3 BRUIN trial is currently enrolling patients, Eli Lilly announced. The company also indicated the list price would be $21,000 for a 30-day supply of the 200-mg dose.
Serious adverse events believed to be associated with the use of pirtobrutinib or any medicine or device should be reported to the FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.
A version of this article first appeared on Medscape.com.
Mastocytosis: Rare, underdiagnosed, potentially fatal
Nationwide, approximately 1,000 adults are diagnosed with systemic mastocytosis annually. This rare disease is a myeloid neoplasm with a highly variable phenotypic expression, in which abnormal mast cells proliferate and infiltrate organs and tissues. It swings widely from a nonadvanced form, composed of indolent or smoldering disease, to advanced disease that progresses to leukemia in 6% of cases.
More than 80% of systemic mastocytosis is driven by the KIT D816V mutation. Along with a host of other rare KIT mutations, KIT D816V activates KIT-receptor tyrosine kinase to trigger mast cell proliferation.
Dr. Gotlib could not be contacted for an interview. However, there are many good reasons to identify patients with systemic mastocytosis, according to Attilio Orazi, MD, professor and chair of the department of pathology at Texas Tech University, El Paso. The chief reason is that the patient may be in grave peril.
“The degree of heterogeneity is amazing. ... There’s very indolent [disease], which is really not a big deal. And then you have a disease in which you’re dead in 3 months,” Dr. Orazi said. “So you run the gamut between an indolent, no-problem cutaneous disease to a very nasty systemic, aggressive leukemia-like neoplasm.”
Since 2001, the diagnosis of mastocytosis has been guided by the World Health Organization Classification of Tumours, or “Blue Book.” In 2022, Dr. Orazi along with 137 other senior experts, most of whom were involved in past editions of the Blue Book, published their own version: The International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (the ICC 2022).
In September 2021, this group of specialists held a virtual/in-person advisory committee meeting at the University of Chicago to create the document. One factor in their decision to go it alone, Dr. Orazi said, was that WHO decided to proceed with the fifth edition of the Blue Book using its own internal editorial group without convening an advisory committee, despite repeated requests to do so.
ICC 2022 divides advanced systemic mastocytosis into three subtypes: aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Median survival is 3.5 years for patients with ASM, 2 years for those with SM-AHN and as low as 2 months for MCL.
The second key reason to increase awareness of mastocytosis among physicians, said Dr. Orazi, is that patients falling through the net are likely to be ambulatory, and their presentation can be “a little confusing.”
Patients with indolent disease are relatively straightforward to recognize, explained Dr. Orazi. Similarly, very sick patients with SM-AHN or MCL are easily recognized by hem-oncs.
“But if you see a patient in an ambulatory setting, in your clinic or whatever, and you’re suspicious, then you need to decide [how] you’re going to investigate that patient further,” he said, Dr. Orazi noted the next step is not always obvious, especially for primary-practice or internal medicine physicians likely to be unfamiliar with such a rare disease.
A practice survey published in 2022 by other researchers backed up Dr. Orazi’s remarks. The study found that community/solo-practice physicians were less likely to have tested systemic mastocytosis patients for KIT816V mutation than academic/specialty physicians (58% vs. 80%; P = .004; n = 111). Clinicians treating these patients estimated that it took an average of 8.5 months for a “typical” patient to receive the diagnosis from the time of symptom onset.
The research was headed by Ruben Mesa, MD, director of University of Texas Health, San Antonio, and funded by Blueprint Medicines, the manufacturer of avapritinib (Ayvakit), a new drug for the disease.
Dr. Orazi urged clinicians to have a high degree of suspicion for mastocytosis in a patient who walks into the clinic with any combination of the following: urticarial-type skin manifestations, especially if persistent into adulthood; history of undue reaction to an insect sting; a big spleen in a patient with a history of cutaneous flushing or rash; chronic diarrhea, especially if a biopsy has shown “too many mast cells” in the lamina propria of the small bowel; and positivity for KIT816V mutation.
Dr. Orazi stressed that the majority of patients will have indolent disease, but for the few patients for whom immediate treatment is essential, “the distinction between indolent and aggressive [disease] is really very, very important.”
Patients with advanced systemic mastocytosis can now be effectively treated, following the arrival of midostaurin (Rydapt, Tauritmo) and avapritinib.
Midostaurin, a multikinase/KIT inhibitor, was approved by the Food and Drug Administration in 2017 for the treatment of advanced systemic mastocytosis (ASM, SM-AHN, and MCL). Avapritinib, a selective kinase inhibitor of KIT816V and platelet-derived growth factor receptor alpha as well as multiple KIT exon 11, 11/17 and 17 mutants, gained the same indication in June 2021.
As with all rare diseases, it is challenging to obtain accurate numbers on how many patients are affected by systemic mastocytosis. The first population-based study of the disorder, presented at the 2018 annual meeting of the American Society of Hematology, used the Surveillance, Epidemiology, and End Results database from 2000 to 2014 to estimate incidence at 0.046 per 10,000, which translates to 1,050 new adult cases per year. The study data have never been published in full.
How many of these cases are advanced disease? There are no U.S. data but extrapolating from a Danish registry study that found 82% of systemic mastocytosis cases to be indolent disease, the incidence of advanced systemic mastocytosis in the United States could be as low as 200 adults a year.
This information, in turn, suggests that identifying more patients with advanced disease would not only benefit those patients but would also benefit clinical trial investigators who are seeking the proverbial needle in the haystack.
Nationwide, five clinical trials are recruiting individuals with advanced systemic mastocytosis, collectively looking for 352 patients in the United States. Two of the studies focus on mast-cell activation (NCT0544944) and cutaneous mastocytoses (NCT04846348). Two trials in a range of hematological malignancies are testing bispecific antibodies flotetuzumab and MGD024 (both from Macrogenics; NCT04681105, NCT05362773).
Apex, a phase 2 study of tyrosine-kinase inhibitor bezuclastinib (a Cogent hopeful), is specifically focusing on advanced disease. Dr. Gotlib and coinvestigators are aiming for 140 participants.
As a pathologist, Dr. Orazi said he find mastocytosis fascinating because he believes he has “a truly useful role,” contrasting with some other hematological diseases in which the molecular profile rules.
“Pathology plays a major role here,” he explained, “because you have to correlate what you see at the microscope with the full clinical picture, selected laboratory tests such as CBC and serum tryptase, and molecular results. You often need integration through a pathologist to put all the pieces together.
“It’s easier to treat once you know exactly what disease you’re dealing with and whether it is an aggressive or indolent subtype,” Dr. Orazi concluded.
Dr. Orazi disclosed no conflicts of interest. Dr. Gotlib has disclosed ties with Blueprint Medicines, Deciphera, Incyte, and Kartos Therapeutics, and has led committees for Blueprint Medicine’s EXPLORER and PATHFINDER studies, Deciphera’s Study Steering Committee for ripretinib in AdvSM, and the Central Response Review Committee for the phase 2 study of bezuclastinib in AdvSM.
Nationwide, approximately 1,000 adults are diagnosed with systemic mastocytosis annually. This rare disease is a myeloid neoplasm with a highly variable phenotypic expression, in which abnormal mast cells proliferate and infiltrate organs and tissues. It swings widely from a nonadvanced form, composed of indolent or smoldering disease, to advanced disease that progresses to leukemia in 6% of cases.
More than 80% of systemic mastocytosis is driven by the KIT D816V mutation. Along with a host of other rare KIT mutations, KIT D816V activates KIT-receptor tyrosine kinase to trigger mast cell proliferation.
Dr. Gotlib could not be contacted for an interview. However, there are many good reasons to identify patients with systemic mastocytosis, according to Attilio Orazi, MD, professor and chair of the department of pathology at Texas Tech University, El Paso. The chief reason is that the patient may be in grave peril.
