Myelodysplastic Syndrome

Results from the latest survey by the National Comprehensive Cancer Network (NCCN) showed that numerous critical systemic anticancer therapies, primarily generic drugs, are currently in shortage.

Nearly 90% of the 28 NCCN member centers who responded to the survey, conducted between May 28 and June 11, said they were experiencing a shortage of at least one drug.

“Many drugs that are currently in shortage form the backbones of effective multiagent regimens across both curative and palliative treatment settings,” NCCN’s CEO Crystal S. Denlinger, MD, said in an interview.

The good news is that carboplatin and cisplatin shortages have fallen dramatically since 2023. At the peak of the shortage in 2023, 93% of centers surveyed reported experiencing a shortage of carboplatin and 70% were experiencing a shortage of cisplatin, whereas in 2024, only 11% reported a carboplatin shortage and 7% reported a cisplatin shortage.

“Thankfully, the shortages for carboplatin and cisplatin are mostly resolved at this time,” Dr. Denlinger said.

However, all three NCCN surveys conducted in the past year, including the most recent one, have found shortages of various chemotherapies and supportive care medications, which suggests this is an ongoing issue affecting a significant spectrum of generic drugs.

“The acute crisis associated with the shortage of carboplatin and cisplatin was a singular event that brought the issue into the national spotlight,” but it’s “important to note that the current broad drug shortages found on this survey are not new,” said Dr. Denlinger.

In the latest survey, 89% of NCCN centers continue to report shortages of one or more drugs, and 75% said they are experiencing shortages of two or more drugs.

Overall, 57% of centers are short on vinblastine, 46% are short on etoposide, and 43% are short on topotecan. Other common chemotherapy and supportive care agents in short supply include dacarbazine (18% of centers) as well as 5-fluorouracil (5-FU) and methotrexate (14% of centers).

In 2023, however, shortages of methotrexate and 5-FU were worse, with 67% of centers reporting shortages of methotrexate and 26% of 5-FU.

In the current survey, 75% of NCCN centers also noted they were aware of drug shortages within community practices in their area, and more than one in four centers reported treatment delays requiring additional prior authorization.

Cancer drug shortages impact not only routine treatments but also clinical trials. The recent survey found that 43% of respondents said drug shortages disrupted clinical trials at their center. The biggest issues centers flagged included greater administrative burdens, lower patient enrollment, and fewer open trials.

How are centers dealing with ongoing supply issues?

Top mitigation strategies include reducing waste, limiting use of current stock, and adjusting the timing and dosage within evidence-based ranges.

“The current situation underscores the need for sustainable, long-term solutions that ensure a stable supply of high-quality cancer medications,” Alyssa Schatz, MSW, NCCN senior director of policy and advocacy, said in a news release.

Three-quarters (75%) of survey respondents said they would like to see economic incentives put in place to encourage the high-quality manufacturing of medications, especially generic versions that are often in short supply. Nearly two-thirds (64%) cited a need for a broader buffer stock payment, and the same percentage would like to see more information on user experiences with various generic suppliers to help hospitals contract with those engaging in high-quality practices.

The NCCN also continues to work with federal regulators, agencies, and lawmakers to implement long-term solutions to cancer drug shortages.

“The federal government has a key role to play in addressing this issue,” Ms. Schatz said. “Establishing economic incentives, such as tax breaks or manufacturing grants for generic drugmakers, will help support a robust and resilient supply chain — ultimately safeguarding care for people with cancer across the country.”

A version of this article appeared on Medscape.com.

Results from the latest survey by the National Comprehensive Cancer Network (NCCN) showed that numerous critical systemic anticancer therapies, primarily generic drugs, are currently in shortage.

Nearly 90% of the 28 NCCN member centers who responded to the survey, conducted between May 28 and June 11, said they were experiencing a shortage of at least one drug.

“Many drugs that are currently in shortage form the backbones of effective multiagent regimens across both curative and palliative treatment settings,” NCCN’s CEO Crystal S. Denlinger, MD, said in an interview.

The good news is that carboplatin and cisplatin shortages have fallen dramatically since 2023. At the peak of the shortage in 2023, 93% of centers surveyed reported experiencing a shortage of carboplatin and 70% were experiencing a shortage of cisplatin, whereas in 2024, only 11% reported a carboplatin shortage and 7% reported a cisplatin shortage.

“Thankfully, the shortages for carboplatin and cisplatin are mostly resolved at this time,” Dr. Denlinger said.

However, all three NCCN surveys conducted in the past year, including the most recent one, have found shortages of various chemotherapies and supportive care medications, which suggests this is an ongoing issue affecting a significant spectrum of generic drugs.

“The acute crisis associated with the shortage of carboplatin and cisplatin was a singular event that brought the issue into the national spotlight,” but it’s “important to note that the current broad drug shortages found on this survey are not new,” said Dr. Denlinger.

In the latest survey, 89% of NCCN centers continue to report shortages of one or more drugs, and 75% said they are experiencing shortages of two or more drugs.

Overall, 57% of centers are short on vinblastine, 46% are short on etoposide, and 43% are short on topotecan. Other common chemotherapy and supportive care agents in short supply include dacarbazine (18% of centers) as well as 5-fluorouracil (5-FU) and methotrexate (14% of centers).

In 2023, however, shortages of methotrexate and 5-FU were worse, with 67% of centers reporting shortages of methotrexate and 26% of 5-FU.

In the current survey, 75% of NCCN centers also noted they were aware of drug shortages within community practices in their area, and more than one in four centers reported treatment delays requiring additional prior authorization.

Cancer drug shortages impact not only routine treatments but also clinical trials. The recent survey found that 43% of respondents said drug shortages disrupted clinical trials at their center. The biggest issues centers flagged included greater administrative burdens, lower patient enrollment, and fewer open trials.

How are centers dealing with ongoing supply issues?

Top mitigation strategies include reducing waste, limiting use of current stock, and adjusting the timing and dosage within evidence-based ranges.

“The current situation underscores the need for sustainable, long-term solutions that ensure a stable supply of high-quality cancer medications,” Alyssa Schatz, MSW, NCCN senior director of policy and advocacy, said in a news release.

Three-quarters (75%) of survey respondents said they would like to see economic incentives put in place to encourage the high-quality manufacturing of medications, especially generic versions that are often in short supply. Nearly two-thirds (64%) cited a need for a broader buffer stock payment, and the same percentage would like to see more information on user experiences with various generic suppliers to help hospitals contract with those engaging in high-quality practices.

The NCCN also continues to work with federal regulators, agencies, and lawmakers to implement long-term solutions to cancer drug shortages.

“The federal government has a key role to play in addressing this issue,” Ms. Schatz said. “Establishing economic incentives, such as tax breaks or manufacturing grants for generic drugmakers, will help support a robust and resilient supply chain — ultimately safeguarding care for people with cancer across the country.”

A version of this article appeared on Medscape.com.

Results from the latest survey by the National Comprehensive Cancer Network (NCCN) showed that numerous critical systemic anticancer therapies, primarily generic drugs, are currently in shortage.

Nearly 90% of the 28 NCCN member centers who responded to the survey, conducted between May 28 and June 11, said they were experiencing a shortage of at least one drug.

“Many drugs that are currently in shortage form the backbones of effective multiagent regimens across both curative and palliative treatment settings,” NCCN’s CEO Crystal S. Denlinger, MD, said in an interview.

The good news is that carboplatin and cisplatin shortages have fallen dramatically since 2023. At the peak of the shortage in 2023, 93% of centers surveyed reported experiencing a shortage of carboplatin and 70% were experiencing a shortage of cisplatin, whereas in 2024, only 11% reported a carboplatin shortage and 7% reported a cisplatin shortage.

“Thankfully, the shortages for carboplatin and cisplatin are mostly resolved at this time,” Dr. Denlinger said.

However, all three NCCN surveys conducted in the past year, including the most recent one, have found shortages of various chemotherapies and supportive care medications, which suggests this is an ongoing issue affecting a significant spectrum of generic drugs.

“The acute crisis associated with the shortage of carboplatin and cisplatin was a singular event that brought the issue into the national spotlight,” but it’s “important to note that the current broad drug shortages found on this survey are not new,” said Dr. Denlinger.

In the latest survey, 89% of NCCN centers continue to report shortages of one or more drugs, and 75% said they are experiencing shortages of two or more drugs.

Overall, 57% of centers are short on vinblastine, 46% are short on etoposide, and 43% are short on topotecan. Other common chemotherapy and supportive care agents in short supply include dacarbazine (18% of centers) as well as 5-fluorouracil (5-FU) and methotrexate (14% of centers).

In 2023, however, shortages of methotrexate and 5-FU were worse, with 67% of centers reporting shortages of methotrexate and 26% of 5-FU.

In the current survey, 75% of NCCN centers also noted they were aware of drug shortages within community practices in their area, and more than one in four centers reported treatment delays requiring additional prior authorization.

Cancer drug shortages impact not only routine treatments but also clinical trials. The recent survey found that 43% of respondents said drug shortages disrupted clinical trials at their center. The biggest issues centers flagged included greater administrative burdens, lower patient enrollment, and fewer open trials.

How are centers dealing with ongoing supply issues?

Top mitigation strategies include reducing waste, limiting use of current stock, and adjusting the timing and dosage within evidence-based ranges.

“The current situation underscores the need for sustainable, long-term solutions that ensure a stable supply of high-quality cancer medications,” Alyssa Schatz, MSW, NCCN senior director of policy and advocacy, said in a news release.

Three-quarters (75%) of survey respondents said they would like to see economic incentives put in place to encourage the high-quality manufacturing of medications, especially generic versions that are often in short supply. Nearly two-thirds (64%) cited a need for a broader buffer stock payment, and the same percentage would like to see more information on user experiences with various generic suppliers to help hospitals contract with those engaging in high-quality practices.

The NCCN also continues to work with federal regulators, agencies, and lawmakers to implement long-term solutions to cancer drug shortages.

“The federal government has a key role to play in addressing this issue,” Ms. Schatz said. “Establishing economic incentives, such as tax breaks or manufacturing grants for generic drugmakers, will help support a robust and resilient supply chain — ultimately safeguarding care for people with cancer across the country.”

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved imetelstat (Rytelo, Geron Corporation) for certain patients with relapsed or refractory low- to intermediate-risk myelodysplastic syndromes (MDS).

Specifically, the first-in-class oligonucleotide telomerase inhibitor, which received orphan drug designation, is indicated for adults with MDS who have transfusion-dependent anemia requiring four or more red blood cell units over 8 weeks and who have not responded to erythropoiesis-stimulating agents or who have lost response to or are not eligible for erythropoiesis-stimulating agents, according to an FDA press release.

“For patients with lower-risk MDS and anemia who are transfusion dependent, we have very few options today and often cycle through available therapies, making the approval of RYTELO potentially practice changing for us,” co-investigator Rami Komrokji, MD, of Moffitt Cancer Center, Tampa, Florida, said in the Geron Corporation’s announcement of the approval.

Approval was based on efficacy and safety findings from the randomized, placebo-controlled, phase 3 IMerge trial, which found significantly improved red blood cell transfusion independence with treatment vs with placebo.

Overall, 178 patients were randomly assigned to the imetelstat arm (n = 118) and the placebo arm (n = 60). The median follow-up was 19.5 months in the treatment arm and 17.5 months in the placebo arm.

Patients received infusions of either 7.1 mg/kg of imetelstat or placebo in 28-day cycles until disease progression or unacceptable toxicity. All patients received supportive care, including red blood cell transfusions.

The rate of 8-week-or-greater red blood cell transfusion independence was 39.8% in the imetelstat vs 15% placebo arm. The rate of 24-week-or-greater red blood cell transfusion independence was 28% in the treatment arm vs 3.3% in the placebo arm.

An exploratory analysis among patients who achieved at least 8 weeks of red blood cell transfusion independence revealed that median increases in hemoglobin were 3.6 g/dL in the treatment group vs 0.8 g/dL in the placebo group.

Adverse reactions, occurring in at least 10% of patients and in at least 5% more patients in the treatment arm than in the placebo arm, included decreased platelets, white blood cells, and neutrophils; increased aspartate aminotransferase, alkaline phosphatase, and alanine aminotransferase; and fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19, and headache.

The recommended imetelstat dose is 7.1 mg/kg administered as an intravenous infusion over 2 hours every 28 days, according to the full prescribing information. 

“What is exciting about RYTELO is the totality of the clinical benefit across [lower risk] MDS patients irrespective of ring sideroblast status or high transfusion burden, including sustained and durable transfusion independence and increases in hemoglobin levels, all within a well-characterized safety profile of generally manageable cytopenias,” Dr. Komrokji stated. The treatment goal for patients with this condition “is transfusion-independence and before today, this wasn’t possible for many patients.”
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved imetelstat (Rytelo, Geron Corporation) for certain patients with relapsed or refractory low- to intermediate-risk myelodysplastic syndromes (MDS).

Specifically, the first-in-class oligonucleotide telomerase inhibitor, which received orphan drug designation, is indicated for adults with MDS who have transfusion-dependent anemia requiring four or more red blood cell units over 8 weeks and who have not responded to erythropoiesis-stimulating agents or who have lost response to or are not eligible for erythropoiesis-stimulating agents, according to an FDA press release.

“For patients with lower-risk MDS and anemia who are transfusion dependent, we have very few options today and often cycle through available therapies, making the approval of RYTELO potentially practice changing for us,” co-investigator Rami Komrokji, MD, of Moffitt Cancer Center, Tampa, Florida, said in the Geron Corporation’s announcement of the approval.

Approval was based on efficacy and safety findings from the randomized, placebo-controlled, phase 3 IMerge trial, which found significantly improved red blood cell transfusion independence with treatment vs with placebo.

Overall, 178 patients were randomly assigned to the imetelstat arm (n = 118) and the placebo arm (n = 60). The median follow-up was 19.5 months in the treatment arm and 17.5 months in the placebo arm.

Patients received infusions of either 7.1 mg/kg of imetelstat or placebo in 28-day cycles until disease progression or unacceptable toxicity. All patients received supportive care, including red blood cell transfusions.

The rate of 8-week-or-greater red blood cell transfusion independence was 39.8% in the imetelstat vs 15% placebo arm. The rate of 24-week-or-greater red blood cell transfusion independence was 28% in the treatment arm vs 3.3% in the placebo arm.

An exploratory analysis among patients who achieved at least 8 weeks of red blood cell transfusion independence revealed that median increases in hemoglobin were 3.6 g/dL in the treatment group vs 0.8 g/dL in the placebo group.

Adverse reactions, occurring in at least 10% of patients and in at least 5% more patients in the treatment arm than in the placebo arm, included decreased platelets, white blood cells, and neutrophils; increased aspartate aminotransferase, alkaline phosphatase, and alanine aminotransferase; and fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19, and headache.

The recommended imetelstat dose is 7.1 mg/kg administered as an intravenous infusion over 2 hours every 28 days, according to the full prescribing information. 

“What is exciting about RYTELO is the totality of the clinical benefit across [lower risk] MDS patients irrespective of ring sideroblast status or high transfusion burden, including sustained and durable transfusion independence and increases in hemoglobin levels, all within a well-characterized safety profile of generally manageable cytopenias,” Dr. Komrokji stated. The treatment goal for patients with this condition “is transfusion-independence and before today, this wasn’t possible for many patients.”
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved imetelstat (Rytelo, Geron Corporation) for certain patients with relapsed or refractory low- to intermediate-risk myelodysplastic syndromes (MDS).

Specifically, the first-in-class oligonucleotide telomerase inhibitor, which received orphan drug designation, is indicated for adults with MDS who have transfusion-dependent anemia requiring four or more red blood cell units over 8 weeks and who have not responded to erythropoiesis-stimulating agents or who have lost response to or are not eligible for erythropoiesis-stimulating agents, according to an FDA press release.

“For patients with lower-risk MDS and anemia who are transfusion dependent, we have very few options today and often cycle through available therapies, making the approval of RYTELO potentially practice changing for us,” co-investigator Rami Komrokji, MD, of Moffitt Cancer Center, Tampa, Florida, said in the Geron Corporation’s announcement of the approval.

Approval was based on efficacy and safety findings from the randomized, placebo-controlled, phase 3 IMerge trial, which found significantly improved red blood cell transfusion independence with treatment vs with placebo.

Overall, 178 patients were randomly assigned to the imetelstat arm (n = 118) and the placebo arm (n = 60). The median follow-up was 19.5 months in the treatment arm and 17.5 months in the placebo arm.

Patients received infusions of either 7.1 mg/kg of imetelstat or placebo in 28-day cycles until disease progression or unacceptable toxicity. All patients received supportive care, including red blood cell transfusions.

The rate of 8-week-or-greater red blood cell transfusion independence was 39.8% in the imetelstat vs 15% placebo arm. The rate of 24-week-or-greater red blood cell transfusion independence was 28% in the treatment arm vs 3.3% in the placebo arm.

An exploratory analysis among patients who achieved at least 8 weeks of red blood cell transfusion independence revealed that median increases in hemoglobin were 3.6 g/dL in the treatment group vs 0.8 g/dL in the placebo group.

Adverse reactions, occurring in at least 10% of patients and in at least 5% more patients in the treatment arm than in the placebo arm, included decreased platelets, white blood cells, and neutrophils; increased aspartate aminotransferase, alkaline phosphatase, and alanine aminotransferase; and fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19, and headache.

The recommended imetelstat dose is 7.1 mg/kg administered as an intravenous infusion over 2 hours every 28 days, according to the full prescribing information. 

