Patient & Survivor Care

Patients who are profoundly immunosuppressed after extensive cancer treatment, and who fall ill with COVID-19, can shed viable SARS-CoV-2 virus for at least 2 months after symptom onset and may need extended periods of isolation.

Live-virus shedding was detected in 18 patients who had undergone hematopoietic stem cell transplants or chimeric antigen receptor (CAR) T-cell therapy and in 2 patients with lymphoma. 

The finding was reported Dec. 1 in a research letter in the New England Journal of Medicine. 

Individuals who are otherwise healthy when they get COVID-19 are “no longer infectious after the first week of illness,” said lead author Mini Kamboj, MD, chief medical epidemiologist, Memorial Sloan Kettering Cancer Center, New York. 

“We need to keep an open mind about how [much] longer immunocompromised patients could pose an infection risk to others,” she added.

Dr. Kamboj said in an interview that her team’s previous experience with stem cell transplant recipients had suggested that severely immunocompromised patients shed other viruses (such as respiratory syncytial virus, parainfluenza, and influenza) for longer periods of time than do healthy controls.

Based on their latest findings, the investigators suggest that current guidelines for COVID-19 isolation precautions may need to be revised for immunocompromised patients. Even if only a small proportion of patients with cancer who have COVID-19 remain contagious for prolonged periods of time, “it’s a residual risk that we need to address,” Dr. Kamboj said. 

Dr. Kamboj also suggested that physicians follow test-based criteria to determine when a patient undergoing transplant can be released from isolation.
 

Shedding of viable virus

For this study, the investigators used cell cultures to detect viable virus in serially collected nasopharyngeal and sputum samples from 20 immunocompromised patients who had COVID-19 (diagnosed with COVID-19 between March 10 and April 20).  

Patients had lymphoma (n = 8), multiple myeloma (n= 7), acute leukemia/myelodysplastic syndrome (n = 4), and chronic leukemia (n = 1). There were 16 patients who had undergone transplant, 2 who had received CAR T-cell therapy, and 2 who had received other therapy.

There were 15 patients receiving active treatment or chemotherapy, and 11 developed severe COVID-19 infection. 

In total, 78 respiratory samples were collected.

“Viral RNA was detected for up to 78 days after the onset of symptoms,” the researchers reported, “[and] viable virus was detected in 10 of 14 nasopharyngeal samples (71%) that were available from the first day of laboratory testing.”

Five patients were followed up, and from these patients, the team grew virus in culture for up to 61 days after symptom onset. Two among this small group of five patients had received allogenic hematopoietic stem cell transplantation and one patient had been treated with CAR T-cell therapy within the previous 6 months. This patient remained seronegative for antibodies to the coronavirus.

For 11 patients, the team obtained serial sample genomes and found that  “each patient was infected by a distinct virus and there were no major changes in the consensus sequences of the original serial specimens or cultured isolates.” These findings were consistent with persistent infection, they noted.

The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients who are profoundly immunosuppressed after extensive cancer treatment, and who fall ill with COVID-19, can shed viable SARS-CoV-2 virus for at least 2 months after symptom onset and may need extended periods of isolation.

Live-virus shedding was detected in 18 patients who had undergone hematopoietic stem cell transplants or chimeric antigen receptor (CAR) T-cell therapy and in 2 patients with lymphoma. 

The finding was reported Dec. 1 in a research letter in the New England Journal of Medicine. 

Individuals who are otherwise healthy when they get COVID-19 are “no longer infectious after the first week of illness,” said lead author Mini Kamboj, MD, chief medical epidemiologist, Memorial Sloan Kettering Cancer Center, New York. 

“We need to keep an open mind about how [much] longer immunocompromised patients could pose an infection risk to others,” she added.

Dr. Kamboj said in an interview that her team’s previous experience with stem cell transplant recipients had suggested that severely immunocompromised patients shed other viruses (such as respiratory syncytial virus, parainfluenza, and influenza) for longer periods of time than do healthy controls.

Based on their latest findings, the investigators suggest that current guidelines for COVID-19 isolation precautions may need to be revised for immunocompromised patients. Even if only a small proportion of patients with cancer who have COVID-19 remain contagious for prolonged periods of time, “it’s a residual risk that we need to address,” Dr. Kamboj said. 

Dr. Kamboj also suggested that physicians follow test-based criteria to determine when a patient undergoing transplant can be released from isolation.
 

Shedding of viable virus

For this study, the investigators used cell cultures to detect viable virus in serially collected nasopharyngeal and sputum samples from 20 immunocompromised patients who had COVID-19 (diagnosed with COVID-19 between March 10 and April 20).  

Patients had lymphoma (n = 8), multiple myeloma (n= 7), acute leukemia/myelodysplastic syndrome (n = 4), and chronic leukemia (n = 1). There were 16 patients who had undergone transplant, 2 who had received CAR T-cell therapy, and 2 who had received other therapy.

There were 15 patients receiving active treatment or chemotherapy, and 11 developed severe COVID-19 infection. 

In total, 78 respiratory samples were collected.

“Viral RNA was detected for up to 78 days after the onset of symptoms,” the researchers reported, “[and] viable virus was detected in 10 of 14 nasopharyngeal samples (71%) that were available from the first day of laboratory testing.”

Five patients were followed up, and from these patients, the team grew virus in culture for up to 61 days after symptom onset. Two among this small group of five patients had received allogenic hematopoietic stem cell transplantation and one patient had been treated with CAR T-cell therapy within the previous 6 months. This patient remained seronegative for antibodies to the coronavirus.

For 11 patients, the team obtained serial sample genomes and found that  “each patient was infected by a distinct virus and there were no major changes in the consensus sequences of the original serial specimens or cultured isolates.” These findings were consistent with persistent infection, they noted.

The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients who are profoundly immunosuppressed after extensive cancer treatment, and who fall ill with COVID-19, can shed viable SARS-CoV-2 virus for at least 2 months after symptom onset and may need extended periods of isolation.

Live-virus shedding was detected in 18 patients who had undergone hematopoietic stem cell transplants or chimeric antigen receptor (CAR) T-cell therapy and in 2 patients with lymphoma. 

The finding was reported Dec. 1 in a research letter in the New England Journal of Medicine. 

Individuals who are otherwise healthy when they get COVID-19 are “no longer infectious after the first week of illness,” said lead author Mini Kamboj, MD, chief medical epidemiologist, Memorial Sloan Kettering Cancer Center, New York. 

“We need to keep an open mind about how [much] longer immunocompromised patients could pose an infection risk to others,” she added.

Dr. Kamboj said in an interview that her team’s previous experience with stem cell transplant recipients had suggested that severely immunocompromised patients shed other viruses (such as respiratory syncytial virus, parainfluenza, and influenza) for longer periods of time than do healthy controls.

Based on their latest findings, the investigators suggest that current guidelines for COVID-19 isolation precautions may need to be revised for immunocompromised patients. Even if only a small proportion of patients with cancer who have COVID-19 remain contagious for prolonged periods of time, “it’s a residual risk that we need to address,” Dr. Kamboj said. 

Dr. Kamboj also suggested that physicians follow test-based criteria to determine when a patient undergoing transplant can be released from isolation.
 

Shedding of viable virus

For this study, the investigators used cell cultures to detect viable virus in serially collected nasopharyngeal and sputum samples from 20 immunocompromised patients who had COVID-19 (diagnosed with COVID-19 between March 10 and April 20).  

Patients had lymphoma (n = 8), multiple myeloma (n= 7), acute leukemia/myelodysplastic syndrome (n = 4), and chronic leukemia (n = 1). There were 16 patients who had undergone transplant, 2 who had received CAR T-cell therapy, and 2 who had received other therapy.

There were 15 patients receiving active treatment or chemotherapy, and 11 developed severe COVID-19 infection. 

In total, 78 respiratory samples were collected.

“Viral RNA was detected for up to 78 days after the onset of symptoms,” the researchers reported, “[and] viable virus was detected in 10 of 14 nasopharyngeal samples (71%) that were available from the first day of laboratory testing.”

Five patients were followed up, and from these patients, the team grew virus in culture for up to 61 days after symptom onset. Two among this small group of five patients had received allogenic hematopoietic stem cell transplantation and one patient had been treated with CAR T-cell therapy within the previous 6 months. This patient remained seronegative for antibodies to the coronavirus.

For 11 patients, the team obtained serial sample genomes and found that  “each patient was infected by a distinct virus and there were no major changes in the consensus sequences of the original serial specimens or cultured isolates.” These findings were consistent with persistent infection, they noted.

The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Every medical oncologist who has described a combination chemotherapy regimen to a patient with advanced cancer has likely been asked whether the benefits of tumor shrinkage, disease-free survival (DFS), and overall survival are worth the risks of adverse events (AEs).

Single-agent immunotherapy and, more recently, combinations of immunotherapy drugs have been approved for a variety of metastatic tumors. In general, combination immunotherapy regimens have more AEs and a higher frequency of premature treatment discontinuation for toxicity.

Michael Postow, MD, of Memorial Sloan Kettering Cancer Center in New York, reflected on new ways to evaluate the benefits and risks of immunotherapy combinations during a plenary session on novel combinations at the American Association for Cancer Research’s Virtual Special Conference on Tumor Immunology and Immunotherapy.
 

Potential targets

As with chemotherapy drugs, immunotherapy combinations make the most sense when drugs targeting independent processes are employed.

As described in a paper published in Nature in 2011, the process for recruiting the immune system to combat cancer is as follows:

• Dendritic cells must sample antigens derived from the tumor.
• The dendritic cells must receive an activation signal so they promote immunity rather than tolerance.
• The tumor antigen–loaded dendritic cells need to generate protective T-cell responses, instead of T-regulatory responses, in lymphoid tissues.
• Cancer antigen–specific T cells must enter tumor tissues.
• Tumor-derived mechanisms for promoting immunosuppression need to be circumvented.

Since each step in the cascade is a potential therapeutic target, there are large numbers of potential drug combinations.
 

Measuring impact

Conventional measurements of tumor response may not be adequately sensitive to the impact from immunotherapy drugs. A case in point is sipuleucel-T, which is approved to treat advanced prostate cancer.

In the pivotal phase 3 trial, only 1 of 341 patients receiving sipuleucel-T achieved a partial response by RECIST criteria. Only 2.6% of patients had a 50% reduction in prostate-specific antigen levels. Nonetheless, a 4.1-month improvement in median overall survival was achieved. These results were published in the New England Journal of Medicine.

The discrepancy between tumor shrinkage and survival benefit for immunotherapy is not unexpected. As many as 10% of patients treated with ipilimumab (ipi) for stage IV malignant melanoma have progressive disease by tumor size but experience prolongation of survival, according to guidelines published in Clinical Cancer Research.

Accurate assessment of the ultimate efficacy of immunotherapy over time would benefit patients and clinicians since immune checkpoint inhibitors are often administered for several years, are financially costly, and treatment-associated AEs emerge unpredictably at any time.

Curtailing the duration of ineffective treatment could be valuable from many perspectives.
 

Immunotherapy combinations in metastatic melanoma

In the CheckMate 067 study, there was an improvement in response, progression-free survival (PFS), and overall survival for nivolumab (nivo) plus ipi or nivo alone, in comparison with ipi alone, in patients with advanced melanoma. Initial results from this trial were published in the New England Journal of Medicine in 2017.

At a minimum follow-up of 60 months, the 5-year overall survival was 52% for the nivo/ipi regimen, 44% for nivo alone, and 26% for ipi alone. These results were published in the New England Journal of Medicine in 2019.

The trial was not statistically powered to conclude whether the overall survival for the combination was superior to that of single-agent nivo alone, but both nivo regimens were superior to ipi alone.

Unfortunately, the combination also produced the highest treatment-related AE rates – 59% with nivo/ipi, 23% with nivo, and 28% with ipi in 2019. In the 2017 report, the combination regimen had more than twice as many premature treatment discontinuations as the other two study arms.

Is there a better way to quantify the risk-benefit ratio and explain it to patients?
 

Alternative strategies for assessing benefit: Treatment-free survival

Researchers have proposed treatment-free survival (TFS) as a potential new metric to characterize not only antitumor activity but also toxicity experienced after the cessation of therapy and before initiation of subsequent systemic therapy or death.

TFS is defined as the area between Kaplan-Meier curves from immunotherapy cessation until the reinitiation of systemic therapy or death. All patients who began immunotherapy are included – not just those achieving response or concluding a predefined number of cycles of treatment.

The curves can be partitioned into states with and without toxicity to establish a unique endpoint: time to cessation of both immunotherapy and toxicity.

Researchers conducted a pooled analysis of 3-year follow-up data from the 1,077 patients who participated in CheckMate 069, testing nivo/ipi versus nivo alone, and CheckMate 067, comparing nivo/ipi, nivo alone, and ipi alone. The results were published in the Journal of Clinical Oncology.

The TFS without grade 3 or higher AEs was 28% for nivo/ipi, 11% for nivo alone, and 23% for ipi alone. The restricted mean time without either treatment or grade 3 or greater AEs was 10.1 months, 4.1 months, and 8.5 months, respectively.

TFS incentivizes the use of regimens that have:

• A short duration of treatment
• Prolonged time to subsequent therapy or death
• Only mild AEs of brief duration.

A higher TFS corresponds with the goals that patients and their providers would have for a treatment regimen.
 

Adaptive models provide clues about benefit from extended therapy

In contrast to cytotoxic chemotherapy and molecularly targeted agents, benefit from immune-targeted therapy can deepen and persist after treatment discontinuation.

In advanced melanoma, researchers observed that overall survival was similar for patients who discontinued nivo/ipi because of AEs during the induction phase of treatment and those who did not. These results were published in the Journal of Clinical Oncology.

This observation has led to an individualized, adaptive approach to de-escalating combination immunotherapy, described in Clinical Cancer Research. The approach is dubbed “SMART,” which stands for sequential multiple assignment randomized trial designs.

With the SMART approach, each stage of a trial corresponds to an important treatment decision point. The goal is to define the population of patients who can safely discontinue treatment based on response, rather than doing so after the development of AEs.

In the Adapt-IT prospective study, 60 patients with advanced melanoma with poor prognostic features were given two doses of nivo/ipi followed by a CT scan at week 6. They were triaged to stopping ipi and proceeding with maintenance therapy with nivo alone or continuing the combination for an additional two cycles of treatment. Results from this trial were presented at ASCO 2020 (abstract 10003).

The investigators found that 68% of patients had no tumor burden increase at week 6 and could discontinue ipi. For those patients, their response rate of 57% approached the expected results from a full course of ipi.

At median follow-up of 22.3 months, median response duration, PFS, and overall survival had not been reached for the responders who received an abbreviated course of the combination regimen.

There were two observations that suggested the first two cycles of treatment drove not only toxicity but also tumor control:

• The rate of grade 3-4 toxicity from only two cycles was high (57%).
• Of the 19 patients (32% of the original 60 patients) who had progressive disease after two cycles of nivo/ipi, there were no responders with continued therapy.

Dr. Postow commented that, in correlative studies conducted as part of Adapt-IT, the Ki-67 of CD8-positive T cells increased after the initial dose of nivo/ipi. However, proliferation did not continue with subsequent cycles (that is, Ki-67 did not continue to rise).

When they examined markers of T-cell stimulation such as inducible costimulator of CD8-positive T cells, the researchers observed the same effect. The “immune boost” occurred with cycle one but not after subsequent doses of the nivo/ipi combination.

Although unproven in clinical trials at this time, these data suggest that response and risks of toxicity may not support giving patients more than one cycle of combination treatment.
 

More nuanced ways of assessing tumor growth

Dr. Postow noted that judgment about treatment effects over time are often made by displaying spider plots of changes from baseline tumor size from “time zero” – the time at which combination therapy is commenced.

He speculated that it might be worthwhile to give a dose or two of immune-targeted monotherapy (such as a PD-1 or PD-L1 inhibitor alone) before time zero, measure tumor growth prior to and after the single agent, and reserve using combination immunotherapy only for those patients who do not experience a dampening of the growth curve.

Patients whose tumor growth kinetics are improved with single-agent treatment could be spared the additional toxicity (and uncertain additive benefit) from the second agent.
 

Treatment optimization: More than ‘messaging’

Oncology practice has passed through a long era of “more is better,” an era that gave rise to intensive cytotoxic chemotherapy for hematologic and solid tumors in the metastatic and adjuvant settings. In some cases, that approach proved to be curative, but not in all.

More recently, because of better staging, improved outcomes with newer technology and treatments, and concern about immediate- and late-onset health risks, there has been an effort to deintensify therapy when it can be done safely.

Once a treatment regimen and treatment duration become established, however, patients and their physicians are reluctant to deintensity therapy.

Dr. Postow’s presentation demonstrated that, with regard to immunotherapy combinations – as in other realms of medical practice – science can lead the way to treatment optimization for individual patients.

We have the potential to reassure patients that treatment de-escalation is a rational and personalized component of treatment optimization through the combination of:

• Identifying new endpoints to quantify treatment benefits and risks.
• SMART trial designs.
• Innovative ways to assess tumor response during each phase of a treatment course.

Precision assessment of immunotherapy effect in individual patients can be a key part of precision medicine.

Dr. Postow disclosed relationships with Aduro, Array BioPharma, Bristol Myers Squibb, Eisai, Incyte, Infinity, Merck, NewLink Genetics, Novartis, and RGenix.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Every medical oncologist who has described a combination chemotherapy regimen to a patient with advanced cancer has likely been asked whether the benefits of tumor shrinkage, disease-free survival (DFS), and overall survival are worth the risks of adverse events (AEs).

Single-agent immunotherapy and, more recently, combinations of immunotherapy drugs have been approved for a variety of metastatic tumors. In general, combination immunotherapy regimens have more AEs and a higher frequency of premature treatment discontinuation for toxicity.

Michael Postow, MD, of Memorial Sloan Kettering Cancer Center in New York, reflected on new ways to evaluate the benefits and risks of immunotherapy combinations during a plenary session on novel combinations at the American Association for Cancer Research’s Virtual Special Conference on Tumor Immunology and Immunotherapy.
 

Potential targets

As with chemotherapy drugs, immunotherapy combinations make the most sense when drugs targeting independent processes are employed.

As described in a paper published in Nature in 2011, the process for recruiting the immune system to combat cancer is as follows:

• Dendritic cells must sample antigens derived from the tumor.
• The dendritic cells must receive an activation signal so they promote immunity rather than tolerance.
• The tumor antigen–loaded dendritic cells need to generate protective T-cell responses, instead of T-regulatory responses, in lymphoid tissues.
• Cancer antigen–specific T cells must enter tumor tissues.
• Tumor-derived mechanisms for promoting immunosuppression need to be circumvented.

Since each step in the cascade is a potential therapeutic target, there are large numbers of potential drug combinations.
 

Measuring impact

Conventional measurements of tumor response may not be adequately sensitive to the impact from immunotherapy drugs. A case in point is sipuleucel-T, which is approved to treat advanced prostate cancer.

In the pivotal phase 3 trial, only 1 of 341 patients receiving sipuleucel-T achieved a partial response by RECIST criteria. Only 2.6% of patients had a 50% reduction in prostate-specific antigen levels. Nonetheless, a 4.1-month improvement in median overall survival was achieved. These results were published in the New England Journal of Medicine.

The discrepancy between tumor shrinkage and survival benefit for immunotherapy is not unexpected. As many as 10% of patients treated with ipilimumab (ipi) for stage IV malignant melanoma have progressive disease by tumor size but experience prolongation of survival, according to guidelines published in Clinical Cancer Research.

Accurate assessment of the ultimate efficacy of immunotherapy over time would benefit patients and clinicians since immune checkpoint inhibitors are often administered for several years, are financially costly, and treatment-associated AEs emerge unpredictably at any time.

Curtailing the duration of ineffective treatment could be valuable from many perspectives.
 

Immunotherapy combinations in metastatic melanoma

In the CheckMate 067 study, there was an improvement in response, progression-free survival (PFS), and overall survival for nivolumab (nivo) plus ipi or nivo alone, in comparison with ipi alone, in patients with advanced melanoma. Initial results from this trial were published in the New England Journal of Medicine in 2017.