“The degree of heterogeneity is amazing. ... There’s very indolent [disease], which is really not a big deal. And then you have a disease in which you’re dead in 3 months,” Dr. Orazi said. “So you run the gamut between an indolent, no-problem cutaneous disease to a very nasty systemic, aggressive leukemia-like neoplasm.”
Since 2001, the diagnosis of mastocytosis has been guided by the World Health Organization Classification of Tumours, or “Blue Book.” In 2022, Dr. Orazi along with 137 other senior experts, most of whom were involved in past editions of the Blue Book, published their own version: The International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (the ICC 2022).
In September 2021, this group of specialists held a virtual/in-person advisory committee meeting at the University of Chicago to create the document. One factor in their decision to go it alone, Dr. Orazi said, was that WHO decided to proceed with the fifth edition of the Blue Book using its own internal editorial group without convening an advisory committee, despite repeated requests to do so.
ICC 2022 divides advanced systemic mastocytosis into three subtypes: aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Median survival is 3.5 years for patients with ASM, 2 years for those with SM-AHN and as low as 2 months for MCL.
The second key reason to increase awareness of mastocytosis among physicians, said Dr. Orazi, is that patients falling through the net are likely to be ambulatory, and their presentation can be “a little confusing.”
Patients with indolent disease are relatively straightforward to recognize, explained Dr. Orazi. Similarly, very sick patients with SM-AHN or MCL are easily recognized by hem-oncs.
“But if you see a patient in an ambulatory setting, in your clinic or whatever, and you’re suspicious, then you need to decide [how] you’re going to investigate that patient further,” he said, Dr. Orazi noted the next step is not always obvious, especially for primary-practice or internal medicine physicians likely to be unfamiliar with such a rare disease.
A practice survey published in 2022 by other researchers backed up Dr. Orazi’s remarks. The study found that community/solo-practice physicians were less likely to have tested systemic mastocytosis patients for KIT816V mutation than academic/specialty physicians (58% vs. 80%; P = .004; n = 111). Clinicians treating these patients estimated that it took an average of 8.5 months for a “typical” patient to receive the diagnosis from the time of symptom onset.
The research was headed by Ruben Mesa, MD, director of University of Texas Health, San Antonio, and funded by Blueprint Medicines, the manufacturer of avapritinib (Ayvakit), a new drug for the disease.
Dr. Orazi urged clinicians to have a high degree of suspicion for mastocytosis in a patient who walks into the clinic with any combination of the following: urticarial-type skin manifestations, especially if persistent into adulthood; history of undue reaction to an insect sting; a big spleen in a patient with a history of cutaneous flushing or rash; chronic diarrhea, especially if a biopsy has shown “too many mast cells” in the lamina propria of the small bowel; and positivity for KIT816V mutation.
Dr. Orazi stressed that the majority of patients will have indolent disease, but for the few patients for whom immediate treatment is essential, “the distinction between indolent and aggressive [disease] is really very, very important.”
Patients with advanced systemic mastocytosis can now be effectively treated, following the arrival of midostaurin (Rydapt, Tauritmo) and avapritinib.
Midostaurin, a multikinase/KIT inhibitor, was approved by the Food and Drug Administration in 2017 for the treatment of advanced systemic mastocytosis (ASM, SM-AHN, and MCL). Avapritinib, a selective kinase inhibitor of KIT816V and platelet-derived growth factor receptor alpha as well as multiple KIT exon 11, 11/17 and 17 mutants, gained the same indication in June 2021.
As with all rare diseases, it is challenging to obtain accurate numbers on how many patients are affected by systemic mastocytosis. The first population-based study of the disorder, presented at the 2018 annual meeting of the American Society of Hematology, used the Surveillance, Epidemiology, and End Results database from 2000 to 2014 to estimate incidence at 0.046 per 10,000, which translates to 1,050 new adult cases per year. The study data have never been published in full.
How many of these cases are advanced disease? There are no U.S. data but extrapolating from a Danish registry study that found 82% of systemic mastocytosis cases to be indolent disease, the incidence of advanced systemic mastocytosis in the United States could be as low as 200 adults a year.
This information, in turn, suggests that identifying more patients with advanced disease would not only benefit those patients but would also benefit clinical trial investigators who are seeking the proverbial needle in the haystack.
Nationwide, five clinical trials are recruiting individuals with advanced systemic mastocytosis, collectively looking for 352 patients in the United States. Two of the studies focus on mast-cell activation (NCT0544944) and cutaneous mastocytoses (NCT04846348). Two trials in a range of hematological malignancies are testing bispecific antibodies flotetuzumab and MGD024 (both from Macrogenics; NCT04681105, NCT05362773).
Apex, a phase 2 study of tyrosine-kinase inhibitor bezuclastinib (a Cogent hopeful), is specifically focusing on advanced disease. Dr. Gotlib and coinvestigators are aiming for 140 participants.
As a pathologist, Dr. Orazi said he find mastocytosis fascinating because he believes he has “a truly useful role,” contrasting with some other hematological diseases in which the molecular profile rules.
“Pathology plays a major role here,” he explained, “because you have to correlate what you see at the microscope with the full clinical picture, selected laboratory tests such as CBC and serum tryptase, and molecular results. You often need integration through a pathologist to put all the pieces together.
“It’s easier to treat once you know exactly what disease you’re dealing with and whether it is an aggressive or indolent subtype,” Dr. Orazi concluded.
Dr. Orazi disclosed no conflicts of interest. Dr. Gotlib has disclosed ties with Blueprint Medicines, Deciphera, Incyte, and Kartos Therapeutics, and has led committees for Blueprint Medicine’s EXPLORER and PATHFINDER studies, Deciphera’s Study Steering Committee for ripretinib in AdvSM, and the Central Response Review Committee for the phase 2 study of bezuclastinib in AdvSM.
Nationwide, approximately 1,000 adults are diagnosed with systemic mastocytosis annually. This rare disease is a myeloid neoplasm with a highly variable phenotypic expression, in which abnormal mast cells proliferate and infiltrate organs and tissues. It swings widely from a nonadvanced form, composed of indolent or smoldering disease, to advanced disease that progresses to leukemia in 6% of cases.
More than 80% of systemic mastocytosis is driven by the KIT D816V mutation. Along with a host of other rare KIT mutations, KIT D816V activates KIT-receptor tyrosine kinase to trigger mast cell proliferation.
Dr. Gotlib could not be contacted for an interview. However, there are many good reasons to identify patients with systemic mastocytosis, according to Attilio Orazi, MD, professor and chair of the department of pathology at Texas Tech University, El Paso. The chief reason is that the patient may be in grave peril.
“The degree of heterogeneity is amazing. ... There’s very indolent [disease], which is really not a big deal. And then you have a disease in which you’re dead in 3 months,” Dr. Orazi said. “So you run the gamut between an indolent, no-problem cutaneous disease to a very nasty systemic, aggressive leukemia-like neoplasm.”
Since 2001, the diagnosis of mastocytosis has been guided by the World Health Organization Classification of Tumours, or “Blue Book.” In 2022, Dr. Orazi along with 137 other senior experts, most of whom were involved in past editions of the Blue Book, published their own version: The International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (the ICC 2022).
In September 2021, this group of specialists held a virtual/in-person advisory committee meeting at the University of Chicago to create the document. One factor in their decision to go it alone, Dr. Orazi said, was that WHO decided to proceed with the fifth edition of the Blue Book using its own internal editorial group without convening an advisory committee, despite repeated requests to do so.
ICC 2022 divides advanced systemic mastocytosis into three subtypes: aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Median survival is 3.5 years for patients with ASM, 2 years for those with SM-AHN and as low as 2 months for MCL.