“What is exciting about RYTELO is the totality of the clinical benefit across [lower risk] MDS patients irrespective of ring sideroblast status or high transfusion burden, including sustained and durable transfusion independence and increases in hemoglobin levels, all within a well-characterized safety profile of generally manageable cytopenias,” Dr. Komrokji stated. The treatment goal for patients with this condition “is transfusion-independence and before today, this wasn’t possible for many patients.”
 

A version of this article appeared on Medscape.com.

BERLIN — To date, mRNA vaccines have had their largest global presence in combating the COVID-19 pandemic. Intensive research is underway on many other potential applications for this vaccine technology, which suggests a promising future. Martina Prelog, MD, a pediatric and adolescent medicine specialist at the University Hospital of Würzburg in Germany, reported on the principles, research status, and perspectives for these vaccines at the 25th Travel and Health Forum of the Center for Travel Medicine in Berlin.

To understand the future, the immunologist first examined the past. “The induction of cellular and humoral immune responses by externally injected mRNA was discovered in the 1990s,” she said.
 

Instability Challenge

Significant hurdles in mRNA vaccinations included the instability of mRNA and the immune system’s ability to identify foreign mRNA as a threat and destroy mRNA fragments. “The breakthrough toward vaccination came through Dr. Katalin Karikó, who, along with Dr. Drew Weissman, both of the University of Pennsylvania School of Medicine, discovered in 2005 that modifications of mRNA (replacing the nucleoside uridine with pseudouridine) enable better stability of mRNA, reduced immunogenicity, and higher translational capacity at the ribosomes,” said Dr. Prelog.

With this discovery, the two researchers paved the way for the development of mRNA vaccines against COVID-19 and other diseases. They were awarded the Nobel Prize in medicine for their discovery last year.
 

Improved Scalability

“Since 2009, mRNA vaccines have been studied as a treatment option for cancer,” said Dr. Prelog. “Since 2012, they have been studied for the influenza virus and respiratory syncytial virus [RSV].” Consequently, several mRNA vaccines are currently in development or in approval studies. “The mRNA technology offers the advantage of quickly and flexibly responding to new variants of pathogens and the ability to scale up production when there is high demand for a particular vaccine.”

Different forms and designations of mRNA vaccines are used, depending on the application and desired effect, said Dr. Prelog.

In nucleoside-modified mRNA vaccines, modifications in the mRNA sequence enable the mRNA to remain in the body longer and to induce protein synthesis more effectively.

Lipid nanoparticle (LNP)–encapsulated mRNA vaccines protect the coding mRNA sequences against degradation by the body’s enzymes and facilitate the uptake of mRNA into cells, where it then triggers the production of the desired protein. In addition, LNPs are involved in cell stimulation and support the self-adjuvant effect of mRNA vaccines, thus eliminating the need for adjuvants.

Self-amplifying mRNA vaccines include a special mRNA that replicates itself in the cell and contains a sequence for RNA replicase, in addition to the coding sequence for the protein. This composition enables increased production of the target protein without the need for a high amount of external mRNA administration. Such vaccines could trigger a longer and stronger immune response because the immune system has more time to interact with the protein.
 

Cancer Immunotherapy

Dr. Prelog also discussed personalized vaccines for cancer immunotherapy. Personalized mRNA vaccines are tailored to the patient’s genetic characteristics and antigens. They could be used in cancer immunotherapy to activate the immune system selectively against tumor cells.

Multivalent mRNA vaccines contain mRNA that codes for multiple antigens rather than just one protein to generate an immune response. These vaccines could be particularly useful in fighting pathogens with variable or changing surface structures or in eliciting protection against multiple pathogens simultaneously.

The technology of mRNA-encoded antibodies involves introducing mRNA into the cell, which creates light and heavy chains of antibodies. This step leads to the formation of antibodies targeted against toxins (eg, diphtheria and tetanus), animal venoms, infectious agents, or tumor cells.
 

Genetic Engineering

Dr. Prelog also reviewed genetic engineering techniques. In regenerative therapy or protein replacement therapy, skin fibroblasts or other cells are transfected with mRNA to enable conversion into induced pluripotent stem cells. This approach avoids the risk for DNA integration into the genome and associated mutation risks.

Another approach is making post-transcriptional modifications through RNA interference. For example, RNA structures can be used to inhibit the translation of disease-causing proteins. This technique is currently being tested against HIV and tumors such as melanoma.

In addition, mRNA technologies can be combined with CRISPR/Cas9 technology (“gene scissors”) to influence the creation of gene products even more precisely. The advantage of this technique is that mRNA is only transiently expressed, thus preventing unwanted side effects. Furthermore, mRNA is translated directly in the cytoplasm, leading to a faster initiation of gene editing.

Of the numerous ongoing clinical mRNA vaccine studies, around 70% focus on infections, about 12% on cancer, and the rest on autoimmune diseases and neurodegenerative disorders, said Dr. Prelog.
 

Research in Infections

Research in the fields of infectious diseases and oncology is the most advanced: mRNA vaccines against influenza and RSV are already in advanced clinical trials, Dr. Prelog told this news organization.

“Conventional influenza vaccines contain immunogenic surface molecules against hemagglutinin and neuraminidase in various combinations of influenza strains A and B and are produced in egg or cell cultures,” she said. “This is a time-consuming manufacturing process that takes months and, particularly with the egg-based process, bears the risk of changing the vaccine strain.”

“Additionally, influenza viruses undergo antigenic shift and drift through recombination, thus requiring annual adjustments to the vaccines. Thus, these influenza vaccines often lose accuracy in targeting circulating seasonal influenza strains.”

Several mRNA vaccines being tested contain not only coding sequences against hemagglutinin and neuraminidase but also for structural proteins of influenza viruses. “These are more conserved and mutate less easily, meaning they could serve as the basis for universal pandemic influenza vaccines,” said Dr. Prelog.

An advantage of mRNA vaccines, she added, is the strong cellular immune response that they elicit. This response is intended to provide additional protection alongside specific antibodies. An mRNA vaccine with coding sequences for the pre-fusion protein of RSV is in phase 3 trials for approval for vaccination in patients aged 60 years and older. It shows high effectiveness even in older patients and those with comorbidities.
 

Elaborate Purification Process

Bacterial origin plasmid DNA is used to produce mRNA vaccines. The mRNA vaccines for COVID-19 raised concerns that production-related DNA residues could pose a safety risk and cause autoimmune diseases.

These vaccines “typically undergo a very elaborate purification process,” said Dr. Prelog. “This involves enzymatic digestion with DNase to fragment and deplete plasmid DNA, followed by purification using chromatography columns, so that no safety-relevant DNA fragments should remain afterward.”

Thus, the Paul-Ehrlich-Institut also pointed out the very small, fragmented plasmid DNA residues of bacterial origin in mRNA COVID-19 vaccines pose no risk, unlike residual DNA from animal cell culture might pose in other vaccines.
 

Prevention and Therapy

In addition to the numerous advantages of mRNA vaccines (such as rapid adaptability to new or mutated pathogens, scalability, rapid production capability, self-adjuvant effect, strong induction of cellular immune responses, and safety), there are also challenges in RNA technology as a preventive and therapeutic measure, according to Dr. Prelog.

“Stability and storability, as well as the costs of new vaccine developments, play a role, as do the long-term effects regarding the persistence of antibody and cellular responses,” she said. The COVID-19 mRNA vaccines, for example, showed a well-maintained cellular immune response despite a tendency toward a rapid decline in humoral immune response.

“The experience with COVID-19 mRNA vaccines and the new vaccine developments based on mRNA technology give hope for an efficient and safe preventive and therapeutic use, particularly in the fields of infectious diseases and oncology,” Dr. Prelog concluded.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

BERLIN — To date, mRNA vaccines have had their largest global presence in combating the COVID-19 pandemic. Intensive research is underway on many other potential applications for this vaccine technology, which suggests a promising future. Martina Prelog, MD, a pediatric and adolescent medicine specialist at the University Hospital of Würzburg in Germany, reported on the principles, research status, and perspectives for these vaccines at the 25th Travel and Health Forum of the Center for Travel Medicine in Berlin.

To understand the future, the immunologist first examined the past. “The induction of cellular and humoral immune responses by externally injected mRNA was discovered in the 1990s,” she said.
 

Instability Challenge

Significant hurdles in mRNA vaccinations included the instability of mRNA and the immune system’s ability to identify foreign mRNA as a threat and destroy mRNA fragments. “The breakthrough toward vaccination came through Dr. Katalin Karikó, who, along with Dr. Drew Weissman, both of the University of Pennsylvania School of Medicine, discovered in 2005 that modifications of mRNA (replacing the nucleoside uridine with pseudouridine) enable better stability of mRNA, reduced immunogenicity, and higher translational capacity at the ribosomes,” said Dr. Prelog.

With this discovery, the two researchers paved the way for the development of mRNA vaccines against COVID-19 and other diseases. They were awarded the Nobel Prize in medicine for their discovery last year.
 

Improved Scalability

“Since 2009, mRNA vaccines have been studied as a treatment option for cancer,” said Dr. Prelog. “Since 2012, they have been studied for the influenza virus and respiratory syncytial virus [RSV].” Consequently, several mRNA vaccines are currently in development or in approval studies. “The mRNA technology offers the advantage of quickly and flexibly responding to new variants of pathogens and the ability to scale up production when there is high demand for a particular vaccine.”

Different forms and designations of mRNA vaccines are used, depending on the application and desired effect, said Dr. Prelog.

In nucleoside-modified mRNA vaccines, modifications in the mRNA sequence enable the mRNA to remain in the body longer and to induce protein synthesis more effectively.

Lipid nanoparticle (LNP)–encapsulated mRNA vaccines protect the coding mRNA sequences against degradation by the body’s enzymes and facilitate the uptake of mRNA into cells, where it then triggers the production of the desired protein. In addition, LNPs are involved in cell stimulation and support the self-adjuvant effect of mRNA vaccines, thus eliminating the need for adjuvants.

Self-amplifying mRNA vaccines include a special mRNA that replicates itself in the cell and contains a sequence for RNA replicase, in addition to the coding sequence for the protein. This composition enables increased production of the target protein without the need for a high amount of external mRNA administration. Such vaccines could trigger a longer and stronger immune response because the immune system has more time to interact with the protein.
 

Cancer Immunotherapy

Dr. Prelog also discussed personalized vaccines for cancer immunotherapy. Personalized mRNA vaccines are tailored to the patient’s genetic characteristics and antigens. They could be used in cancer immunotherapy to activate the immune system selectively against tumor cells.

Multivalent mRNA vaccines contain mRNA that codes for multiple antigens rather than just one protein to generate an immune response. These vaccines could be particularly useful in fighting pathogens with variable or changing surface structures or in eliciting protection against multiple pathogens simultaneously.

The technology of mRNA-encoded antibodies involves introducing mRNA into the cell, which creates light and heavy chains of antibodies. This step leads to the formation of antibodies targeted against toxins (eg, diphtheria and tetanus), animal venoms, infectious agents, or tumor cells.
 

Genetic Engineering

Dr. Prelog also reviewed genetic engineering techniques. In regenerative therapy or protein replacement therapy, skin fibroblasts or other cells are transfected with mRNA to enable conversion into induced pluripotent stem cells. This approach avoids the risk for DNA integration into the genome and associated mutation risks.

Another approach is making post-transcriptional modifications through RNA interference. For example, RNA structures can be used to inhibit the translation of disease-causing proteins. This technique is currently being tested against HIV and tumors such as melanoma.

In addition, mRNA technologies can be combined with CRISPR/Cas9 technology (“gene scissors”) to influence the creation of gene products even more precisely. The advantage of this technique is that mRNA is only transiently expressed, thus preventing unwanted side effects. Furthermore, mRNA is translated directly in the cytoplasm, leading to a faster initiation of gene editing.

Of the numerous ongoing clinical mRNA vaccine studies, around 70% focus on infections, about 12% on cancer, and the rest on autoimmune diseases and neurodegenerative disorders, said Dr. Prelog.
 

Research in Infections

Research in the fields of infectious diseases and oncology is the most advanced: mRNA vaccines against influenza and RSV are already in advanced clinical trials, Dr. Prelog told this news organization.

“Conventional influenza vaccines contain immunogenic surface molecules against hemagglutinin and neuraminidase in various combinations of influenza strains A and B and are produced in egg or cell cultures,” she said. “This is a time-consuming manufacturing process that takes months and, particularly with the egg-based process, bears the risk of changing the vaccine strain.”

“Additionally, influenza viruses undergo antigenic shift and drift through recombination, thus requiring annual adjustments to the vaccines. Thus, these influenza vaccines often lose accuracy in targeting circulating seasonal influenza strains.”

Several mRNA vaccines being tested contain not only coding sequences against hemagglutinin and neuraminidase but also for structural proteins of influenza viruses. “These are more conserved and mutate less easily, meaning they could serve as the basis for universal pandemic influenza vaccines,” said Dr. Prelog.

An advantage of mRNA vaccines, she added, is the strong cellular immune response that they elicit. This response is intended to provide additional protection alongside specific antibodies. An mRNA vaccine with coding sequences for the pre-fusion protein of RSV is in phase 3 trials for approval for vaccination in patients aged 60 years and older. It shows high effectiveness even in older patients and those with comorbidities.
 

Elaborate Purification Process

Bacterial origin plasmid DNA is used to produce mRNA vaccines. The mRNA vaccines for COVID-19 raised concerns that production-related DNA residues could pose a safety risk and cause autoimmune diseases.

These vaccines “typically undergo a very elaborate purification process,” said Dr. Prelog. “This involves enzymatic digestion with DNase to fragment and deplete plasmid DNA, followed by purification using chromatography columns, so that no safety-relevant DNA fragments should remain afterward.”

Thus, the Paul-Ehrlich-Institut also pointed out the very small, fragmented plasmid DNA residues of bacterial origin in mRNA COVID-19 vaccines pose no risk, unlike residual DNA from animal cell culture might pose in other vaccines.
 

Prevention and Therapy

In addition to the numerous advantages of mRNA vaccines (such as rapid adaptability to new or mutated pathogens, scalability, rapid production capability, self-adjuvant effect, strong induction of cellular immune responses, and safety), there are also challenges in RNA technology as a preventive and therapeutic measure, according to Dr. Prelog.

“Stability and storability, as well as the costs of new vaccine developments, play a role, as do the long-term effects regarding the persistence of antibody and cellular responses,” she said. The COVID-19 mRNA vaccines, for example, showed a well-maintained cellular immune response despite a tendency toward a rapid decline in humoral immune response.

“The experience with COVID-19 mRNA vaccines and the new vaccine developments based on mRNA technology give hope for an efficient and safe preventive and therapeutic use, particularly in the fields of infectious diseases and oncology,” Dr. Prelog concluded.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

BERLIN — To date, mRNA vaccines have had their largest global presence in combating the COVID-19 pandemic. Intensive research is underway on many other potential applications for this vaccine technology, which suggests a promising future. Martina Prelog, MD, a pediatric and adolescent medicine specialist at the University Hospital of Würzburg in Germany, reported on the principles, research status, and perspectives for these vaccines at the 25th Travel and Health Forum of the Center for Travel Medicine in Berlin.

To understand the future, the immunologist first examined the past. “The induction of cellular and humoral immune responses by externally injected mRNA was discovered in the 1990s,” she said.
 

Instability Challenge

Significant hurdles in mRNA vaccinations included the instability of mRNA and the immune system’s ability to identify foreign mRNA as a threat and destroy mRNA fragments. “The breakthrough toward vaccination came through Dr. Katalin Karikó, who, along with Dr. Drew Weissman, both of the University of Pennsylvania School of Medicine, discovered in 2005 that modifications of mRNA (replacing the nucleoside uridine with pseudouridine) enable better stability of mRNA, reduced immunogenicity, and higher translational capacity at the ribosomes,” said Dr. Prelog.

With this discovery, the two researchers paved the way for the development of mRNA vaccines against COVID-19 and other diseases. They were awarded the Nobel Prize in medicine for their discovery last year.
 

Improved Scalability

“Since 2009, mRNA vaccines have been studied as a treatment option for cancer,” said Dr. Prelog. “Since 2012, they have been studied for the influenza virus and respiratory syncytial virus [RSV].” Consequently, several mRNA vaccines are currently in development or in approval studies. “The mRNA technology offers the advantage of quickly and flexibly responding to new variants of pathogens and the ability to scale up production when there is high demand for a particular vaccine.”

Different forms and designations of mRNA vaccines are used, depending on the application and desired effect, said Dr. Prelog.

In nucleoside-modified mRNA vaccines, modifications in the mRNA sequence enable the mRNA to remain in the body longer and to induce protein synthesis more effectively.

Lipid nanoparticle (LNP)–encapsulated mRNA vaccines protect the coding mRNA sequences against degradation by the body’s enzymes and facilitate the uptake of mRNA into cells, where it then triggers the production of the desired protein. In addition, LNPs are involved in cell stimulation and support the self-adjuvant effect of mRNA vaccines, thus eliminating the need for adjuvants.

Self-amplifying mRNA vaccines include a special mRNA that replicates itself in the cell and contains a sequence for RNA replicase, in addition to the coding sequence for the protein. This composition enables increased production of the target protein without the need for a high amount of external mRNA administration. Such vaccines could trigger a longer and stronger immune response because the immune system has more time to interact with the protein.
 

Cancer Immunotherapy

Dr. Prelog also discussed personalized vaccines for cancer immunotherapy. Personalized mRNA vaccines are tailored to the patient’s genetic characteristics and antigens. They could be used in cancer immunotherapy to activate the immune system selectively against tumor cells.

Multivalent mRNA vaccines contain mRNA that codes for multiple antigens rather than just one protein to generate an immune response. These vaccines could be particularly useful in fighting pathogens with variable or changing surface structures or in eliciting protection against multiple pathogens simultaneously.