At a minimum follow-up of 60 months, the 5-year overall survival was 52% for the nivo/ipi regimen, 44% for nivo alone, and 26% for ipi alone. These results were published in the New England Journal of Medicine in 2019.

The trial was not statistically powered to conclude whether the overall survival for the combination was superior to that of single-agent nivo alone, but both nivo regimens were superior to ipi alone.

Unfortunately, the combination also produced the highest treatment-related AE rates – 59% with nivo/ipi, 23% with nivo, and 28% with ipi in 2019. In the 2017 report, the combination regimen had more than twice as many premature treatment discontinuations as the other two study arms.

Is there a better way to quantify the risk-benefit ratio and explain it to patients?
 

Alternative strategies for assessing benefit: Treatment-free survival

Researchers have proposed treatment-free survival (TFS) as a potential new metric to characterize not only antitumor activity but also toxicity experienced after the cessation of therapy and before initiation of subsequent systemic therapy or death.

TFS is defined as the area between Kaplan-Meier curves from immunotherapy cessation until the reinitiation of systemic therapy or death. All patients who began immunotherapy are included – not just those achieving response or concluding a predefined number of cycles of treatment.

The curves can be partitioned into states with and without toxicity to establish a unique endpoint: time to cessation of both immunotherapy and toxicity.

Researchers conducted a pooled analysis of 3-year follow-up data from the 1,077 patients who participated in CheckMate 069, testing nivo/ipi versus nivo alone, and CheckMate 067, comparing nivo/ipi, nivo alone, and ipi alone. The results were published in the Journal of Clinical Oncology.

The TFS without grade 3 or higher AEs was 28% for nivo/ipi, 11% for nivo alone, and 23% for ipi alone. The restricted mean time without either treatment or grade 3 or greater AEs was 10.1 months, 4.1 months, and 8.5 months, respectively.

TFS incentivizes the use of regimens that have:

• A short duration of treatment
• Prolonged time to subsequent therapy or death
• Only mild AEs of brief duration.

A higher TFS corresponds with the goals that patients and their providers would have for a treatment regimen.
 

Adaptive models provide clues about benefit from extended therapy

In contrast to cytotoxic chemotherapy and molecularly targeted agents, benefit from immune-targeted therapy can deepen and persist after treatment discontinuation.

In advanced melanoma, researchers observed that overall survival was similar for patients who discontinued nivo/ipi because of AEs during the induction phase of treatment and those who did not. These results were published in the Journal of Clinical Oncology.

This observation has led to an individualized, adaptive approach to de-escalating combination immunotherapy, described in Clinical Cancer Research. The approach is dubbed “SMART,” which stands for sequential multiple assignment randomized trial designs.

With the SMART approach, each stage of a trial corresponds to an important treatment decision point. The goal is to define the population of patients who can safely discontinue treatment based on response, rather than doing so after the development of AEs.

In the Adapt-IT prospective study, 60 patients with advanced melanoma with poor prognostic features were given two doses of nivo/ipi followed by a CT scan at week 6. They were triaged to stopping ipi and proceeding with maintenance therapy with nivo alone or continuing the combination for an additional two cycles of treatment. Results from this trial were presented at ASCO 2020 (abstract 10003).

The investigators found that 68% of patients had no tumor burden increase at week 6 and could discontinue ipi. For those patients, their response rate of 57% approached the expected results from a full course of ipi.

At median follow-up of 22.3 months, median response duration, PFS, and overall survival had not been reached for the responders who received an abbreviated course of the combination regimen.

There were two observations that suggested the first two cycles of treatment drove not only toxicity but also tumor control:

• The rate of grade 3-4 toxicity from only two cycles was high (57%).
• Of the 19 patients (32% of the original 60 patients) who had progressive disease after two cycles of nivo/ipi, there were no responders with continued therapy.

Dr. Postow commented that, in correlative studies conducted as part of Adapt-IT, the Ki-67 of CD8-positive T cells increased after the initial dose of nivo/ipi. However, proliferation did not continue with subsequent cycles (that is, Ki-67 did not continue to rise).

When they examined markers of T-cell stimulation such as inducible costimulator of CD8-positive T cells, the researchers observed the same effect. The “immune boost” occurred with cycle one but not after subsequent doses of the nivo/ipi combination.

Although unproven in clinical trials at this time, these data suggest that response and risks of toxicity may not support giving patients more than one cycle of combination treatment.
 

More nuanced ways of assessing tumor growth

Dr. Postow noted that judgment about treatment effects over time are often made by displaying spider plots of changes from baseline tumor size from “time zero” – the time at which combination therapy is commenced.

He speculated that it might be worthwhile to give a dose or two of immune-targeted monotherapy (such as a PD-1 or PD-L1 inhibitor alone) before time zero, measure tumor growth prior to and after the single agent, and reserve using combination immunotherapy only for those patients who do not experience a dampening of the growth curve.

Patients whose tumor growth kinetics are improved with single-agent treatment could be spared the additional toxicity (and uncertain additive benefit) from the second agent.
 

Treatment optimization: More than ‘messaging’

Oncology practice has passed through a long era of “more is better,” an era that gave rise to intensive cytotoxic chemotherapy for hematologic and solid tumors in the metastatic and adjuvant settings. In some cases, that approach proved to be curative, but not in all.

More recently, because of better staging, improved outcomes with newer technology and treatments, and concern about immediate- and late-onset health risks, there has been an effort to deintensify therapy when it can be done safely.

Once a treatment regimen and treatment duration become established, however, patients and their physicians are reluctant to deintensity therapy.

Dr. Postow’s presentation demonstrated that, with regard to immunotherapy combinations – as in other realms of medical practice – science can lead the way to treatment optimization for individual patients.

We have the potential to reassure patients that treatment de-escalation is a rational and personalized component of treatment optimization through the combination of:

• Identifying new endpoints to quantify treatment benefits and risks.
• SMART trial designs.
• Innovative ways to assess tumor response during each phase of a treatment course.

Precision assessment of immunotherapy effect in individual patients can be a key part of precision medicine.

Dr. Postow disclosed relationships with Aduro, Array BioPharma, Bristol Myers Squibb, Eisai, Incyte, Infinity, Merck, NewLink Genetics, Novartis, and RGenix.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Every medical oncologist who has described a combination chemotherapy regimen to a patient with advanced cancer has likely been asked whether the benefits of tumor shrinkage, disease-free survival (DFS), and overall survival are worth the risks of adverse events (AEs).

Single-agent immunotherapy and, more recently, combinations of immunotherapy drugs have been approved for a variety of metastatic tumors. In general, combination immunotherapy regimens have more AEs and a higher frequency of premature treatment discontinuation for toxicity.

Michael Postow, MD, of Memorial Sloan Kettering Cancer Center in New York, reflected on new ways to evaluate the benefits and risks of immunotherapy combinations during a plenary session on novel combinations at the American Association for Cancer Research’s Virtual Special Conference on Tumor Immunology and Immunotherapy.
 

Potential targets

As with chemotherapy drugs, immunotherapy combinations make the most sense when drugs targeting independent processes are employed.

As described in a paper published in Nature in 2011, the process for recruiting the immune system to combat cancer is as follows:

• Dendritic cells must sample antigens derived from the tumor.
• The dendritic cells must receive an activation signal so they promote immunity rather than tolerance.
• The tumor antigen–loaded dendritic cells need to generate protective T-cell responses, instead of T-regulatory responses, in lymphoid tissues.
• Cancer antigen–specific T cells must enter tumor tissues.
• Tumor-derived mechanisms for promoting immunosuppression need to be circumvented.

Since each step in the cascade is a potential therapeutic target, there are large numbers of potential drug combinations.
 

Measuring impact

Conventional measurements of tumor response may not be adequately sensitive to the impact from immunotherapy drugs. A case in point is sipuleucel-T, which is approved to treat advanced prostate cancer.

In the pivotal phase 3 trial, only 1 of 341 patients receiving sipuleucel-T achieved a partial response by RECIST criteria. Only 2.6% of patients had a 50% reduction in prostate-specific antigen levels. Nonetheless, a 4.1-month improvement in median overall survival was achieved. These results were published in the New England Journal of Medicine.

The discrepancy between tumor shrinkage and survival benefit for immunotherapy is not unexpected. As many as 10% of patients treated with ipilimumab (ipi) for stage IV malignant melanoma have progressive disease by tumor size but experience prolongation of survival, according to guidelines published in Clinical Cancer Research.

Accurate assessment of the ultimate efficacy of immunotherapy over time would benefit patients and clinicians since immune checkpoint inhibitors are often administered for several years, are financially costly, and treatment-associated AEs emerge unpredictably at any time.

Curtailing the duration of ineffective treatment could be valuable from many perspectives.
 

Immunotherapy combinations in metastatic melanoma

In the CheckMate 067 study, there was an improvement in response, progression-free survival (PFS), and overall survival for nivolumab (nivo) plus ipi or nivo alone, in comparison with ipi alone, in patients with advanced melanoma. Initial results from this trial were published in the New England Journal of Medicine in 2017.

At a minimum follow-up of 60 months, the 5-year overall survival was 52% for the nivo/ipi regimen, 44% for nivo alone, and 26% for ipi alone. These results were published in the New England Journal of Medicine in 2019.

The trial was not statistically powered to conclude whether the overall survival for the combination was superior to that of single-agent nivo alone, but both nivo regimens were superior to ipi alone.

Unfortunately, the combination also produced the highest treatment-related AE rates – 59% with nivo/ipi, 23% with nivo, and 28% with ipi in 2019. In the 2017 report, the combination regimen had more than twice as many premature treatment discontinuations as the other two study arms.

Is there a better way to quantify the risk-benefit ratio and explain it to patients?
 

Alternative strategies for assessing benefit: Treatment-free survival

Researchers have proposed treatment-free survival (TFS) as a potential new metric to characterize not only antitumor activity but also toxicity experienced after the cessation of therapy and before initiation of subsequent systemic therapy or death.

TFS is defined as the area between Kaplan-Meier curves from immunotherapy cessation until the reinitiation of systemic therapy or death. All patients who began immunotherapy are included – not just those achieving response or concluding a predefined number of cycles of treatment.

The curves can be partitioned into states with and without toxicity to establish a unique endpoint: time to cessation of both immunotherapy and toxicity.

Researchers conducted a pooled analysis of 3-year follow-up data from the 1,077 patients who participated in CheckMate 069, testing nivo/ipi versus nivo alone, and CheckMate 067, comparing nivo/ipi, nivo alone, and ipi alone. The results were published in the Journal of Clinical Oncology.

The TFS without grade 3 or higher AEs was 28% for nivo/ipi, 11% for nivo alone, and 23% for ipi alone. The restricted mean time without either treatment or grade 3 or greater AEs was 10.1 months, 4.1 months, and 8.5 months, respectively.

TFS incentivizes the use of regimens that have:

• A short duration of treatment
• Prolonged time to subsequent therapy or death
• Only mild AEs of brief duration.

A higher TFS corresponds with the goals that patients and their providers would have for a treatment regimen.
 

Adaptive models provide clues about benefit from extended therapy

In contrast to cytotoxic chemotherapy and molecularly targeted agents, benefit from immune-targeted therapy can deepen and persist after treatment discontinuation.

In advanced melanoma, researchers observed that overall survival was similar for patients who discontinued nivo/ipi because of AEs during the induction phase of treatment and those who did not. These results were published in the Journal of Clinical Oncology.

This observation has led to an individualized, adaptive approach to de-escalating combination immunotherapy, described in Clinical Cancer Research. The approach is dubbed “SMART,” which stands for sequential multiple assignment randomized trial designs.

With the SMART approach, each stage of a trial corresponds to an important treatment decision point. The goal is to define the population of patients who can safely discontinue treatment based on response, rather than doing so after the development of AEs.

In the Adapt-IT prospective study, 60 patients with advanced melanoma with poor prognostic features were given two doses of nivo/ipi followed by a CT scan at week 6. They were triaged to stopping ipi and proceeding with maintenance therapy with nivo alone or continuing the combination for an additional two cycles of treatment. Results from this trial were presented at ASCO 2020 (abstract 10003).

The investigators found that 68% of patients had no tumor burden increase at week 6 and could discontinue ipi. For those patients, their response rate of 57% approached the expected results from a full course of ipi.

At median follow-up of 22.3 months, median response duration, PFS, and overall survival had not been reached for the responders who received an abbreviated course of the combination regimen.

There were two observations that suggested the first two cycles of treatment drove not only toxicity but also tumor control:

• The rate of grade 3-4 toxicity from only two cycles was high (57%).
• Of the 19 patients (32% of the original 60 patients) who had progressive disease after two cycles of nivo/ipi, there were no responders with continued therapy.

Dr. Postow commented that, in correlative studies conducted as part of Adapt-IT, the Ki-67 of CD8-positive T cells increased after the initial dose of nivo/ipi. However, proliferation did not continue with subsequent cycles (that is, Ki-67 did not continue to rise).

When they examined markers of T-cell stimulation such as inducible costimulator of CD8-positive T cells, the researchers observed the same effect. The “immune boost” occurred with cycle one but not after subsequent doses of the nivo/ipi combination.

Although unproven in clinical trials at this time, these data suggest that response and risks of toxicity may not support giving patients more than one cycle of combination treatment.
 

More nuanced ways of assessing tumor growth

Dr. Postow noted that judgment about treatment effects over time are often made by displaying spider plots of changes from baseline tumor size from “time zero” – the time at which combination therapy is commenced.

He speculated that it might be worthwhile to give a dose or two of immune-targeted monotherapy (such as a PD-1 or PD-L1 inhibitor alone) before time zero, measure tumor growth prior to and after the single agent, and reserve using combination immunotherapy only for those patients who do not experience a dampening of the growth curve.

Patients whose tumor growth kinetics are improved with single-agent treatment could be spared the additional toxicity (and uncertain additive benefit) from the second agent.
 

Treatment optimization: More than ‘messaging’

Oncology practice has passed through a long era of “more is better,” an era that gave rise to intensive cytotoxic chemotherapy for hematologic and solid tumors in the metastatic and adjuvant settings. In some cases, that approach proved to be curative, but not in all.

More recently, because of better staging, improved outcomes with newer technology and treatments, and concern about immediate- and late-onset health risks, there has been an effort to deintensify therapy when it can be done safely.

Once a treatment regimen and treatment duration become established, however, patients and their physicians are reluctant to deintensity therapy.

Dr. Postow’s presentation demonstrated that, with regard to immunotherapy combinations – as in other realms of medical practice – science can lead the way to treatment optimization for individual patients.

We have the potential to reassure patients that treatment de-escalation is a rational and personalized component of treatment optimization through the combination of:

• Identifying new endpoints to quantify treatment benefits and risks.
• SMART trial designs.
• Innovative ways to assess tumor response during each phase of a treatment course.

Precision assessment of immunotherapy effect in individual patients can be a key part of precision medicine.

Dr. Postow disclosed relationships with Aduro, Array BioPharma, Bristol Myers Squibb, Eisai, Incyte, Infinity, Merck, NewLink Genetics, Novartis, and RGenix.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

When chronic graft-versus-host disease (cGVHD) develops as a complication of allogeneic hematopoietic stem cell transplant (alloHSCT), treatment options are limited. New findings show that ruxolitinib (Jakafi) was superior to standard therapy in reducing symptoms of cGVHD in the second-line setting, and the results are potentially practice changing.  

The new data, from the REACH3 trial, were presented at the annual meeting of the American Society of Hematology, held virtually this year.

This trial is “almost certainly a practice changer,” Robert Brodsky, MD, ASH secretary, said during a press preview webinar.  

Chronic GVHD occurs in approximately 30%-70% of patients who undergo alloSCT, and “has been really hard to treat,” said Dr. Brodsky, of Johns Hopkins University, Baltimore. “Steroids are the first-line treatment, but after that, nothing else has shown any improvement and even steroids don’t work that well.”

Of the patients assessed, 50% of those who received ruxolitinib responded to therapy compared with only 25% who received standard therapies.

“This is the first multicenter randomized controlled trial for chronic GVHD that is positive,” said senior study author Robert Zeiser, PhD, of University Medical Center, Freiburg, Germany. “It shows a significant advantage for ruxolitinib. It is likely that this trial will lead to approval for this indication and change the guidelines for the treatment of this disease.”

Ruxolitinib, a JAK inhibitor first marketed for use in myelofibrosis, is already  approved for acute GVHD. The Food and Drug Administration approved that indication last year on the basis of data from two previous trials, REACH 1 and REACH 2. The trials found that ruxolitinib was superior to best available therapy for treating patients with acute GVHD.
 

Superior to best available therapy

In the current REACH 3 study, Dr. Zeiser and colleagues compared ruxolitinib with best available therapy in 329 patients with moderate-to-severe cGVHD (both steroid dependent and steroid resistant).

All patients had undergone alloSCT and were randomly assigned to ruxolitinib (10 mg twice daily) for six 28-day cycles or investigator-selected best available therapy (BAT), of which there were 10 options. Patients continued receiving their regimen of corticosteroids, and viral prophylaxis and antibiotics were allowed as needed for infection prevention and treatment.

The study permitted crossover: Patients on BAT were allowed to start on ruxolitinib on or after cycle 7 day 1 for those who did not achieve or maintain a response, developed toxicity to BAT, or had a cGVHD flare.

The study met its primary endpoint of overall response rate (ORR), with a clear and substantial improvement among patients taking ruxolitinib (50% vs 26%; odds ratio, 2.99; P < .0001a), Dr. Zeiser noted. The complete response rate was also higher (7% vs. 3%).

Both key secondary endpoints also showed that ruxolitinib was superior to BAT. Failure-free survival was significantly longer in the ruxolitinib group (median not reached vs 5.7 months; hazard ratio, 0.370; P < .0001). There was also an improvement in symptoms based on changes in the modified Lee symptom score (mLSS; 0 [no symptoms] to 100 [worst symptoms]) at cycle 7 day 1; the results show that the mLSS responder rate was higher in patients on ruxolitinib (24% vs. 11%; odds ratio, 2.62; P = .0011).

A total of 31 patients in the ruxolitinib group died (19%) along with 27 in the BAT group (16%), with the cGVHD as the main cause of death.

Adverse events were comparable in both groups (ruxolitinib 98% [grade ≥ 3, 57%]; BAT, 92% [grade ≥ 3, 58%], with the most common being anemia (29% vs. 13%), hypertension (16% vs. 13%), pyrexia (16% vs. 9%), and ALT increase (15% vs 4%).
 

More options for patients

“The addition of ruxolitinib is definitely practice changing for this very difficult to treat population,” said James Essell, MD,  medical director of the Blood Cancer Center at Mercy Health, Cincinnati, who was not involved in the study.

However, he added, “more options are still required, as evidenced by the continued deaths of patients despite this new option.”

Dr. Essell pointed out that ibrutinib (Imbruvica) is already approved for the treatment of cGVHD. “Ruxolitinib offers another option for treating this group of patients,” he said, and predicted that “it will be used frequently and has a different toxicity profile, ultimately improving the care for patients with cGVHD.”

It is likely that ruxolitinib will be considered earlier in the treatment of cGVHD to avoid the toxicity of chronic steroid use, he added, but price is a consideration. “The cost of ruxolitinib is over 200 times more than prednisone, limiting the adoption front line without a clinical trial.”

Another expert approached for comment was enthusiastic. “The abstract gave good evidence and efficacy with chronic GVHD,” said Ryotaro Nakamura, MD, associate professor of hematology & hematopoietic cell transplantation at City of Hope, Duarte, Calif. He noted that there have been two previous REACH trials which showed a benefit for ruxolitinib in acute GVHD.

What this means is that there is now global evidence that ruxolitinib is better than anything else so far, he said, and this latest trial is just part of the “practice-changing data,” from the three studies. “It is practice changing in that it is providing options now for these patients,” he said.