The second key reason to increase awareness of mastocytosis among physicians, said Dr. Orazi, is that patients falling through the net are likely to be ambulatory, and their presentation can be “a little confusing.”
Patients with indolent disease are relatively straightforward to recognize, explained Dr. Orazi. Similarly, very sick patients with SM-AHN or MCL are easily recognized by hem-oncs.
“But if you see a patient in an ambulatory setting, in your clinic or whatever, and you’re suspicious, then you need to decide [how] you’re going to investigate that patient further,” he said, Dr. Orazi noted the next step is not always obvious, especially for primary-practice or internal medicine physicians likely to be unfamiliar with such a rare disease.
A practice survey published in 2022 by other researchers backed up Dr. Orazi’s remarks. The study found that community/solo-practice physicians were less likely to have tested systemic mastocytosis patients for KIT816V mutation than academic/specialty physicians (58% vs. 80%; P = .004; n = 111). Clinicians treating these patients estimated that it took an average of 8.5 months for a “typical” patient to receive the diagnosis from the time of symptom onset.
The research was headed by Ruben Mesa, MD, director of University of Texas Health, San Antonio, and funded by Blueprint Medicines, the manufacturer of avapritinib (Ayvakit), a new drug for the disease.
Dr. Orazi urged clinicians to have a high degree of suspicion for mastocytosis in a patient who walks into the clinic with any combination of the following: urticarial-type skin manifestations, especially if persistent into adulthood; history of undue reaction to an insect sting; a big spleen in a patient with a history of cutaneous flushing or rash; chronic diarrhea, especially if a biopsy has shown “too many mast cells” in the lamina propria of the small bowel; and positivity for KIT816V mutation.
Dr. Orazi stressed that the majority of patients will have indolent disease, but for the few patients for whom immediate treatment is essential, “the distinction between indolent and aggressive [disease] is really very, very important.”
Patients with advanced systemic mastocytosis can now be effectively treated, following the arrival of midostaurin (Rydapt, Tauritmo) and avapritinib.
Midostaurin, a multikinase/KIT inhibitor, was approved by the Food and Drug Administration in 2017 for the treatment of advanced systemic mastocytosis (ASM, SM-AHN, and MCL). Avapritinib, a selective kinase inhibitor of KIT816V and platelet-derived growth factor receptor alpha as well as multiple KIT exon 11, 11/17 and 17 mutants, gained the same indication in June 2021.
As with all rare diseases, it is challenging to obtain accurate numbers on how many patients are affected by systemic mastocytosis. The first population-based study of the disorder, presented at the 2018 annual meeting of the American Society of Hematology, used the Surveillance, Epidemiology, and End Results database from 2000 to 2014 to estimate incidence at 0.046 per 10,000, which translates to 1,050 new adult cases per year. The study data have never been published in full.
How many of these cases are advanced disease? There are no U.S. data but extrapolating from a Danish registry study that found 82% of systemic mastocytosis cases to be indolent disease, the incidence of advanced systemic mastocytosis in the United States could be as low as 200 adults a year.
This information, in turn, suggests that identifying more patients with advanced disease would not only benefit those patients but would also benefit clinical trial investigators who are seeking the proverbial needle in the haystack.
Nationwide, five clinical trials are recruiting individuals with advanced systemic mastocytosis, collectively looking for 352 patients in the United States. Two of the studies focus on mast-cell activation (NCT0544944) and cutaneous mastocytoses (NCT04846348). Two trials in a range of hematological malignancies are testing bispecific antibodies flotetuzumab and MGD024 (both from Macrogenics; NCT04681105, NCT05362773).
Apex, a phase 2 study of tyrosine-kinase inhibitor bezuclastinib (a Cogent hopeful), is specifically focusing on advanced disease. Dr. Gotlib and coinvestigators are aiming for 140 participants.
As a pathologist, Dr. Orazi said he find mastocytosis fascinating because he believes he has “a truly useful role,” contrasting with some other hematological diseases in which the molecular profile rules.
“Pathology plays a major role here,” he explained, “because you have to correlate what you see at the microscope with the full clinical picture, selected laboratory tests such as CBC and serum tryptase, and molecular results. You often need integration through a pathologist to put all the pieces together.
“It’s easier to treat once you know exactly what disease you’re dealing with and whether it is an aggressive or indolent subtype,” Dr. Orazi concluded.
Dr. Orazi disclosed no conflicts of interest. Dr. Gotlib has disclosed ties with Blueprint Medicines, Deciphera, Incyte, and Kartos Therapeutics, and has led committees for Blueprint Medicine’s EXPLORER and PATHFINDER studies, Deciphera’s Study Steering Committee for ripretinib in AdvSM, and the Central Response Review Committee for the phase 2 study of bezuclastinib in AdvSM.
Adding venetoclax improves ibrutinib outcomes in CLL
Investigators led by Philip Thompson, MD, a hematologist/oncologist at the center, explained that CLL patients receiving ibrutinib, a Bruton’s kinase inhibitor, “rarely achieve complete remission with undetectable measurable residual disease,” so they stay on the costly treatment indefinitely or until disease progression or accumulating adverse events force a switch to venetoclax.
Using the two agents together, instead of consecutively, may allow strong responders to stop treatment altogether and suboptimal responders to have longer remissions, they said.
“We would not advocate prolonged Bruton’s kinase inhibitor use prior to starting venetoclax in treatment-naive patients, as the safety and efficacy of commencing venetoclax after a 3-month ibrutinib monotherapy phase has been repeatedly demonstrated,” the team said.
However, the investigators noted that their “study was not intended to directly answer the question of whether combination therapy is superior to the current paradigm of sequential monotherapy.” Randomized trials are looking into the matter. The study was published recently as a preprint on ResearchSquare.com and has not been peer reviewed.
Complete remission in over half
The 45 adult subjects had one or more high-risk features for CLL progression and had received at least 1 year of ibrutinib at 140-420 mg once daily, depending on tolerance. They had bone marrow detectable disease at study entry but did not meet criteria for progression. Median duration of ibrutinib at baseline was 32 months, and about half the subjects were on it as their initial therapy.
Venetoclax, a BCL2 inhibitor with a completely different mechanisms of action, was added to ibrutinib for up to 2 years, escalated up to a target dose of 400 mg once daily.
On intention-to-treat analysis, venetoclax add-on improved ibrutinib response to complete remission in 55% of patients; complete remission was defined as less than 1 CLL cell per 10,000 leukocytes in bone marrow on two consecutive occasions 6 months apart.
The rate of undetectable bone marrow disease was 57% after 1 year of combined treatment and 71% after venetoclax completion, at which point 23 patients with undetectable disease stopped ibrutinib along with venetoclax.
Five patients had disease progression at a median of 41 months after venetoclax initiation, one during combined therapy, three during ibrutinib maintenance afterward, and one with Richter transformation after complete remission and discontinuation of all treatment. No patient had died from CLL.
“There has so far been no significant difference noted in” time to residual disease re-emergence, the team said, based on whether or not patients continued ibrutinib after venetoclax add-on.
There was no significant difference in the rate of bone marrow clearance according to the presence or absence of TP53 abnormalities, complex karyotypes, or prior treatment status.
The most common grade 3/4 adverse event was neutropenia in 20% of patients. Nine patients developed nonmelanoma skin cancer during the trial; six were diagnosed with other solid tumors; three came down with grade 3 infections, and two developed myelodysplastic syndrome, both with a prior history of chemotherapy.
No one stopped venetoclax because of toxicity, but about a third of subjects required dose reductions, most often because of neutropenia.
The study was funded by AbbVie, which is commercializing venetoclax along with Genentech. Investigators disclosed ties to both companies and many others. Dr. Thompson disclosed ties to AbbVie, Pharmacyclics, Lilly, Adaptive Biotechnologies, Janssen, Beigene, and Genentech.