The technology of mRNA-encoded antibodies involves introducing mRNA into the cell, which creates light and heavy chains of antibodies. This step leads to the formation of antibodies targeted against toxins (eg, diphtheria and tetanus), animal venoms, infectious agents, or tumor cells.
 

Genetic Engineering

Dr. Prelog also reviewed genetic engineering techniques. In regenerative therapy or protein replacement therapy, skin fibroblasts or other cells are transfected with mRNA to enable conversion into induced pluripotent stem cells. This approach avoids the risk for DNA integration into the genome and associated mutation risks.

Another approach is making post-transcriptional modifications through RNA interference. For example, RNA structures can be used to inhibit the translation of disease-causing proteins. This technique is currently being tested against HIV and tumors such as melanoma.

In addition, mRNA technologies can be combined with CRISPR/Cas9 technology (“gene scissors”) to influence the creation of gene products even more precisely. The advantage of this technique is that mRNA is only transiently expressed, thus preventing unwanted side effects. Furthermore, mRNA is translated directly in the cytoplasm, leading to a faster initiation of gene editing.

Of the numerous ongoing clinical mRNA vaccine studies, around 70% focus on infections, about 12% on cancer, and the rest on autoimmune diseases and neurodegenerative disorders, said Dr. Prelog.
 

Research in Infections

Research in the fields of infectious diseases and oncology is the most advanced: mRNA vaccines against influenza and RSV are already in advanced clinical trials, Dr. Prelog told this news organization.

“Conventional influenza vaccines contain immunogenic surface molecules against hemagglutinin and neuraminidase in various combinations of influenza strains A and B and are produced in egg or cell cultures,” she said. “This is a time-consuming manufacturing process that takes months and, particularly with the egg-based process, bears the risk of changing the vaccine strain.”

“Additionally, influenza viruses undergo antigenic shift and drift through recombination, thus requiring annual adjustments to the vaccines. Thus, these influenza vaccines often lose accuracy in targeting circulating seasonal influenza strains.”

Several mRNA vaccines being tested contain not only coding sequences against hemagglutinin and neuraminidase but also for structural proteins of influenza viruses. “These are more conserved and mutate less easily, meaning they could serve as the basis for universal pandemic influenza vaccines,” said Dr. Prelog.

An advantage of mRNA vaccines, she added, is the strong cellular immune response that they elicit. This response is intended to provide additional protection alongside specific antibodies. An mRNA vaccine with coding sequences for the pre-fusion protein of RSV is in phase 3 trials for approval for vaccination in patients aged 60 years and older. It shows high effectiveness even in older patients and those with comorbidities.
 

Elaborate Purification Process

Bacterial origin plasmid DNA is used to produce mRNA vaccines. The mRNA vaccines for COVID-19 raised concerns that production-related DNA residues could pose a safety risk and cause autoimmune diseases.

These vaccines “typically undergo a very elaborate purification process,” said Dr. Prelog. “This involves enzymatic digestion with DNase to fragment and deplete plasmid DNA, followed by purification using chromatography columns, so that no safety-relevant DNA fragments should remain afterward.”

Thus, the Paul-Ehrlich-Institut also pointed out the very small, fragmented plasmid DNA residues of bacterial origin in mRNA COVID-19 vaccines pose no risk, unlike residual DNA from animal cell culture might pose in other vaccines.
 

Prevention and Therapy

In addition to the numerous advantages of mRNA vaccines (such as rapid adaptability to new or mutated pathogens, scalability, rapid production capability, self-adjuvant effect, strong induction of cellular immune responses, and safety), there are also challenges in RNA technology as a preventive and therapeutic measure, according to Dr. Prelog.

“Stability and storability, as well as the costs of new vaccine developments, play a role, as do the long-term effects regarding the persistence of antibody and cellular responses,” she said. The COVID-19 mRNA vaccines, for example, showed a well-maintained cellular immune response despite a tendency toward a rapid decline in humoral immune response.

“The experience with COVID-19 mRNA vaccines and the new vaccine developments based on mRNA technology give hope for an efficient and safe preventive and therapeutic use, particularly in the fields of infectious diseases and oncology,” Dr. Prelog concluded.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Cisplatin is a preferred treatment for a wide range of cancers, including breast, head and neck, lung, ovary, and more. However, its side effects — particularly nephrotoxicity — can be severe. Kidney injury on cisplatin is associated with higher mortality and can jeopardize a patient’s eligibility for other therapies.

Now, in a large study using data from six US cancer centers, researchers have developed a risk algorithm to predict acute kidney injury (AKI) after cisplatin administration.

A risk prediction calculator based on the algorithm is available online for patients and providers to determine an individual patient›s risk for kidney injury from cisplatin using readily available clinical data.

Other risk scores and risk prediction models have been developed to help clinicians assess in advance whether a patient might develop AKI after receiving cisplatin, so that more careful monitoring, dose adjustments, or an alternative treatment, if available, might be considered.

However, previous models were limited by factors such as small sample sizes, lack of external validation, older data, and liberal definitions of AKI, said Shruti Gupta, MD, MPH, director of onco-nephrology at Brigham and Women’s Hospital (BWH) and Dana-Farber Cancer Institute, and David E. Leaf, MD, MMSc, director of clinical and translational research in AKI, Division of Renal Medicine, BWH, Boston.

Dr. Gupta and Dr. Leaf believe their risk score for predicting severe AKI after intravenous (IV) cisplatin, published online in The BMJ, is “more accurate and generalizable than prior models for several reasons,” they told this news organization in a joint email.

“First, we externally validated our findings across cancer centers other than the one where it was developed,” they said. “Second, we focused on moderate to severe kidney injury, the most clinically relevant form of kidney damage, whereas prior models examined more mild forms of kidney injury. Third, we collected data on nearly 25,000 patients receiving their first dose of IV cisplatin, which is larger than all previous studies combined.”
 

‘Herculean Effort’

“We conceived of this study back in 2018, contacted collaborators at each participating cancer center, and had numerous meetings to try to gather granular data on patients treated with their first dose of intravenous (IV) cisplatin,” Dr. Gupta and Dr. Leaf explained. They also incorporated patient feedback from focus groups and surveys.

“This was truly a Herculean effort that involved physicians, programmers, research coordinators, and patients,” they said.

The multicenter study included 24,717 patients — 11,766 in the derivation cohort and 12,951 in the validation cohort. Overall, the median age was about 60 years, about 58% were men, and about 78% were White.

The primary outcome was cisplatin-induced AKI (CP-AKI), defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of IV cisplatin.

The researchers found that the incidence of CP-AKI was 5.2% in the derivation cohort and 3.3% in the validation cohort. Their simple risk score consisting of nine covariates — age, hypertension, type 2 diabetes, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose — predicted a higher risk for CP-AKI in both cohorts.

Notably, adding serum creatinine to the model did not change the area under the curve, and therefore, serum creatinine, though also an independent risk factor for CP-AKI, was not included in the score.

Patients in the highest risk category had 24-fold higher odds of CP-AKI in the derivation cohort and close to 18-fold higher odds in the validation cohort than those in the lowest risk category.

The primary model had a C statistic of 0.75 (95% CI, 0.73-0.76) and showed better discrimination for CP-AKI than previously published models, for which the C statistics ranged from 0.60 to 0.68. The first author of a paper on an earlier model, Shveta Motwani, MD, MMSc, of BWH and Dana-Farber Cancer Institute in Boston, is also a coauthor of the new study.

Greater severity of CP-AKI was associated with shorter 90-day survival (adjusted hazard ratio, 4.63; 95% CI, 3.56-6.02) for stage III CP-AKI vs no CP-AKI.
 

‘Definitive Work’

Joel M. Topf, MD, a nephrologist with expertise in chronic kidney disease in Detroit, who wasn’t involved in the development of the risk score, called the study “a definitive work on an important concept in oncology and nephrology.”

“While this is not the first attempt to devise a risk score, it is by far the biggest,” he told this news organization. Furthermore, the authors “used a diverse population, recruiting patients with a variety of cancers (previous attempts had often used a homogenous diagnosis, putting into question how generalizable the results were) from six different cancer centers.”

In addition, he said, “The authors did not restrict patients with chronic kidney disease or other significant comorbidities and used the geographic diversity to produce a cohort that has an age, gender, racial, and ethnic distribution, which is more representative of the US than previous, single-center attempts to risk score patients.”

An earlier model used the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI of an increase in serum creatinine of 0.3 mg/dL, he noted. “While a sensitive definition of AKI, it captures mild, hemodynamic increases in creatinine of questionable significance,” he said.

By contrast, the new score uses KDIGO stage II and above to define AKI. “This is a better choice, as we do not want to dissuade patients and doctors from choosing chemotherapy due to a fear of insignificant kidney damage,” he said.

All that said, Dr. Topf noted that neither the current score nor the earlier model included serum creatinine. “This is curious to me and may represent the small number of patients with representative elevated creatinine in the derivation cohort (only 1.3% with an estimated glomerular filtration rate [eGFR] < 45).”

“Since the cohort is made up of people who received cis-platinum, the low prevalence of eGFRs < 45 may be due to physicians steering away from cis-platinum in this group,” he suggested. “It would be unfortunate if this risk score gave an unintentional ‘green light’ to these patients, exposing them to predictable harm.”
 

‘Certainly Useful’

Anushree Shirali, MD, an associate professor in the Section of Nephrology and consulting physician, Yale Onco-Nephrology, Yale School of Medicine, in New Haven, Connecticut, said that having a prediction score for which patients are more likely to develop AKI after a single dose of cisplatin would be helpful for oncologists, as well as nephrologists.

As a nephrologist, Dr. Shirali mostly sees patients who already have AKI, she told this news organization. But there are circumstances in which the tool could still be helpful.

“Let’s say someone has abnormal kidney function at baseline — ie, creatinine is higher than the normal range — and they were on dialysis 5 years ago for something else, and now, they have cancer and may be given cisplatin. They worry about their chances of getting AKI and needing dialysis again,” she said. “That’s just one scenario in which I might be asked to answer that question and the tool would certainly be useful.”

Other scenarios could include someone who has just one kidney because they donated a kidney for transplant years ago, and now, they have a malignancy and wonder what their actual risk is of getting kidney issues on cisplatin.

Oncologists could use the tool to determine whether a patient should be treated with cisplatin, or if they’re at high risk, whether an alternative that’s not nephrotoxic might be used. By contrast, “if somebody’s low risk and an oncologist thinks cisplatin is the best agent they have, then they might want to go ahead and use it,” Dr. Shirali said.

Future research could take into consideration that CP-AKI is dose dependent, she suggested, because a prediction score that included the number of cisplatin doses could be even more helpful to determine risk. And, even though the derivation and validation cohorts for the new tool are representative of the US population, additional research should also include more racial/ethnic diversity, she said.

Dr. Gupta and Dr. Leaf hope their tool “will be utilized immediately by patients and providers to help predict an individual’s risk of cisplatin-associated kidney damage. It is easy to use, available for free online, and incorporates readily available clinical variables.”

If a patient is at high risk, the clinical team can consider preventive measures such as administering more IV fluids before receiving cisplatin or monitoring kidney function more closely afterward, they suggested.

Dr. Gupta reported research support from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. She also reported research funding from BTG International, GE HealthCare, and AstraZeneca outside the submitted work. She is a member of GlaxoSmithKline’s Global Anemia Council, a consultant for Secretome and Proletariat Therapeutics, and founder and president emeritus of the American Society of Onconephrology (unpaid). Dr. Leaf is supported by NIH grants, reported research support from BioPorto, BTG International, and Metro International Biotech, and has served as a consultant. Dr. Topf reported an ownership stake in a few DaVita-run dialysis clinics. He also runs a vascular access center and has participated in advisory boards with Cara Therapeutics, Vifor, Astra Zeneca, Bayer, Renibus Therapeutics, Travere Therapeutics, and GlaxoSmithKline. He is president of NephJC, a nonprofit educational organization with no industry support. Dr. Shirali declared no competing interests.

A version of this article appeared on Medscape.com.

Cisplatin is a preferred treatment for a wide range of cancers, including breast, head and neck, lung, ovary, and more. However, its side effects — particularly nephrotoxicity — can be severe. Kidney injury on cisplatin is associated with higher mortality and can jeopardize a patient’s eligibility for other therapies.

Now, in a large study using data from six US cancer centers, researchers have developed a risk algorithm to predict acute kidney injury (AKI) after cisplatin administration.

A risk prediction calculator based on the algorithm is available online for patients and providers to determine an individual patient›s risk for kidney injury from cisplatin using readily available clinical data.

Other risk scores and risk prediction models have been developed to help clinicians assess in advance whether a patient might develop AKI after receiving cisplatin, so that more careful monitoring, dose adjustments, or an alternative treatment, if available, might be considered.

However, previous models were limited by factors such as small sample sizes, lack of external validation, older data, and liberal definitions of AKI, said Shruti Gupta, MD, MPH, director of onco-nephrology at Brigham and Women’s Hospital (BWH) and Dana-Farber Cancer Institute, and David E. Leaf, MD, MMSc, director of clinical and translational research in AKI, Division of Renal Medicine, BWH, Boston.

Dr. Gupta and Dr. Leaf believe their risk score for predicting severe AKI after intravenous (IV) cisplatin, published online in The BMJ, is “more accurate and generalizable than prior models for several reasons,” they told this news organization in a joint email.

“First, we externally validated our findings across cancer centers other than the one where it was developed,” they said. “Second, we focused on moderate to severe kidney injury, the most clinically relevant form of kidney damage, whereas prior models examined more mild forms of kidney injury. Third, we collected data on nearly 25,000 patients receiving their first dose of IV cisplatin, which is larger than all previous studies combined.”
 

‘Herculean Effort’

“We conceived of this study back in 2018, contacted collaborators at each participating cancer center, and had numerous meetings to try to gather granular data on patients treated with their first dose of intravenous (IV) cisplatin,” Dr. Gupta and Dr. Leaf explained. They also incorporated patient feedback from focus groups and surveys.

“This was truly a Herculean effort that involved physicians, programmers, research coordinators, and patients,” they said.

The multicenter study included 24,717 patients — 11,766 in the derivation cohort and 12,951 in the validation cohort. Overall, the median age was about 60 years, about 58% were men, and about 78% were White.

The primary outcome was cisplatin-induced AKI (CP-AKI), defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of IV cisplatin.

The researchers found that the incidence of CP-AKI was 5.2% in the derivation cohort and 3.3% in the validation cohort. Their simple risk score consisting of nine covariates — age, hypertension, type 2 diabetes, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose — predicted a higher risk for CP-AKI in both cohorts.

Notably, adding serum creatinine to the model did not change the area under the curve, and therefore, serum creatinine, though also an independent risk factor for CP-AKI, was not included in the score.

Patients in the highest risk category had 24-fold higher odds of CP-AKI in the derivation cohort and close to 18-fold higher odds in the validation cohort than those in the lowest risk category.

The primary model had a C statistic of 0.75 (95% CI, 0.73-0.76) and showed better discrimination for CP-AKI than previously published models, for which the C statistics ranged from 0.60 to 0.68. The first author of a paper on an earlier model, Shveta Motwani, MD, MMSc, of BWH and Dana-Farber Cancer Institute in Boston, is also a coauthor of the new study.

Greater severity of CP-AKI was associated with shorter 90-day survival (adjusted hazard ratio, 4.63; 95% CI, 3.56-6.02) for stage III CP-AKI vs no CP-AKI.
 

‘Definitive Work’

Joel M. Topf, MD, a nephrologist with expertise in chronic kidney disease in Detroit, who wasn’t involved in the development of the risk score, called the study “a definitive work on an important concept in oncology and nephrology.”

“While this is not the first attempt to devise a risk score, it is by far the biggest,” he told this news organization. Furthermore, the authors “used a diverse population, recruiting patients with a variety of cancers (previous attempts had often used a homogenous diagnosis, putting into question how generalizable the results were) from six different cancer centers.”

In addition, he said, “The authors did not restrict patients with chronic kidney disease or other significant comorbidities and used the geographic diversity to produce a cohort that has an age, gender, racial, and ethnic distribution, which is more representative of the US than previous, single-center attempts to risk score patients.”

An earlier model used the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI of an increase in serum creatinine of 0.3 mg/dL, he noted. “While a sensitive definition of AKI, it captures mild, hemodynamic increases in creatinine of questionable significance,” he said.

By contrast, the new score uses KDIGO stage II and above to define AKI. “This is a better choice, as we do not want to dissuade patients and doctors from choosing chemotherapy due to a fear of insignificant kidney damage,” he said.

All that said, Dr. Topf noted that neither the current score nor the earlier model included serum creatinine. “This is curious to me and may represent the small number of patients with representative elevated creatinine in the derivation cohort (only 1.3% with an estimated glomerular filtration rate [eGFR] < 45).”

“Since the cohort is made up of people who received cis-platinum, the low prevalence of eGFRs < 45 may be due to physicians steering away from cis-platinum in this group,” he suggested. “It would be unfortunate if this risk score gave an unintentional ‘green light’ to these patients, exposing them to predictable harm.”
 

‘Certainly Useful’

Anushree Shirali, MD, an associate professor in the Section of Nephrology and consulting physician, Yale Onco-Nephrology, Yale School of Medicine, in New Haven, Connecticut, said that having a prediction score for which patients are more likely to develop AKI after a single dose of cisplatin would be helpful for oncologists, as well as nephrologists.

As a nephrologist, Dr. Shirali mostly sees patients who already have AKI, she told this news organization. But there are circumstances in which the tool could still be helpful.