Dr. Zeiser has disclosed relationships with Incyte, Novartis and Mallinckrodt; other authors disclosed relationships with industry as noted in the abstract. Dr. Essell and Dr. Nakamura have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

When chronic graft-versus-host disease (cGVHD) develops as a complication of allogeneic hematopoietic stem cell transplant (alloHSCT), treatment options are limited. New findings show that ruxolitinib (Jakafi) was superior to standard therapy in reducing symptoms of cGVHD in the second-line setting, and the results are potentially practice changing.  

The new data, from the REACH3 trial, were presented at the annual meeting of the American Society of Hematology, held virtually this year.

This trial is “almost certainly a practice changer,” Robert Brodsky, MD, ASH secretary, said during a press preview webinar.  

Chronic GVHD occurs in approximately 30%-70% of patients who undergo alloSCT, and “has been really hard to treat,” said Dr. Brodsky, of Johns Hopkins University, Baltimore. “Steroids are the first-line treatment, but after that, nothing else has shown any improvement and even steroids don’t work that well.”

Of the patients assessed, 50% of those who received ruxolitinib responded to therapy compared with only 25% who received standard therapies.

“This is the first multicenter randomized controlled trial for chronic GVHD that is positive,” said senior study author Robert Zeiser, PhD, of University Medical Center, Freiburg, Germany. “It shows a significant advantage for ruxolitinib. It is likely that this trial will lead to approval for this indication and change the guidelines for the treatment of this disease.”

Ruxolitinib, a JAK inhibitor first marketed for use in myelofibrosis, is already  approved for acute GVHD. The Food and Drug Administration approved that indication last year on the basis of data from two previous trials, REACH 1 and REACH 2. The trials found that ruxolitinib was superior to best available therapy for treating patients with acute GVHD.
 

Superior to best available therapy

In the current REACH 3 study, Dr. Zeiser and colleagues compared ruxolitinib with best available therapy in 329 patients with moderate-to-severe cGVHD (both steroid dependent and steroid resistant).

All patients had undergone alloSCT and were randomly assigned to ruxolitinib (10 mg twice daily) for six 28-day cycles or investigator-selected best available therapy (BAT), of which there were 10 options. Patients continued receiving their regimen of corticosteroids, and viral prophylaxis and antibiotics were allowed as needed for infection prevention and treatment.

The study permitted crossover: Patients on BAT were allowed to start on ruxolitinib on or after cycle 7 day 1 for those who did not achieve or maintain a response, developed toxicity to BAT, or had a cGVHD flare.

The study met its primary endpoint of overall response rate (ORR), with a clear and substantial improvement among patients taking ruxolitinib (50% vs 26%; odds ratio, 2.99; P < .0001a), Dr. Zeiser noted. The complete response rate was also higher (7% vs. 3%).

Both key secondary endpoints also showed that ruxolitinib was superior to BAT. Failure-free survival was significantly longer in the ruxolitinib group (median not reached vs 5.7 months; hazard ratio, 0.370; P < .0001). There was also an improvement in symptoms based on changes in the modified Lee symptom score (mLSS; 0 [no symptoms] to 100 [worst symptoms]) at cycle 7 day 1; the results show that the mLSS responder rate was higher in patients on ruxolitinib (24% vs. 11%; odds ratio, 2.62; P = .0011).

A total of 31 patients in the ruxolitinib group died (19%) along with 27 in the BAT group (16%), with the cGVHD as the main cause of death.

Adverse events were comparable in both groups (ruxolitinib 98% [grade ≥ 3, 57%]; BAT, 92% [grade ≥ 3, 58%], with the most common being anemia (29% vs. 13%), hypertension (16% vs. 13%), pyrexia (16% vs. 9%), and ALT increase (15% vs 4%).
 

More options for patients

“The addition of ruxolitinib is definitely practice changing for this very difficult to treat population,” said James Essell, MD,  medical director of the Blood Cancer Center at Mercy Health, Cincinnati, who was not involved in the study.

However, he added, “more options are still required, as evidenced by the continued deaths of patients despite this new option.”

Dr. Essell pointed out that ibrutinib (Imbruvica) is already approved for the treatment of cGVHD. “Ruxolitinib offers another option for treating this group of patients,” he said, and predicted that “it will be used frequently and has a different toxicity profile, ultimately improving the care for patients with cGVHD.”

It is likely that ruxolitinib will be considered earlier in the treatment of cGVHD to avoid the toxicity of chronic steroid use, he added, but price is a consideration. “The cost of ruxolitinib is over 200 times more than prednisone, limiting the adoption front line without a clinical trial.”

Another expert approached for comment was enthusiastic. “The abstract gave good evidence and efficacy with chronic GVHD,” said Ryotaro Nakamura, MD, associate professor of hematology & hematopoietic cell transplantation at City of Hope, Duarte, Calif. He noted that there have been two previous REACH trials which showed a benefit for ruxolitinib in acute GVHD.

What this means is that there is now global evidence that ruxolitinib is better than anything else so far, he said, and this latest trial is just part of the “practice-changing data,” from the three studies. “It is practice changing in that it is providing options now for these patients,” he said.

Dr. Zeiser has disclosed relationships with Incyte, Novartis and Mallinckrodt; other authors disclosed relationships with industry as noted in the abstract. Dr. Essell and Dr. Nakamura have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

When chronic graft-versus-host disease (cGVHD) develops as a complication of allogeneic hematopoietic stem cell transplant (alloHSCT), treatment options are limited. New findings show that ruxolitinib (Jakafi) was superior to standard therapy in reducing symptoms of cGVHD in the second-line setting, and the results are potentially practice changing.  

The new data, from the REACH3 trial, were presented at the annual meeting of the American Society of Hematology, held virtually this year.

This trial is “almost certainly a practice changer,” Robert Brodsky, MD, ASH secretary, said during a press preview webinar.  

Chronic GVHD occurs in approximately 30%-70% of patients who undergo alloSCT, and “has been really hard to treat,” said Dr. Brodsky, of Johns Hopkins University, Baltimore. “Steroids are the first-line treatment, but after that, nothing else has shown any improvement and even steroids don’t work that well.”

Of the patients assessed, 50% of those who received ruxolitinib responded to therapy compared with only 25% who received standard therapies.

“This is the first multicenter randomized controlled trial for chronic GVHD that is positive,” said senior study author Robert Zeiser, PhD, of University Medical Center, Freiburg, Germany. “It shows a significant advantage for ruxolitinib. It is likely that this trial will lead to approval for this indication and change the guidelines for the treatment of this disease.”

Ruxolitinib, a JAK inhibitor first marketed for use in myelofibrosis, is already  approved for acute GVHD. The Food and Drug Administration approved that indication last year on the basis of data from two previous trials, REACH 1 and REACH 2. The trials found that ruxolitinib was superior to best available therapy for treating patients with acute GVHD.
 

Superior to best available therapy

In the current REACH 3 study, Dr. Zeiser and colleagues compared ruxolitinib with best available therapy in 329 patients with moderate-to-severe cGVHD (both steroid dependent and steroid resistant).

All patients had undergone alloSCT and were randomly assigned to ruxolitinib (10 mg twice daily) for six 28-day cycles or investigator-selected best available therapy (BAT), of which there were 10 options. Patients continued receiving their regimen of corticosteroids, and viral prophylaxis and antibiotics were allowed as needed for infection prevention and treatment.

The study permitted crossover: Patients on BAT were allowed to start on ruxolitinib on or after cycle 7 day 1 for those who did not achieve or maintain a response, developed toxicity to BAT, or had a cGVHD flare.

The study met its primary endpoint of overall response rate (ORR), with a clear and substantial improvement among patients taking ruxolitinib (50% vs 26%; odds ratio, 2.99; P < .0001a), Dr. Zeiser noted. The complete response rate was also higher (7% vs. 3%).

Both key secondary endpoints also showed that ruxolitinib was superior to BAT. Failure-free survival was significantly longer in the ruxolitinib group (median not reached vs 5.7 months; hazard ratio, 0.370; P < .0001). There was also an improvement in symptoms based on changes in the modified Lee symptom score (mLSS; 0 [no symptoms] to 100 [worst symptoms]) at cycle 7 day 1; the results show that the mLSS responder rate was higher in patients on ruxolitinib (24% vs. 11%; odds ratio, 2.62; P = .0011).

A total of 31 patients in the ruxolitinib group died (19%) along with 27 in the BAT group (16%), with the cGVHD as the main cause of death.

Adverse events were comparable in both groups (ruxolitinib 98% [grade ≥ 3, 57%]; BAT, 92% [grade ≥ 3, 58%], with the most common being anemia (29% vs. 13%), hypertension (16% vs. 13%), pyrexia (16% vs. 9%), and ALT increase (15% vs 4%).
 

More options for patients

“The addition of ruxolitinib is definitely practice changing for this very difficult to treat population,” said James Essell, MD,  medical director of the Blood Cancer Center at Mercy Health, Cincinnati, who was not involved in the study.

However, he added, “more options are still required, as evidenced by the continued deaths of patients despite this new option.”

Dr. Essell pointed out that ibrutinib (Imbruvica) is already approved for the treatment of cGVHD. “Ruxolitinib offers another option for treating this group of patients,” he said, and predicted that “it will be used frequently and has a different toxicity profile, ultimately improving the care for patients with cGVHD.”

It is likely that ruxolitinib will be considered earlier in the treatment of cGVHD to avoid the toxicity of chronic steroid use, he added, but price is a consideration. “The cost of ruxolitinib is over 200 times more than prednisone, limiting the adoption front line without a clinical trial.”

Another expert approached for comment was enthusiastic. “The abstract gave good evidence and efficacy with chronic GVHD,” said Ryotaro Nakamura, MD, associate professor of hematology & hematopoietic cell transplantation at City of Hope, Duarte, Calif. He noted that there have been two previous REACH trials which showed a benefit for ruxolitinib in acute GVHD.

What this means is that there is now global evidence that ruxolitinib is better than anything else so far, he said, and this latest trial is just part of the “practice-changing data,” from the three studies. “It is practice changing in that it is providing options now for these patients,” he said.

Dr. Zeiser has disclosed relationships with Incyte, Novartis and Mallinckrodt; other authors disclosed relationships with industry as noted in the abstract. Dr. Essell and Dr. Nakamura have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Despite being routinely used in clinical settings, prophylactic use of tranexamic acid, an antifibrinolytic agent administered with platelet transfusions, did not reduce bleeding among patients with blood cancers and severe thrombocytopenia, according to a new study.

The study compared tranexamic acid to placebo and found no significant differences in terms of the number of bleeding events, the number of red blood cell transfusions, or the number of platelet transfusions that were required.

However, the rate of occlusions in the central venous line was significantly higher for patients in the tranexamic acid group, although there was no difference between groups for other types of thrombotic events.

The findings were presented at the annual meeting of the American Society of Hematology, which was held online.

The study was highlighted as potentially practice changing at a press preview webinar by ASH Secretary Robert Brodsky, MD.

“They found absolutely no difference in bleeding or need for transfusion,” said Brodsky. “What they did find was more catheter-associated blood clots in the tranexamic acid group. This is a practice changer in that it probably should not be given prophylactically to patients with thrombocytopenia.”

Senior author Terry B. Gernsheimer, MD, of the University of Washington, Seattle, noted that tranexamic acid has been found to be effective in the treatment of bleeding related to childbirth, surgery, and inherited blood disorders.

It is also used for patients with blood cancers and severe thrombocytopenia. There is little evidence to support this use, which is why the researchers decided to investigate.

“Clearly patients with low platelet counts and blood cancers have a different kind of bleeding than the bleeding experienced by patients who have suffered some kind of trauma or surgery,” Dr. Gernsheimer said in a statement.

“Their bleeding likely is due to endothelial damage – damage to the lining of blood vessels – that tranexamic acid would not treat,” she added.

“To prevent bleeding in these patients, we may need to look at ways to speed the healing of the endothelium that occurs with chemotherapy, radiation, and graft-vs-host disease in patients receiving a transplant,” Dr. Gernsheimer commented.
 

Temper enthusiasm

“Overall, I think these results will temper enthusiasm for using tranexamic acid in this setting,” said Mitul Gandhi, MD, a medical oncologist with Virginia Cancer Specialists, who was approached for comment.

These data do not support the routine use of prophylactic tranexamic acid in chemotherapy-induced thrombocytopenia for patients with platelet counts lower than 30,000/μL, he added.

“The primary objective was not met, and there was an observed increased rate of catheter-associated thrombosis,” he said. “Continued use of judicious transfusion support and correction of a concomitant coagulopathy remains the main clinical approach to these patients.”

Dr. Gandhi commented that tranexamic acid “remains a potentially useful adjunct agent in certain cases of recalcitrant bleeding related to thrombocytopenia or coagulopathy.

“While there is no uniform scenario, it is typically reserved on a case-by-case basis after addressing vascular defects, utilization of platelet, fresh frozen plasma, cryoprecipitate transfusions, vitamin K repletion, and of course excluding any antiplatelet or anticoagulant therapy,» he told this news organization. “For persistent bleeding in spite of all corrective measures or hemorrhage into noncompressible vascular beds, such as with intracranial bleeds, antifibrinolytic therapy may assist in mitigating further blood loss.”

However, this has to be balanced with the potential increased risk for thrombosis after correction of the hemostatic insult.

At present, tranexamic acid “only has an FDA indication for uterine bleeding, but it is frequently used in trauma settings and obstetrical emergencies,” said Douglas Tremblay, MD, an internist at the Icahn School of Medicine at Mount Sinai, New York, who was also approached for comment.

“There is evidence from prior studies that were done 20 or 30 years ago that it may help in this setting, so it is used in some institutions, although we don’t give it prophylactically for patients with a hematologic malignancy.”

Although this was a negative study, Dr. Tremblay pointed out that one thing that may come out of it is that there may be subgroups who can benefit from the prophylactic use of tranexamic acid. “There is very wide inclusion criteria for the study – any type of hematologic malignancy in patients undergoing chemotherapy or stem cell transplant,” he said in an interview. “Even among chemotherapy and transplant patients, there are different risks for bleeding.”

For example, patients undergoing induction chemotherapy for acute myeloid leukemia are at an increased risk of bleeding in comparison with patients with other hematologic malignancies, and those undergoing allogeneic transplant are at an increased risk of bleeding in comparison with patients undergoing autologous transplant. “So while its unclear if a subgroup may benefit from this strategy, lumped together, it doesn’t appear it is of any benefit and potentially harmful, in terms of line occlusions,” he said. “While that may seem to be a nuisance, it can delay chemotherapy or supportive infusions, and that can be a big deal.”
 

No evidence of benefit

Dr. Gernsheimer and colleagues conducted the American Trial Using Tranexamic Acid in Thrombocytopenia (A-TREAT), which evaluated the effects of prophylactic tranexamic acid as an adjunct to routine transfusion therapy on bleeding and transfusion requirements.

A total of 330 patients were randomly assigned to receive either tranexamic acid 1,000 mg IV or 1,300 mg or placebo. Randomization was stratified by site and therapy: chemotherapy, allogeneic transplant, or autologous transplant. It was anticipated that all patients had hypoproliferative thrombocytopenia (expected platelet count, 10,000/µL for at least 5 days).

Treatment continued for 30 days or platelet count recovery (>30,000/µL), diagnosis of thrombosis or veno-occlusive disease, recurrent line occlusion, visible hematuria, or physician or patient request.

The primary endpoint of the study was the proportion of patients with bleeding of World Health Organization grade 2 or above over 30 days after beginning therapy. Secondary endpoints included the number of transfusions and the number of days alive without WHO grade 2+ bleeding during the first 30 days post activation of study drug.

The time to first WHO 2+ bleeding was “remarkably similar” between the tranexamic acid groups and the placebo group, said Dr. Gernsheimer.

In the cohort as a whole, 48.8% in the placebo group experienced a grade 2+ bleed vs. 45.4% in the tranexamic group (odds ratio, 0.86).

Similar results were observed across subgroups: allogeneic transplant, 57.3% vs. 58.8% (OR, 0.94); autologous transplant, 19.9% vs. 24.7% ( OR, 0.71); or chemotherapy, 48% vs. 52.1% (OR, 0.84).

There were no significant differences in mean number of transfusions (difference, 0.1; 95% confidence interval, –1.9 to 2) or days alive without grade 2 or higher bleeding (difference, 0.1; 95% CI, –1.4 to 1.5).

“A post hoc analysis of WHO 3+ bleeding showed these events to be rare and without any improvement with tranexamic acid,” she said.

A higher percentage of patients in the tranexamic acid group experienced thrombotic events (19.5% vs. 11%). “But importantly, in both groups, it was primarily due to central line occlusions without an associated thrombus,” said Dr. Gernsheimer. “This was statistically significant.”

Fewer non–catheter related thrombotic events occurred in the tranexamic acid group (3.7% vs. 5.5%), but the difference was not statistically significant.

There was also no significant difference between groups in veno-occlusive disease after 30 days (1.8% vs. 1.2%) or all-cause mortality at 30 days (2.4% vs. 3%) or 100 days (11.5% vs. 11.5%). No deaths associated with thrombosis had occurred in either group at 120 days.

The study was supported by the University of Washington and the National Heart, Lung, and Blood Institute. Dr. Gernsheimer has relationships with Amgen, Cellphire, Dova Pharmaceuticals, Novartis, Principia, Rigel, Sanofi, and Vertex. Dr. Tremblay and Dr. Gandhi have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Despite being routinely used in clinical settings, prophylactic use of tranexamic acid, an antifibrinolytic agent administered with platelet transfusions, did not reduce bleeding among patients with blood cancers and severe thrombocytopenia, according to a new study.

The study compared tranexamic acid to placebo and found no significant differences in terms of the number of bleeding events, the number of red blood cell transfusions, or the number of platelet transfusions that were required.

However, the rate of occlusions in the central venous line was significantly higher for patients in the tranexamic acid group, although there was no difference between groups for other types of thrombotic events.

The findings were presented at the annual meeting of the American Society of Hematology, which was held online.

The study was highlighted as potentially practice changing at a press preview webinar by ASH Secretary Robert Brodsky, MD.

“They found absolutely no difference in bleeding or need for transfusion,” said Brodsky. “What they did find was more catheter-associated blood clots in the tranexamic acid group. This is a practice changer in that it probably should not be given prophylactically to patients with thrombocytopenia.”

Senior author Terry B. Gernsheimer, MD, of the University of Washington, Seattle, noted that tranexamic acid has been found to be effective in the treatment of bleeding related to childbirth, surgery, and inherited blood disorders.

It is also used for patients with blood cancers and severe thrombocytopenia. There is little evidence to support this use, which is why the researchers decided to investigate.

“Clearly patients with low platelet counts and blood cancers have a different kind of bleeding than the bleeding experienced by patients who have suffered some kind of trauma or surgery,” Dr. Gernsheimer said in a statement.

“Their bleeding likely is due to endothelial damage – damage to the lining of blood vessels – that tranexamic acid would not treat,” she added.

“To prevent bleeding in these patients, we may need to look at ways to speed the healing of the endothelium that occurs with chemotherapy, radiation, and graft-vs-host disease in patients receiving a transplant,” Dr. Gernsheimer commented.
 

Temper enthusiasm

“Overall, I think these results will temper enthusiasm for using tranexamic acid in this setting,” said Mitul Gandhi, MD, a medical oncologist with Virginia Cancer Specialists, who was approached for comment.

These data do not support the routine use of prophylactic tranexamic acid in chemotherapy-induced thrombocytopenia for patients with platelet counts lower than 30,000/μL, he added.

“The primary objective was not met, and there was an observed increased rate of catheter-associated thrombosis,” he said. “Continued use of judicious transfusion support and correction of a concomitant coagulopathy remains the main clinical approach to these patients.”

Dr. Gandhi commented that tranexamic acid “remains a potentially useful adjunct agent in certain cases of recalcitrant bleeding related to thrombocytopenia or coagulopathy.