Investigators led by Philip Thompson, MD, a hematologist/oncologist at the center, explained that CLL patients receiving ibrutinib, a Bruton’s kinase inhibitor, “rarely achieve complete remission with undetectable measurable residual disease,” so they stay on the costly treatment indefinitely or until disease progression or accumulating adverse events force a switch to venetoclax.
Using the two agents together, instead of consecutively, may allow strong responders to stop treatment altogether and suboptimal responders to have longer remissions, they said.
“We would not advocate prolonged Bruton’s kinase inhibitor use prior to starting venetoclax in treatment-naive patients, as the safety and efficacy of commencing venetoclax after a 3-month ibrutinib monotherapy phase has been repeatedly demonstrated,” the team said.
However, the investigators noted that their “study was not intended to directly answer the question of whether combination therapy is superior to the current paradigm of sequential monotherapy.” Randomized trials are looking into the matter. The study was published recently as a preprint on ResearchSquare.com and has not been peer reviewed.
Complete remission in over half
The 45 adult subjects had one or more high-risk features for CLL progression and had received at least 1 year of ibrutinib at 140-420 mg once daily, depending on tolerance. They had bone marrow detectable disease at study entry but did not meet criteria for progression. Median duration of ibrutinib at baseline was 32 months, and about half the subjects were on it as their initial therapy.
Venetoclax, a BCL2 inhibitor with a completely different mechanisms of action, was added to ibrutinib for up to 2 years, escalated up to a target dose of 400 mg once daily.
On intention-to-treat analysis, venetoclax add-on improved ibrutinib response to complete remission in 55% of patients; complete remission was defined as less than 1 CLL cell per 10,000 leukocytes in bone marrow on two consecutive occasions 6 months apart.
The rate of undetectable bone marrow disease was 57% after 1 year of combined treatment and 71% after venetoclax completion, at which point 23 patients with undetectable disease stopped ibrutinib along with venetoclax.
Five patients had disease progression at a median of 41 months after venetoclax initiation, one during combined therapy, three during ibrutinib maintenance afterward, and one with Richter transformation after complete remission and discontinuation of all treatment. No patient had died from CLL.
“There has so far been no significant difference noted in” time to residual disease re-emergence, the team said, based on whether or not patients continued ibrutinib after venetoclax add-on.
There was no significant difference in the rate of bone marrow clearance according to the presence or absence of TP53 abnormalities, complex karyotypes, or prior treatment status.
The most common grade 3/4 adverse event was neutropenia in 20% of patients. Nine patients developed nonmelanoma skin cancer during the trial; six were diagnosed with other solid tumors; three came down with grade 3 infections, and two developed myelodysplastic syndrome, both with a prior history of chemotherapy.
No one stopped venetoclax because of toxicity, but about a third of subjects required dose reductions, most often because of neutropenia.
The study was funded by AbbVie, which is commercializing venetoclax along with Genentech. Investigators disclosed ties to both companies and many others. Dr. Thompson disclosed ties to AbbVie, Pharmacyclics, Lilly, Adaptive Biotechnologies, Janssen, Beigene, and Genentech.
Investigators led by Philip Thompson, MD, a hematologist/oncologist at the center, explained that CLL patients receiving ibrutinib, a Bruton’s kinase inhibitor, “rarely achieve complete remission with undetectable measurable residual disease,” so they stay on the costly treatment indefinitely or until disease progression or accumulating adverse events force a switch to venetoclax.
Using the two agents together, instead of consecutively, may allow strong responders to stop treatment altogether and suboptimal responders to have longer remissions, they said.
“We would not advocate prolonged Bruton’s kinase inhibitor use prior to starting venetoclax in treatment-naive patients, as the safety and efficacy of commencing venetoclax after a 3-month ibrutinib monotherapy phase has been repeatedly demonstrated,” the team said.
However, the investigators noted that their “study was not intended to directly answer the question of whether combination therapy is superior to the current paradigm of sequential monotherapy.” Randomized trials are looking into the matter. The study was published recently as a preprint on ResearchSquare.com and has not been peer reviewed.
Complete remission in over half
The 45 adult subjects had one or more high-risk features for CLL progression and had received at least 1 year of ibrutinib at 140-420 mg once daily, depending on tolerance. They had bone marrow detectable disease at study entry but did not meet criteria for progression. Median duration of ibrutinib at baseline was 32 months, and about half the subjects were on it as their initial therapy.
Venetoclax, a BCL2 inhibitor with a completely different mechanisms of action, was added to ibrutinib for up to 2 years, escalated up to a target dose of 400 mg once daily.
On intention-to-treat analysis, venetoclax add-on improved ibrutinib response to complete remission in 55% of patients; complete remission was defined as less than 1 CLL cell per 10,000 leukocytes in bone marrow on two consecutive occasions 6 months apart.
The rate of undetectable bone marrow disease was 57% after 1 year of combined treatment and 71% after venetoclax completion, at which point 23 patients with undetectable disease stopped ibrutinib along with venetoclax.
Five patients had disease progression at a median of 41 months after venetoclax initiation, one during combined therapy, three during ibrutinib maintenance afterward, and one with Richter transformation after complete remission and discontinuation of all treatment. No patient had died from CLL.
“There has so far been no significant difference noted in” time to residual disease re-emergence, the team said, based on whether or not patients continued ibrutinib after venetoclax add-on.
There was no significant difference in the rate of bone marrow clearance according to the presence or absence of TP53 abnormalities, complex karyotypes, or prior treatment status.
The most common grade 3/4 adverse event was neutropenia in 20% of patients. Nine patients developed nonmelanoma skin cancer during the trial; six were diagnosed with other solid tumors; three came down with grade 3 infections, and two developed myelodysplastic syndrome, both with a prior history of chemotherapy.
No one stopped venetoclax because of toxicity, but about a third of subjects required dose reductions, most often because of neutropenia.
The study was funded by AbbVie, which is commercializing venetoclax along with Genentech. Investigators disclosed ties to both companies and many others. Dr. Thompson disclosed ties to AbbVie, Pharmacyclics, Lilly, Adaptive Biotechnologies, Janssen, Beigene, and Genentech.
FROM RESEARCHSQUARE
Off their pricey CML meds, many thrive
When imatinib (Gleevec) appeared on the market just over 2 decades ago, it revolutionized the treatment of chronic myelogenous leukemia (CML) and transformed it from a grim diagnosis into a largely treatable form of blood cancer. New generations of tyrosine kinase inhibitors (TKIs) have continued to expand options for patients, and many can look forward to normal lifespans.
But these medications cause side effects and can be expensive. Long-term data doesn’t exist for the newer therapies, so no one knows whether they can harm patients over time. None of this is particularly unusual for medications to treat chronic illness, but now there’s a twist:
“Our focus has changed because the results of treatment are so good,” hematologist-oncologist Ehab L. Atallah, MD, of the Medical College of Wisconsin, Milwaukee, said in an interview. “We’re trying to get people off their medication.”
Still, research estimates that only 20% of patients with CML will be eligible for treatment discontinuation and benefit from it in the long term. As a result, the wide majority of patients will need to be on drugs indefinitely.
Gleevec: A new age dawns
In the early 1990s, before the era of TKIs, the 5-year relative survival rate from CML was just 27%, and the 10-year rate was only 9.5%, according to a 2008 report. “If someone showed up with CML, their only option was to go to a bone marrow transplant. About half survived the transplant, and half of those had significant complications from it,” Dr. Atallah said. According to him, just about everyone who didn’t get transplantation would go on to die.
Then came Gleevec, which received Food and Drug Administration approval in 2001. It ushered in the era of “targeted” cancer treatment by specifically killing CML cells, instead of relying on traditional chemotherapy’s carpet-bombing approach.