“Let’s say someone has abnormal kidney function at baseline — ie, creatinine is higher than the normal range — and they were on dialysis 5 years ago for something else, and now, they have cancer and may be given cisplatin. They worry about their chances of getting AKI and needing dialysis again,” she said. “That’s just one scenario in which I might be asked to answer that question and the tool would certainly be useful.”

Other scenarios could include someone who has just one kidney because they donated a kidney for transplant years ago, and now, they have a malignancy and wonder what their actual risk is of getting kidney issues on cisplatin.

Oncologists could use the tool to determine whether a patient should be treated with cisplatin, or if they’re at high risk, whether an alternative that’s not nephrotoxic might be used. By contrast, “if somebody’s low risk and an oncologist thinks cisplatin is the best agent they have, then they might want to go ahead and use it,” Dr. Shirali said.

Future research could take into consideration that CP-AKI is dose dependent, she suggested, because a prediction score that included the number of cisplatin doses could be even more helpful to determine risk. And, even though the derivation and validation cohorts for the new tool are representative of the US population, additional research should also include more racial/ethnic diversity, she said.

Dr. Gupta and Dr. Leaf hope their tool “will be utilized immediately by patients and providers to help predict an individual’s risk of cisplatin-associated kidney damage. It is easy to use, available for free online, and incorporates readily available clinical variables.”

If a patient is at high risk, the clinical team can consider preventive measures such as administering more IV fluids before receiving cisplatin or monitoring kidney function more closely afterward, they suggested.

Dr. Gupta reported research support from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. She also reported research funding from BTG International, GE HealthCare, and AstraZeneca outside the submitted work. She is a member of GlaxoSmithKline’s Global Anemia Council, a consultant for Secretome and Proletariat Therapeutics, and founder and president emeritus of the American Society of Onconephrology (unpaid). Dr. Leaf is supported by NIH grants, reported research support from BioPorto, BTG International, and Metro International Biotech, and has served as a consultant. Dr. Topf reported an ownership stake in a few DaVita-run dialysis clinics. He also runs a vascular access center and has participated in advisory boards with Cara Therapeutics, Vifor, Astra Zeneca, Bayer, Renibus Therapeutics, Travere Therapeutics, and GlaxoSmithKline. He is president of NephJC, a nonprofit educational organization with no industry support. Dr. Shirali declared no competing interests.

A version of this article appeared on Medscape.com.

Cisplatin is a preferred treatment for a wide range of cancers, including breast, head and neck, lung, ovary, and more. However, its side effects — particularly nephrotoxicity — can be severe. Kidney injury on cisplatin is associated with higher mortality and can jeopardize a patient’s eligibility for other therapies.

Now, in a large study using data from six US cancer centers, researchers have developed a risk algorithm to predict acute kidney injury (AKI) after cisplatin administration.

A risk prediction calculator based on the algorithm is available online for patients and providers to determine an individual patient›s risk for kidney injury from cisplatin using readily available clinical data.

Other risk scores and risk prediction models have been developed to help clinicians assess in advance whether a patient might develop AKI after receiving cisplatin, so that more careful monitoring, dose adjustments, or an alternative treatment, if available, might be considered.

However, previous models were limited by factors such as small sample sizes, lack of external validation, older data, and liberal definitions of AKI, said Shruti Gupta, MD, MPH, director of onco-nephrology at Brigham and Women’s Hospital (BWH) and Dana-Farber Cancer Institute, and David E. Leaf, MD, MMSc, director of clinical and translational research in AKI, Division of Renal Medicine, BWH, Boston.

Dr. Gupta and Dr. Leaf believe their risk score for predicting severe AKI after intravenous (IV) cisplatin, published online in The BMJ, is “more accurate and generalizable than prior models for several reasons,” they told this news organization in a joint email.

“First, we externally validated our findings across cancer centers other than the one where it was developed,” they said. “Second, we focused on moderate to severe kidney injury, the most clinically relevant form of kidney damage, whereas prior models examined more mild forms of kidney injury. Third, we collected data on nearly 25,000 patients receiving their first dose of IV cisplatin, which is larger than all previous studies combined.”
 

‘Herculean Effort’

“We conceived of this study back in 2018, contacted collaborators at each participating cancer center, and had numerous meetings to try to gather granular data on patients treated with their first dose of intravenous (IV) cisplatin,” Dr. Gupta and Dr. Leaf explained. They also incorporated patient feedback from focus groups and surveys.

“This was truly a Herculean effort that involved physicians, programmers, research coordinators, and patients,” they said.

The multicenter study included 24,717 patients — 11,766 in the derivation cohort and 12,951 in the validation cohort. Overall, the median age was about 60 years, about 58% were men, and about 78% were White.

The primary outcome was cisplatin-induced AKI (CP-AKI), defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of IV cisplatin.

The researchers found that the incidence of CP-AKI was 5.2% in the derivation cohort and 3.3% in the validation cohort. Their simple risk score consisting of nine covariates — age, hypertension, type 2 diabetes, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose — predicted a higher risk for CP-AKI in both cohorts.

Notably, adding serum creatinine to the model did not change the area under the curve, and therefore, serum creatinine, though also an independent risk factor for CP-AKI, was not included in the score.

Patients in the highest risk category had 24-fold higher odds of CP-AKI in the derivation cohort and close to 18-fold higher odds in the validation cohort than those in the lowest risk category.

The primary model had a C statistic of 0.75 (95% CI, 0.73-0.76) and showed better discrimination for CP-AKI than previously published models, for which the C statistics ranged from 0.60 to 0.68. The first author of a paper on an earlier model, Shveta Motwani, MD, MMSc, of BWH and Dana-Farber Cancer Institute in Boston, is also a coauthor of the new study.

Greater severity of CP-AKI was associated with shorter 90-day survival (adjusted hazard ratio, 4.63; 95% CI, 3.56-6.02) for stage III CP-AKI vs no CP-AKI.
 

‘Definitive Work’

Joel M. Topf, MD, a nephrologist with expertise in chronic kidney disease in Detroit, who wasn’t involved in the development of the risk score, called the study “a definitive work on an important concept in oncology and nephrology.”

“While this is not the first attempt to devise a risk score, it is by far the biggest,” he told this news organization. Furthermore, the authors “used a diverse population, recruiting patients with a variety of cancers (previous attempts had often used a homogenous diagnosis, putting into question how generalizable the results were) from six different cancer centers.”

In addition, he said, “The authors did not restrict patients with chronic kidney disease or other significant comorbidities and used the geographic diversity to produce a cohort that has an age, gender, racial, and ethnic distribution, which is more representative of the US than previous, single-center attempts to risk score patients.”

An earlier model used the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI of an increase in serum creatinine of 0.3 mg/dL, he noted. “While a sensitive definition of AKI, it captures mild, hemodynamic increases in creatinine of questionable significance,” he said.

By contrast, the new score uses KDIGO stage II and above to define AKI. “This is a better choice, as we do not want to dissuade patients and doctors from choosing chemotherapy due to a fear of insignificant kidney damage,” he said.

All that said, Dr. Topf noted that neither the current score nor the earlier model included serum creatinine. “This is curious to me and may represent the small number of patients with representative elevated creatinine in the derivation cohort (only 1.3% with an estimated glomerular filtration rate [eGFR] < 45).”

“Since the cohort is made up of people who received cis-platinum, the low prevalence of eGFRs < 45 may be due to physicians steering away from cis-platinum in this group,” he suggested. “It would be unfortunate if this risk score gave an unintentional ‘green light’ to these patients, exposing them to predictable harm.”
 

‘Certainly Useful’

Anushree Shirali, MD, an associate professor in the Section of Nephrology and consulting physician, Yale Onco-Nephrology, Yale School of Medicine, in New Haven, Connecticut, said that having a prediction score for which patients are more likely to develop AKI after a single dose of cisplatin would be helpful for oncologists, as well as nephrologists.

As a nephrologist, Dr. Shirali mostly sees patients who already have AKI, she told this news organization. But there are circumstances in which the tool could still be helpful.

“Let’s say someone has abnormal kidney function at baseline — ie, creatinine is higher than the normal range — and they were on dialysis 5 years ago for something else, and now, they have cancer and may be given cisplatin. They worry about their chances of getting AKI and needing dialysis again,” she said. “That’s just one scenario in which I might be asked to answer that question and the tool would certainly be useful.”

Other scenarios could include someone who has just one kidney because they donated a kidney for transplant years ago, and now, they have a malignancy and wonder what their actual risk is of getting kidney issues on cisplatin.

Oncologists could use the tool to determine whether a patient should be treated with cisplatin, or if they’re at high risk, whether an alternative that’s not nephrotoxic might be used. By contrast, “if somebody’s low risk and an oncologist thinks cisplatin is the best agent they have, then they might want to go ahead and use it,” Dr. Shirali said.

Future research could take into consideration that CP-AKI is dose dependent, she suggested, because a prediction score that included the number of cisplatin doses could be even more helpful to determine risk. And, even though the derivation and validation cohorts for the new tool are representative of the US population, additional research should also include more racial/ethnic diversity, she said.

Dr. Gupta and Dr. Leaf hope their tool “will be utilized immediately by patients and providers to help predict an individual’s risk of cisplatin-associated kidney damage. It is easy to use, available for free online, and incorporates readily available clinical variables.”

If a patient is at high risk, the clinical team can consider preventive measures such as administering more IV fluids before receiving cisplatin or monitoring kidney function more closely afterward, they suggested.

Dr. Gupta reported research support from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. She also reported research funding from BTG International, GE HealthCare, and AstraZeneca outside the submitted work. She is a member of GlaxoSmithKline’s Global Anemia Council, a consultant for Secretome and Proletariat Therapeutics, and founder and president emeritus of the American Society of Onconephrology (unpaid). Dr. Leaf is supported by NIH grants, reported research support from BioPorto, BTG International, and Metro International Biotech, and has served as a consultant. Dr. Topf reported an ownership stake in a few DaVita-run dialysis clinics. He also runs a vascular access center and has participated in advisory boards with Cara Therapeutics, Vifor, Astra Zeneca, Bayer, Renibus Therapeutics, Travere Therapeutics, and GlaxoSmithKline. He is president of NephJC, a nonprofit educational organization with no industry support. Dr. Shirali declared no competing interests.

A version of this article appeared on Medscape.com.

What’s most important to patients with terminal cancer and their caregivers?

New research found that patients and caregivers both tend to prioritize symptom control over life extension but often preferring a balance. Patients and caregivers, however, are less aligned on decisions about cost containment, with patients more likely to prioritize cost containment.

“Our research has revealed that patients and caregivers generally share similar end-of-life goals,” with a “notable exception” when it comes to costs, first author Semra Ozdemir, PhD, with the Lien Centre for Palliative Care, Duke-NUS Medical School, Singapore, told this news organization.

However, when patients and caregivers have a better understanding of the patient’s prognosis, both may be more inclined to avoid costly life-extending treatments and prioritize symptom management.

In other words, the survey suggests that “knowing the prognosis helps patients and their families set realistic expectations for care and adequately prepare for end-of-life decisions,” said Dr. Ozdemir.

This study was published online in JAMA Network Open.

Patients with advanced cancer often face difficult decisions: Do they opt for treatments that may — or may not — extend life or do they focus more on symptom control?

Family caregivers, who also play an important role in this decision-making process, may have different care goals. Some research suggests that caregivers tend to prioritize treatments that could extend life, whereas patients prioritize symptom management, but it’s less clear how these priorities may change over time and how patients and caregivers may influence each other.

In the current study, the researchers examined goals of care among patients with stage IV solid tumors and caregivers during the last 2 years of life, focusing on life extension vs symptom management and cost containment, as well as how these goals changed over time.

The survey included 210 patient-caregiver pairs, recruited from outpatient clinics at two major cancer centers in Singapore. Patients had a mean age of 63 years, and about half were men. The caregivers had a mean age of 49 years, and almost two third (63%) were women.

Overall, 34% patients and 29% caregivers prioritized symptom management over life extension, whereas 24% patients and 19% caregivers prioritized life extension. Most patients and caregivers preferred balancing the two, with 34%-47% patients and 37%-69% caregivers supporting this approach.

When balancing cost and treatment decisions, however, patients were more likely to prioritize containing costs — 28% vs 17% for caregivers — over extending life — 26% of patients vs 35% of caregivers.

Cost containment tended to be more of a priority for older patients, those with a higher symptom burden, and those with less family caregiver support. For caregivers, cost containment was more of a priority for those who reported that caregiving had a big impact on their finances, those with worse self-esteem related to their caregiving abilities, as well as those caring for older patients.

To better align cost containment priorities between patients and caregivers, it’s essential for families to engage in open and thorough discussions about the allocation of resources, Dr. Ozdemir said.

Although “patients, families, and physicians often avoid discussions about prognosis,” such conversations are essential for setting realistic expectations for care and adequately preparing for end-of-life decisions, Dr. Ozdemir told this news organization.

“These conversations should aim to balance competing interests and create care plans that are mutually acceptable to both patients and caregivers,” she said, adding that “this approach will help in minimizing any potential conflicts and ensure that both parties feel respected and understood in their decision-making process.”

Managing Unrealistic Expectations

As patients approached the end of life, neither patients nor caregivers shifted their priorities from life extension to symptom management.

This finding raises concerns because it suggests that many patients hold unrealistic expectations regarding their care and “underscores the need for continuous dialogue and reassessment of care goals throughout the progression of illness,” Dr. Ozdemir said.

“This stability in preferences over time suggests that initial care decisions are deeply ingrained or that there may be a lack of ongoing communication about evolving care needs and possibilities as conditions change,” Ozdemir said.

Yet, it can be hard to define what unrealistic expectations mean, said Olivia Seecof, MD, who wasn’t involved in the study.

“I think people are hopeful that a devastating diagnosis won’t lead to the end of their life and that there will be a treatment or something that will change [their prognosis], and they’ll get better,” said Dr. Seecof, palliative care expert with the Supportive Oncology Program at NYU Langone Health’s Perlmutter Cancer Center in New York City.

Giving patients and caregivers a realistic understanding of the prognosis is important, but “there’s more to it than just telling the patient their diagnosis,” she said.

“We have to plan for end of life, what it can look like,” said Dr. Seecof, adding that “often we don’t do a very good job of talking about that early on in an illness course.”

Overall, though, Dr. Seecof stressed that no two patients or situations are the same, and it’s important to understand what’s important in each scenario. End-of-life care requires “an individual approach because every patient is different, even if they have the same diagnosis as someone else,” she said.

This work was supported by funding from the Singapore Millennium Foundation and the Lien Centre for Palliative Care. Dr. Ozdemir and Dr. Seecof had no relevant disclosures.

A version of this article appeared on Medscape.com.

What’s most important to patients with terminal cancer and their caregivers?

New research found that patients and caregivers both tend to prioritize symptom control over life extension but often preferring a balance. Patients and caregivers, however, are less aligned on decisions about cost containment, with patients more likely to prioritize cost containment.

“Our research has revealed that patients and caregivers generally share similar end-of-life goals,” with a “notable exception” when it comes to costs, first author Semra Ozdemir, PhD, with the Lien Centre for Palliative Care, Duke-NUS Medical School, Singapore, told this news organization.

However, when patients and caregivers have a better understanding of the patient’s prognosis, both may be more inclined to avoid costly life-extending treatments and prioritize symptom management.

In other words, the survey suggests that “knowing the prognosis helps patients and their families set realistic expectations for care and adequately prepare for end-of-life decisions,” said Dr. Ozdemir.

This study was published online in JAMA Network Open.

Patients with advanced cancer often face difficult decisions: Do they opt for treatments that may — or may not — extend life or do they focus more on symptom control?

Family caregivers, who also play an important role in this decision-making process, may have different care goals. Some research suggests that caregivers tend to prioritize treatments that could extend life, whereas patients prioritize symptom management, but it’s less clear how these priorities may change over time and how patients and caregivers may influence each other.

In the current study, the researchers examined goals of care among patients with stage IV solid tumors and caregivers during the last 2 years of life, focusing on life extension vs symptom management and cost containment, as well as how these goals changed over time.

The survey included 210 patient-caregiver pairs, recruited from outpatient clinics at two major cancer centers in Singapore. Patients had a mean age of 63 years, and about half were men. The caregivers had a mean age of 49 years, and almost two third (63%) were women.

Overall, 34% patients and 29% caregivers prioritized symptom management over life extension, whereas 24% patients and 19% caregivers prioritized life extension. Most patients and caregivers preferred balancing the two, with 34%-47% patients and 37%-69% caregivers supporting this approach.

When balancing cost and treatment decisions, however, patients were more likely to prioritize containing costs — 28% vs 17% for caregivers — over extending life — 26% of patients vs 35% of caregivers.

Cost containment tended to be more of a priority for older patients, those with a higher symptom burden, and those with less family caregiver support. For caregivers, cost containment was more of a priority for those who reported that caregiving had a big impact on their finances, those with worse self-esteem related to their caregiving abilities, as well as those caring for older patients.

To better align cost containment priorities between patients and caregivers, it’s essential for families to engage in open and thorough discussions about the allocation of resources, Dr. Ozdemir said.

Although “patients, families, and physicians often avoid discussions about prognosis,” such conversations are essential for setting realistic expectations for care and adequately preparing for end-of-life decisions, Dr. Ozdemir told this news organization.

“These conversations should aim to balance competing interests and create care plans that are mutually acceptable to both patients and caregivers,” she said, adding that “this approach will help in minimizing any potential conflicts and ensure that both parties feel respected and understood in their decision-making process.”

Managing Unrealistic Expectations

As patients approached the end of life, neither patients nor caregivers shifted their priorities from life extension to symptom management.

This finding raises concerns because it suggests that many patients hold unrealistic expectations regarding their care and “underscores the need for continuous dialogue and reassessment of care goals throughout the progression of illness,” Dr. Ozdemir said.