“While there is no uniform scenario, it is typically reserved on a case-by-case basis after addressing vascular defects, utilization of platelet, fresh frozen plasma, cryoprecipitate transfusions, vitamin K repletion, and of course excluding any antiplatelet or anticoagulant therapy,» he told this news organization. “For persistent bleeding in spite of all corrective measures or hemorrhage into noncompressible vascular beds, such as with intracranial bleeds, antifibrinolytic therapy may assist in mitigating further blood loss.”

However, this has to be balanced with the potential increased risk for thrombosis after correction of the hemostatic insult.

At present, tranexamic acid “only has an FDA indication for uterine bleeding, but it is frequently used in trauma settings and obstetrical emergencies,” said Douglas Tremblay, MD, an internist at the Icahn School of Medicine at Mount Sinai, New York, who was also approached for comment.

“There is evidence from prior studies that were done 20 or 30 years ago that it may help in this setting, so it is used in some institutions, although we don’t give it prophylactically for patients with a hematologic malignancy.”

Although this was a negative study, Dr. Tremblay pointed out that one thing that may come out of it is that there may be subgroups who can benefit from the prophylactic use of tranexamic acid. “There is very wide inclusion criteria for the study – any type of hematologic malignancy in patients undergoing chemotherapy or stem cell transplant,” he said in an interview. “Even among chemotherapy and transplant patients, there are different risks for bleeding.”

For example, patients undergoing induction chemotherapy for acute myeloid leukemia are at an increased risk of bleeding in comparison with patients with other hematologic malignancies, and those undergoing allogeneic transplant are at an increased risk of bleeding in comparison with patients undergoing autologous transplant. “So while its unclear if a subgroup may benefit from this strategy, lumped together, it doesn’t appear it is of any benefit and potentially harmful, in terms of line occlusions,” he said. “While that may seem to be a nuisance, it can delay chemotherapy or supportive infusions, and that can be a big deal.”
 

No evidence of benefit

Dr. Gernsheimer and colleagues conducted the American Trial Using Tranexamic Acid in Thrombocytopenia (A-TREAT), which evaluated the effects of prophylactic tranexamic acid as an adjunct to routine transfusion therapy on bleeding and transfusion requirements.

A total of 330 patients were randomly assigned to receive either tranexamic acid 1,000 mg IV or 1,300 mg or placebo. Randomization was stratified by site and therapy: chemotherapy, allogeneic transplant, or autologous transplant. It was anticipated that all patients had hypoproliferative thrombocytopenia (expected platelet count, 10,000/µL for at least 5 days).

Treatment continued for 30 days or platelet count recovery (>30,000/µL), diagnosis of thrombosis or veno-occlusive disease, recurrent line occlusion, visible hematuria, or physician or patient request.

The primary endpoint of the study was the proportion of patients with bleeding of World Health Organization grade 2 or above over 30 days after beginning therapy. Secondary endpoints included the number of transfusions and the number of days alive without WHO grade 2+ bleeding during the first 30 days post activation of study drug.

The time to first WHO 2+ bleeding was “remarkably similar” between the tranexamic acid groups and the placebo group, said Dr. Gernsheimer.

In the cohort as a whole, 48.8% in the placebo group experienced a grade 2+ bleed vs. 45.4% in the tranexamic group (odds ratio, 0.86).

Similar results were observed across subgroups: allogeneic transplant, 57.3% vs. 58.8% (OR, 0.94); autologous transplant, 19.9% vs. 24.7% ( OR, 0.71); or chemotherapy, 48% vs. 52.1% (OR, 0.84).

There were no significant differences in mean number of transfusions (difference, 0.1; 95% confidence interval, –1.9 to 2) or days alive without grade 2 or higher bleeding (difference, 0.1; 95% CI, –1.4 to 1.5).

“A post hoc analysis of WHO 3+ bleeding showed these events to be rare and without any improvement with tranexamic acid,” she said.

A higher percentage of patients in the tranexamic acid group experienced thrombotic events (19.5% vs. 11%). “But importantly, in both groups, it was primarily due to central line occlusions without an associated thrombus,” said Dr. Gernsheimer. “This was statistically significant.”

Fewer non–catheter related thrombotic events occurred in the tranexamic acid group (3.7% vs. 5.5%), but the difference was not statistically significant.

There was also no significant difference between groups in veno-occlusive disease after 30 days (1.8% vs. 1.2%) or all-cause mortality at 30 days (2.4% vs. 3%) or 100 days (11.5% vs. 11.5%). No deaths associated with thrombosis had occurred in either group at 120 days.

The study was supported by the University of Washington and the National Heart, Lung, and Blood Institute. Dr. Gernsheimer has relationships with Amgen, Cellphire, Dova Pharmaceuticals, Novartis, Principia, Rigel, Sanofi, and Vertex. Dr. Tremblay and Dr. Gandhi have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Despite being routinely used in clinical settings, prophylactic use of tranexamic acid, an antifibrinolytic agent administered with platelet transfusions, did not reduce bleeding among patients with blood cancers and severe thrombocytopenia, according to a new study.

The study compared tranexamic acid to placebo and found no significant differences in terms of the number of bleeding events, the number of red blood cell transfusions, or the number of platelet transfusions that were required.

However, the rate of occlusions in the central venous line was significantly higher for patients in the tranexamic acid group, although there was no difference between groups for other types of thrombotic events.

The findings were presented at the annual meeting of the American Society of Hematology, which was held online.

The study was highlighted as potentially practice changing at a press preview webinar by ASH Secretary Robert Brodsky, MD.

“They found absolutely no difference in bleeding or need for transfusion,” said Brodsky. “What they did find was more catheter-associated blood clots in the tranexamic acid group. This is a practice changer in that it probably should not be given prophylactically to patients with thrombocytopenia.”

Senior author Terry B. Gernsheimer, MD, of the University of Washington, Seattle, noted that tranexamic acid has been found to be effective in the treatment of bleeding related to childbirth, surgery, and inherited blood disorders.

It is also used for patients with blood cancers and severe thrombocytopenia. There is little evidence to support this use, which is why the researchers decided to investigate.

“Clearly patients with low platelet counts and blood cancers have a different kind of bleeding than the bleeding experienced by patients who have suffered some kind of trauma or surgery,” Dr. Gernsheimer said in a statement.

“Their bleeding likely is due to endothelial damage – damage to the lining of blood vessels – that tranexamic acid would not treat,” she added.

“To prevent bleeding in these patients, we may need to look at ways to speed the healing of the endothelium that occurs with chemotherapy, radiation, and graft-vs-host disease in patients receiving a transplant,” Dr. Gernsheimer commented.
 

Temper enthusiasm

“Overall, I think these results will temper enthusiasm for using tranexamic acid in this setting,” said Mitul Gandhi, MD, a medical oncologist with Virginia Cancer Specialists, who was approached for comment.

These data do not support the routine use of prophylactic tranexamic acid in chemotherapy-induced thrombocytopenia for patients with platelet counts lower than 30,000/μL, he added.

“The primary objective was not met, and there was an observed increased rate of catheter-associated thrombosis,” he said. “Continued use of judicious transfusion support and correction of a concomitant coagulopathy remains the main clinical approach to these patients.”

Dr. Gandhi commented that tranexamic acid “remains a potentially useful adjunct agent in certain cases of recalcitrant bleeding related to thrombocytopenia or coagulopathy.

“While there is no uniform scenario, it is typically reserved on a case-by-case basis after addressing vascular defects, utilization of platelet, fresh frozen plasma, cryoprecipitate transfusions, vitamin K repletion, and of course excluding any antiplatelet or anticoagulant therapy,» he told this news organization. “For persistent bleeding in spite of all corrective measures or hemorrhage into noncompressible vascular beds, such as with intracranial bleeds, antifibrinolytic therapy may assist in mitigating further blood loss.”

However, this has to be balanced with the potential increased risk for thrombosis after correction of the hemostatic insult.

At present, tranexamic acid “only has an FDA indication for uterine bleeding, but it is frequently used in trauma settings and obstetrical emergencies,” said Douglas Tremblay, MD, an internist at the Icahn School of Medicine at Mount Sinai, New York, who was also approached for comment.

“There is evidence from prior studies that were done 20 or 30 years ago that it may help in this setting, so it is used in some institutions, although we don’t give it prophylactically for patients with a hematologic malignancy.”

Although this was a negative study, Dr. Tremblay pointed out that one thing that may come out of it is that there may be subgroups who can benefit from the prophylactic use of tranexamic acid. “There is very wide inclusion criteria for the study – any type of hematologic malignancy in patients undergoing chemotherapy or stem cell transplant,” he said in an interview. “Even among chemotherapy and transplant patients, there are different risks for bleeding.”

For example, patients undergoing induction chemotherapy for acute myeloid leukemia are at an increased risk of bleeding in comparison with patients with other hematologic malignancies, and those undergoing allogeneic transplant are at an increased risk of bleeding in comparison with patients undergoing autologous transplant. “So while its unclear if a subgroup may benefit from this strategy, lumped together, it doesn’t appear it is of any benefit and potentially harmful, in terms of line occlusions,” he said. “While that may seem to be a nuisance, it can delay chemotherapy or supportive infusions, and that can be a big deal.”
 

No evidence of benefit

Dr. Gernsheimer and colleagues conducted the American Trial Using Tranexamic Acid in Thrombocytopenia (A-TREAT), which evaluated the effects of prophylactic tranexamic acid as an adjunct to routine transfusion therapy on bleeding and transfusion requirements.

A total of 330 patients were randomly assigned to receive either tranexamic acid 1,000 mg IV or 1,300 mg or placebo. Randomization was stratified by site and therapy: chemotherapy, allogeneic transplant, or autologous transplant. It was anticipated that all patients had hypoproliferative thrombocytopenia (expected platelet count, 10,000/µL for at least 5 days).

Treatment continued for 30 days or platelet count recovery (>30,000/µL), diagnosis of thrombosis or veno-occlusive disease, recurrent line occlusion, visible hematuria, or physician or patient request.

The primary endpoint of the study was the proportion of patients with bleeding of World Health Organization grade 2 or above over 30 days after beginning therapy. Secondary endpoints included the number of transfusions and the number of days alive without WHO grade 2+ bleeding during the first 30 days post activation of study drug.

The time to first WHO 2+ bleeding was “remarkably similar” between the tranexamic acid groups and the placebo group, said Dr. Gernsheimer.

In the cohort as a whole, 48.8% in the placebo group experienced a grade 2+ bleed vs. 45.4% in the tranexamic group (odds ratio, 0.86).

Similar results were observed across subgroups: allogeneic transplant, 57.3% vs. 58.8% (OR, 0.94); autologous transplant, 19.9% vs. 24.7% ( OR, 0.71); or chemotherapy, 48% vs. 52.1% (OR, 0.84).

There were no significant differences in mean number of transfusions (difference, 0.1; 95% confidence interval, –1.9 to 2) or days alive without grade 2 or higher bleeding (difference, 0.1; 95% CI, –1.4 to 1.5).

“A post hoc analysis of WHO 3+ bleeding showed these events to be rare and without any improvement with tranexamic acid,” she said.

A higher percentage of patients in the tranexamic acid group experienced thrombotic events (19.5% vs. 11%). “But importantly, in both groups, it was primarily due to central line occlusions without an associated thrombus,” said Dr. Gernsheimer. “This was statistically significant.”

Fewer non–catheter related thrombotic events occurred in the tranexamic acid group (3.7% vs. 5.5%), but the difference was not statistically significant.

There was also no significant difference between groups in veno-occlusive disease after 30 days (1.8% vs. 1.2%) or all-cause mortality at 30 days (2.4% vs. 3%) or 100 days (11.5% vs. 11.5%). No deaths associated with thrombosis had occurred in either group at 120 days.

The study was supported by the University of Washington and the National Heart, Lung, and Blood Institute. Dr. Gernsheimer has relationships with Amgen, Cellphire, Dova Pharmaceuticals, Novartis, Principia, Rigel, Sanofi, and Vertex. Dr. Tremblay and Dr. Gandhi have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

The “hottest” presentation at the upcoming 2020 San Antonio Breast Cancer Symposium comes from RxPONDER (abstract GS3-00), a major randomized clinical trial assessing use of a recurrence score among women with lymph node–positive, early-stage breast cancer to determine who might safely forgo chemotherapy.

That’s the word from Virginia Kaklamani, MD, from the University of Texas Health Sciences Center San Antonio. Dr. Kaklamani, a professor of medicine in the division of hematology/oncology, is codirector of the meeting that runs online Dec. 8-11.

If the new trial sounds familiar, that’s because it’s a lot like the TAILORx trial, the results of which were first presented in 2018 and have changed practice in women with early-stage disease and no lymph node involvement.

“This is the lymph-node positive TAILORx. It’s extremely important,” Dr. Kaklamani said in an interview, adding that both trials involved women with hormone receptor (HR)–positive, HER2-negative disease.

If the RxPONDER trial shows similar outcomes between women randomized to adjuvant endocrine therapy alone versus endocrine therapy plus chemotherapy, then clinicians “can potentially avoid giving chemotherapy to a large number of women who are currently receiving it,” she explained.

Because women with nodal involvement (one to three positive axillary nodes) are at a higher risk of recurrence, RxPONDER may provide needed insight on the management of these types of breast cancers, Dr. Kaklamani suggested.

Both trials have used the 21-tumor gene expression assay (Oncotype Dx) to determine recurrence-risk status.

Dr. Kaklamani also spotlighted the phase 3 CONTESSA trial (abstract GS4-01) in 600+ patients with locally advanced or metastatic breast cancer that is HR positive and HER2 negative and has been previously treated with a taxane.

The trial features an experimental oral taxane, tesetaxel. The primary objective is to compare the efficacy of tesetaxel plus a reduced dose of capecitabine (Xeloda) versus the approved dose of capecitabine alone. Presented data will include progression-free survival results, indicating about a 3-month PFS advantage with tesetaxel, which is taken once every 3 weeks.

“Oral drugs are convenient for patients and, despite limitations, they are, all in all, a revolution in cancer treatment,” noted Dr. Kaklamani, adding that they beneficially eliminate the need for time-consuming infusions and related clinic visits as well as drug ports. 

It will be interesting to see what Steven Vogl, MD, a private practitioner in New Yorky, has to say about CONTESSA and the rest of the SABCS.

He is usually a commentator from the meeting floor, whose self-introduction, “Vogl, New York,” is well known to perennial meeting attendees, according to a profile piece published some years ago.

This year the medical oncologist will also serve as the chair of the “View from the Trenches” session, which is devoted to summarizing the meeting’s most important findings for everyday practitioners.

A number of years ago, Dr. Vogl proposed the idea of this where-the-rubber-meets-the-road session to SABCS meeting planners, which they then adopted. This year, Dr. Kaklamani invited Dr. Vogl to run the session and he accepted.

Dr. Vogl is a “really smart guy who is always right on” with his comments and questions, and he will be the first-ever independent, community-based oncologist to chair a meeting session, said Dr. Kaklamani.
 

Other hot topics

Another hot topic featured at the meeting will be the use of CDK4/6 inhibitors in the adjuvant treatment of HR-positive and HER2-negative disease that has a high risk of recurrence, Dr. Kaklamani said. New data from two trials, monarchE and PENELOPE-B, will be presented.

First, there will be an update from the monarchE trial (abstract GS1-01). The first results from this trial were reported in September at the European Society for Medical Oncology Virtual Congress 2020. They showed that adding abemaciclib (Verzenio) to endocrine therapy reduced the risk of early recurrence. The positive outcome represented the first treatment improvement in this high-risk setting in more than 20 years, according to experts.

A similar trial, PENELOPE-B (abstract GS1-02), looks at palbociclib (Ibrance) in a somewhat different population – those patients with high relapse risk after neoadjuvant chemotherapy. “These are even higher risk ER+ patients [than those in monarchE], which is why they received chemotherapy before surgery,” commented Dr. Kaklamani.

In triple-negative disease, there will be overall survival (OS) results from the phase 3 KEYNOTE-355 study (abstract GS3-01) of pembrolizumab (Keytruda) versus placebo (plus chemotherapy for all patients) as first-line therapy for locally recurrent inoperable or metastatic triple-negative breast cancer. “It’s potentially a huge deal,” said Dr. Kaklamani about the OS data, if they are statistically significant.

A meta-analysis (abstract GS4-08) of data on circulating tumor cells (CTCs), which are shed from the primary tumor into the bloodstream, may point to their value as a tool to determine whether or not a breast cancer treatment is effective. “CTCs allow you to assess how a treatment is doing before you do scans, which typically occur 3 months or so later,” explained Dr. Kaklamani.

CTC results can be assessed in 3-4 weeks and allow clinicians to change treatments if CTC volume increases. However, a previous study of CTCs did not show a clinical benefit with the tool among patients treated mainly with chemotherapies. What’s different about the new study, which is from an international group of investigators, is in the treatments patients with metastatic breast cancer received. “This study is from a different era – with targeted therapies,” said Dr. Kaklamani.

In the new study, changes in CTC levels (with a reduction being a good result) between baseline (pretreatment) and follow-up were analyzed to determine whether they were associated with overall survival.
 

COVID sessions

On the meeting’s first day, SABCS will feature a special session on COVID-19 and breast cancer. The meeting organizers sought to separate the wheat from the chaff in this subject, as much has already been written, published, or presented.

“We received a lot of abstracts on COVID that were studies that were poorly done. We tried to tease through them and select the well-researched ones,” acknowledged Dr. Kaklamani.

The organizers included two patient advocates who have had COVID-19, including during treatment for breast cancer, as participants in the meeting session. The session will also feature global perspectives, with presenters from Brazil, Italy, and the Netherlands. 
 

Plenary lectures

The meeting’s two plenary lectures will focus, respectively, on the increasingly used clinical approach of neoadjuvant therapy in breast cancer, and research in the time of a pandemic.

Elizabeth Mittendorf, MD, PhD, a surgical oncologist and director of the Breast lmmuno-Oncology program and co-director of the Breast Cancer Clinical Research Program at the Dana-Farber/Brigham and Women’s Cancer Center, Boston, will present “Local regional management following neoadjuvant therapy: Minding the knowledge gaps.”

Ned Sharpless, MD, director of the National Cancer Institute, will present “Advancing cancer research during challenging times.”

Dr. Kaklamani disclosed recieving consulting fees with Amgen, Eisai, Puma, Celldex, AstraZeneca, and Athenex; receiving fees for non-CME services received directly from commercial interest or their agents from Pfizer, Celgene, Genentech, Genomic Health, Puma, Eisai, and Novartis; and contracted research with Eisai.

This article first appeared on Medscape.com.

The “hottest” presentation at the upcoming 2020 San Antonio Breast Cancer Symposium comes from RxPONDER (abstract GS3-00), a major randomized clinical trial assessing use of a recurrence score among women with lymph node–positive, early-stage breast cancer to determine who might safely forgo chemotherapy.

That’s the word from Virginia Kaklamani, MD, from the University of Texas Health Sciences Center San Antonio. Dr. Kaklamani, a professor of medicine in the division of hematology/oncology, is codirector of the meeting that runs online Dec. 8-11.

If the new trial sounds familiar, that’s because it’s a lot like the TAILORx trial, the results of which were first presented in 2018 and have changed practice in women with early-stage disease and no lymph node involvement.

“This is the lymph-node positive TAILORx. It’s extremely important,” Dr. Kaklamani said in an interview, adding that both trials involved women with hormone receptor (HR)–positive, HER2-negative disease.

If the RxPONDER trial shows similar outcomes between women randomized to adjuvant endocrine therapy alone versus endocrine therapy plus chemotherapy, then clinicians “can potentially avoid giving chemotherapy to a large number of women who are currently receiving it,” she explained.

Because women with nodal involvement (one to three positive axillary nodes) are at a higher risk of recurrence, RxPONDER may provide needed insight on the management of these types of breast cancers, Dr. Kaklamani suggested.

Both trials have used the 21-tumor gene expression assay (Oncotype Dx) to determine recurrence-risk status.

Dr. Kaklamani also spotlighted the phase 3 CONTESSA trial (abstract GS4-01) in 600+ patients with locally advanced or metastatic breast cancer that is HR positive and HER2 negative and has been previously treated with a taxane.