“Gleevec and other TKIs have revolutionized how CML is treated, and patients are now living normal lives,” hematologist-oncologist Catherine Lai, MD, MPH, of the University of Pennsylvania, Philadelphia, said in an interview.
Alan Fahnestock, a 68-year-old retired telecommunications specialist in north-central Washington state, is one of the fortunate patients.
He was diagnosed with CML in 2004 after he underwent a thoracic CT scan in light of his tobacco use. “My GP found something odd in my lungs and referred me to a pulmonologist, who couldn’t figure it out either. He transmitted blood samples to my eventual hematologist/oncologist,” Mr. Fahnestock said in an interview. “It’s not clear to me that anybody ever figured out what the ‘oddity’ was. It has since apparently gone away. But the oncologist ran all the tests and came up with CML.”
Mr. Fahnestock hadn’t noticed any symptoms, although “this is, perhaps, because I tend not to pay a lot of attention to such things, having abused my body fairly severely over the years and having been borderline anemic since I was a kid. I don’t really expect to feel great and am a bit of a fatalist: I just get on with things until I no longer can.”
His physician prescribed Gleevec. “I had no particularly notable side effects, and carried on with my life pretty much as if nothing had happened,” Mr. Fahnestock said. He stayed on the drug for almost 20 years.
CML rooted in chromosome swap
It’s not clear exactly what causes CML, although the Mayo Clinic says most cases are linked to an abnormal, extra-short “Philadelphia chromosome,” created when two chromosomes swap material. This happens after birth.
Mr. Fahnestock thinks he happened to develop a random mutation. He also wonders if his work stints in the former Soviet Union in Vladivostok, “where the Soviet nuclear submarine fleet was decomposing,” and in Kiev, Ukraine, “which is not all that far from Chernobyl,” may be responsible.
Most patients, like Mr. Fahnestock, are men. Males will account for about 5,190 of the cases diagnosed in 2023, according to the American Cancer Society, compared to 3,740 in females.
Mr. Fahnestock’s CML diagnosis came at a fairly young age, when he was in his 40s. The average patient is diagnosed at 64. But it’s not unusual that he experienced no apparent symptoms when the cancer was found. In fact, that’s the norm.
Most patients with the disease – which is diagnosed in about 8,900 patients in the United States each year – are asymptomatic or have mild symptoms, Dr. Lai said. Their disease is discovered when “an elevated white count is found on routine blood work,” she said.
“The other group of patients typically present with very elevated white blood cell counts and splenomegaly with symptoms of fatigue and other constitutional symptoms. When the WBC count is very high, it is important to rule out transformation to accelerated or blast phase and also rule out an acute leukemia.”
Polymerase chain reaction is an especially important test during diagnosis, Dr. Atallah said, since it provides baseline data about the cancer that can be tracked.
TKIs: Mainstay of treatment
Four drugs are FDA approved for initial treatment of CML: imatinib (Gleevec), the second-generation TKIs dasatinib (Sprycel) and the third-generation TKI nilotinib (Tasigna). The third-generation TKIs bosutinib (Bosulif) and ponatinib (Iclusig) are approved for use as first-line treatments for patients who cannot tolerate the other drugs or are resistant to them.
The first-in-class drug asciminib (Scemblix), approved by the FDA in 2021, is a third-line drug for patients who failed treatment with two other TKIs and certain patients with the T315I mutation.
Dr. Lai said that it’s crucial to avoid side effects as much as possible “since the goal is for patients to be compliant and take the pill every day and not miss doses.” In younger patients, “I typically choose a second-generation TKI as my first choice, since there is a higher likelihood of getting into a deep molecular remission more quickly. If treatment-free remission is something a patient is interested in, a second-generation TKI is more likely to make this happen.”
According to Dr. Atallah, about half of patients end up using more than one drug because their initial choices either don’t work or cause intolerable side effects. Nevertheless, Dr. Lai noted: “Overall, patients do extremely well if compliant with their medication.”
Exceptions include the noncompliant and patients with more aggressive disease, like an accelerated or a blast phase, she said. For the latter patients, “allogenic bone marrow transplant should be considered once the patient is in remission.”
In remission, consider drug omission
How should patients be monitored if they are doing well?
“In general, I tend to follow patients monthly for the first six months after starting therapy, to make sure they are tolerating it well and to help manage side effects,” Dr. Lai said. “After that, I follow once every three months, and then often space out visits depending on whether they hit their molecular milestones and how long they’re in remission.”
In certain cases, patients may be taken off medication. The most recent National Comprehensive Cancer Network guidelines for treatment of CML, published in 2021, say that “discontinuation of TKI therapy (with close monitoring) is feasible in carefully selected, consenting patients” with early stage CML who’ve reached remission, defined as deep molecular response (DMR) of at least MR 4.0 for at least 2 years.
The guidelines caution that disease recurrence appears in “approximately 40%-60% of patients who discontinue TKI therapy after achieving DMR experience recurrence within 12 months of treatment cessation, in some cases as early as one month after discontinuation of TKI therapy.”
Still, the guidelines add that “resumption of TKI therapy immediately after recurrence results in the achievement of DMR in almost all patients.”
Dr. Atallah said stopping medication can be especially helpful for patients who grapple with side effects such as fatigue, diarrhea, and muscle aches. Some patients who take the drugs fear losing their health insurance and facing sky-high drug expenses. In 2018, average daily TKI costs for patients with CML were over $350, a 2020 report found.
Many patients were prescribed hugely expensive second-line treatments rather than inexpensive generic imatinib, the report said, despite “no evidence that later-generation TKIs provide superior progression free or overall survival.”
Many patients, however, refuse to consider stopping their medication, Dr. Atallah said. More data about treatment-free remission is needed, and the 21 U.S. academic medical centers in the H. Jean Khoury Cure CML Consortium are gathering information about patient outcomes.
Mr. Fahnestock is a fan of treatment-free remission. He stopped taking Gleevec about 2 years ago on the advice of his physician after he reached undetectable levels of disease.
“It was sort of a nonevent, really, with no discernible physical effects beyond exacerbation of the osteoarthritis in my hands,” he said. According to him, it’s not clear if this effect is linked to his eliminating the medication.
“I also vaguely hoped I’d feel better, even though I’d never been able to nail down any deleterious side effects,” he said. “No such luck, as it happens.”
Blood work has indicated no resurgence of the disease, and Mr. Fahnestock continues to volunteer as a rural firefighter.
“In general, I’m apparently reasonably healthy for my age, despite my folly [in younger years], and firefighting requires me to stay in reasonable shape,” he said. “I’ve recently been made aware of minor kidney issues and prediabetes. But, hell, I’m genetically scheduled to croak within 5 years or so, so why worry?”
National survival statistics in CML vary by factors such as gender and age, as a 2021 study revealed, and men have worse outcomes. Still, there’s a good chance Mr. Fahnestock won’t need to worry about CML ever again.
Dr. Atallah disclosed research support from Novartis and Takeda and has served both of those firms and Bristol-Myers Squibb as a consultant advisor. Dr. Lai discloses tied with Bristol-Myers Squibb, Jazz, Genentech, Novartis, Abbvie, Daiichi Sankyo, Astellas, MacroGenics, Servier, and Taiho. Mr. Fahnestock has no disclosures.
When imatinib (Gleevec) appeared on the market just over 2 decades ago, it revolutionized the treatment of chronic myelogenous leukemia (CML) and transformed it from a grim diagnosis into a largely treatable form of blood cancer. New generations of tyrosine kinase inhibitors (TKIs) have continued to expand options for patients, and many can look forward to normal lifespans.