“This stability in preferences over time suggests that initial care decisions are deeply ingrained or that there may be a lack of ongoing communication about evolving care needs and possibilities as conditions change,” Ozdemir said.

Yet, it can be hard to define what unrealistic expectations mean, said Olivia Seecof, MD, who wasn’t involved in the study.

“I think people are hopeful that a devastating diagnosis won’t lead to the end of their life and that there will be a treatment or something that will change [their prognosis], and they’ll get better,” said Dr. Seecof, palliative care expert with the Supportive Oncology Program at NYU Langone Health’s Perlmutter Cancer Center in New York City.

Giving patients and caregivers a realistic understanding of the prognosis is important, but “there’s more to it than just telling the patient their diagnosis,” she said.

“We have to plan for end of life, what it can look like,” said Dr. Seecof, adding that “often we don’t do a very good job of talking about that early on in an illness course.”

Overall, though, Dr. Seecof stressed that no two patients or situations are the same, and it’s important to understand what’s important in each scenario. End-of-life care requires “an individual approach because every patient is different, even if they have the same diagnosis as someone else,” she said.

This work was supported by funding from the Singapore Millennium Foundation and the Lien Centre for Palliative Care. Dr. Ozdemir and Dr. Seecof had no relevant disclosures.

A version of this article appeared on Medscape.com.

What’s most important to patients with terminal cancer and their caregivers?

New research found that patients and caregivers both tend to prioritize symptom control over life extension but often preferring a balance. Patients and caregivers, however, are less aligned on decisions about cost containment, with patients more likely to prioritize cost containment.

“Our research has revealed that patients and caregivers generally share similar end-of-life goals,” with a “notable exception” when it comes to costs, first author Semra Ozdemir, PhD, with the Lien Centre for Palliative Care, Duke-NUS Medical School, Singapore, told this news organization.

However, when patients and caregivers have a better understanding of the patient’s prognosis, both may be more inclined to avoid costly life-extending treatments and prioritize symptom management.

In other words, the survey suggests that “knowing the prognosis helps patients and their families set realistic expectations for care and adequately prepare for end-of-life decisions,” said Dr. Ozdemir.

This study was published online in JAMA Network Open.

Patients with advanced cancer often face difficult decisions: Do they opt for treatments that may — or may not — extend life or do they focus more on symptom control?

Family caregivers, who also play an important role in this decision-making process, may have different care goals. Some research suggests that caregivers tend to prioritize treatments that could extend life, whereas patients prioritize symptom management, but it’s less clear how these priorities may change over time and how patients and caregivers may influence each other.

In the current study, the researchers examined goals of care among patients with stage IV solid tumors and caregivers during the last 2 years of life, focusing on life extension vs symptom management and cost containment, as well as how these goals changed over time.

The survey included 210 patient-caregiver pairs, recruited from outpatient clinics at two major cancer centers in Singapore. Patients had a mean age of 63 years, and about half were men. The caregivers had a mean age of 49 years, and almost two third (63%) were women.

Overall, 34% patients and 29% caregivers prioritized symptom management over life extension, whereas 24% patients and 19% caregivers prioritized life extension. Most patients and caregivers preferred balancing the two, with 34%-47% patients and 37%-69% caregivers supporting this approach.

When balancing cost and treatment decisions, however, patients were more likely to prioritize containing costs — 28% vs 17% for caregivers — over extending life — 26% of patients vs 35% of caregivers.

Cost containment tended to be more of a priority for older patients, those with a higher symptom burden, and those with less family caregiver support. For caregivers, cost containment was more of a priority for those who reported that caregiving had a big impact on their finances, those with worse self-esteem related to their caregiving abilities, as well as those caring for older patients.

To better align cost containment priorities between patients and caregivers, it’s essential for families to engage in open and thorough discussions about the allocation of resources, Dr. Ozdemir said.

Although “patients, families, and physicians often avoid discussions about prognosis,” such conversations are essential for setting realistic expectations for care and adequately preparing for end-of-life decisions, Dr. Ozdemir told this news organization.

“These conversations should aim to balance competing interests and create care plans that are mutually acceptable to both patients and caregivers,” she said, adding that “this approach will help in minimizing any potential conflicts and ensure that both parties feel respected and understood in their decision-making process.”

Managing Unrealistic Expectations

As patients approached the end of life, neither patients nor caregivers shifted their priorities from life extension to symptom management.

This finding raises concerns because it suggests that many patients hold unrealistic expectations regarding their care and “underscores the need for continuous dialogue and reassessment of care goals throughout the progression of illness,” Dr. Ozdemir said.

“This stability in preferences over time suggests that initial care decisions are deeply ingrained or that there may be a lack of ongoing communication about evolving care needs and possibilities as conditions change,” Ozdemir said.

Yet, it can be hard to define what unrealistic expectations mean, said Olivia Seecof, MD, who wasn’t involved in the study.

“I think people are hopeful that a devastating diagnosis won’t lead to the end of their life and that there will be a treatment or something that will change [their prognosis], and they’ll get better,” said Dr. Seecof, palliative care expert with the Supportive Oncology Program at NYU Langone Health’s Perlmutter Cancer Center in New York City.

Giving patients and caregivers a realistic understanding of the prognosis is important, but “there’s more to it than just telling the patient their diagnosis,” she said.

“We have to plan for end of life, what it can look like,” said Dr. Seecof, adding that “often we don’t do a very good job of talking about that early on in an illness course.”

Overall, though, Dr. Seecof stressed that no two patients or situations are the same, and it’s important to understand what’s important in each scenario. End-of-life care requires “an individual approach because every patient is different, even if they have the same diagnosis as someone else,” she said.

This work was supported by funding from the Singapore Millennium Foundation and the Lien Centre for Palliative Care. Dr. Ozdemir and Dr. Seecof had no relevant disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

A recent survey highlighted ethical concerns US oncologists have about using artificial intelligence (AI) to help make cancer treatment decisions and revealed some contradictory views about how best to integrate these tools into practice. Most respondents, for instance, said patients should not be expected to understand how AI tools work, but many also felt patients could make treatment decisions based on AI-generated recommendations. Most oncologists also felt responsible for protecting patients from biased AI, but few were confident that they could do so.

METHODOLOGY:

• The US Food and Drug Administration (FDA) has  for use in various medical specialties over the past few decades, and increasingly, AI tools are being integrated into cancer care.
• However, the uptake of these tools in oncology has raised ethical questions and concerns, including challenges with AI bias, error, or misuse, as well as issues explaining how an AI model reached a result.
• In the current study, researchers asked 204 oncologists from 37 states for their views on the ethical implications of using AI for cancer care.
• Among the survey respondents, 64% were men and 63% were non-Hispanic White; 29% were from academic practices, 47% had received some education on AI use in healthcare, and 45% were familiar with clinical decision models.
• The researchers assessed respondents’ answers to various questions, including whether to provide informed consent for AI use and how oncologists would approach a scenario where the AI model and the oncologist recommended a different treatment regimen.

TAKEAWAY:

• Overall, 81% of oncologists supported having patient consent to use an AI model during treatment decisions, and 85% felt that oncologists needed to be able to explain an AI-based clinical decision model to use it in the clinic; however, only 23% felt that patients also needed to be able to explain an AI model.
• When an AI decision model recommended a different treatment regimen than the treating oncologist, the most common response (36.8%) was to present both options to the patient and let the patient decide. Oncologists from academic settings were about 2.5 times more likely than those from other settings to let the patient decide. About 34% of respondents said they would present both options but recommend the oncologist’s regimen, whereas about 22% said they would present both but recommend the AI’s regimen. A small percentage would only present the oncologist’s regimen (5%) or the AI’s regimen (about 2.5%).
• About three of four respondents (76.5%) agreed that oncologists should protect patients from biased AI tools; however, only about one of four (27.9%) felt confident they could identify biased AI models.
• Most oncologists (91%) felt that AI developers were responsible for the medico-legal problems associated with AI use; less than half (47%) said oncologists or hospitals (43%) shared this responsibility.

IN PRACTICE:

“Together, these data characterize barriers that may impede the ethical adoption of AI into cancer care. The findings suggest that the implementation of AI in oncology must include rigorous assessments of its effect on care decisions, as well as decisional responsibility when problems related to AI use arise,” the authors concluded.

SOURCE:

The study, with first author Andrew Hantel, MD, from Dana-Farber Cancer Institute, Boston, was published last month in JAMA Network Open.

LIMITATIONS:

The study had a moderate sample size and response rate, although demographics of participating oncologists appear to be nationally representative. The cross-sectional study design limited the generalizability of the findings over time as AI is integrated into cancer care.

DISCLOSURES:

The study was funded by the National Cancer Institute, the Dana-Farber McGraw/Patterson Research Fund, and the Mark Foundation Emerging Leader Award. Dr. Hantel reported receiving personal fees from AbbVie, AstraZeneca, the American Journal of Managed Care, Genentech, and GSK.

A version of this article appeared on Medscape.com.

TOPLINE:

A recent survey highlighted ethical concerns US oncologists have about using artificial intelligence (AI) to help make cancer treatment decisions and revealed some contradictory views about how best to integrate these tools into practice. Most respondents, for instance, said patients should not be expected to understand how AI tools work, but many also felt patients could make treatment decisions based on AI-generated recommendations. Most oncologists also felt responsible for protecting patients from biased AI, but few were confident that they could do so.

METHODOLOGY:

• The US Food and Drug Administration (FDA) has  for use in various medical specialties over the past few decades, and increasingly, AI tools are being integrated into cancer care.
• However, the uptake of these tools in oncology has raised ethical questions and concerns, including challenges with AI bias, error, or misuse, as well as issues explaining how an AI model reached a result.
• In the current study, researchers asked 204 oncologists from 37 states for their views on the ethical implications of using AI for cancer care.
• Among the survey respondents, 64% were men and 63% were non-Hispanic White; 29% were from academic practices, 47% had received some education on AI use in healthcare, and 45% were familiar with clinical decision models.
• The researchers assessed respondents’ answers to various questions, including whether to provide informed consent for AI use and how oncologists would approach a scenario where the AI model and the oncologist recommended a different treatment regimen.

TAKEAWAY:

• Overall, 81% of oncologists supported having patient consent to use an AI model during treatment decisions, and 85% felt that oncologists needed to be able to explain an AI-based clinical decision model to use it in the clinic; however, only 23% felt that patients also needed to be able to explain an AI model.
• When an AI decision model recommended a different treatment regimen than the treating oncologist, the most common response (36.8%) was to present both options to the patient and let the patient decide. Oncologists from academic settings were about 2.5 times more likely than those from other settings to let the patient decide. About 34% of respondents said they would present both options but recommend the oncologist’s regimen, whereas about 22% said they would present both but recommend the AI’s regimen. A small percentage would only present the oncologist’s regimen (5%) or the AI’s regimen (about 2.5%).
• About three of four respondents (76.5%) agreed that oncologists should protect patients from biased AI tools; however, only about one of four (27.9%) felt confident they could identify biased AI models.
• Most oncologists (91%) felt that AI developers were responsible for the medico-legal problems associated with AI use; less than half (47%) said oncologists or hospitals (43%) shared this responsibility.

IN PRACTICE:

“Together, these data characterize barriers that may impede the ethical adoption of AI into cancer care. The findings suggest that the implementation of AI in oncology must include rigorous assessments of its effect on care decisions, as well as decisional responsibility when problems related to AI use arise,” the authors concluded.

SOURCE:

The study, with first author Andrew Hantel, MD, from Dana-Farber Cancer Institute, Boston, was published last month in JAMA Network Open.

LIMITATIONS:

The study had a moderate sample size and response rate, although demographics of participating oncologists appear to be nationally representative. The cross-sectional study design limited the generalizability of the findings over time as AI is integrated into cancer care.

DISCLOSURES:

The study was funded by the National Cancer Institute, the Dana-Farber McGraw/Patterson Research Fund, and the Mark Foundation Emerging Leader Award. Dr. Hantel reported receiving personal fees from AbbVie, AstraZeneca, the American Journal of Managed Care, Genentech, and GSK.

A version of this article appeared on Medscape.com.

TOPLINE:

A recent survey highlighted ethical concerns US oncologists have about using artificial intelligence (AI) to help make cancer treatment decisions and revealed some contradictory views about how best to integrate these tools into practice. Most respondents, for instance, said patients should not be expected to understand how AI tools work, but many also felt patients could make treatment decisions based on AI-generated recommendations. Most oncologists also felt responsible for protecting patients from biased AI, but few were confident that they could do so.

METHODOLOGY:

• The US Food and Drug Administration (FDA) has  for use in various medical specialties over the past few decades, and increasingly, AI tools are being integrated into cancer care.
• However, the uptake of these tools in oncology has raised ethical questions and concerns, including challenges with AI bias, error, or misuse, as well as issues explaining how an AI model reached a result.
• In the current study, researchers asked 204 oncologists from 37 states for their views on the ethical implications of using AI for cancer care.
• Among the survey respondents, 64% were men and 63% were non-Hispanic White; 29% were from academic practices, 47% had received some education on AI use in healthcare, and 45% were familiar with clinical decision models.
• The researchers assessed respondents’ answers to various questions, including whether to provide informed consent for AI use and how oncologists would approach a scenario where the AI model and the oncologist recommended a different treatment regimen.

TAKEAWAY:

• Overall, 81% of oncologists supported having patient consent to use an AI model during treatment decisions, and 85% felt that oncologists needed to be able to explain an AI-based clinical decision model to use it in the clinic; however, only 23% felt that patients also needed to be able to explain an AI model.
• When an AI decision model recommended a different treatment regimen than the treating oncologist, the most common response (36.8%) was to present both options to the patient and let the patient decide. Oncologists from academic settings were about 2.5 times more likely than those from other settings to let the patient decide. About 34% of respondents said they would present both options but recommend the oncologist’s regimen, whereas about 22% said they would present both but recommend the AI’s regimen. A small percentage would only present the oncologist’s regimen (5%) or the AI’s regimen (about 2.5%).
• About three of four respondents (76.5%) agreed that oncologists should protect patients from biased AI tools; however, only about one of four (27.9%) felt confident they could identify biased AI models.
• Most oncologists (91%) felt that AI developers were responsible for the medico-legal problems associated with AI use; less than half (47%) said oncologists or hospitals (43%) shared this responsibility.

IN PRACTICE:

“Together, these data characterize barriers that may impede the ethical adoption of AI into cancer care. The findings suggest that the implementation of AI in oncology must include rigorous assessments of its effect on care decisions, as well as decisional responsibility when problems related to AI use arise,” the authors concluded.

SOURCE:

The study, with first author Andrew Hantel, MD, from Dana-Farber Cancer Institute, Boston, was published last month in JAMA Network Open.

LIMITATIONS:

The study had a moderate sample size and response rate, although demographics of participating oncologists appear to be nationally representative. The cross-sectional study design limited the generalizability of the findings over time as AI is integrated into cancer care.

DISCLOSURES:

The study was funded by the National Cancer Institute, the Dana-Farber McGraw/Patterson Research Fund, and the Mark Foundation Emerging Leader Award. Dr. Hantel reported receiving personal fees from AbbVie, AstraZeneca, the American Journal of Managed Care, Genentech, and GSK.

A version of this article appeared on Medscape.com.

Healthcare providers hold wide-ranging opinions about prescribing opioids for chronic cancer pain, and many are haunted by the conflicting factors driving their views, from legal concerns to threats of violence, say the authors of new research.

These findings suggest that evidence-based, systematic guidance is needed to steer opioid usage in cancer survivorship, wrote lead author Hailey W. Bulls, PhD, of the University of Pittsburgh, and colleagues.

“Prescription opioids are considered the standard of care to treat moderate to severe cancer pain during active treatment, yet guidance in the posttreatment survivorship phase is much less clear,” the investigators wrote. “Existing clinical resources recognize that opioid prescribing in survivorship is complex and nuanced and that the relative benefits and risks in this population are not fully understood.”
 

Who Should Manage Chronic Cancer Pain?

Despite the knowledge gap, survivors are typically excluded from long-term opioid use studies, leaving providers in a largely data-free zone. Simultaneously, patients who had been receiving focused care during their cancer treatment find themselves with an ill-defined health care team.

“Without a clear transition of care, survivors may seek pain management services from a variety of specialties, including oncologists, palliative care clinicians, primary care clinicians, and pain management specialists,” the investigators wrote. “However, many clinicians may view pain management to be outside of their skill set and may not be well equipped to handle opioid continuation or deprescribing [or] to manage the potential consequences of long‐term opioid use like side effects, misuse, and/or opioid use disorder.”
 

What Factors Guide Opioid Prescribing Practices for Chronic Cancer Pain?

To learn more about prescribing practices in this setting, Dr. Bulls and colleagues conducted qualitative interviews with 20 providers representing four specialties: oncology (n = 5), palliative care (n = 8), primary care (n = 5), and pain management (n = 2). Eighteen of these participants were physicians and two were advanced practice providers. Average time in clinical practice was about 16 years.

These interviews yielded three themes.

First, no “medical home” exists for chronic pain management in cancer survivors.

“Although clinicians generally agreed that minimizing the role of opioids in chronic pain management in cancer survivors was desirable, they described a lack of common treatment protocols to guide pain management in survivorship,” the investigators wrote.

Second, the interviews revealed that prescribing strategies are partly driven by peer pressure, sometimes leading to tension between providers and feelings of self-doubt.

“I feel like there’s been this weird judgment thing that’s happened [to] the prescribers,” one primary care provider said during the interview. “Because, when I trained … pain was a vital sign, and we were supposed to treat pain, and now I feel like we’re all being judged for that.”

The third theme revolved around fear of consequences resulting from prescribing practices, including fears of violent repercussions.