The trial features an experimental oral taxane, tesetaxel. The primary objective is to compare the efficacy of tesetaxel plus a reduced dose of capecitabine (Xeloda) versus the approved dose of capecitabine alone. Presented data will include progression-free survival results, indicating about a 3-month PFS advantage with tesetaxel, which is taken once every 3 weeks.

“Oral drugs are convenient for patients and, despite limitations, they are, all in all, a revolution in cancer treatment,” noted Dr. Kaklamani, adding that they beneficially eliminate the need for time-consuming infusions and related clinic visits as well as drug ports. 

It will be interesting to see what Steven Vogl, MD, a private practitioner in New Yorky, has to say about CONTESSA and the rest of the SABCS.

He is usually a commentator from the meeting floor, whose self-introduction, “Vogl, New York,” is well known to perennial meeting attendees, according to a profile piece published some years ago.

This year the medical oncologist will also serve as the chair of the “View from the Trenches” session, which is devoted to summarizing the meeting’s most important findings for everyday practitioners.

A number of years ago, Dr. Vogl proposed the idea of this where-the-rubber-meets-the-road session to SABCS meeting planners, which they then adopted. This year, Dr. Kaklamani invited Dr. Vogl to run the session and he accepted.

Dr. Vogl is a “really smart guy who is always right on” with his comments and questions, and he will be the first-ever independent, community-based oncologist to chair a meeting session, said Dr. Kaklamani.
 

Other hot topics

Another hot topic featured at the meeting will be the use of CDK4/6 inhibitors in the adjuvant treatment of HR-positive and HER2-negative disease that has a high risk of recurrence, Dr. Kaklamani said. New data from two trials, monarchE and PENELOPE-B, will be presented.

First, there will be an update from the monarchE trial (abstract GS1-01). The first results from this trial were reported in September at the European Society for Medical Oncology Virtual Congress 2020. They showed that adding abemaciclib (Verzenio) to endocrine therapy reduced the risk of early recurrence. The positive outcome represented the first treatment improvement in this high-risk setting in more than 20 years, according to experts.

A similar trial, PENELOPE-B (abstract GS1-02), looks at palbociclib (Ibrance) in a somewhat different population – those patients with high relapse risk after neoadjuvant chemotherapy. “These are even higher risk ER+ patients [than those in monarchE], which is why they received chemotherapy before surgery,” commented Dr. Kaklamani.

In triple-negative disease, there will be overall survival (OS) results from the phase 3 KEYNOTE-355 study (abstract GS3-01) of pembrolizumab (Keytruda) versus placebo (plus chemotherapy for all patients) as first-line therapy for locally recurrent inoperable or metastatic triple-negative breast cancer. “It’s potentially a huge deal,” said Dr. Kaklamani about the OS data, if they are statistically significant.

A meta-analysis (abstract GS4-08) of data on circulating tumor cells (CTCs), which are shed from the primary tumor into the bloodstream, may point to their value as a tool to determine whether or not a breast cancer treatment is effective. “CTCs allow you to assess how a treatment is doing before you do scans, which typically occur 3 months or so later,” explained Dr. Kaklamani.

CTC results can be assessed in 3-4 weeks and allow clinicians to change treatments if CTC volume increases. However, a previous study of CTCs did not show a clinical benefit with the tool among patients treated mainly with chemotherapies. What’s different about the new study, which is from an international group of investigators, is in the treatments patients with metastatic breast cancer received. “This study is from a different era – with targeted therapies,” said Dr. Kaklamani.

In the new study, changes in CTC levels (with a reduction being a good result) between baseline (pretreatment) and follow-up were analyzed to determine whether they were associated with overall survival.
 

COVID sessions

On the meeting’s first day, SABCS will feature a special session on COVID-19 and breast cancer. The meeting organizers sought to separate the wheat from the chaff in this subject, as much has already been written, published, or presented.

“We received a lot of abstracts on COVID that were studies that were poorly done. We tried to tease through them and select the well-researched ones,” acknowledged Dr. Kaklamani.

The organizers included two patient advocates who have had COVID-19, including during treatment for breast cancer, as participants in the meeting session. The session will also feature global perspectives, with presenters from Brazil, Italy, and the Netherlands. 
 

Plenary lectures

The meeting’s two plenary lectures will focus, respectively, on the increasingly used clinical approach of neoadjuvant therapy in breast cancer, and research in the time of a pandemic.

Elizabeth Mittendorf, MD, PhD, a surgical oncologist and director of the Breast lmmuno-Oncology program and co-director of the Breast Cancer Clinical Research Program at the Dana-Farber/Brigham and Women’s Cancer Center, Boston, will present “Local regional management following neoadjuvant therapy: Minding the knowledge gaps.”

Ned Sharpless, MD, director of the National Cancer Institute, will present “Advancing cancer research during challenging times.”

Dr. Kaklamani disclosed recieving consulting fees with Amgen, Eisai, Puma, Celldex, AstraZeneca, and Athenex; receiving fees for non-CME services received directly from commercial interest or their agents from Pfizer, Celgene, Genentech, Genomic Health, Puma, Eisai, and Novartis; and contracted research with Eisai.

This article first appeared on Medscape.com.

The “hottest” presentation at the upcoming 2020 San Antonio Breast Cancer Symposium comes from RxPONDER (abstract GS3-00), a major randomized clinical trial assessing use of a recurrence score among women with lymph node–positive, early-stage breast cancer to determine who might safely forgo chemotherapy.

That’s the word from Virginia Kaklamani, MD, from the University of Texas Health Sciences Center San Antonio. Dr. Kaklamani, a professor of medicine in the division of hematology/oncology, is codirector of the meeting that runs online Dec. 8-11.

If the new trial sounds familiar, that’s because it’s a lot like the TAILORx trial, the results of which were first presented in 2018 and have changed practice in women with early-stage disease and no lymph node involvement.

“This is the lymph-node positive TAILORx. It’s extremely important,” Dr. Kaklamani said in an interview, adding that both trials involved women with hormone receptor (HR)–positive, HER2-negative disease.

If the RxPONDER trial shows similar outcomes between women randomized to adjuvant endocrine therapy alone versus endocrine therapy plus chemotherapy, then clinicians “can potentially avoid giving chemotherapy to a large number of women who are currently receiving it,” she explained.

Because women with nodal involvement (one to three positive axillary nodes) are at a higher risk of recurrence, RxPONDER may provide needed insight on the management of these types of breast cancers, Dr. Kaklamani suggested.

Both trials have used the 21-tumor gene expression assay (Oncotype Dx) to determine recurrence-risk status.

Dr. Kaklamani also spotlighted the phase 3 CONTESSA trial (abstract GS4-01) in 600+ patients with locally advanced or metastatic breast cancer that is HR positive and HER2 negative and has been previously treated with a taxane.

The trial features an experimental oral taxane, tesetaxel. The primary objective is to compare the efficacy of tesetaxel plus a reduced dose of capecitabine (Xeloda) versus the approved dose of capecitabine alone. Presented data will include progression-free survival results, indicating about a 3-month PFS advantage with tesetaxel, which is taken once every 3 weeks.

“Oral drugs are convenient for patients and, despite limitations, they are, all in all, a revolution in cancer treatment,” noted Dr. Kaklamani, adding that they beneficially eliminate the need for time-consuming infusions and related clinic visits as well as drug ports. 

It will be interesting to see what Steven Vogl, MD, a private practitioner in New Yorky, has to say about CONTESSA and the rest of the SABCS.

He is usually a commentator from the meeting floor, whose self-introduction, “Vogl, New York,” is well known to perennial meeting attendees, according to a profile piece published some years ago.

This year the medical oncologist will also serve as the chair of the “View from the Trenches” session, which is devoted to summarizing the meeting’s most important findings for everyday practitioners.

A number of years ago, Dr. Vogl proposed the idea of this where-the-rubber-meets-the-road session to SABCS meeting planners, which they then adopted. This year, Dr. Kaklamani invited Dr. Vogl to run the session and he accepted.

Dr. Vogl is a “really smart guy who is always right on” with his comments and questions, and he will be the first-ever independent, community-based oncologist to chair a meeting session, said Dr. Kaklamani.
 

Other hot topics

Another hot topic featured at the meeting will be the use of CDK4/6 inhibitors in the adjuvant treatment of HR-positive and HER2-negative disease that has a high risk of recurrence, Dr. Kaklamani said. New data from two trials, monarchE and PENELOPE-B, will be presented.

First, there will be an update from the monarchE trial (abstract GS1-01). The first results from this trial were reported in September at the European Society for Medical Oncology Virtual Congress 2020. They showed that adding abemaciclib (Verzenio) to endocrine therapy reduced the risk of early recurrence. The positive outcome represented the first treatment improvement in this high-risk setting in more than 20 years, according to experts.

A similar trial, PENELOPE-B (abstract GS1-02), looks at palbociclib (Ibrance) in a somewhat different population – those patients with high relapse risk after neoadjuvant chemotherapy. “These are even higher risk ER+ patients [than those in monarchE], which is why they received chemotherapy before surgery,” commented Dr. Kaklamani.

In triple-negative disease, there will be overall survival (OS) results from the phase 3 KEYNOTE-355 study (abstract GS3-01) of pembrolizumab (Keytruda) versus placebo (plus chemotherapy for all patients) as first-line therapy for locally recurrent inoperable or metastatic triple-negative breast cancer. “It’s potentially a huge deal,” said Dr. Kaklamani about the OS data, if they are statistically significant.

A meta-analysis (abstract GS4-08) of data on circulating tumor cells (CTCs), which are shed from the primary tumor into the bloodstream, may point to their value as a tool to determine whether or not a breast cancer treatment is effective. “CTCs allow you to assess how a treatment is doing before you do scans, which typically occur 3 months or so later,” explained Dr. Kaklamani.

CTC results can be assessed in 3-4 weeks and allow clinicians to change treatments if CTC volume increases. However, a previous study of CTCs did not show a clinical benefit with the tool among patients treated mainly with chemotherapies. What’s different about the new study, which is from an international group of investigators, is in the treatments patients with metastatic breast cancer received. “This study is from a different era – with targeted therapies,” said Dr. Kaklamani.

In the new study, changes in CTC levels (with a reduction being a good result) between baseline (pretreatment) and follow-up were analyzed to determine whether they were associated with overall survival.
 

COVID sessions

On the meeting’s first day, SABCS will feature a special session on COVID-19 and breast cancer. The meeting organizers sought to separate the wheat from the chaff in this subject, as much has already been written, published, or presented.

“We received a lot of abstracts on COVID that were studies that were poorly done. We tried to tease through them and select the well-researched ones,” acknowledged Dr. Kaklamani.

The organizers included two patient advocates who have had COVID-19, including during treatment for breast cancer, as participants in the meeting session. The session will also feature global perspectives, with presenters from Brazil, Italy, and the Netherlands. 
 

Plenary lectures

The meeting’s two plenary lectures will focus, respectively, on the increasingly used clinical approach of neoadjuvant therapy in breast cancer, and research in the time of a pandemic.

Elizabeth Mittendorf, MD, PhD, a surgical oncologist and director of the Breast lmmuno-Oncology program and co-director of the Breast Cancer Clinical Research Program at the Dana-Farber/Brigham and Women’s Cancer Center, Boston, will present “Local regional management following neoadjuvant therapy: Minding the knowledge gaps.”

Ned Sharpless, MD, director of the National Cancer Institute, will present “Advancing cancer research during challenging times.”

Dr. Kaklamani disclosed recieving consulting fees with Amgen, Eisai, Puma, Celldex, AstraZeneca, and Athenex; receiving fees for non-CME services received directly from commercial interest or their agents from Pfizer, Celgene, Genentech, Genomic Health, Puma, Eisai, and Novartis; and contracted research with Eisai.

This article first appeared on Medscape.com.

Rates of cancer increased by 30% from 1973 to 2015 in adolescents and young adults (AYAs) aged 15–39 years in the United States, according to a review of almost a half million cases in the National Institutes of Health’s Surveillance, Epidemiology, and End Results database.

There was an annual increase of 0.537 new cases per 100,000 people, from 57.2 cases per 100,000 in 1973 to 74.2 in 2015.

Kidney carcinoma led with the highest rate increase. There were also marked increases in thyroid and colorectal carcinoma, germ cell and trophoblastic neoplasms, and melanoma, among others.

The report was published online December 1 in JAMA Network Open.

“Clinicians should be on the lookout for these cancers in their adolescent and young adult patients,” said senior investigator Nicholas Zaorsky, MD, an assistant professor of radiation oncology and public health sciences at the Penn State Cancer Institute, Hershey, Pennsylvania.

“Now that there is a better understanding of the types of cancer that are prevalent and rising in this age group, prevention, screening, diagnosis and treatment protocols specifically targeted to this population should be developed,” he said in a press release.

The reasons for the increases are unclear, but environmental and dietary factors, increasing obesity, and changing screening practices are likely in play, the authors comment. In addition, “cancer screening and overdiagnosis are thought to account for much of the increasing rates of thyroid and kidney carcinoma, among others,” they add.

The American Cancer Society (ACS) recently found similar increases in thyroid, kidney, and colorectal cancer among AYAs, as well as an increase in uterine cancer.

It’s important to note, however, that “this phenomenon is largely driven by trends for thyroid cancer, which is thought to be a result of overdiagnosis,” said ACS surveillance researcher Kimberly Miller, MPH, when asked to comment on the new study.

“As such, it is extremely important to also consider trends in cancer mortality rates among this age group, which are declining overall but are increasing for colorectal and uterine cancers. The fact that both incidence and mortality rates are increasing for these two cancers suggests a true increase in disease burden and certainly requires further attention and research,” she said.

Historically, management of cancer in AYAs has fallen somewhere between pediatric and adult oncology, neither of which capture the distinct biological, social, and economic needs of AYAs. Research has also focused on childhood and adult cancers, leaving cancer in AYAs inadequately studied.

The new findings are “valuable to guide more targeted research and interventions specifically to AYAs,” Zaorsky and colleagues say in their report.

Among female patients ― 59.1% of the study population ― incidence increased for 15 cancers, including kidney carcinoma (annual percent change [APC], 3.632), thyroid carcinoma (APC, 3.456), and myeloma, mast cell, and miscellaneous lymphoreticular neoplasms not otherwise specified (APC, 2.805). Rates of five cancers declined, led by astrocytoma not otherwise specified (APC, –3.369) and carcinoma of the gonads (APC, –1.743).

Among male patients, incidence increased for 14 cancers, including kidney carcinoma (APC, 3.572), unspecified soft tissue sarcoma (APC 2.543), and thyroid carcinoma (APC, 2.273). Incidence fell for seven, led by astrocytoma not otherwise specified (APC, –3.759) and carcinoma of the trachea, bronchus, and lung (APC, –2.635).

Increased testicular cancer rates (APC, 1.246) could be related to greater prenatal exposure to estrogen and progesterone or through dairy consumption; increasing survival of premature infants; and greater exposure to cannabis, among other possibilities, the investigators say.

Increases in colorectal cancer might be related to fewer vegetables and more fat and processed meat in the diet; lack of exercise; and increasing obesity. Human papillomavirus infection has also been implicated.

Higher rates of melanoma could be related to tanning bed use.

Declines in some cancers could be related to greater use of oral contraceptives; laws reducing exposure to benzene and other chemicals; and fewer people smoking.

Although kidney carcinoma has increased at the greatest rate, it’s uncommon. Colorectal and thyroid carcinoma, melanoma, non-Hodgkin lymphoma, and germ cell and trophoblastic neoplasms of the gonads contribute more to the overall increase in cancers among AYAs, the investigators note.

Almost 80% of the patients were White; 10.3% were Black.

The study was funded by the National Center for Advancing Translational Sciences. The investigators have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Rates of cancer increased by 30% from 1973 to 2015 in adolescents and young adults (AYAs) aged 15–39 years in the United States, according to a review of almost a half million cases in the National Institutes of Health’s Surveillance, Epidemiology, and End Results database.

There was an annual increase of 0.537 new cases per 100,000 people, from 57.2 cases per 100,000 in 1973 to 74.2 in 2015.

Kidney carcinoma led with the highest rate increase. There were also marked increases in thyroid and colorectal carcinoma, germ cell and trophoblastic neoplasms, and melanoma, among others.

The report was published online December 1 in JAMA Network Open.

“Clinicians should be on the lookout for these cancers in their adolescent and young adult patients,” said senior investigator Nicholas Zaorsky, MD, an assistant professor of radiation oncology and public health sciences at the Penn State Cancer Institute, Hershey, Pennsylvania.

“Now that there is a better understanding of the types of cancer that are prevalent and rising in this age group, prevention, screening, diagnosis and treatment protocols specifically targeted to this population should be developed,” he said in a press release.

The reasons for the increases are unclear, but environmental and dietary factors, increasing obesity, and changing screening practices are likely in play, the authors comment. In addition, “cancer screening and overdiagnosis are thought to account for much of the increasing rates of thyroid and kidney carcinoma, among others,” they add.

The American Cancer Society (ACS) recently found similar increases in thyroid, kidney, and colorectal cancer among AYAs, as well as an increase in uterine cancer.

It’s important to note, however, that “this phenomenon is largely driven by trends for thyroid cancer, which is thought to be a result of overdiagnosis,” said ACS surveillance researcher Kimberly Miller, MPH, when asked to comment on the new study.

“As such, it is extremely important to also consider trends in cancer mortality rates among this age group, which are declining overall but are increasing for colorectal and uterine cancers. The fact that both incidence and mortality rates are increasing for these two cancers suggests a true increase in disease burden and certainly requires further attention and research,” she said.

Historically, management of cancer in AYAs has fallen somewhere between pediatric and adult oncology, neither of which capture the distinct biological, social, and economic needs of AYAs. Research has also focused on childhood and adult cancers, leaving cancer in AYAs inadequately studied.

The new findings are “valuable to guide more targeted research and interventions specifically to AYAs,” Zaorsky and colleagues say in their report.

Among female patients ― 59.1% of the study population ― incidence increased for 15 cancers, including kidney carcinoma (annual percent change [APC], 3.632), thyroid carcinoma (APC, 3.456), and myeloma, mast cell, and miscellaneous lymphoreticular neoplasms not otherwise specified (APC, 2.805). Rates of five cancers declined, led by astrocytoma not otherwise specified (APC, –3.369) and carcinoma of the gonads (APC, –1.743).

Among male patients, incidence increased for 14 cancers, including kidney carcinoma (APC, 3.572), unspecified soft tissue sarcoma (APC 2.543), and thyroid carcinoma (APC, 2.273). Incidence fell for seven, led by astrocytoma not otherwise specified (APC, –3.759) and carcinoma of the trachea, bronchus, and lung (APC, –2.635).

Increased testicular cancer rates (APC, 1.246) could be related to greater prenatal exposure to estrogen and progesterone or through dairy consumption; increasing survival of premature infants; and greater exposure to cannabis, among other possibilities, the investigators say.

Increases in colorectal cancer might be related to fewer vegetables and more fat and processed meat in the diet; lack of exercise; and increasing obesity. Human papillomavirus infection has also been implicated.

Higher rates of melanoma could be related to tanning bed use.

Declines in some cancers could be related to greater use of oral contraceptives; laws reducing exposure to benzene and other chemicals; and fewer people smoking.

Although kidney carcinoma has increased at the greatest rate, it’s uncommon. Colorectal and thyroid carcinoma, melanoma, non-Hodgkin lymphoma, and germ cell and trophoblastic neoplasms of the gonads contribute more to the overall increase in cancers among AYAs, the investigators note.

Almost 80% of the patients were White; 10.3% were Black.

The study was funded by the National Center for Advancing Translational Sciences. The investigators have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Rates of cancer increased by 30% from 1973 to 2015 in adolescents and young adults (AYAs) aged 15–39 years in the United States, according to a review of almost a half million cases in the National Institutes of Health’s Surveillance, Epidemiology, and End Results database.