But these medications cause side effects and can be expensive. Long-term data doesn’t exist for the newer therapies, so no one knows whether they can harm patients over time. None of this is particularly unusual for medications to treat chronic illness, but now there’s a twist:
“Our focus has changed because the results of treatment are so good,” hematologist-oncologist Ehab L. Atallah, MD, of the Medical College of Wisconsin, Milwaukee, said in an interview. “We’re trying to get people off their medication.”
Still, research estimates that only 20% of patients with CML will be eligible for treatment discontinuation and benefit from it in the long term. As a result, the wide majority of patients will need to be on drugs indefinitely.
Gleevec: A new age dawns
In the early 1990s, before the era of TKIs, the 5-year relative survival rate from CML was just 27%, and the 10-year rate was only 9.5%, according to a 2008 report. “If someone showed up with CML, their only option was to go to a bone marrow transplant. About half survived the transplant, and half of those had significant complications from it,” Dr. Atallah said. According to him, just about everyone who didn’t get transplantation would go on to die.
Then came Gleevec, which received Food and Drug Administration approval in 2001. It ushered in the era of “targeted” cancer treatment by specifically killing CML cells, instead of relying on traditional chemotherapy’s carpet-bombing approach.
“Gleevec and other TKIs have revolutionized how CML is treated, and patients are now living normal lives,” hematologist-oncologist Catherine Lai, MD, MPH, of the University of Pennsylvania, Philadelphia, said in an interview.
Alan Fahnestock, a 68-year-old retired telecommunications specialist in north-central Washington state, is one of the fortunate patients.
He was diagnosed with CML in 2004 after he underwent a thoracic CT scan in light of his tobacco use. “My GP found something odd in my lungs and referred me to a pulmonologist, who couldn’t figure it out either. He transmitted blood samples to my eventual hematologist/oncologist,” Mr. Fahnestock said in an interview. “It’s not clear to me that anybody ever figured out what the ‘oddity’ was. It has since apparently gone away. But the oncologist ran all the tests and came up with CML.”
Mr. Fahnestock hadn’t noticed any symptoms, although “this is, perhaps, because I tend not to pay a lot of attention to such things, having abused my body fairly severely over the years and having been borderline anemic since I was a kid. I don’t really expect to feel great and am a bit of a fatalist: I just get on with things until I no longer can.”
His physician prescribed Gleevec. “I had no particularly notable side effects, and carried on with my life pretty much as if nothing had happened,” Mr. Fahnestock said. He stayed on the drug for almost 20 years.
CML rooted in chromosome swap
It’s not clear exactly what causes CML, although the Mayo Clinic says most cases are linked to an abnormal, extra-short “Philadelphia chromosome,” created when two chromosomes swap material. This happens after birth.
Mr. Fahnestock thinks he happened to develop a random mutation. He also wonders if his work stints in the former Soviet Union in Vladivostok, “where the Soviet nuclear submarine fleet was decomposing,” and in Kiev, Ukraine, “which is not all that far from Chernobyl,” may be responsible.
Most patients, like Mr. Fahnestock, are men. Males will account for about 5,190 of the cases diagnosed in 2023, according to the American Cancer Society, compared to 3,740 in females.
Mr. Fahnestock’s CML diagnosis came at a fairly young age, when he was in his 40s. The average patient is diagnosed at 64. But it’s not unusual that he experienced no apparent symptoms when the cancer was found. In fact, that’s the norm.
Most patients with the disease – which is diagnosed in about 8,900 patients in the United States each year – are asymptomatic or have mild symptoms, Dr. Lai said. Their disease is discovered when “an elevated white count is found on routine blood work,” she said.
“The other group of patients typically present with very elevated white blood cell counts and splenomegaly with symptoms of fatigue and other constitutional symptoms. When the WBC count is very high, it is important to rule out transformation to accelerated or blast phase and also rule out an acute leukemia.”
Polymerase chain reaction is an especially important test during diagnosis, Dr. Atallah said, since it provides baseline data about the cancer that can be tracked.
TKIs: Mainstay of treatment
Four drugs are FDA approved for initial treatment of CML: imatinib (Gleevec), the second-generation TKIs dasatinib (Sprycel) and the third-generation TKI nilotinib (Tasigna). The third-generation TKIs bosutinib (Bosulif) and ponatinib (Iclusig) are approved for use as first-line treatments for patients who cannot tolerate the other drugs or are resistant to them.
The first-in-class drug asciminib (Scemblix), approved by the FDA in 2021, is a third-line drug for patients who failed treatment with two other TKIs and certain patients with the T315I mutation.
Dr. Lai said that it’s crucial to avoid side effects as much as possible “since the goal is for patients to be compliant and take the pill every day and not miss doses.” In younger patients, “I typically choose a second-generation TKI as my first choice, since there is a higher likelihood of getting into a deep molecular remission more quickly. If treatment-free remission is something a patient is interested in, a second-generation TKI is more likely to make this happen.”
According to Dr. Atallah, about half of patients end up using more than one drug because their initial choices either don’t work or cause intolerable side effects. Nevertheless, Dr. Lai noted: “Overall, patients do extremely well if compliant with their medication.”
Exceptions include the noncompliant and patients with more aggressive disease, like an accelerated or a blast phase, she said. For the latter patients, “allogenic bone marrow transplant should be considered once the patient is in remission.”
In remission, consider drug omission
How should patients be monitored if they are doing well?
“In general, I tend to follow patients monthly for the first six months after starting therapy, to make sure they are tolerating it well and to help manage side effects,” Dr. Lai said. “After that, I follow once every three months, and then often space out visits depending on whether they hit their molecular milestones and how long they’re in remission.”
In certain cases, patients may be taken off medication. The most recent National Comprehensive Cancer Network guidelines for treatment of CML, published in 2021, say that “discontinuation of TKI therapy (with close monitoring) is feasible in carefully selected, consenting patients” with early stage CML who’ve reached remission, defined as deep molecular response (DMR) of at least MR 4.0 for at least 2 years.
The guidelines caution that disease recurrence appears in “approximately 40%-60% of patients who discontinue TKI therapy after achieving DMR experience recurrence within 12 months of treatment cessation, in some cases as early as one month after discontinuation of TKI therapy.”
Still, the guidelines add that “resumption of TKI therapy immediately after recurrence results in the achievement of DMR in almost all patients.”
Dr. Atallah said stopping medication can be especially helpful for patients who grapple with side effects such as fatigue, diarrhea, and muscle aches. Some patients who take the drugs fear losing their health insurance and facing sky-high drug expenses. In 2018, average daily TKI costs for patients with CML were over $350, a 2020 report found.
Many patients were prescribed hugely expensive second-line treatments rather than inexpensive generic imatinib, the report said, despite “no evidence that later-generation TKIs provide superior progression free or overall survival.”
Many patients, however, refuse to consider stopping their medication, Dr. Atallah said. More data about treatment-free remission is needed, and the 21 U.S. academic medical centers in the H. Jean Khoury Cure CML Consortium are gathering information about patient outcomes.
Mr. Fahnestock is a fan of treatment-free remission. He stopped taking Gleevec about 2 years ago on the advice of his physician after he reached undetectable levels of disease.
“It was sort of a nonevent, really, with no discernible physical effects beyond exacerbation of the osteoarthritis in my hands,” he said. According to him, it’s not clear if this effect is linked to his eliminating the medication.
“I also vaguely hoped I’d feel better, even though I’d never been able to nail down any deleterious side effects,” he said. “No such luck, as it happens.”
Blood work has indicated no resurgence of the disease, and Mr. Fahnestock continues to volunteer as a rural firefighter.
“In general, I’m apparently reasonably healthy for my age, despite my folly [in younger years], and firefighting requires me to stay in reasonable shape,” he said. “I’ve recently been made aware of minor kidney issues and prediabetes. But, hell, I’m genetically scheduled to croak within 5 years or so, so why worry?”