“You may not know, but pain specialists have been shot in this country for [refusing to prescribe opioids],” one pain management specialist said during the interview. “There’s been a number of shootings of pain specialists who would not prescribe opioids. So, I mean, there’s real issues of violence.”

Meanwhile, a palliative care provider described legal pressure from the opposite direction:

“I think there’s a lot of fear of litigiousness … and loss of licenses. That sort of makes them pressure us into not prescribing opioids or sticking with a certain number per day that might not be therapeutic for a patient.”

Reflecting on these themes, the investigators identified “a fundamental uncertainty in survivorship pain management.”
 

What Strategies Might Improve Opioid Prescribing Practices for Chronic Cancer Pain?

After sharing their attitudes about prescribing opioids for chronic cancer pain, the clinicians were asked for suggestions to improve the situation.

They offered four main suggestions: create relevant guidelines, increase education and access to pain management options for clinicians, increase interdisciplinary communication across medical subspecialties, and promote multidisciplinary care in the survivorship setting.

Dr. Bulls and colleagues supported these strategies in their concluding remarks and called for more research.

This study was supported by the National Institute of Drug Abuse, the National Institutes of Health, the National Center for Advancing Translational Sciences, and the National Cancer Institute. The investigators disclosed relationships with Arcadia Health Solutions and Biomotivate.

Healthcare providers hold wide-ranging opinions about prescribing opioids for chronic cancer pain, and many are haunted by the conflicting factors driving their views, from legal concerns to threats of violence, say the authors of new research.

These findings suggest that evidence-based, systematic guidance is needed to steer opioid usage in cancer survivorship, wrote lead author Hailey W. Bulls, PhD, of the University of Pittsburgh, and colleagues.

“Prescription opioids are considered the standard of care to treat moderate to severe cancer pain during active treatment, yet guidance in the posttreatment survivorship phase is much less clear,” the investigators wrote. “Existing clinical resources recognize that opioid prescribing in survivorship is complex and nuanced and that the relative benefits and risks in this population are not fully understood.”
 

Who Should Manage Chronic Cancer Pain?

Despite the knowledge gap, survivors are typically excluded from long-term opioid use studies, leaving providers in a largely data-free zone. Simultaneously, patients who had been receiving focused care during their cancer treatment find themselves with an ill-defined health care team.

“Without a clear transition of care, survivors may seek pain management services from a variety of specialties, including oncologists, palliative care clinicians, primary care clinicians, and pain management specialists,” the investigators wrote. “However, many clinicians may view pain management to be outside of their skill set and may not be well equipped to handle opioid continuation or deprescribing [or] to manage the potential consequences of long‐term opioid use like side effects, misuse, and/or opioid use disorder.”
 

What Factors Guide Opioid Prescribing Practices for Chronic Cancer Pain?

To learn more about prescribing practices in this setting, Dr. Bulls and colleagues conducted qualitative interviews with 20 providers representing four specialties: oncology (n = 5), palliative care (n = 8), primary care (n = 5), and pain management (n = 2). Eighteen of these participants were physicians and two were advanced practice providers. Average time in clinical practice was about 16 years.

These interviews yielded three themes.

First, no “medical home” exists for chronic pain management in cancer survivors.

“Although clinicians generally agreed that minimizing the role of opioids in chronic pain management in cancer survivors was desirable, they described a lack of common treatment protocols to guide pain management in survivorship,” the investigators wrote.

Second, the interviews revealed that prescribing strategies are partly driven by peer pressure, sometimes leading to tension between providers and feelings of self-doubt.

“I feel like there’s been this weird judgment thing that’s happened [to] the prescribers,” one primary care provider said during the interview. “Because, when I trained … pain was a vital sign, and we were supposed to treat pain, and now I feel like we’re all being judged for that.”

The third theme revolved around fear of consequences resulting from prescribing practices, including fears of violent repercussions.

“You may not know, but pain specialists have been shot in this country for [refusing to prescribe opioids],” one pain management specialist said during the interview. “There’s been a number of shootings of pain specialists who would not prescribe opioids. So, I mean, there’s real issues of violence.”

Meanwhile, a palliative care provider described legal pressure from the opposite direction:

“I think there’s a lot of fear of litigiousness … and loss of licenses. That sort of makes them pressure us into not prescribing opioids or sticking with a certain number per day that might not be therapeutic for a patient.”

Reflecting on these themes, the investigators identified “a fundamental uncertainty in survivorship pain management.”
 

What Strategies Might Improve Opioid Prescribing Practices for Chronic Cancer Pain?

After sharing their attitudes about prescribing opioids for chronic cancer pain, the clinicians were asked for suggestions to improve the situation.

They offered four main suggestions: create relevant guidelines, increase education and access to pain management options for clinicians, increase interdisciplinary communication across medical subspecialties, and promote multidisciplinary care in the survivorship setting.

Dr. Bulls and colleagues supported these strategies in their concluding remarks and called for more research.

This study was supported by the National Institute of Drug Abuse, the National Institutes of Health, the National Center for Advancing Translational Sciences, and the National Cancer Institute. The investigators disclosed relationships with Arcadia Health Solutions and Biomotivate.

Healthcare providers hold wide-ranging opinions about prescribing opioids for chronic cancer pain, and many are haunted by the conflicting factors driving their views, from legal concerns to threats of violence, say the authors of new research.

These findings suggest that evidence-based, systematic guidance is needed to steer opioid usage in cancer survivorship, wrote lead author Hailey W. Bulls, PhD, of the University of Pittsburgh, and colleagues.

“Prescription opioids are considered the standard of care to treat moderate to severe cancer pain during active treatment, yet guidance in the posttreatment survivorship phase is much less clear,” the investigators wrote. “Existing clinical resources recognize that opioid prescribing in survivorship is complex and nuanced and that the relative benefits and risks in this population are not fully understood.”
 

Who Should Manage Chronic Cancer Pain?

Despite the knowledge gap, survivors are typically excluded from long-term opioid use studies, leaving providers in a largely data-free zone. Simultaneously, patients who had been receiving focused care during their cancer treatment find themselves with an ill-defined health care team.

“Without a clear transition of care, survivors may seek pain management services from a variety of specialties, including oncologists, palliative care clinicians, primary care clinicians, and pain management specialists,” the investigators wrote. “However, many clinicians may view pain management to be outside of their skill set and may not be well equipped to handle opioid continuation or deprescribing [or] to manage the potential consequences of long‐term opioid use like side effects, misuse, and/or opioid use disorder.”
 

What Factors Guide Opioid Prescribing Practices for Chronic Cancer Pain?

To learn more about prescribing practices in this setting, Dr. Bulls and colleagues conducted qualitative interviews with 20 providers representing four specialties: oncology (n = 5), palliative care (n = 8), primary care (n = 5), and pain management (n = 2). Eighteen of these participants were physicians and two were advanced practice providers. Average time in clinical practice was about 16 years.

These interviews yielded three themes.

First, no “medical home” exists for chronic pain management in cancer survivors.

“Although clinicians generally agreed that minimizing the role of opioids in chronic pain management in cancer survivors was desirable, they described a lack of common treatment protocols to guide pain management in survivorship,” the investigators wrote.

Second, the interviews revealed that prescribing strategies are partly driven by peer pressure, sometimes leading to tension between providers and feelings of self-doubt.

“I feel like there’s been this weird judgment thing that’s happened [to] the prescribers,” one primary care provider said during the interview. “Because, when I trained … pain was a vital sign, and we were supposed to treat pain, and now I feel like we’re all being judged for that.”

The third theme revolved around fear of consequences resulting from prescribing practices, including fears of violent repercussions.

“You may not know, but pain specialists have been shot in this country for [refusing to prescribe opioids],” one pain management specialist said during the interview. “There’s been a number of shootings of pain specialists who would not prescribe opioids. So, I mean, there’s real issues of violence.”

Meanwhile, a palliative care provider described legal pressure from the opposite direction:

“I think there’s a lot of fear of litigiousness … and loss of licenses. That sort of makes them pressure us into not prescribing opioids or sticking with a certain number per day that might not be therapeutic for a patient.”

Reflecting on these themes, the investigators identified “a fundamental uncertainty in survivorship pain management.”
 

What Strategies Might Improve Opioid Prescribing Practices for Chronic Cancer Pain?

After sharing their attitudes about prescribing opioids for chronic cancer pain, the clinicians were asked for suggestions to improve the situation.

They offered four main suggestions: create relevant guidelines, increase education and access to pain management options for clinicians, increase interdisciplinary communication across medical subspecialties, and promote multidisciplinary care in the survivorship setting.

Dr. Bulls and colleagues supported these strategies in their concluding remarks and called for more research.

This study was supported by the National Institute of Drug Abuse, the National Institutes of Health, the National Center for Advancing Translational Sciences, and the National Cancer Institute. The investigators disclosed relationships with Arcadia Health Solutions and Biomotivate.

TOPLINE: 

“Optimizing vaccination status should be considered a key element in the care of patients with cancer,” according to the authors of newly released American of Clinical Oncology (ASCO) guidelines. Optimizing vaccination status includes ensuring patients and household members receive recommended vaccines and adjusting this strategy depending on patients’ underlying immune status and their anticancer therapy.

METHODOLOGY: 

• “Infections are the second most common cause of noncancer-related mortality within the first year after a cancer diagnosis,” highlighting the need for oncologists to help ensure patients are up to date on key vaccines, an ASCO panel of experts wrote. 
• The expert panel reviewed the existing evidence and made recommendations to guide vaccination of adults with solid tumors or hematologic malignancies, including those who received hematopoietic stem-cell transplantation (HSCT), chimeric antigen T-cell (CAR T-cell) therapy and B-cell-depleting therapy, as well as guide vaccination of their household contacts. 
• The panel reviewed 102 publications, including 24 systematic reviews, 14 randomized controlled trials, and 64 nonrandomized studies. 
• Vaccines evaluated included those for COVID-19, influenza, hepatitis A and B, respiratory syncytial virus, Tdap, human papillomavirus, inactivated polio, and rabies. 
• The authors noted that patients’ underlying immune status and their cancer therapy could affect vaccination and revaccination strategies compared with recommendations for a general adult population without cancer. 

TAKEAWAY:

• The first step is to determine patients’ vaccination status and ensure adults newly diagnosed with cancer (as well as their household contacts) are up to date on seasonal and age or risk-based vaccines before starting their cancer treatment. If there are gaps, patients would ideally receive their vaccinations 2-4 weeks before their cancer treatment begins; however, non-live vaccines can be given during or after treatment. 
• The authors recommended complete revaccination of patients 6-12 months following HSCT to restore vaccine-induced immunity. The caveats: COVID-19, influenza, and pneumococcal vaccines can be given as early as 3 months after transplant, and patients should receive live and live attenuated vaccines only in the absence of active GVHD or immunosuppression and only ≥ 2 years following HSCT. 
• After CAR T-cell therapy directed against B-cell antigens (CD19/BCMA), patients should not receive influenza and COVID-19 vaccines sooner than 3 months after completing therapy and nonlive vaccines should not be given before 6 months. 
• After B-cell depleting therapy, revaccinate patients for COVID-19 only and no sooner than 6 months after completing treatment. Long-term survivors of hematologic cancer with or without active disease or those with long-standing B-cell dysfunction or hypogammaglobulinemia from therapy or B-cell lineage malignancies should receive the recommended nonlive vaccines. 
• Adults with solid and hematologic cancers traveling to an area of risk should follow the CDC standard recommendations for the destination. Hepatitis A, intramuscular typhoid vaccine, inactivated polio, hepatitis B, rabies, meningococcal, and nonlive Japanese encephalitis vaccines are safe. 

IN PRACTICE:

“Enhancing vaccine uptake against preventable illnesses will help the community and improve the quality of care for patients with cancer,” the authors said. “Clinicians play a critical role in helping the patient and caregiver to understand the potential benefits and risks of recommended vaccination[s]. In addition, clinicians should provide authoritative resources, such as fact-based vaccine informational handouts and Internet sites, to help patients and caregivers learn more about the topic.”

SOURCE:

Mini Kamboj, MD, with Memorial Sloan Kettering Cancer Center, New York City, and Elise Kohn, MD, with the National Cancer Institute, Rockville, Maryland, served as cochairs for the expert panel. The guideline was published March 18 in the Journal of Clinical Oncology.

LIMITATIONS:

The evidence for some vaccines in cancer patients continues to evolve, particularly for new vaccines like COVID-19 vaccines.

DISCLOSURES:

This research had no commercial funding. Disclosures for the guideline panel are available with the original article.

A version of this article appeared on Medscape.com.

TOPLINE: 

“Optimizing vaccination status should be considered a key element in the care of patients with cancer,” according to the authors of newly released American of Clinical Oncology (ASCO) guidelines. Optimizing vaccination status includes ensuring patients and household members receive recommended vaccines and adjusting this strategy depending on patients’ underlying immune status and their anticancer therapy.

METHODOLOGY: 

• “Infections are the second most common cause of noncancer-related mortality within the first year after a cancer diagnosis,” highlighting the need for oncologists to help ensure patients are up to date on key vaccines, an ASCO panel of experts wrote. 
• The expert panel reviewed the existing evidence and made recommendations to guide vaccination of adults with solid tumors or hematologic malignancies, including those who received hematopoietic stem-cell transplantation (HSCT), chimeric antigen T-cell (CAR T-cell) therapy and B-cell-depleting therapy, as well as guide vaccination of their household contacts. 
• The panel reviewed 102 publications, including 24 systematic reviews, 14 randomized controlled trials, and 64 nonrandomized studies. 
• Vaccines evaluated included those for COVID-19, influenza, hepatitis A and B, respiratory syncytial virus, Tdap, human papillomavirus, inactivated polio, and rabies. 
• The authors noted that patients’ underlying immune status and their cancer therapy could affect vaccination and revaccination strategies compared with recommendations for a general adult population without cancer. 

TAKEAWAY:

• The first step is to determine patients’ vaccination status and ensure adults newly diagnosed with cancer (as well as their household contacts) are up to date on seasonal and age or risk-based vaccines before starting their cancer treatment. If there are gaps, patients would ideally receive their vaccinations 2-4 weeks before their cancer treatment begins; however, non-live vaccines can be given during or after treatment. 
• The authors recommended complete revaccination of patients 6-12 months following HSCT to restore vaccine-induced immunity. The caveats: COVID-19, influenza, and pneumococcal vaccines can be given as early as 3 months after transplant, and patients should receive live and live attenuated vaccines only in the absence of active GVHD or immunosuppression and only ≥ 2 years following HSCT. 
• After CAR T-cell therapy directed against B-cell antigens (CD19/BCMA), patients should not receive influenza and COVID-19 vaccines sooner than 3 months after completing therapy and nonlive vaccines should not be given before 6 months. 
• After B-cell depleting therapy, revaccinate patients for COVID-19 only and no sooner than 6 months after completing treatment. Long-term survivors of hematologic cancer with or without active disease or those with long-standing B-cell dysfunction or hypogammaglobulinemia from therapy or B-cell lineage malignancies should receive the recommended nonlive vaccines. 
• Adults with solid and hematologic cancers traveling to an area of risk should follow the CDC standard recommendations for the destination. Hepatitis A, intramuscular typhoid vaccine, inactivated polio, hepatitis B, rabies, meningococcal, and nonlive Japanese encephalitis vaccines are safe. 

IN PRACTICE:

“Enhancing vaccine uptake against preventable illnesses will help the community and improve the quality of care for patients with cancer,” the authors said. “Clinicians play a critical role in helping the patient and caregiver to understand the potential benefits and risks of recommended vaccination[s]. In addition, clinicians should provide authoritative resources, such as fact-based vaccine informational handouts and Internet sites, to help patients and caregivers learn more about the topic.”

SOURCE:

Mini Kamboj, MD, with Memorial Sloan Kettering Cancer Center, New York City, and Elise Kohn, MD, with the National Cancer Institute, Rockville, Maryland, served as cochairs for the expert panel. The guideline was published March 18 in the Journal of Clinical Oncology.

LIMITATIONS:

The evidence for some vaccines in cancer patients continues to evolve, particularly for new vaccines like COVID-19 vaccines.

DISCLOSURES:

This research had no commercial funding. Disclosures for the guideline panel are available with the original article.

A version of this article appeared on Medscape.com.

TOPLINE: 

“Optimizing vaccination status should be considered a key element in the care of patients with cancer,” according to the authors of newly released American of Clinical Oncology (ASCO) guidelines. Optimizing vaccination status includes ensuring patients and household members receive recommended vaccines and adjusting this strategy depending on patients’ underlying immune status and their anticancer therapy.

METHODOLOGY: 

• “Infections are the second most common cause of noncancer-related mortality within the first year after a cancer diagnosis,” highlighting the need for oncologists to help ensure patients are up to date on key vaccines, an ASCO panel of experts wrote. 
• The expert panel reviewed the existing evidence and made recommendations to guide vaccination of adults with solid tumors or hematologic malignancies, including those who received hematopoietic stem-cell transplantation (HSCT), chimeric antigen T-cell (CAR T-cell) therapy and B-cell-depleting therapy, as well as guide vaccination of their household contacts. 
• The panel reviewed 102 publications, including 24 systematic reviews, 14 randomized controlled trials, and 64 nonrandomized studies. 
• Vaccines evaluated included those for COVID-19, influenza, hepatitis A and B, respiratory syncytial virus, Tdap, human papillomavirus, inactivated polio, and rabies. 
• The authors noted that patients’ underlying immune status and their cancer therapy could affect vaccination and revaccination strategies compared with recommendations for a general adult population without cancer. 