There was an annual increase of 0.537 new cases per 100,000 people, from 57.2 cases per 100,000 in 1973 to 74.2 in 2015.

Kidney carcinoma led with the highest rate increase. There were also marked increases in thyroid and colorectal carcinoma, germ cell and trophoblastic neoplasms, and melanoma, among others.

The report was published online December 1 in JAMA Network Open.

“Clinicians should be on the lookout for these cancers in their adolescent and young adult patients,” said senior investigator Nicholas Zaorsky, MD, an assistant professor of radiation oncology and public health sciences at the Penn State Cancer Institute, Hershey, Pennsylvania.

“Now that there is a better understanding of the types of cancer that are prevalent and rising in this age group, prevention, screening, diagnosis and treatment protocols specifically targeted to this population should be developed,” he said in a press release.

The reasons for the increases are unclear, but environmental and dietary factors, increasing obesity, and changing screening practices are likely in play, the authors comment. In addition, “cancer screening and overdiagnosis are thought to account for much of the increasing rates of thyroid and kidney carcinoma, among others,” they add.

The American Cancer Society (ACS) recently found similar increases in thyroid, kidney, and colorectal cancer among AYAs, as well as an increase in uterine cancer.

It’s important to note, however, that “this phenomenon is largely driven by trends for thyroid cancer, which is thought to be a result of overdiagnosis,” said ACS surveillance researcher Kimberly Miller, MPH, when asked to comment on the new study.

“As such, it is extremely important to also consider trends in cancer mortality rates among this age group, which are declining overall but are increasing for colorectal and uterine cancers. The fact that both incidence and mortality rates are increasing for these two cancers suggests a true increase in disease burden and certainly requires further attention and research,” she said.

Historically, management of cancer in AYAs has fallen somewhere between pediatric and adult oncology, neither of which capture the distinct biological, social, and economic needs of AYAs. Research has also focused on childhood and adult cancers, leaving cancer in AYAs inadequately studied.

The new findings are “valuable to guide more targeted research and interventions specifically to AYAs,” Zaorsky and colleagues say in their report.

Among female patients ― 59.1% of the study population ― incidence increased for 15 cancers, including kidney carcinoma (annual percent change [APC], 3.632), thyroid carcinoma (APC, 3.456), and myeloma, mast cell, and miscellaneous lymphoreticular neoplasms not otherwise specified (APC, 2.805). Rates of five cancers declined, led by astrocytoma not otherwise specified (APC, –3.369) and carcinoma of the gonads (APC, –1.743).

Among male patients, incidence increased for 14 cancers, including kidney carcinoma (APC, 3.572), unspecified soft tissue sarcoma (APC 2.543), and thyroid carcinoma (APC, 2.273). Incidence fell for seven, led by astrocytoma not otherwise specified (APC, –3.759) and carcinoma of the trachea, bronchus, and lung (APC, –2.635).

Increased testicular cancer rates (APC, 1.246) could be related to greater prenatal exposure to estrogen and progesterone or through dairy consumption; increasing survival of premature infants; and greater exposure to cannabis, among other possibilities, the investigators say.

Increases in colorectal cancer might be related to fewer vegetables and more fat and processed meat in the diet; lack of exercise; and increasing obesity. Human papillomavirus infection has also been implicated.

Higher rates of melanoma could be related to tanning bed use.

Declines in some cancers could be related to greater use of oral contraceptives; laws reducing exposure to benzene and other chemicals; and fewer people smoking.

Although kidney carcinoma has increased at the greatest rate, it’s uncommon. Colorectal and thyroid carcinoma, melanoma, non-Hodgkin lymphoma, and germ cell and trophoblastic neoplasms of the gonads contribute more to the overall increase in cancers among AYAs, the investigators note.

Almost 80% of the patients were White; 10.3% were Black.

The study was funded by the National Center for Advancing Translational Sciences. The investigators have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Primary thromboprophylaxis is feasible and worth considering for high-risk ambulatory patients with cancer who are initiating systemic chemotherapy, according to Marc Carrier, MD.

Risk scores can identify patients at high risk for venous thromboembolism (VTE), and treatments that are effective and associated with low bleeding risk are available, Dr. Carrier explained at the biennial summit of the Thrombosis & Hemostasis Societies of North America.

However, caution is advised in patients with certain types of cancer, including some gastrointestinal and genitourinary cancers, because of the possibility of increased major and clinically relevant nonmajor bleeding risk, he said.
 

VTE and cancer

VTE is relatively rare in the general population, occurring in about 1 or 2 per 1,000 people annually. The risk increases 4.1-fold in patients with cancer, and 6.5-fold in patients with cancer receiving chemotherapy.

“So just putting these numbers together, we’re no longer talking about 1 in 1,000, but 1 in 200, so [this is] something that is very common among cancer patients,” said Dr. Carrier, a professor at the University of Ottawa and chief of the division of hematology at The Ottawa Hospital.

The mortality rate associated with cancer-associated thrombosis is about 9%, comparable to that associated with infection in the cancer outpatient setting, which underscores the importance of educating patients about the signs and symptoms of VTE so they can seek medical treatment quickly if necessary, he added.

It may also be useful to discuss prophylaxis or other ways to prevent venous thromboembolic complications with certain patients, he said, noting that in an observational cohort study of nearly 600 patients at the University of Ottawa, 25% of those initiating chemotherapy were identified as intermediate or high risk using the validated Khorana risk score, and thus would likely benefit from thromboprophylaxis.
 

Risk assessment

The Khorana risk score assesses VTE risk based on cancer site, blood counts, and body mass index. It is simple to use and has been validated in more than 20,000 people in multiple countries, Dr. Carrier said.

In a well-known validation study, Ay et al. showed a VTE complication rate of 10% in patients with a Khorana risk score of 2 or higher who were followed up to 6 months.

“This is huge,” Dr. Carrier stressed. “This is much higher than what we tolerate for all sorts of different populations for which we would recommend anticoagulation or thromboprophylaxis.”

The question is whether the risk score can be helpful in a real-world clinic setting, he said, adding: “I’d like to think the answer to that is yes.”

In the University of Ottawa cohort study, 11% of high-risk patients experienced a VTE complication, compared with 4% of those with lower risk, suggesting that the validation data for the Khorana risk score is not only accurate, it is “actually applicable in real-world practice, and you can use it in your own center,” he said.

Further, recent studies have demonstrated that treatment based on Khorana risk score assessment reduces VTE complications.
 

Prophylaxis options

Low-molecular-weight heparin (LMWH) has been shown in several studies to be associated with a significant relative VTE risk reduction in patients with cancer initiating chemotherapy – with only a slight, nonsignificant increase in the risk of major bleeding.

However, the absolute benefit was small, and LMWH is “parenteral, relatively costly, and, based on that, although we showed relatively good risk-benefit ratio, it never really got translated to clinical practice,” Dr. Carrier said.

In fact, a 2015 American Society of Clinical Oncology guidelines update recommended against routine thromboprophylaxis in this setting, but stated that it could be considered in select high-risk patients identified using a validated risk-assessment tool.

The guidelines noted that “individual risk factors such as biomarkers and cancer site don’t reliably identify high-risk patients.”

More recent data provide additional support for risk assessment and treatment based on Khorana risk score of 2 or higher.

The AVERT trial, for which Dr. Carrier was the first author, showed that the direct-acting oral anticoagulant (DOAC) apixaban reduced VTE incidence, compared with placebo, in patients with Khorana score of 2 or higher (4.2% vs. 10.2%; hazard ratio, 0.41 overall, and 1.0 vs. 7.3; HR, 0.14 on treatment), and the CASSINI trial showed that another DOAC, rivaroxaban, reduced VTE incidence, compared with placebo, in those with Khorana score of 2 or higher (5.9 vs. 6.7; HR, 0.6 overall, and 2.6 vs. 6.4; HR, 0.40 on treatment). The differences in the on-treatment populations were statistically significant.

The two trials, which included a variety of tumor types, showed similar rates of major bleeding, with an absolute difference of about 1% between treatment and placebo, which was not statistically significant in the on-treatment analyses (HR, 1.89 in AVERT and HR, 1.96 in CASSINI).

A systematic review of these trials showed an overall significant decrease in VTE complication risk with treatment in high-risk patients, and a nonstatistically significant major bleeding risk increase.

Based on these findings, ASCO guidelines were updated in 2020 to state that “routine thromboprophylaxis should not be offered to all patients with cancer. ... However, high-risk outpatients with cancer may be offered thromboprophylaxis with apixaban, rivaroxaban or LMWH, providing there are no significant risk factors for bleeding or drug-drug interactions, and after having a full discussion with patients ... to make sure they understand the risk-benefit ratio and the rationale for that particular recommendation,” he said.
 

Real-world implementation

Implementing this approach in the clinic setting requires a practical model, such as the Venous Thromboembolism Prevention in the Ambulatory Cancer Clinic (VTEPACC) program, a prospective quality improvement research initiative developed in collaboration with the Jeffords Institute for Quality at the University of Vermont Medical Center and described in a recent report, Dr. Carrier said.

The “Vermont model” is “really a comprehensive model that includes identifying patients with the electronic medical records, gathering the formal education and insight from other health care providers like pharmacists and nurses in order to really come up with personalized care for your patients,” he explained.

In 918 outpatients with cancer who were included in the program, VTE awareness increased from less than 5% before VTEPACC to nearly 82% during the implementation phase and 94.7% after 2 years, with nearly 94% of high-risk patients receiving VTE prophylaxis at that time.

“So we can certainly do that in our own center.” he said. “It’s a matter of coming up with the model and making sure that the patients are seen at the right time.”

Given the high frequency of VTE in patients with cancer initiating chemotherapy, the usefulness of risk scores such as the Khorana risk score for identifying those at high risk, and the availability of safe and effective interventions for reducing risk, “we should probably use the data and incorporate them into clinical practice by implementation of programs for primary prevention,” he said.
 

A word of caution

Caution is warranted, however, when it comes to using DOACs in patients with higher-risk or potentially higher-risk tumor types, he added.

“It’s an important question we are facing as clinicians on a daily basis,” he said, responding to an attendee’s query, as shared by session moderator James Douketis, MD, professor of medicine at McMaster University, Hamilton, Ont., regarding possible bleeding risks in certain genitourinary cancers.

A recent meta-analysis published in Nature, for example, noted that, in the SELECT-D trial, rivaroxaban was associated with significantly higher incidence of clinically relevant nonmajor bleeding, most often in bladder and colorectal cancers, and most often at genitourinary and gastrointestinal sites.

Both Dr. Carrier and fellow panelist Michael Streiff, MD, professor of medicine at Johns Hopkins University and medical director at the Johns Hopkins Hospital Special Coagulation Laboratory, Baltimore, said they approach DOAC use cautiously, but don’t rule it out entirely, in patients with unresected genitourinary tumors that could pose a risk of bleeding.

“It’s worth mentioning and being cautious. In my own personal practice, I’m very careful with unresected urothelial-type tumors or, for example, bladder cancer, for the same reason as [with] unresected luminal GI tumors,” Dr. Carrier said, adding that he’s also mindful that patients with nephropathy were excluded from U.S. DOAC trials because of bleeding risk.

He said he sometimes tries a LMWH challenge first in higher-risk patients, and then might try a DOAC if no bleeding occurs.

“But it certainly is controversial,” he noted.

Dr. Streiff added that he also worries less with genitourinary cancers than with upper GI lesions because “the signals weren’t as big as in GI” cancers, but he noted that “the drugs are going out through the kidneys ... so I’m cautious in those populations.”

“So caution, but not complete exclusion, is the operative management,” Dr. Douketis said, summarizing the panelists’ consensus.

Dr. Carrier reported clinical trial or advisory board participation for Bayer, Pfizer, Servier, Leo Pharma, and/or BMS.

[email protected]

Primary thromboprophylaxis is feasible and worth considering for high-risk ambulatory patients with cancer who are initiating systemic chemotherapy, according to Marc Carrier, MD.

Risk scores can identify patients at high risk for venous thromboembolism (VTE), and treatments that are effective and associated with low bleeding risk are available, Dr. Carrier explained at the biennial summit of the Thrombosis & Hemostasis Societies of North America.

However, caution is advised in patients with certain types of cancer, including some gastrointestinal and genitourinary cancers, because of the possibility of increased major and clinically relevant nonmajor bleeding risk, he said.
 

VTE and cancer

VTE is relatively rare in the general population, occurring in about 1 or 2 per 1,000 people annually. The risk increases 4.1-fold in patients with cancer, and 6.5-fold in patients with cancer receiving chemotherapy.

“So just putting these numbers together, we’re no longer talking about 1 in 1,000, but 1 in 200, so [this is] something that is very common among cancer patients,” said Dr. Carrier, a professor at the University of Ottawa and chief of the division of hematology at The Ottawa Hospital.

The mortality rate associated with cancer-associated thrombosis is about 9%, comparable to that associated with infection in the cancer outpatient setting, which underscores the importance of educating patients about the signs and symptoms of VTE so they can seek medical treatment quickly if necessary, he added.

It may also be useful to discuss prophylaxis or other ways to prevent venous thromboembolic complications with certain patients, he said, noting that in an observational cohort study of nearly 600 patients at the University of Ottawa, 25% of those initiating chemotherapy were identified as intermediate or high risk using the validated Khorana risk score, and thus would likely benefit from thromboprophylaxis.
 

Risk assessment

The Khorana risk score assesses VTE risk based on cancer site, blood counts, and body mass index. It is simple to use and has been validated in more than 20,000 people in multiple countries, Dr. Carrier said.

In a well-known validation study, Ay et al. showed a VTE complication rate of 10% in patients with a Khorana risk score of 2 or higher who were followed up to 6 months.

“This is huge,” Dr. Carrier stressed. “This is much higher than what we tolerate for all sorts of different populations for which we would recommend anticoagulation or thromboprophylaxis.”

The question is whether the risk score can be helpful in a real-world clinic setting, he said, adding: “I’d like to think the answer to that is yes.”

In the University of Ottawa cohort study, 11% of high-risk patients experienced a VTE complication, compared with 4% of those with lower risk, suggesting that the validation data for the Khorana risk score is not only accurate, it is “actually applicable in real-world practice, and you can use it in your own center,” he said.

Further, recent studies have demonstrated that treatment based on Khorana risk score assessment reduces VTE complications.
 

Prophylaxis options

Low-molecular-weight heparin (LMWH) has been shown in several studies to be associated with a significant relative VTE risk reduction in patients with cancer initiating chemotherapy – with only a slight, nonsignificant increase in the risk of major bleeding.

However, the absolute benefit was small, and LMWH is “parenteral, relatively costly, and, based on that, although we showed relatively good risk-benefit ratio, it never really got translated to clinical practice,” Dr. Carrier said.

In fact, a 2015 American Society of Clinical Oncology guidelines update recommended against routine thromboprophylaxis in this setting, but stated that it could be considered in select high-risk patients identified using a validated risk-assessment tool.

The guidelines noted that “individual risk factors such as biomarkers and cancer site don’t reliably identify high-risk patients.”

More recent data provide additional support for risk assessment and treatment based on Khorana risk score of 2 or higher.

The AVERT trial, for which Dr. Carrier was the first author, showed that the direct-acting oral anticoagulant (DOAC) apixaban reduced VTE incidence, compared with placebo, in patients with Khorana score of 2 or higher (4.2% vs. 10.2%; hazard ratio, 0.41 overall, and 1.0 vs. 7.3; HR, 0.14 on treatment), and the CASSINI trial showed that another DOAC, rivaroxaban, reduced VTE incidence, compared with placebo, in those with Khorana score of 2 or higher (5.9 vs. 6.7; HR, 0.6 overall, and 2.6 vs. 6.4; HR, 0.40 on treatment). The differences in the on-treatment populations were statistically significant.

The two trials, which included a variety of tumor types, showed similar rates of major bleeding, with an absolute difference of about 1% between treatment and placebo, which was not statistically significant in the on-treatment analyses (HR, 1.89 in AVERT and HR, 1.96 in CASSINI).

A systematic review of these trials showed an overall significant decrease in VTE complication risk with treatment in high-risk patients, and a nonstatistically significant major bleeding risk increase.

Based on these findings, ASCO guidelines were updated in 2020 to state that “routine thromboprophylaxis should not be offered to all patients with cancer. ... However, high-risk outpatients with cancer may be offered thromboprophylaxis with apixaban, rivaroxaban or LMWH, providing there are no significant risk factors for bleeding or drug-drug interactions, and after having a full discussion with patients ... to make sure they understand the risk-benefit ratio and the rationale for that particular recommendation,” he said.
 

Real-world implementation

Implementing this approach in the clinic setting requires a practical model, such as the Venous Thromboembolism Prevention in the Ambulatory Cancer Clinic (VTEPACC) program, a prospective quality improvement research initiative developed in collaboration with the Jeffords Institute for Quality at the University of Vermont Medical Center and described in a recent report, Dr. Carrier said.

The “Vermont model” is “really a comprehensive model that includes identifying patients with the electronic medical records, gathering the formal education and insight from other health care providers like pharmacists and nurses in order to really come up with personalized care for your patients,” he explained.

In 918 outpatients with cancer who were included in the program, VTE awareness increased from less than 5% before VTEPACC to nearly 82% during the implementation phase and 94.7% after 2 years, with nearly 94% of high-risk patients receiving VTE prophylaxis at that time.

“So we can certainly do that in our own center.” he said. “It’s a matter of coming up with the model and making sure that the patients are seen at the right time.”

Given the high frequency of VTE in patients with cancer initiating chemotherapy, the usefulness of risk scores such as the Khorana risk score for identifying those at high risk, and the availability of safe and effective interventions for reducing risk, “we should probably use the data and incorporate them into clinical practice by implementation of programs for primary prevention,” he said.
 

A word of caution

Caution is warranted, however, when it comes to using DOACs in patients with higher-risk or potentially higher-risk tumor types, he added.

“It’s an important question we are facing as clinicians on a daily basis,” he said, responding to an attendee’s query, as shared by session moderator James Douketis, MD, professor of medicine at McMaster University, Hamilton, Ont., regarding possible bleeding risks in certain genitourinary cancers.

A recent meta-analysis published in Nature, for example, noted that, in the SELECT-D trial, rivaroxaban was associated with significantly higher incidence of clinically relevant nonmajor bleeding, most often in bladder and colorectal cancers, and most often at genitourinary and gastrointestinal sites.

Both Dr. Carrier and fellow panelist Michael Streiff, MD, professor of medicine at Johns Hopkins University and medical director at the Johns Hopkins Hospital Special Coagulation Laboratory, Baltimore, said they approach DOAC use cautiously, but don’t rule it out entirely, in patients with unresected genitourinary tumors that could pose a risk of bleeding.

“It’s worth mentioning and being cautious. In my own personal practice, I’m very careful with unresected urothelial-type tumors or, for example, bladder cancer, for the same reason as [with] unresected luminal GI tumors,” Dr. Carrier said, adding that he’s also mindful that patients with nephropathy were excluded from U.S. DOAC trials because of bleeding risk.

He said he sometimes tries a LMWH challenge first in higher-risk patients, and then might try a DOAC if no bleeding occurs.

“But it certainly is controversial,” he noted.

Dr. Streiff added that he also worries less with genitourinary cancers than with upper GI lesions because “the signals weren’t as big as in GI” cancers, but he noted that “the drugs are going out through the kidneys ... so I’m cautious in those populations.”

“So caution, but not complete exclusion, is the operative management,” Dr. Douketis said, summarizing the panelists’ consensus.

Dr. Carrier reported clinical trial or advisory board participation for Bayer, Pfizer, Servier, Leo Pharma, and/or BMS.

[email protected]

Primary thromboprophylaxis is feasible and worth considering for high-risk ambulatory patients with cancer who are initiating systemic chemotherapy, according to Marc Carrier, MD.

Risk scores can identify patients at high risk for venous thromboembolism (VTE), and treatments that are effective and associated with low bleeding risk are available, Dr. Carrier explained at the biennial summit of the Thrombosis & Hemostasis Societies of North America.