National survival statistics in CML vary by factors such as gender and age, as a 2021 study revealed, and men have worse outcomes. Still, there’s a good chance Mr. Fahnestock won’t need to worry about CML ever again.
Dr. Atallah disclosed research support from Novartis and Takeda and has served both of those firms and Bristol-Myers Squibb as a consultant advisor. Dr. Lai discloses tied with Bristol-Myers Squibb, Jazz, Genentech, Novartis, Abbvie, Daiichi Sankyo, Astellas, MacroGenics, Servier, and Taiho. Mr. Fahnestock has no disclosures.
When imatinib (Gleevec) appeared on the market just over 2 decades ago, it revolutionized the treatment of chronic myelogenous leukemia (CML) and transformed it from a grim diagnosis into a largely treatable form of blood cancer. New generations of tyrosine kinase inhibitors (TKIs) have continued to expand options for patients, and many can look forward to normal lifespans.
But these medications cause side effects and can be expensive. Long-term data doesn’t exist for the newer therapies, so no one knows whether they can harm patients over time. None of this is particularly unusual for medications to treat chronic illness, but now there’s a twist:
“Our focus has changed because the results of treatment are so good,” hematologist-oncologist Ehab L. Atallah, MD, of the Medical College of Wisconsin, Milwaukee, said in an interview. “We’re trying to get people off their medication.”
Still, research estimates that only 20% of patients with CML will be eligible for treatment discontinuation and benefit from it in the long term. As a result, the wide majority of patients will need to be on drugs indefinitely.
Gleevec: A new age dawns
In the early 1990s, before the era of TKIs, the 5-year relative survival rate from CML was just 27%, and the 10-year rate was only 9.5%, according to a 2008 report. “If someone showed up with CML, their only option was to go to a bone marrow transplant. About half survived the transplant, and half of those had significant complications from it,” Dr. Atallah said. According to him, just about everyone who didn’t get transplantation would go on to die.
Then came Gleevec, which received Food and Drug Administration approval in 2001. It ushered in the era of “targeted” cancer treatment by specifically killing CML cells, instead of relying on traditional chemotherapy’s carpet-bombing approach.
“Gleevec and other TKIs have revolutionized how CML is treated, and patients are now living normal lives,” hematologist-oncologist Catherine Lai, MD, MPH, of the University of Pennsylvania, Philadelphia, said in an interview.
Alan Fahnestock, a 68-year-old retired telecommunications specialist in north-central Washington state, is one of the fortunate patients.
He was diagnosed with CML in 2004 after he underwent a thoracic CT scan in light of his tobacco use. “My GP found something odd in my lungs and referred me to a pulmonologist, who couldn’t figure it out either. He transmitted blood samples to my eventual hematologist/oncologist,” Mr. Fahnestock said in an interview. “It’s not clear to me that anybody ever figured out what the ‘oddity’ was. It has since apparently gone away. But the oncologist ran all the tests and came up with CML.”
Mr. Fahnestock hadn’t noticed any symptoms, although “this is, perhaps, because I tend not to pay a lot of attention to such things, having abused my body fairly severely over the years and having been borderline anemic since I was a kid. I don’t really expect to feel great and am a bit of a fatalist: I just get on with things until I no longer can.”
His physician prescribed Gleevec. “I had no particularly notable side effects, and carried on with my life pretty much as if nothing had happened,” Mr. Fahnestock said. He stayed on the drug for almost 20 years.
CML rooted in chromosome swap
It’s not clear exactly what causes CML, although the Mayo Clinic says most cases are linked to an abnormal, extra-short “Philadelphia chromosome,” created when two chromosomes swap material. This happens after birth.
Mr. Fahnestock thinks he happened to develop a random mutation. He also wonders if his work stints in the former Soviet Union in Vladivostok, “where the Soviet nuclear submarine fleet was decomposing,” and in Kiev, Ukraine, “which is not all that far from Chernobyl,” may be responsible.
Most patients, like Mr. Fahnestock, are men. Males will account for about 5,190 of the cases diagnosed in 2023, according to the American Cancer Society, compared to 3,740 in females.
Mr. Fahnestock’s CML diagnosis came at a fairly young age, when he was in his 40s. The average patient is diagnosed at 64. But it’s not unusual that he experienced no apparent symptoms when the cancer was found. In fact, that’s the norm.
Most patients with the disease – which is diagnosed in about 8,900 patients in the United States each year – are asymptomatic or have mild symptoms, Dr. Lai said. Their disease is discovered when “an elevated white count is found on routine blood work,” she said.
“The other group of patients typically present with very elevated white blood cell counts and splenomegaly with symptoms of fatigue and other constitutional symptoms. When the WBC count is very high, it is important to rule out transformation to accelerated or blast phase and also rule out an acute leukemia.”
Polymerase chain reaction is an especially important test during diagnosis, Dr. Atallah said, since it provides baseline data about the cancer that can be tracked.
TKIs: Mainstay of treatment
Four drugs are FDA approved for initial treatment of CML: imatinib (Gleevec), the second-generation TKIs dasatinib (Sprycel) and the third-generation TKI nilotinib (Tasigna). The third-generation TKIs bosutinib (Bosulif) and ponatinib (Iclusig) are approved for use as first-line treatments for patients who cannot tolerate the other drugs or are resistant to them.
The first-in-class drug asciminib (Scemblix), approved by the FDA in 2021, is a third-line drug for patients who failed treatment with two other TKIs and certain patients with the T315I mutation.
Dr. Lai said that it’s crucial to avoid side effects as much as possible “since the goal is for patients to be compliant and take the pill every day and not miss doses.” In younger patients, “I typically choose a second-generation TKI as my first choice, since there is a higher likelihood of getting into a deep molecular remission more quickly. If treatment-free remission is something a patient is interested in, a second-generation TKI is more likely to make this happen.”
According to Dr. Atallah, about half of patients end up using more than one drug because their initial choices either don’t work or cause intolerable side effects. Nevertheless, Dr. Lai noted: “Overall, patients do extremely well if compliant with their medication.”
Exceptions include the noncompliant and patients with more aggressive disease, like an accelerated or a blast phase, she said. For the latter patients, “allogenic bone marrow transplant should be considered once the patient is in remission.”
In remission, consider drug omission
How should patients be monitored if they are doing well?
“In general, I tend to follow patients monthly for the first six months after starting therapy, to make sure they are tolerating it well and to help manage side effects,” Dr. Lai said. “After that, I follow once every three months, and then often space out visits depending on whether they hit their molecular milestones and how long they’re in remission.”
In certain cases, patients may be taken off medication. The most recent National Comprehensive Cancer Network guidelines for treatment of CML, published in 2021, say that “discontinuation of TKI therapy (with close monitoring) is feasible in carefully selected, consenting patients” with early stage CML who’ve reached remission, defined as deep molecular response (DMR) of at least MR 4.0 for at least 2 years.
The guidelines caution that disease recurrence appears in “approximately 40%-60% of patients who discontinue TKI therapy after achieving DMR experience recurrence within 12 months of treatment cessation, in some cases as early as one month after discontinuation of TKI therapy.”
Still, the guidelines add that “resumption of TKI therapy immediately after recurrence results in the achievement of DMR in almost all patients.”
Dr. Atallah said stopping medication can be especially helpful for patients who grapple with side effects such as fatigue, diarrhea, and muscle aches. Some patients who take the drugs fear losing their health insurance and facing sky-high drug expenses. In 2018, average daily TKI costs for patients with CML were over $350, a 2020 report found.
Many patients were prescribed hugely expensive second-line treatments rather than inexpensive generic imatinib, the report said, despite “no evidence that later-generation TKIs provide superior progression free or overall survival.”