TAKEAWAY:

• The first step is to determine patients’ vaccination status and ensure adults newly diagnosed with cancer (as well as their household contacts) are up to date on seasonal and age or risk-based vaccines before starting their cancer treatment. If there are gaps, patients would ideally receive their vaccinations 2-4 weeks before their cancer treatment begins; however, non-live vaccines can be given during or after treatment. 
• The authors recommended complete revaccination of patients 6-12 months following HSCT to restore vaccine-induced immunity. The caveats: COVID-19, influenza, and pneumococcal vaccines can be given as early as 3 months after transplant, and patients should receive live and live attenuated vaccines only in the absence of active GVHD or immunosuppression and only ≥ 2 years following HSCT. 
• After CAR T-cell therapy directed against B-cell antigens (CD19/BCMA), patients should not receive influenza and COVID-19 vaccines sooner than 3 months after completing therapy and nonlive vaccines should not be given before 6 months. 
• After B-cell depleting therapy, revaccinate patients for COVID-19 only and no sooner than 6 months after completing treatment. Long-term survivors of hematologic cancer with or without active disease or those with long-standing B-cell dysfunction or hypogammaglobulinemia from therapy or B-cell lineage malignancies should receive the recommended nonlive vaccines. 
• Adults with solid and hematologic cancers traveling to an area of risk should follow the CDC standard recommendations for the destination. Hepatitis A, intramuscular typhoid vaccine, inactivated polio, hepatitis B, rabies, meningococcal, and nonlive Japanese encephalitis vaccines are safe. 

IN PRACTICE:

“Enhancing vaccine uptake against preventable illnesses will help the community and improve the quality of care for patients with cancer,” the authors said. “Clinicians play a critical role in helping the patient and caregiver to understand the potential benefits and risks of recommended vaccination[s]. In addition, clinicians should provide authoritative resources, such as fact-based vaccine informational handouts and Internet sites, to help patients and caregivers learn more about the topic.”

SOURCE:

Mini Kamboj, MD, with Memorial Sloan Kettering Cancer Center, New York City, and Elise Kohn, MD, with the National Cancer Institute, Rockville, Maryland, served as cochairs for the expert panel. The guideline was published March 18 in the Journal of Clinical Oncology.

LIMITATIONS:

The evidence for some vaccines in cancer patients continues to evolve, particularly for new vaccines like COVID-19 vaccines.

DISCLOSURES:

This research had no commercial funding. Disclosures for the guideline panel are available with the original article.

A version of this article appeared on Medscape.com.

While it is increasingly apparent that clonal hematopoiesis of indeterminate potential (CHIP) is associated with conditions that can dramatically affect an individual’s risk for both malignant and cardiovascular diseases, and even death, it has not been clear what to do about it.

Now, researchers at the cutting edge of both oncologic and cardiovascular research are not only defining the prognosis of CHIP with greater granularity but are also finding clues to mitigate the risks.

“It’s a very, very rapidly moving area,” said Christie M. Ballantyne, MD, Director, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, adding that, in many respects, “it’s a totally new area.”
 

CHIP Defined

CHIP was first recognized in the 1990s, when Martin F. Fey, MD, and colleagues from University and Inselspital, Bern, Switzerland, found X-linked inactivation in older women and suggested it was the result of acquired clonality later referred to as being of “indeterminate potential,” although that added syntax is currently a matter of debate.

Further work showed that, while somatic gene mutations occur spontaneously and are an unavoidable consequence of aging, their impact can vary widely.

The majority are “functionally silent,” while others may affect genes crucial to tissue self-renewal and differentiation, Lukasz Gondek, MD, PhD, assistant professor, Johns Hopkins Cellular and Molecular Medicine Program, Baltimore, and colleagues, noted in a recent review.

This results in the outgrowth of affected cells, known as clonal expansion, further dubbed clonal hematopoiesis when it occurs in hematopoietic tissue.

“Even though there’s clonal expansion, there’s no one CHIP,” Dr. Gondek said. “There are different flavors, and it depends on the genes that are mutated in the hematopoietic cells.”

He continued: “The older we get, the more mutations we acquire, and the probability that this mutation will hit the gene that’s responsible for expansion of the clone is higher.”

“That’s why CHIP is very uncommon in people under the age of 40, but it becomes more common in the fifth, sixth, and seventh decade of life and beyond.”

Indeed, it occurs in 10% to 15% of people aged 65 years or older, and in at least 30% of individuals by 80 years of age. In contrast, just 1% of those aged less than 50 years have the condition.

The most commonly affected genes, in around 80% of patients with CHIP, are the epigenetic regulators DNMT3A, TET2, and ASXL1; the DNA damage repair genes PPM1D and TP53; the regulatory tyrosine kinase JAK2; and the messenger RNA spliceosome components SF3B1 and SRSF2.

These mutations can have “two potential consequences,” explained Lachelle D. Weeks, MD, PhD, a hematologist at the Dana-Farber Cancer Institute, Boston.

“One is that there’s a risk of blood cancer development,” as several of the mutations are known drivers of leukemia or myelodysplastic syndromes (MDS).

Although the majority of individuals who acquire clonal hematopoiesis with age will never develop MDS, it nevertheless confers an 11- to 13-fold increased risk or an absolute risk of approximately 0.5%-1.0% per year.

Dr. Weeks continued that “the other side of it, though, is that those cells that have these mutations can also accelerate the risk of developing nonmalignant diseases like cardiovascular disease.”

This, Dr. Gondek explained, is because the mutations will be retained when the stem cells become monocytes or macrophages and, by either silencing or activating individual genes, they can make the cells more pro-inflammatory.

The result is that CHIP is associated with a marked increased risk for arteriosclerotic events such as stroke, myocardial infarction, decompensated heart failure, and cardiogenic shock, and worse outcomes after these events.

Researchers have shown that CHIP-related somatic mutations are associated with a twofold increased risk for coronary heart disease, a more than 2.5-fold increased risk for ischemic stroke, and a fourfold greater risk for myocardial infarction. A study from earlier this year found that CHIP also increases the risk for heart failure with preserved ejection fraction more than twofold.

There is even evidence to suggest that CHIP is associated with more severe acute kidney injury (AKI) and greater post-AKI kidney fibrosis.

The consequence is that individuals with CHIP face a 40% increased risk for all-cause mortality over 8 years.
 

No CHIP Test Yet

All of which has led for some to call for CHIP testing.

However, there are currently no screening programs for CHIP and no plans to introduce any. “So most CHIP is actually being diagnosed incidentally, when patients get genetic testing for some other indication,” said Dr. Weeks.

“The patients that we see in our CHIP clinic at Dana-Farber have genetic testing because they have low blood counts,” she continued, “and somebody’s trying to figure out: Do you have MDS?”

Other patients have genetic testing due to a family history of other cancers, “and so they’re getting hereditary cancer panels to determine if they have Lynch syndrome, or other hereditary syndromes,” which are picking up gene mutations associated with CHIP.

In other cases, study protocols are identifying CHIP “in various research contexts, and then as a follow-up, some of those patients end up with our clinic,” added Dr. Weeks.

Due to the associated risks for CHIP, “obviously everyone wants to know whether they are at risk for hematologic malignancy, or not,” said Dr. Gondek. To those ends, Dr. Weeks and colleagues developed the clonal hematopoiesis risk score (CHRS).

Published by NEJM Evidence in 2023, the score takes a range of predictive variables, such as age, number of mutations and their degree of associated risk, the variant allele fraction, and a series of blood indices to define patients as low-, intermediate-, or high-risk.

“A little over half” of high-risk individuals “will develop a blood cancer” such as MDS or acute myeloid leukemia (AML)” over the next 10 years, Weeks explained, while “for your intermediate risk folks, in that same time period, 7%-8% of them will develop a blood cancer.”

In low-risk individuals, the 10-year risk for MDS or AML is just 1%.

Dr. Weeks noted the “caveat that there are environmental factors or patient-specific issues that might increase your risk that are not considered in the calculator,” such the presence of hereditary cancer syndromes, “or if you’re getting chemotherapy for other cancers.”

From a cardiology point of view, Dr. Ballantyne said that, above all, “cardiologists need to be aware that some of these people are at increased risk for cardiovascular events.” This prompted a team including Dr. Weeks and Dr. Ballantyne to study whether the CHRS can also predict cardiovascular risk.

They found that people designated low-risk on the score faced an 8% increased risk for all-cause mortality vs individuals without CHIP during a median follow-up of 7 years. This rose to a 12% increase in intermediate-risk individuals.

And those deemed high-risk had a 2.5-fold increased risk for early mortality and a threefold higher risk for cardiovascular death.

Dr. Weeks noted: “We have not done a dedicated study to define a cardiovascular disease-specific calculator for CHIP,” but in the meantime, the CHRS is a “very reasonable way to estimate what someone’s risk of progression or adverse events is for cardiovascular disease.”

For clinicians, however, the key question becomes: What can be done to mitigate the risks, particularly in high-risk individuals?

For malignant conditions, the approach is to monitor patients, although “we and other centers are in the process of developing various interventional clinical trials to test various agents on their ability to improve blood counts, as well as to mitigate the risk of progression to overt blood cancer,” said Dr. Weeks.
 

Treat CHIP Like Lipoprotein(a)?

As for cardiovascular risk, Dr. Ballantyne believes that, because CHIP is an unmodifiable risk factor, an example to follow could be lipoprotein(a) (LP[a]).

“We don’t have a therapy specifically to target LP(a) yet, but we do know that the things that benefit in general,” he said, such as “taking a statin, lowering blood pressure into the optimal zone, diet ,and exercise.”

“What we do in our clinic, and what others have been doing,” Dr. Weeks added, “is for every patient who comes in and is diagnosed with CHIP, we are referring them to preventative cardiology for very aggressive preventative management.”

Finally, both Dr. Ballantyne and Dr. Weeks agree that there are many potential innovations on the horizon.

“It’s pretty exciting in terms of beginning to understand some of the links between aging, cardiovascular disease, and cancer that we had not been thinking about,” Dr. Ballantyne said.

On the malignant side, Dr. Weeks is already working on a prospective study to determine how the risks associated with CHIP evolve when patients undergo chemotherapy and radiation for other cancers.

“That will be really exciting and will help us to develop a specific calculator in that context,” she said, adding that a cardiovascular-specific calculator “is also coming down the line.”

Dr. Weeks declared relationships with Abbvie, Vertex, and Sobi. Dr. Ballantyne declared a relationship with Ten Sixteen Bio, and funding from the National Heart, Lung, and Blood Institute. No other relevant financial relationships were declared.
 

A version of this article appeared on Medscape.com.

While it is increasingly apparent that clonal hematopoiesis of indeterminate potential (CHIP) is associated with conditions that can dramatically affect an individual’s risk for both malignant and cardiovascular diseases, and even death, it has not been clear what to do about it.

Now, researchers at the cutting edge of both oncologic and cardiovascular research are not only defining the prognosis of CHIP with greater granularity but are also finding clues to mitigate the risks.

“It’s a very, very rapidly moving area,” said Christie M. Ballantyne, MD, Director, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, adding that, in many respects, “it’s a totally new area.”
 

CHIP Defined

CHIP was first recognized in the 1990s, when Martin F. Fey, MD, and colleagues from University and Inselspital, Bern, Switzerland, found X-linked inactivation in older women and suggested it was the result of acquired clonality later referred to as being of “indeterminate potential,” although that added syntax is currently a matter of debate.

Further work showed that, while somatic gene mutations occur spontaneously and are an unavoidable consequence of aging, their impact can vary widely.

The majority are “functionally silent,” while others may affect genes crucial to tissue self-renewal and differentiation, Lukasz Gondek, MD, PhD, assistant professor, Johns Hopkins Cellular and Molecular Medicine Program, Baltimore, and colleagues, noted in a recent review.

This results in the outgrowth of affected cells, known as clonal expansion, further dubbed clonal hematopoiesis when it occurs in hematopoietic tissue.

“Even though there’s clonal expansion, there’s no one CHIP,” Dr. Gondek said. “There are different flavors, and it depends on the genes that are mutated in the hematopoietic cells.”

He continued: “The older we get, the more mutations we acquire, and the probability that this mutation will hit the gene that’s responsible for expansion of the clone is higher.”

“That’s why CHIP is very uncommon in people under the age of 40, but it becomes more common in the fifth, sixth, and seventh decade of life and beyond.”

Indeed, it occurs in 10% to 15% of people aged 65 years or older, and in at least 30% of individuals by 80 years of age. In contrast, just 1% of those aged less than 50 years have the condition.

The most commonly affected genes, in around 80% of patients with CHIP, are the epigenetic regulators DNMT3A, TET2, and ASXL1; the DNA damage repair genes PPM1D and TP53; the regulatory tyrosine kinase JAK2; and the messenger RNA spliceosome components SF3B1 and SRSF2.

These mutations can have “two potential consequences,” explained Lachelle D. Weeks, MD, PhD, a hematologist at the Dana-Farber Cancer Institute, Boston.

“One is that there’s a risk of blood cancer development,” as several of the mutations are known drivers of leukemia or myelodysplastic syndromes (MDS).

Although the majority of individuals who acquire clonal hematopoiesis with age will never develop MDS, it nevertheless confers an 11- to 13-fold increased risk or an absolute risk of approximately 0.5%-1.0% per year.

Dr. Weeks continued that “the other side of it, though, is that those cells that have these mutations can also accelerate the risk of developing nonmalignant diseases like cardiovascular disease.”

This, Dr. Gondek explained, is because the mutations will be retained when the stem cells become monocytes or macrophages and, by either silencing or activating individual genes, they can make the cells more pro-inflammatory.

The result is that CHIP is associated with a marked increased risk for arteriosclerotic events such as stroke, myocardial infarction, decompensated heart failure, and cardiogenic shock, and worse outcomes after these events.

Researchers have shown that CHIP-related somatic mutations are associated with a twofold increased risk for coronary heart disease, a more than 2.5-fold increased risk for ischemic stroke, and a fourfold greater risk for myocardial infarction. A study from earlier this year found that CHIP also increases the risk for heart failure with preserved ejection fraction more than twofold.

There is even evidence to suggest that CHIP is associated with more severe acute kidney injury (AKI) and greater post-AKI kidney fibrosis.

The consequence is that individuals with CHIP face a 40% increased risk for all-cause mortality over 8 years.
 

No CHIP Test Yet

All of which has led for some to call for CHIP testing.

However, there are currently no screening programs for CHIP and no plans to introduce any. “So most CHIP is actually being diagnosed incidentally, when patients get genetic testing for some other indication,” said Dr. Weeks.

“The patients that we see in our CHIP clinic at Dana-Farber have genetic testing because they have low blood counts,” she continued, “and somebody’s trying to figure out: Do you have MDS?”

Other patients have genetic testing due to a family history of other cancers, “and so they’re getting hereditary cancer panels to determine if they have Lynch syndrome, or other hereditary syndromes,” which are picking up gene mutations associated with CHIP.

In other cases, study protocols are identifying CHIP “in various research contexts, and then as a follow-up, some of those patients end up with our clinic,” added Dr. Weeks.

Due to the associated risks for CHIP, “obviously everyone wants to know whether they are at risk for hematologic malignancy, or not,” said Dr. Gondek. To those ends, Dr. Weeks and colleagues developed the clonal hematopoiesis risk score (CHRS).

Published by NEJM Evidence in 2023, the score takes a range of predictive variables, such as age, number of mutations and their degree of associated risk, the variant allele fraction, and a series of blood indices to define patients as low-, intermediate-, or high-risk.

“A little over half” of high-risk individuals “will develop a blood cancer” such as MDS or acute myeloid leukemia (AML)” over the next 10 years, Weeks explained, while “for your intermediate risk folks, in that same time period, 7%-8% of them will develop a blood cancer.”

In low-risk individuals, the 10-year risk for MDS or AML is just 1%.

Dr. Weeks noted the “caveat that there are environmental factors or patient-specific issues that might increase your risk that are not considered in the calculator,” such the presence of hereditary cancer syndromes, “or if you’re getting chemotherapy for other cancers.”

From a cardiology point of view, Dr. Ballantyne said that, above all, “cardiologists need to be aware that some of these people are at increased risk for cardiovascular events.” This prompted a team including Dr. Weeks and Dr. Ballantyne to study whether the CHRS can also predict cardiovascular risk.

They found that people designated low-risk on the score faced an 8% increased risk for all-cause mortality vs individuals without CHIP during a median follow-up of 7 years. This rose to a 12% increase in intermediate-risk individuals.

And those deemed high-risk had a 2.5-fold increased risk for early mortality and a threefold higher risk for cardiovascular death.

Dr. Weeks noted: “We have not done a dedicated study to define a cardiovascular disease-specific calculator for CHIP,” but in the meantime, the CHRS is a “very reasonable way to estimate what someone’s risk of progression or adverse events is for cardiovascular disease.”

For clinicians, however, the key question becomes: What can be done to mitigate the risks, particularly in high-risk individuals?

For malignant conditions, the approach is to monitor patients, although “we and other centers are in the process of developing various interventional clinical trials to test various agents on their ability to improve blood counts, as well as to mitigate the risk of progression to overt blood cancer,” said Dr. Weeks.
 

Treat CHIP Like Lipoprotein(a)?

As for cardiovascular risk, Dr. Ballantyne believes that, because CHIP is an unmodifiable risk factor, an example to follow could be lipoprotein(a) (LP[a]).

“We don’t have a therapy specifically to target LP(a) yet, but we do know that the things that benefit in general,” he said, such as “taking a statin, lowering blood pressure into the optimal zone, diet ,and exercise.”

“What we do in our clinic, and what others have been doing,” Dr. Weeks added, “is for every patient who comes in and is diagnosed with CHIP, we are referring them to preventative cardiology for very aggressive preventative management.”