However, caution is advised in patients with certain types of cancer, including some gastrointestinal and genitourinary cancers, because of the possibility of increased major and clinically relevant nonmajor bleeding risk, he said.
 

VTE and cancer

VTE is relatively rare in the general population, occurring in about 1 or 2 per 1,000 people annually. The risk increases 4.1-fold in patients with cancer, and 6.5-fold in patients with cancer receiving chemotherapy.

“So just putting these numbers together, we’re no longer talking about 1 in 1,000, but 1 in 200, so [this is] something that is very common among cancer patients,” said Dr. Carrier, a professor at the University of Ottawa and chief of the division of hematology at The Ottawa Hospital.

The mortality rate associated with cancer-associated thrombosis is about 9%, comparable to that associated with infection in the cancer outpatient setting, which underscores the importance of educating patients about the signs and symptoms of VTE so they can seek medical treatment quickly if necessary, he added.

It may also be useful to discuss prophylaxis or other ways to prevent venous thromboembolic complications with certain patients, he said, noting that in an observational cohort study of nearly 600 patients at the University of Ottawa, 25% of those initiating chemotherapy were identified as intermediate or high risk using the validated Khorana risk score, and thus would likely benefit from thromboprophylaxis.
 

Risk assessment

The Khorana risk score assesses VTE risk based on cancer site, blood counts, and body mass index. It is simple to use and has been validated in more than 20,000 people in multiple countries, Dr. Carrier said.

In a well-known validation study, Ay et al. showed a VTE complication rate of 10% in patients with a Khorana risk score of 2 or higher who were followed up to 6 months.

“This is huge,” Dr. Carrier stressed. “This is much higher than what we tolerate for all sorts of different populations for which we would recommend anticoagulation or thromboprophylaxis.”

The question is whether the risk score can be helpful in a real-world clinic setting, he said, adding: “I’d like to think the answer to that is yes.”

In the University of Ottawa cohort study, 11% of high-risk patients experienced a VTE complication, compared with 4% of those with lower risk, suggesting that the validation data for the Khorana risk score is not only accurate, it is “actually applicable in real-world practice, and you can use it in your own center,” he said.

Further, recent studies have demonstrated that treatment based on Khorana risk score assessment reduces VTE complications.
 

Prophylaxis options

Low-molecular-weight heparin (LMWH) has been shown in several studies to be associated with a significant relative VTE risk reduction in patients with cancer initiating chemotherapy – with only a slight, nonsignificant increase in the risk of major bleeding.

However, the absolute benefit was small, and LMWH is “parenteral, relatively costly, and, based on that, although we showed relatively good risk-benefit ratio, it never really got translated to clinical practice,” Dr. Carrier said.

In fact, a 2015 American Society of Clinical Oncology guidelines update recommended against routine thromboprophylaxis in this setting, but stated that it could be considered in select high-risk patients identified using a validated risk-assessment tool.

The guidelines noted that “individual risk factors such as biomarkers and cancer site don’t reliably identify high-risk patients.”

More recent data provide additional support for risk assessment and treatment based on Khorana risk score of 2 or higher.

The AVERT trial, for which Dr. Carrier was the first author, showed that the direct-acting oral anticoagulant (DOAC) apixaban reduced VTE incidence, compared with placebo, in patients with Khorana score of 2 or higher (4.2% vs. 10.2%; hazard ratio, 0.41 overall, and 1.0 vs. 7.3; HR, 0.14 on treatment), and the CASSINI trial showed that another DOAC, rivaroxaban, reduced VTE incidence, compared with placebo, in those with Khorana score of 2 or higher (5.9 vs. 6.7; HR, 0.6 overall, and 2.6 vs. 6.4; HR, 0.40 on treatment). The differences in the on-treatment populations were statistically significant.

The two trials, which included a variety of tumor types, showed similar rates of major bleeding, with an absolute difference of about 1% between treatment and placebo, which was not statistically significant in the on-treatment analyses (HR, 1.89 in AVERT and HR, 1.96 in CASSINI).

A systematic review of these trials showed an overall significant decrease in VTE complication risk with treatment in high-risk patients, and a nonstatistically significant major bleeding risk increase.

Based on these findings, ASCO guidelines were updated in 2020 to state that “routine thromboprophylaxis should not be offered to all patients with cancer. ... However, high-risk outpatients with cancer may be offered thromboprophylaxis with apixaban, rivaroxaban or LMWH, providing there are no significant risk factors for bleeding or drug-drug interactions, and after having a full discussion with patients ... to make sure they understand the risk-benefit ratio and the rationale for that particular recommendation,” he said.
 

Real-world implementation

Implementing this approach in the clinic setting requires a practical model, such as the Venous Thromboembolism Prevention in the Ambulatory Cancer Clinic (VTEPACC) program, a prospective quality improvement research initiative developed in collaboration with the Jeffords Institute for Quality at the University of Vermont Medical Center and described in a recent report, Dr. Carrier said.

The “Vermont model” is “really a comprehensive model that includes identifying patients with the electronic medical records, gathering the formal education and insight from other health care providers like pharmacists and nurses in order to really come up with personalized care for your patients,” he explained.

In 918 outpatients with cancer who were included in the program, VTE awareness increased from less than 5% before VTEPACC to nearly 82% during the implementation phase and 94.7% after 2 years, with nearly 94% of high-risk patients receiving VTE prophylaxis at that time.

“So we can certainly do that in our own center.” he said. “It’s a matter of coming up with the model and making sure that the patients are seen at the right time.”

Given the high frequency of VTE in patients with cancer initiating chemotherapy, the usefulness of risk scores such as the Khorana risk score for identifying those at high risk, and the availability of safe and effective interventions for reducing risk, “we should probably use the data and incorporate them into clinical practice by implementation of programs for primary prevention,” he said.
 

A word of caution

Caution is warranted, however, when it comes to using DOACs in patients with higher-risk or potentially higher-risk tumor types, he added.

“It’s an important question we are facing as clinicians on a daily basis,” he said, responding to an attendee’s query, as shared by session moderator James Douketis, MD, professor of medicine at McMaster University, Hamilton, Ont., regarding possible bleeding risks in certain genitourinary cancers.

A recent meta-analysis published in Nature, for example, noted that, in the SELECT-D trial, rivaroxaban was associated with significantly higher incidence of clinically relevant nonmajor bleeding, most often in bladder and colorectal cancers, and most often at genitourinary and gastrointestinal sites.

Both Dr. Carrier and fellow panelist Michael Streiff, MD, professor of medicine at Johns Hopkins University and medical director at the Johns Hopkins Hospital Special Coagulation Laboratory, Baltimore, said they approach DOAC use cautiously, but don’t rule it out entirely, in patients with unresected genitourinary tumors that could pose a risk of bleeding.

“It’s worth mentioning and being cautious. In my own personal practice, I’m very careful with unresected urothelial-type tumors or, for example, bladder cancer, for the same reason as [with] unresected luminal GI tumors,” Dr. Carrier said, adding that he’s also mindful that patients with nephropathy were excluded from U.S. DOAC trials because of bleeding risk.

He said he sometimes tries a LMWH challenge first in higher-risk patients, and then might try a DOAC if no bleeding occurs.

“But it certainly is controversial,” he noted.

Dr. Streiff added that he also worries less with genitourinary cancers than with upper GI lesions because “the signals weren’t as big as in GI” cancers, but he noted that “the drugs are going out through the kidneys ... so I’m cautious in those populations.”

“So caution, but not complete exclusion, is the operative management,” Dr. Douketis said, summarizing the panelists’ consensus.

Dr. Carrier reported clinical trial or advisory board participation for Bayer, Pfizer, Servier, Leo Pharma, and/or BMS.

[email protected]

When a patient with cancer develops venous thromboembolism despite anticoagulation, how to help them comes down to clinical judgment, according to hematologist Neil Zakai, MD, associate professor at the University of Vermont, Burlington.

“Unfortunately,” when it comes to “anticoagulation failure, we are entering an evidence free-zone,” with no large trials to guide management and only a few guiding principles, he said during his presentation at the 2020 Update in Nonneoplastic Hematology virtual conference.

The first thing is to check if there was an inciting incident, such as medical noncompliance, an infection, or an interruption of anticoagulation. Dr. Zakai said he’s even had cancer patients develop heparin-induced thrombocytopenia when switched to enoxaparin from a direct oral anticoagulants (DOAC) for a procedure.

Once the underlying problem is addressed, patients may be able to continue with their original anticoagulant.

However, cancer progression is the main reason anticoagulation fails. “In general, it is very difficult to control cancer thrombosis if you can’t control cancer progression,” Dr. Zakai said.

In those cases, he steps up anticoagulation. Prophylactic dosing is increased to full treatment dosing, and patients on a DOAC are generally switched to a low molecular weight heparin (LMWH).

If patients are already on LMWH once daily, they will be bumped up to twice daily dosing; for instance, enoxaparin 1 mg/kg b.i.d. instead of 1.5 mg/kg q.d. Dr. Zakai said he’s gone as high at 2 or even 2.5 mg/kg to control thrombosis, without excessive bleeding.

In general, anticoagulation for thrombosis prophylaxis continues as long as the cancer is active, and certainly while patients are on hormonal treatments such as tamoxifen, which increases the risk.

Dr. Zakai stressed that both thrombosis and bleeding risk change for cancer patients over time, and treatment needs to keep up.

“I continuously assess the risk and benefit of anticoagulation. At certain times” such as during and for a few months after hospitalization, thrombosis risk increases; at other times, bleeding risk is higher. “You need to actively change your anticoagulation during those periods,” and tailor therapy based on transient risk factors. “People with cancer have peaks and troughs for their risk that we don’t take advantage of,” he said.

Dr. Zakai generally favors apixaban or enoxaparin for prophylaxis, carefully monitoring patients for bleeding and, for the DOAC, drug interactions with antiemetics, dexamethasone, and certain chemotherapy drugs.

He noted a recent trial that found a 59% reduction in venous thromboembolism risk in ambulatory cancer patients with apixaban 2.5 mg twice daily over 6 months, versus placebo, and a 6% absolute reduction, but at the cost of a twofold increase in bleeding risk, with an absolute 1.7% increase.

Dr. Zakai cautioned that patients in trials are selected for higher VTE and lower bleeding risks, so outcomes might “poorly reflect real world populations.” Dr. Zakai did not have any industry disclosures. The conference was sponsored by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.

[email protected]

When a patient with cancer develops venous thromboembolism despite anticoagulation, how to help them comes down to clinical judgment, according to hematologist Neil Zakai, MD, associate professor at the University of Vermont, Burlington.

“Unfortunately,” when it comes to “anticoagulation failure, we are entering an evidence free-zone,” with no large trials to guide management and only a few guiding principles, he said during his presentation at the 2020 Update in Nonneoplastic Hematology virtual conference.

The first thing is to check if there was an inciting incident, such as medical noncompliance, an infection, or an interruption of anticoagulation. Dr. Zakai said he’s even had cancer patients develop heparin-induced thrombocytopenia when switched to enoxaparin from a direct oral anticoagulants (DOAC) for a procedure.

Once the underlying problem is addressed, patients may be able to continue with their original anticoagulant.

However, cancer progression is the main reason anticoagulation fails. “In general, it is very difficult to control cancer thrombosis if you can’t control cancer progression,” Dr. Zakai said.

In those cases, he steps up anticoagulation. Prophylactic dosing is increased to full treatment dosing, and patients on a DOAC are generally switched to a low molecular weight heparin (LMWH).

If patients are already on LMWH once daily, they will be bumped up to twice daily dosing; for instance, enoxaparin 1 mg/kg b.i.d. instead of 1.5 mg/kg q.d. Dr. Zakai said he’s gone as high at 2 or even 2.5 mg/kg to control thrombosis, without excessive bleeding.

In general, anticoagulation for thrombosis prophylaxis continues as long as the cancer is active, and certainly while patients are on hormonal treatments such as tamoxifen, which increases the risk.

Dr. Zakai stressed that both thrombosis and bleeding risk change for cancer patients over time, and treatment needs to keep up.

“I continuously assess the risk and benefit of anticoagulation. At certain times” such as during and for a few months after hospitalization, thrombosis risk increases; at other times, bleeding risk is higher. “You need to actively change your anticoagulation during those periods,” and tailor therapy based on transient risk factors. “People with cancer have peaks and troughs for their risk that we don’t take advantage of,” he said.

Dr. Zakai generally favors apixaban or enoxaparin for prophylaxis, carefully monitoring patients for bleeding and, for the DOAC, drug interactions with antiemetics, dexamethasone, and certain chemotherapy drugs.

He noted a recent trial that found a 59% reduction in venous thromboembolism risk in ambulatory cancer patients with apixaban 2.5 mg twice daily over 6 months, versus placebo, and a 6% absolute reduction, but at the cost of a twofold increase in bleeding risk, with an absolute 1.7% increase.

Dr. Zakai cautioned that patients in trials are selected for higher VTE and lower bleeding risks, so outcomes might “poorly reflect real world populations.” Dr. Zakai did not have any industry disclosures. The conference was sponsored by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.

[email protected]

When a patient with cancer develops venous thromboembolism despite anticoagulation, how to help them comes down to clinical judgment, according to hematologist Neil Zakai, MD, associate professor at the University of Vermont, Burlington.

“Unfortunately,” when it comes to “anticoagulation failure, we are entering an evidence free-zone,” with no large trials to guide management and only a few guiding principles, he said during his presentation at the 2020 Update in Nonneoplastic Hematology virtual conference.

The first thing is to check if there was an inciting incident, such as medical noncompliance, an infection, or an interruption of anticoagulation. Dr. Zakai said he’s even had cancer patients develop heparin-induced thrombocytopenia when switched to enoxaparin from a direct oral anticoagulants (DOAC) for a procedure.

Once the underlying problem is addressed, patients may be able to continue with their original anticoagulant.

However, cancer progression is the main reason anticoagulation fails. “In general, it is very difficult to control cancer thrombosis if you can’t control cancer progression,” Dr. Zakai said.

In those cases, he steps up anticoagulation. Prophylactic dosing is increased to full treatment dosing, and patients on a DOAC are generally switched to a low molecular weight heparin (LMWH).

If patients are already on LMWH once daily, they will be bumped up to twice daily dosing; for instance, enoxaparin 1 mg/kg b.i.d. instead of 1.5 mg/kg q.d. Dr. Zakai said he’s gone as high at 2 or even 2.5 mg/kg to control thrombosis, without excessive bleeding.

In general, anticoagulation for thrombosis prophylaxis continues as long as the cancer is active, and certainly while patients are on hormonal treatments such as tamoxifen, which increases the risk.

Dr. Zakai stressed that both thrombosis and bleeding risk change for cancer patients over time, and treatment needs to keep up.

“I continuously assess the risk and benefit of anticoagulation. At certain times” such as during and for a few months after hospitalization, thrombosis risk increases; at other times, bleeding risk is higher. “You need to actively change your anticoagulation during those periods,” and tailor therapy based on transient risk factors. “People with cancer have peaks and troughs for their risk that we don’t take advantage of,” he said.

Dr. Zakai generally favors apixaban or enoxaparin for prophylaxis, carefully monitoring patients for bleeding and, for the DOAC, drug interactions with antiemetics, dexamethasone, and certain chemotherapy drugs.

He noted a recent trial that found a 59% reduction in venous thromboembolism risk in ambulatory cancer patients with apixaban 2.5 mg twice daily over 6 months, versus placebo, and a 6% absolute reduction, but at the cost of a twofold increase in bleeding risk, with an absolute 1.7% increase.

Dr. Zakai cautioned that patients in trials are selected for higher VTE and lower bleeding risks, so outcomes might “poorly reflect real world populations.” Dr. Zakai did not have any industry disclosures. The conference was sponsored by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.

[email protected]

Men with genetic variants that cause hereditary hemochromatosis have an increased risk of liver cancer and death, according to a large cohort study.

Hereditary hemochromatosis is primarily caused by HFE gene variants. Past research suggested that 81% of patients with hereditary hemochromatosis carry the p.C282Y variant and 5% carry the p.C282Y/p.H63D compound heterozygote genotype.

In a new study, the presence of HFE p.C282Y and p.H63D genotypes was associated with a 10-fold greater risk of developing a hepatic malignancy among men of European ancestry aged 40-70 years. In addition, men with HFE variants were 1.2 times more likely to die of any cause, compared with men who had neither pathogenic variant.

Janice L. Atkins, PhD, of the University of Exeter (England), and colleagues reported these findings in JAMA.

For this study, Dr. Atkins and colleagues used follow-up data from a large genotyped community sample to estimate the incidence of primary hepatic carcinomas and deaths by HFE variant status in participants of European descent.

Data for the two linked coprimary endpoints, incident primary liver carcinoma and all-cause mortality, were derived from hospital and death certificate records. Where available, primary care data was also included.
 

Results: Increased risks for men, not women

The researchers analyzed data from 451,186 men and women, aged 40-70 years, from the UK Biobank. There were 2,890 (0.9%) patients who were p.C282Y homozygous, 1,294 of whom were men.

Among the 1,294 men with HFE p.C282Y homozygosity, 21 were diagnosed with a primary hepatic malignancy. Ten of these patients were not diagnosed with hemochromatosis at baseline.

At a median follow-up of 8.9 years, the risk of primary hepatic malignancy was significantly higher in men with HFE p.C282Y homozygosity, compared with men without HFE pathogenic variants (hazard ratio, 10.5; 95% confidence interval, 6.6-16.7; P < .001).

The risk of all-cause death was significantly higher in men with HFE p.C282Y homozygosity as well (HR, 1.2; 95% CI, 1.0-1.5; P  = .046).

In contrast, female HFE p.C282Y homozygotes had no significant increases in the risk of incident primary hepatic malignancy or all-cause mortality.

Life table projections estimated that 7.2% of men with HFE p.C282Y homozygosity will develop a primary hepatic malignancy by age 75, compared with 0.6% of men without p.C282Y or p.H63D variants.

The researchers acknowledged that a key limitation of this study was the ancestral homogeneity of the cohort. Thus, the findings may not be generalizable to all patient populations.
 

Implications: Earlier diagnosis and treatment

The results of this study underline the importance of early diagnosis and genetic testing, according to the researchers.

“Tragically, men with the hemochromatosis faulty genes have been dying of liver cancer for many years, but this was thought to be rare,” study author David Melzer, MBBCh, PhD, of University of Exeter, said in a press release.

“The large scale of the UK Biobank study allowed us to measure cancer risk accurately. We were shocked to find that more than 7% of men with two faulty genes are likely to develop liver cancer by age 75, particularly considering that the U.K. has the second-highest rate of these faulty genes in the world. Fortunately, most of these cancers could be prevented with early treatment,” Dr. Melzer added.

“Physicians and scientists have long acknowledged that iron overload is an important cofactor fueling the development of many serious diseases, including cancer,” said study author Jeremy Shearman, MBChB, DPhil, of Nuffield Health and South Warwickshire NHS Foundation Trust in the United Kingdom.

“This research is a vital step towards quantifying that risk and should raise awareness of the importance of iron in the minds of both clinicians and patients. Measurement of iron stores and recognition of the genetic risk of iron overload needs to become a routine part of health assessment and monitoring in the U.K.,” Dr. Shearman added.

“The UK Biobank project is a glimpse into the future of medicine where all known genes are tested and then treatable conditions are offered treatment before serious complications develop,” said study author Paul Adams, MD, of the University of Western Ontario in London.

This research was funded by the UK Medical Research Council. Dr. Melzer disclosed financial affiliations with the UK Medical Research Council during the conduct of the study.

SOURCE: Atkins JL et al. JAMA. 2020 Nov 24. doi: 10.1001/jama.2020.21566.

Men with genetic variants that cause hereditary hemochromatosis have an increased risk of liver cancer and death, according to a large cohort study.

Hereditary hemochromatosis is primarily caused by HFE gene variants. Past research suggested that 81% of patients with hereditary hemochromatosis carry the p.C282Y variant and 5% carry the p.C282Y/p.H63D compound heterozygote genotype.