Many patients, however, refuse to consider stopping their medication, Dr. Atallah said. More data about treatment-free remission is needed, and the 21 U.S. academic medical centers in the H. Jean Khoury Cure CML Consortium are gathering information about patient outcomes.
Mr. Fahnestock is a fan of treatment-free remission. He stopped taking Gleevec about 2 years ago on the advice of his physician after he reached undetectable levels of disease.
“It was sort of a nonevent, really, with no discernible physical effects beyond exacerbation of the osteoarthritis in my hands,” he said. According to him, it’s not clear if this effect is linked to his eliminating the medication.
“I also vaguely hoped I’d feel better, even though I’d never been able to nail down any deleterious side effects,” he said. “No such luck, as it happens.”
Blood work has indicated no resurgence of the disease, and Mr. Fahnestock continues to volunteer as a rural firefighter.
“In general, I’m apparently reasonably healthy for my age, despite my folly [in younger years], and firefighting requires me to stay in reasonable shape,” he said. “I’ve recently been made aware of minor kidney issues and prediabetes. But, hell, I’m genetically scheduled to croak within 5 years or so, so why worry?”
National survival statistics in CML vary by factors such as gender and age, as a 2021 study revealed, and men have worse outcomes. Still, there’s a good chance Mr. Fahnestock won’t need to worry about CML ever again.
Dr. Atallah disclosed research support from Novartis and Takeda and has served both of those firms and Bristol-Myers Squibb as a consultant advisor. Dr. Lai discloses tied with Bristol-Myers Squibb, Jazz, Genentech, Novartis, Abbvie, Daiichi Sankyo, Astellas, MacroGenics, Servier, and Taiho. Mr. Fahnestock has no disclosures.
Multiple myeloma diagnosed more via emergency care during COVID
The study covered in this summary was published on Research Square as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
While trying to avoid COVID-19 infection, patients ultimately diagnosed with multiple myeloma may have delayed interactions with healthcare professionals and consequently delayed their cancer diagnosis.
Study design
Researchers collected data on newly diagnosed patients with multiple myeloma from January 2019 until July 2021 across five institutions (three universities and two hospitals) in England. In total, 323 patients with multiple myeloma were identified.
Patients were divided into two groups: those diagnosed between Jan. 1, 2019, until Jan. 31, 2020, or pre-COVID, and those diagnosed from Feb. 1, 2020, to July 31, 2021, or post COVID.
Key results
Among all patients, 80 (24.8%) were diagnosed with smoldering multiple myeloma and 243 (75.2%) were diagnosed with multiple myeloma requiring treatment.
Significantly more patients in the post-COVID group were diagnosed with myeloma through the emergency route (45.5% post COVID vs. 32.7% pre-COVID; P = .03).
Clinical complications leading to emergency admission prior to a myeloma diagnosis also differed between the two cohorts: Acute kidney injury accounted for most emergency admissions in the pre-COVID cohort while skeletal-related events, including spinal cord compression, were the major causes for diagnosis through the emergency route in the post-COVID cohort.
Patients who were diagnosed with symptomatic myeloma pre-COVID were more likely to be treated with a triplet rather than doublet combination compared with those diagnosed in the post-COVID period (triplet pre-COVID 79.1%, post COVID 63.75%; P = .014).
Overall survival at 1 year was not significantly different between the pre-COVID and post-COVID groups: 88.2% pre-COVID, compared with 87.8% post COVID.
Overall, the authors concluded that the COVID pandemic “resulted in a shift in the symptomatology, disease burden, and routes of diagnosis of patients presenting with myeloma” and “this may have significant consequences” over the long term.
Limitations
The study does not provide a clear time frame of delays in diagnosis.
Disclosures
The study authors did not report any conflicts of interest.
A version of this article first appeared on Medscape.com .
The study covered in this summary was published on Research Square as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
While trying to avoid COVID-19 infection, patients ultimately diagnosed with multiple myeloma may have delayed interactions with healthcare professionals and consequently delayed their cancer diagnosis.
Study design
Researchers collected data on newly diagnosed patients with multiple myeloma from January 2019 until July 2021 across five institutions (three universities and two hospitals) in England. In total, 323 patients with multiple myeloma were identified.
Patients were divided into two groups: those diagnosed between Jan. 1, 2019, until Jan. 31, 2020, or pre-COVID, and those diagnosed from Feb. 1, 2020, to July 31, 2021, or post COVID.
Key results
Among all patients, 80 (24.8%) were diagnosed with smoldering multiple myeloma and 243 (75.2%) were diagnosed with multiple myeloma requiring treatment.
Significantly more patients in the post-COVID group were diagnosed with myeloma through the emergency route (45.5% post COVID vs. 32.7% pre-COVID; P = .03).
Clinical complications leading to emergency admission prior to a myeloma diagnosis also differed between the two cohorts: Acute kidney injury accounted for most emergency admissions in the pre-COVID cohort while skeletal-related events, including spinal cord compression, were the major causes for diagnosis through the emergency route in the post-COVID cohort.
Patients who were diagnosed with symptomatic myeloma pre-COVID were more likely to be treated with a triplet rather than doublet combination compared with those diagnosed in the post-COVID period (triplet pre-COVID 79.1%, post COVID 63.75%; P = .014).
Overall survival at 1 year was not significantly different between the pre-COVID and post-COVID groups: 88.2% pre-COVID, compared with 87.8% post COVID.
Overall, the authors concluded that the COVID pandemic “resulted in a shift in the symptomatology, disease burden, and routes of diagnosis of patients presenting with myeloma” and “this may have significant consequences” over the long term.
Limitations
The study does not provide a clear time frame of delays in diagnosis.
Disclosures
The study authors did not report any conflicts of interest.
A version of this article first appeared on Medscape.com .
The study covered in this summary was published on Research Square as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
While trying to avoid COVID-19 infection, patients ultimately diagnosed with multiple myeloma may have delayed interactions with healthcare professionals and consequently delayed their cancer diagnosis.
Study design
Researchers collected data on newly diagnosed patients with multiple myeloma from January 2019 until July 2021 across five institutions (three universities and two hospitals) in England. In total, 323 patients with multiple myeloma were identified.
Patients were divided into two groups: those diagnosed between Jan. 1, 2019, until Jan. 31, 2020, or pre-COVID, and those diagnosed from Feb. 1, 2020, to July 31, 2021, or post COVID.
Key results
Among all patients, 80 (24.8%) were diagnosed with smoldering multiple myeloma and 243 (75.2%) were diagnosed with multiple myeloma requiring treatment.
Significantly more patients in the post-COVID group were diagnosed with myeloma through the emergency route (45.5% post COVID vs. 32.7% pre-COVID; P = .03).
Clinical complications leading to emergency admission prior to a myeloma diagnosis also differed between the two cohorts: Acute kidney injury accounted for most emergency admissions in the pre-COVID cohort while skeletal-related events, including spinal cord compression, were the major causes for diagnosis through the emergency route in the post-COVID cohort.
Patients who were diagnosed with symptomatic myeloma pre-COVID were more likely to be treated with a triplet rather than doublet combination compared with those diagnosed in the post-COVID period (triplet pre-COVID 79.1%, post COVID 63.75%; P = .014).
Overall survival at 1 year was not significantly different between the pre-COVID and post-COVID groups: 88.2% pre-COVID, compared with 87.8% post COVID.
Overall, the authors concluded that the COVID pandemic “resulted in a shift in the symptomatology, disease burden, and routes of diagnosis of patients presenting with myeloma” and “this may have significant consequences” over the long term.
Limitations
The study does not provide a clear time frame of delays in diagnosis.
Disclosures
The study authors did not report any conflicts of interest.
A version of this article first appeared on Medscape.com .