Finally, both Dr. Ballantyne and Dr. Weeks agree that there are many potential innovations on the horizon.

“It’s pretty exciting in terms of beginning to understand some of the links between aging, cardiovascular disease, and cancer that we had not been thinking about,” Dr. Ballantyne said.

On the malignant side, Dr. Weeks is already working on a prospective study to determine how the risks associated with CHIP evolve when patients undergo chemotherapy and radiation for other cancers.

“That will be really exciting and will help us to develop a specific calculator in that context,” she said, adding that a cardiovascular-specific calculator “is also coming down the line.”

Dr. Weeks declared relationships with Abbvie, Vertex, and Sobi. Dr. Ballantyne declared a relationship with Ten Sixteen Bio, and funding from the National Heart, Lung, and Blood Institute. No other relevant financial relationships were declared.
 

A version of this article appeared on Medscape.com.

While it is increasingly apparent that clonal hematopoiesis of indeterminate potential (CHIP) is associated with conditions that can dramatically affect an individual’s risk for both malignant and cardiovascular diseases, and even death, it has not been clear what to do about it.

Now, researchers at the cutting edge of both oncologic and cardiovascular research are not only defining the prognosis of CHIP with greater granularity but are also finding clues to mitigate the risks.

“It’s a very, very rapidly moving area,” said Christie M. Ballantyne, MD, Director, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, adding that, in many respects, “it’s a totally new area.”
 

CHIP Defined

CHIP was first recognized in the 1990s, when Martin F. Fey, MD, and colleagues from University and Inselspital, Bern, Switzerland, found X-linked inactivation in older women and suggested it was the result of acquired clonality later referred to as being of “indeterminate potential,” although that added syntax is currently a matter of debate.

Further work showed that, while somatic gene mutations occur spontaneously and are an unavoidable consequence of aging, their impact can vary widely.

The majority are “functionally silent,” while others may affect genes crucial to tissue self-renewal and differentiation, Lukasz Gondek, MD, PhD, assistant professor, Johns Hopkins Cellular and Molecular Medicine Program, Baltimore, and colleagues, noted in a recent review.

This results in the outgrowth of affected cells, known as clonal expansion, further dubbed clonal hematopoiesis when it occurs in hematopoietic tissue.

“Even though there’s clonal expansion, there’s no one CHIP,” Dr. Gondek said. “There are different flavors, and it depends on the genes that are mutated in the hematopoietic cells.”

He continued: “The older we get, the more mutations we acquire, and the probability that this mutation will hit the gene that’s responsible for expansion of the clone is higher.”

“That’s why CHIP is very uncommon in people under the age of 40, but it becomes more common in the fifth, sixth, and seventh decade of life and beyond.”

Indeed, it occurs in 10% to 15% of people aged 65 years or older, and in at least 30% of individuals by 80 years of age. In contrast, just 1% of those aged less than 50 years have the condition.

The most commonly affected genes, in around 80% of patients with CHIP, are the epigenetic regulators DNMT3A, TET2, and ASXL1; the DNA damage repair genes PPM1D and TP53; the regulatory tyrosine kinase JAK2; and the messenger RNA spliceosome components SF3B1 and SRSF2.

These mutations can have “two potential consequences,” explained Lachelle D. Weeks, MD, PhD, a hematologist at the Dana-Farber Cancer Institute, Boston.

“One is that there’s a risk of blood cancer development,” as several of the mutations are known drivers of leukemia or myelodysplastic syndromes (MDS).

Although the majority of individuals who acquire clonal hematopoiesis with age will never develop MDS, it nevertheless confers an 11- to 13-fold increased risk or an absolute risk of approximately 0.5%-1.0% per year.

Dr. Weeks continued that “the other side of it, though, is that those cells that have these mutations can also accelerate the risk of developing nonmalignant diseases like cardiovascular disease.”

This, Dr. Gondek explained, is because the mutations will be retained when the stem cells become monocytes or macrophages and, by either silencing or activating individual genes, they can make the cells more pro-inflammatory.

The result is that CHIP is associated with a marked increased risk for arteriosclerotic events such as stroke, myocardial infarction, decompensated heart failure, and cardiogenic shock, and worse outcomes after these events.

Researchers have shown that CHIP-related somatic mutations are associated with a twofold increased risk for coronary heart disease, a more than 2.5-fold increased risk for ischemic stroke, and a fourfold greater risk for myocardial infarction. A study from earlier this year found that CHIP also increases the risk for heart failure with preserved ejection fraction more than twofold.

There is even evidence to suggest that CHIP is associated with more severe acute kidney injury (AKI) and greater post-AKI kidney fibrosis.

The consequence is that individuals with CHIP face a 40% increased risk for all-cause mortality over 8 years.
 

No CHIP Test Yet

All of which has led for some to call for CHIP testing.

However, there are currently no screening programs for CHIP and no plans to introduce any. “So most CHIP is actually being diagnosed incidentally, when patients get genetic testing for some other indication,” said Dr. Weeks.

“The patients that we see in our CHIP clinic at Dana-Farber have genetic testing because they have low blood counts,” she continued, “and somebody’s trying to figure out: Do you have MDS?”

Other patients have genetic testing due to a family history of other cancers, “and so they’re getting hereditary cancer panels to determine if they have Lynch syndrome, or other hereditary syndromes,” which are picking up gene mutations associated with CHIP.

In other cases, study protocols are identifying CHIP “in various research contexts, and then as a follow-up, some of those patients end up with our clinic,” added Dr. Weeks.

Due to the associated risks for CHIP, “obviously everyone wants to know whether they are at risk for hematologic malignancy, or not,” said Dr. Gondek. To those ends, Dr. Weeks and colleagues developed the clonal hematopoiesis risk score (CHRS).

Published by NEJM Evidence in 2023, the score takes a range of predictive variables, such as age, number of mutations and their degree of associated risk, the variant allele fraction, and a series of blood indices to define patients as low-, intermediate-, or high-risk.

“A little over half” of high-risk individuals “will develop a blood cancer” such as MDS or acute myeloid leukemia (AML)” over the next 10 years, Weeks explained, while “for your intermediate risk folks, in that same time period, 7%-8% of them will develop a blood cancer.”

In low-risk individuals, the 10-year risk for MDS or AML is just 1%.

Dr. Weeks noted the “caveat that there are environmental factors or patient-specific issues that might increase your risk that are not considered in the calculator,” such the presence of hereditary cancer syndromes, “or if you’re getting chemotherapy for other cancers.”

From a cardiology point of view, Dr. Ballantyne said that, above all, “cardiologists need to be aware that some of these people are at increased risk for cardiovascular events.” This prompted a team including Dr. Weeks and Dr. Ballantyne to study whether the CHRS can also predict cardiovascular risk.

They found that people designated low-risk on the score faced an 8% increased risk for all-cause mortality vs individuals without CHIP during a median follow-up of 7 years. This rose to a 12% increase in intermediate-risk individuals.

And those deemed high-risk had a 2.5-fold increased risk for early mortality and a threefold higher risk for cardiovascular death.

Dr. Weeks noted: “We have not done a dedicated study to define a cardiovascular disease-specific calculator for CHIP,” but in the meantime, the CHRS is a “very reasonable way to estimate what someone’s risk of progression or adverse events is for cardiovascular disease.”

For clinicians, however, the key question becomes: What can be done to mitigate the risks, particularly in high-risk individuals?

For malignant conditions, the approach is to monitor patients, although “we and other centers are in the process of developing various interventional clinical trials to test various agents on their ability to improve blood counts, as well as to mitigate the risk of progression to overt blood cancer,” said Dr. Weeks.
 

Treat CHIP Like Lipoprotein(a)?

As for cardiovascular risk, Dr. Ballantyne believes that, because CHIP is an unmodifiable risk factor, an example to follow could be lipoprotein(a) (LP[a]).

“We don’t have a therapy specifically to target LP(a) yet, but we do know that the things that benefit in general,” he said, such as “taking a statin, lowering blood pressure into the optimal zone, diet ,and exercise.”

“What we do in our clinic, and what others have been doing,” Dr. Weeks added, “is for every patient who comes in and is diagnosed with CHIP, we are referring them to preventative cardiology for very aggressive preventative management.”

Finally, both Dr. Ballantyne and Dr. Weeks agree that there are many potential innovations on the horizon.

“It’s pretty exciting in terms of beginning to understand some of the links between aging, cardiovascular disease, and cancer that we had not been thinking about,” Dr. Ballantyne said.

On the malignant side, Dr. Weeks is already working on a prospective study to determine how the risks associated with CHIP evolve when patients undergo chemotherapy and radiation for other cancers.

“That will be really exciting and will help us to develop a specific calculator in that context,” she said, adding that a cardiovascular-specific calculator “is also coming down the line.”

Dr. Weeks declared relationships with Abbvie, Vertex, and Sobi. Dr. Ballantyne declared a relationship with Ten Sixteen Bio, and funding from the National Heart, Lung, and Blood Institute. No other relevant financial relationships were declared.
 

A version of this article appeared on Medscape.com.

Most major cancer trial centers in the United States are located closer to populations with higher proportions of White, affluent individuals, a new study finds.

This inequity may be potentiating the underrepresentation of racially minoritized and socioeconomically disadvantaged populations in clinical trials, suggesting that employment of satellite hospitals is needed to expand access to investigational therapies, reported lead author Hassal Lee, MD, PhD, of Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, and colleagues.

“Minoritized and socioeconomically disadvantaged populations are underrepresented in clinical trials,” the investigators wrote in JAMA Oncology. “This may reduce the generalizability of trial results and propagate health disparities. Contributors to inequitable trial participation include individual-level factors and structural factors.”

Specifically, travel time to trial centers, as well as socioeconomic deprivation, can reduce likelihood of trial participation.

“Data on these parameters and population data on self-identified race exist, but their interrelation with clinical research facilities has not been systematically analyzed,” they wrote.

To try to draw comparisons between the distribution of patients of different races and socioeconomic statuses and the locations of clinical research facilities, Dr. Lee and colleagues aggregated data from the US Census, National Trial registry, Nature Index of Cancer Research Health Institutions, OpenStreetMap, National Cancer Institute–designated Cancer Centers list, and National Homeland Infrastructure Foundation. They then characterized catchment population demographics within 30-, 60-, and 120-minute driving commute times of all US hospitals, along with a more focused look at centers capable of conducting phase 1, phase 2, and phase 3 trials.

These efforts revealed broad geographic inequity.The 78 major centers that conduct 94% of all US cancer trials are located within 30 minutes of populations that have a 10.1% higher proportion of self-identified White individuals than the average US county, and a median income $18,900 higher than average (unpaired mean differences).

The publication also includes several maps characterizing racial and socioeconomic demographics within various catchment areas. For example, centers in New York City, Houston, and Chicago have the most diverse catchment populations within a 30-minute commute. Maps of all cities in the United States with populations greater than 500,000 are available in a supplementary index.

“This study indicates that geographical population distributions may present barriers to equitable clinical trial access and that data are available to proactively strategize about reduction of such barriers,” Dr. Lee and colleagues wrote.

The findings call attention to modifiable socioeconomic factors associated with trial participation, they added, like financial toxicity and affordable transportation, noting that ethnic and racial groups consent to trials at similar rates after controlling for income.

In addition, Dr. Lee and colleagues advised clinical trial designers to enlist satellite hospitals to increase participant diversity, since long commutes exacerbate “socioeconomic burdens associated with clinical trial participation,” with trial participation decreasing as commute time increases.

“Existing clinical trial centers may build collaborative efforts with nearby hospitals closer to underrepresented populations or set up community centers to support new collaborative networks to improve geographical access equity,” they wrote. “Methodologically, our approach is transferable to any country, region, or global effort with sufficient source data and can inform decision-making along the continuum of cancer care, from screening to implementing specialist care.”

A coauthor disclosed relationships with Flagship Therapeutics, Leidos Holding Ltd, Pershing Square Foundation, and others.

Most major cancer trial centers in the United States are located closer to populations with higher proportions of White, affluent individuals, a new study finds.

This inequity may be potentiating the underrepresentation of racially minoritized and socioeconomically disadvantaged populations in clinical trials, suggesting that employment of satellite hospitals is needed to expand access to investigational therapies, reported lead author Hassal Lee, MD, PhD, of Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, and colleagues.

“Minoritized and socioeconomically disadvantaged populations are underrepresented in clinical trials,” the investigators wrote in JAMA Oncology. “This may reduce the generalizability of trial results and propagate health disparities. Contributors to inequitable trial participation include individual-level factors and structural factors.”

Specifically, travel time to trial centers, as well as socioeconomic deprivation, can reduce likelihood of trial participation.

“Data on these parameters and population data on self-identified race exist, but their interrelation with clinical research facilities has not been systematically analyzed,” they wrote.

To try to draw comparisons between the distribution of patients of different races and socioeconomic statuses and the locations of clinical research facilities, Dr. Lee and colleagues aggregated data from the US Census, National Trial registry, Nature Index of Cancer Research Health Institutions, OpenStreetMap, National Cancer Institute–designated Cancer Centers list, and National Homeland Infrastructure Foundation. They then characterized catchment population demographics within 30-, 60-, and 120-minute driving commute times of all US hospitals, along with a more focused look at centers capable of conducting phase 1, phase 2, and phase 3 trials.

These efforts revealed broad geographic inequity.The 78 major centers that conduct 94% of all US cancer trials are located within 30 minutes of populations that have a 10.1% higher proportion of self-identified White individuals than the average US county, and a median income $18,900 higher than average (unpaired mean differences).

The publication also includes several maps characterizing racial and socioeconomic demographics within various catchment areas. For example, centers in New York City, Houston, and Chicago have the most diverse catchment populations within a 30-minute commute. Maps of all cities in the United States with populations greater than 500,000 are available in a supplementary index.

“This study indicates that geographical population distributions may present barriers to equitable clinical trial access and that data are available to proactively strategize about reduction of such barriers,” Dr. Lee and colleagues wrote.

The findings call attention to modifiable socioeconomic factors associated with trial participation, they added, like financial toxicity and affordable transportation, noting that ethnic and racial groups consent to trials at similar rates after controlling for income.

In addition, Dr. Lee and colleagues advised clinical trial designers to enlist satellite hospitals to increase participant diversity, since long commutes exacerbate “socioeconomic burdens associated with clinical trial participation,” with trial participation decreasing as commute time increases.

“Existing clinical trial centers may build collaborative efforts with nearby hospitals closer to underrepresented populations or set up community centers to support new collaborative networks to improve geographical access equity,” they wrote. “Methodologically, our approach is transferable to any country, region, or global effort with sufficient source data and can inform decision-making along the continuum of cancer care, from screening to implementing specialist care.”

A coauthor disclosed relationships with Flagship Therapeutics, Leidos Holding Ltd, Pershing Square Foundation, and others.

Most major cancer trial centers in the United States are located closer to populations with higher proportions of White, affluent individuals, a new study finds.

This inequity may be potentiating the underrepresentation of racially minoritized and socioeconomically disadvantaged populations in clinical trials, suggesting that employment of satellite hospitals is needed to expand access to investigational therapies, reported lead author Hassal Lee, MD, PhD, of Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, and colleagues.

“Minoritized and socioeconomically disadvantaged populations are underrepresented in clinical trials,” the investigators wrote in JAMA Oncology. “This may reduce the generalizability of trial results and propagate health disparities. Contributors to inequitable trial participation include individual-level factors and structural factors.”

Specifically, travel time to trial centers, as well as socioeconomic deprivation, can reduce likelihood of trial participation.

“Data on these parameters and population data on self-identified race exist, but their interrelation with clinical research facilities has not been systematically analyzed,” they wrote.

To try to draw comparisons between the distribution of patients of different races and socioeconomic statuses and the locations of clinical research facilities, Dr. Lee and colleagues aggregated data from the US Census, National Trial registry, Nature Index of Cancer Research Health Institutions, OpenStreetMap, National Cancer Institute–designated Cancer Centers list, and National Homeland Infrastructure Foundation. They then characterized catchment population demographics within 30-, 60-, and 120-minute driving commute times of all US hospitals, along with a more focused look at centers capable of conducting phase 1, phase 2, and phase 3 trials.

These efforts revealed broad geographic inequity.The 78 major centers that conduct 94% of all US cancer trials are located within 30 minutes of populations that have a 10.1% higher proportion of self-identified White individuals than the average US county, and a median income $18,900 higher than average (unpaired mean differences).

The publication also includes several maps characterizing racial and socioeconomic demographics within various catchment areas. For example, centers in New York City, Houston, and Chicago have the most diverse catchment populations within a 30-minute commute. Maps of all cities in the United States with populations greater than 500,000 are available in a supplementary index.

“This study indicates that geographical population distributions may present barriers to equitable clinical trial access and that data are available to proactively strategize about reduction of such barriers,” Dr. Lee and colleagues wrote.

The findings call attention to modifiable socioeconomic factors associated with trial participation, they added, like financial toxicity and affordable transportation, noting that ethnic and racial groups consent to trials at similar rates after controlling for income.

In addition, Dr. Lee and colleagues advised clinical trial designers to enlist satellite hospitals to increase participant diversity, since long commutes exacerbate “socioeconomic burdens associated with clinical trial participation,” with trial participation decreasing as commute time increases.

“Existing clinical trial centers may build collaborative efforts with nearby hospitals closer to underrepresented populations or set up community centers to support new collaborative networks to improve geographical access equity,” they wrote. “Methodologically, our approach is transferable to any country, region, or global effort with sufficient source data and can inform decision-making along the continuum of cancer care, from screening to implementing specialist care.”

A coauthor disclosed relationships with Flagship Therapeutics, Leidos Holding Ltd, Pershing Square Foundation, and others.