In a new study, the presence of HFE p.C282Y and p.H63D genotypes was associated with a 10-fold greater risk of developing a hepatic malignancy among men of European ancestry aged 40-70 years. In addition, men with HFE variants were 1.2 times more likely to die of any cause, compared with men who had neither pathogenic variant.

Janice L. Atkins, PhD, of the University of Exeter (England), and colleagues reported these findings in JAMA.

For this study, Dr. Atkins and colleagues used follow-up data from a large genotyped community sample to estimate the incidence of primary hepatic carcinomas and deaths by HFE variant status in participants of European descent.

Data for the two linked coprimary endpoints, incident primary liver carcinoma and all-cause mortality, were derived from hospital and death certificate records. Where available, primary care data was also included.
 

Results: Increased risks for men, not women

The researchers analyzed data from 451,186 men and women, aged 40-70 years, from the UK Biobank. There were 2,890 (0.9%) patients who were p.C282Y homozygous, 1,294 of whom were men.

Among the 1,294 men with HFE p.C282Y homozygosity, 21 were diagnosed with a primary hepatic malignancy. Ten of these patients were not diagnosed with hemochromatosis at baseline.

At a median follow-up of 8.9 years, the risk of primary hepatic malignancy was significantly higher in men with HFE p.C282Y homozygosity, compared with men without HFE pathogenic variants (hazard ratio, 10.5; 95% confidence interval, 6.6-16.7; P < .001).

The risk of all-cause death was significantly higher in men with HFE p.C282Y homozygosity as well (HR, 1.2; 95% CI, 1.0-1.5; P  = .046).

In contrast, female HFE p.C282Y homozygotes had no significant increases in the risk of incident primary hepatic malignancy or all-cause mortality.

Life table projections estimated that 7.2% of men with HFE p.C282Y homozygosity will develop a primary hepatic malignancy by age 75, compared with 0.6% of men without p.C282Y or p.H63D variants.

The researchers acknowledged that a key limitation of this study was the ancestral homogeneity of the cohort. Thus, the findings may not be generalizable to all patient populations.
 

Implications: Earlier diagnosis and treatment

The results of this study underline the importance of early diagnosis and genetic testing, according to the researchers.

“Tragically, men with the hemochromatosis faulty genes have been dying of liver cancer for many years, but this was thought to be rare,” study author David Melzer, MBBCh, PhD, of University of Exeter, said in a press release.

“The large scale of the UK Biobank study allowed us to measure cancer risk accurately. We were shocked to find that more than 7% of men with two faulty genes are likely to develop liver cancer by age 75, particularly considering that the U.K. has the second-highest rate of these faulty genes in the world. Fortunately, most of these cancers could be prevented with early treatment,” Dr. Melzer added.

“Physicians and scientists have long acknowledged that iron overload is an important cofactor fueling the development of many serious diseases, including cancer,” said study author Jeremy Shearman, MBChB, DPhil, of Nuffield Health and South Warwickshire NHS Foundation Trust in the United Kingdom.

“This research is a vital step towards quantifying that risk and should raise awareness of the importance of iron in the minds of both clinicians and patients. Measurement of iron stores and recognition of the genetic risk of iron overload needs to become a routine part of health assessment and monitoring in the U.K.,” Dr. Shearman added.

“The UK Biobank project is a glimpse into the future of medicine where all known genes are tested and then treatable conditions are offered treatment before serious complications develop,” said study author Paul Adams, MD, of the University of Western Ontario in London.

This research was funded by the UK Medical Research Council. Dr. Melzer disclosed financial affiliations with the UK Medical Research Council during the conduct of the study.

SOURCE: Atkins JL et al. JAMA. 2020 Nov 24. doi: 10.1001/jama.2020.21566.

Men with genetic variants that cause hereditary hemochromatosis have an increased risk of liver cancer and death, according to a large cohort study.

Hereditary hemochromatosis is primarily caused by HFE gene variants. Past research suggested that 81% of patients with hereditary hemochromatosis carry the p.C282Y variant and 5% carry the p.C282Y/p.H63D compound heterozygote genotype.

In a new study, the presence of HFE p.C282Y and p.H63D genotypes was associated with a 10-fold greater risk of developing a hepatic malignancy among men of European ancestry aged 40-70 years. In addition, men with HFE variants were 1.2 times more likely to die of any cause, compared with men who had neither pathogenic variant.

Janice L. Atkins, PhD, of the University of Exeter (England), and colleagues reported these findings in JAMA.

For this study, Dr. Atkins and colleagues used follow-up data from a large genotyped community sample to estimate the incidence of primary hepatic carcinomas and deaths by HFE variant status in participants of European descent.

Data for the two linked coprimary endpoints, incident primary liver carcinoma and all-cause mortality, were derived from hospital and death certificate records. Where available, primary care data was also included.
 

Results: Increased risks for men, not women

The researchers analyzed data from 451,186 men and women, aged 40-70 years, from the UK Biobank. There were 2,890 (0.9%) patients who were p.C282Y homozygous, 1,294 of whom were men.

Among the 1,294 men with HFE p.C282Y homozygosity, 21 were diagnosed with a primary hepatic malignancy. Ten of these patients were not diagnosed with hemochromatosis at baseline.

At a median follow-up of 8.9 years, the risk of primary hepatic malignancy was significantly higher in men with HFE p.C282Y homozygosity, compared with men without HFE pathogenic variants (hazard ratio, 10.5; 95% confidence interval, 6.6-16.7; P < .001).

The risk of all-cause death was significantly higher in men with HFE p.C282Y homozygosity as well (HR, 1.2; 95% CI, 1.0-1.5; P  = .046).

In contrast, female HFE p.C282Y homozygotes had no significant increases in the risk of incident primary hepatic malignancy or all-cause mortality.

Life table projections estimated that 7.2% of men with HFE p.C282Y homozygosity will develop a primary hepatic malignancy by age 75, compared with 0.6% of men without p.C282Y or p.H63D variants.

The researchers acknowledged that a key limitation of this study was the ancestral homogeneity of the cohort. Thus, the findings may not be generalizable to all patient populations.
 

Implications: Earlier diagnosis and treatment

The results of this study underline the importance of early diagnosis and genetic testing, according to the researchers.

“Tragically, men with the hemochromatosis faulty genes have been dying of liver cancer for many years, but this was thought to be rare,” study author David Melzer, MBBCh, PhD, of University of Exeter, said in a press release.

“The large scale of the UK Biobank study allowed us to measure cancer risk accurately. We were shocked to find that more than 7% of men with two faulty genes are likely to develop liver cancer by age 75, particularly considering that the U.K. has the second-highest rate of these faulty genes in the world. Fortunately, most of these cancers could be prevented with early treatment,” Dr. Melzer added.

“Physicians and scientists have long acknowledged that iron overload is an important cofactor fueling the development of many serious diseases, including cancer,” said study author Jeremy Shearman, MBChB, DPhil, of Nuffield Health and South Warwickshire NHS Foundation Trust in the United Kingdom.

“This research is a vital step towards quantifying that risk and should raise awareness of the importance of iron in the minds of both clinicians and patients. Measurement of iron stores and recognition of the genetic risk of iron overload needs to become a routine part of health assessment and monitoring in the U.K.,” Dr. Shearman added.

“The UK Biobank project is a glimpse into the future of medicine where all known genes are tested and then treatable conditions are offered treatment before serious complications develop,” said study author Paul Adams, MD, of the University of Western Ontario in London.

This research was funded by the UK Medical Research Council. Dr. Melzer disclosed financial affiliations with the UK Medical Research Council during the conduct of the study.

SOURCE: Atkins JL et al. JAMA. 2020 Nov 24. doi: 10.1001/jama.2020.21566.

Immune checkpoint inhibitor (ICI) therapy does not increase the risk of developing or dying from COVID-19, according to a pair of studies presented at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

Cytokine storm plays a major role in the pathogenesis of COVID-19, according to research published in The Lancet Respiratory Medicine. This has generated concern about using ICIs during the pandemic, given their immunostimulatory activity and the risk of immune-related adverse effects.

However, two retrospective studies suggest ICIs do not increase the risk of developing COVID-19 or dying from the disease.

In a study of 1,545 cancer patients prescribed ICIs and 20,418 matched controls, the incidence of COVID-19 was 1.4% with ICI therapy and 1.0% without it (odds ratio, 1.38; P = .15).

In a case-control study of 50 patients with cancer and COVID-19, 28% of patients who had received ICIs died from COVID-19, compared with 36% of patients who had not received ICIs (OR, 0.36; P = .23).

Vartan Pahalyants and Kevin Tyan, both students in Harvard University’s joint MD/MBA program in Boston, presented these studies at the meeting.
 

COVID-19 incidence with ICIs

Mr. Pahalyants and colleagues analyzed data from cancer patients treated in the Mass General Brigham health care system. The researchers compared 1,545 patients with at least one ICI prescription between July 1, 2019, and Feb. 29, 2020, with 20,418 matched cancer patients not prescribed ICIs. The team assessed COVID-19 incidence based on positive test results through June 19, 2020, from public health data.

The incidence of COVID-19 was low in both groups – 1.4% in the ICI group and 1.0% in the matched control group (P = .16). Among COVID-19–positive patients, the all-cause death rate was 40.9% in the ICI group and 28.6% in the control group (P = .23).

In multivariate analysis, patients prescribed ICIs did not have a significantly elevated risk for COVID-19 relative to peers not prescribed ICIs (OR, 1.38; P = .15). However, risk was significantly increased for female patients (OR, 1.74; P < .001), those living in a town or county with higher COVID-19 positivity rate (OR, 1.59; P < .001), and those with severe comorbidity (vs. mild or moderate; OR, 9.77; P = .02).

Among COVID-19–positive patients, those prescribed ICIs did not have a significantly elevated risk for all-cause mortality (OR, 1.60; P = .71), but male sex and lower income were associated with an increased risk of death.

“We did not identify an increased risk of [COVID-19] diagnosis among patients prescribed ICIs compared to the controls,” Mr. Pahalyants said. “This information may assist patients and their providers in decision-making around continuation of therapy during this protracted pandemic. However, more research needs to be conducted to determine potential behavioral and testing factors that may have affected COVID-19 diagnosis susceptibility among patients included in the study.”

COVID-19 mortality with ICIs

For their study, Mr. Tyan and colleagues identified 25 cancer patients who had received ICIs in the year before a COVID-19 diagnosis between March 20, 2020, and June 3, 2020, at the Dana-Farber Cancer Institute and Mass General Brigham network. The researchers then matched each patient with a cancer patient having a COVID-19 diagnosis who had not received ICIs during the preceding year.

Overall, 28% of patients who had received ICIs before their COVID-19 diagnosis died from COVID-19, compared with 36% of those who had not received ICIs.

In multivariate analysis, ICI therapy did not predict COVID-19 mortality (OR, 0.36; P = .23). However, the risk of death from COVID-19 increased with age (OR, 1.14; P = .01) and for patients with chronic obstructive pulmonary disease (OR, 12.26; P = .01), and risk was lower for statin users (OR, 0.08; P = .02). Findings were similar in an analysis restricted to hospitalized patients in the ICI group and their matched controls.

Two ICI-treated patients with COVID-19 had persistent immune-related adverse events (hypophysitis in both cases), and one ICI-treated patient developed a new immune-related adverse event (hypothyroidism).

At COVID-19 presentation, relative to counterparts who had not received ICIs, patients who had received ICIs had higher platelet counts (P = .017) and higher D-dimer levels (P = .037). In the context of similar levels of other biomarkers, this finding is “of unclear significance, as all deaths in the cohort were due to respiratory failure as opposed to hypercoagulability,” Mr. Tyan said.

The patients treated with ICIs were more likely to die from COVID-19 if they had elevated troponin levels (P = .01), whereas no such association was seen for those not treated with ICIs.

“We found that ICI therapy is not associated with greater risk for COVID-19 mortality. Our period of follow-up was relatively short, but we did not observe a high incidence of new or persistent immune-related adverse events among our patients taking ICIs,” Mr. Tyan said.

“While larger prospective trials are needed to evaluate long-term safety in the context of COVID-19 infection, our findings support the continuation of ICI therapy during the pandemic as it does not appear to worsen outcomes for cancer patients,” he concluded.
 

ICI therapy can continue, with precautions

“The question of susceptibility to COVID-19 has been unclear as ICIs do not necessarily cause immunosuppression but certainly result in modulation of a patient’s immune system,” said Deborah Doroshow, MD, PhD, assistant professor at the Tisch Cancer Institute Icahn School of Medicine at Mount Sinai, New York. She was not involved in these studies.

“The findings of the study by Pahalyants and colleagues, which used a very large sample size, appear to convincingly demonstrate that ICI receipt is not associated with an increased susceptibility to COVID-19,” Dr. Doroshow said in an interview.

SOURCE: Pahalyants V et al. SITC 2020, Abstract 826. Tyan K et al. SITC 2020, Abstract 481.

Immune checkpoint inhibitor (ICI) therapy does not increase the risk of developing or dying from COVID-19, according to a pair of studies presented at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

Cytokine storm plays a major role in the pathogenesis of COVID-19, according to research published in The Lancet Respiratory Medicine. This has generated concern about using ICIs during the pandemic, given their immunostimulatory activity and the risk of immune-related adverse effects.

However, two retrospective studies suggest ICIs do not increase the risk of developing COVID-19 or dying from the disease.

In a study of 1,545 cancer patients prescribed ICIs and 20,418 matched controls, the incidence of COVID-19 was 1.4% with ICI therapy and 1.0% without it (odds ratio, 1.38; P = .15).

In a case-control study of 50 patients with cancer and COVID-19, 28% of patients who had received ICIs died from COVID-19, compared with 36% of patients who had not received ICIs (OR, 0.36; P = .23).

Vartan Pahalyants and Kevin Tyan, both students in Harvard University’s joint MD/MBA program in Boston, presented these studies at the meeting.
 

COVID-19 incidence with ICIs

Mr. Pahalyants and colleagues analyzed data from cancer patients treated in the Mass General Brigham health care system. The researchers compared 1,545 patients with at least one ICI prescription between July 1, 2019, and Feb. 29, 2020, with 20,418 matched cancer patients not prescribed ICIs. The team assessed COVID-19 incidence based on positive test results through June 19, 2020, from public health data.

The incidence of COVID-19 was low in both groups – 1.4% in the ICI group and 1.0% in the matched control group (P = .16). Among COVID-19–positive patients, the all-cause death rate was 40.9% in the ICI group and 28.6% in the control group (P = .23).

In multivariate analysis, patients prescribed ICIs did not have a significantly elevated risk for COVID-19 relative to peers not prescribed ICIs (OR, 1.38; P = .15). However, risk was significantly increased for female patients (OR, 1.74; P < .001), those living in a town or county with higher COVID-19 positivity rate (OR, 1.59; P < .001), and those with severe comorbidity (vs. mild or moderate; OR, 9.77; P = .02).

Among COVID-19–positive patients, those prescribed ICIs did not have a significantly elevated risk for all-cause mortality (OR, 1.60; P = .71), but male sex and lower income were associated with an increased risk of death.

“We did not identify an increased risk of [COVID-19] diagnosis among patients prescribed ICIs compared to the controls,” Mr. Pahalyants said. “This information may assist patients and their providers in decision-making around continuation of therapy during this protracted pandemic. However, more research needs to be conducted to determine potential behavioral and testing factors that may have affected COVID-19 diagnosis susceptibility among patients included in the study.”

COVID-19 mortality with ICIs

For their study, Mr. Tyan and colleagues identified 25 cancer patients who had received ICIs in the year before a COVID-19 diagnosis between March 20, 2020, and June 3, 2020, at the Dana-Farber Cancer Institute and Mass General Brigham network. The researchers then matched each patient with a cancer patient having a COVID-19 diagnosis who had not received ICIs during the preceding year.

Overall, 28% of patients who had received ICIs before their COVID-19 diagnosis died from COVID-19, compared with 36% of those who had not received ICIs.

In multivariate analysis, ICI therapy did not predict COVID-19 mortality (OR, 0.36; P = .23). However, the risk of death from COVID-19 increased with age (OR, 1.14; P = .01) and for patients with chronic obstructive pulmonary disease (OR, 12.26; P = .01), and risk was lower for statin users (OR, 0.08; P = .02). Findings were similar in an analysis restricted to hospitalized patients in the ICI group and their matched controls.

Two ICI-treated patients with COVID-19 had persistent immune-related adverse events (hypophysitis in both cases), and one ICI-treated patient developed a new immune-related adverse event (hypothyroidism).

At COVID-19 presentation, relative to counterparts who had not received ICIs, patients who had received ICIs had higher platelet counts (P = .017) and higher D-dimer levels (P = .037). In the context of similar levels of other biomarkers, this finding is “of unclear significance, as all deaths in the cohort were due to respiratory failure as opposed to hypercoagulability,” Mr. Tyan said.

The patients treated with ICIs were more likely to die from COVID-19 if they had elevated troponin levels (P = .01), whereas no such association was seen for those not treated with ICIs.

“We found that ICI therapy is not associated with greater risk for COVID-19 mortality. Our period of follow-up was relatively short, but we did not observe a high incidence of new or persistent immune-related adverse events among our patients taking ICIs,” Mr. Tyan said.

“While larger prospective trials are needed to evaluate long-term safety in the context of COVID-19 infection, our findings support the continuation of ICI therapy during the pandemic as it does not appear to worsen outcomes for cancer patients,” he concluded.
 

ICI therapy can continue, with precautions

“The question of susceptibility to COVID-19 has been unclear as ICIs do not necessarily cause immunosuppression but certainly result in modulation of a patient’s immune system,” said Deborah Doroshow, MD, PhD, assistant professor at the Tisch Cancer Institute Icahn School of Medicine at Mount Sinai, New York. She was not involved in these studies.

“The findings of the study by Pahalyants and colleagues, which used a very large sample size, appear to convincingly demonstrate that ICI receipt is not associated with an increased susceptibility to COVID-19,” Dr. Doroshow said in an interview.

SOURCE: Pahalyants V et al. SITC 2020, Abstract 826. Tyan K et al. SITC 2020, Abstract 481.

Immune checkpoint inhibitor (ICI) therapy does not increase the risk of developing or dying from COVID-19, according to a pair of studies presented at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

Cytokine storm plays a major role in the pathogenesis of COVID-19, according to research published in The Lancet Respiratory Medicine. This has generated concern about using ICIs during the pandemic, given their immunostimulatory activity and the risk of immune-related adverse effects.

However, two retrospective studies suggest ICIs do not increase the risk of developing COVID-19 or dying from the disease.

In a study of 1,545 cancer patients prescribed ICIs and 20,418 matched controls, the incidence of COVID-19 was 1.4% with ICI therapy and 1.0% without it (odds ratio, 1.38; P = .15).

In a case-control study of 50 patients with cancer and COVID-19, 28% of patients who had received ICIs died from COVID-19, compared with 36% of patients who had not received ICIs (OR, 0.36; P = .23).

Vartan Pahalyants and Kevin Tyan, both students in Harvard University’s joint MD/MBA program in Boston, presented these studies at the meeting.
 

COVID-19 incidence with ICIs

Mr. Pahalyants and colleagues analyzed data from cancer patients treated in the Mass General Brigham health care system. The researchers compared 1,545 patients with at least one ICI prescription between July 1, 2019, and Feb. 29, 2020, with 20,418 matched cancer patients not prescribed ICIs. The team assessed COVID-19 incidence based on positive test results through June 19, 2020, from public health data.

The incidence of COVID-19 was low in both groups – 1.4% in the ICI group and 1.0% in the matched control group (P = .16). Among COVID-19–positive patients, the all-cause death rate was 40.9% in the ICI group and 28.6% in the control group (P = .23).

In multivariate analysis, patients prescribed ICIs did not have a significantly elevated risk for COVID-19 relative to peers not prescribed ICIs (OR, 1.38; P = .15). However, risk was significantly increased for female patients (OR, 1.74; P < .001), those living in a town or county with higher COVID-19 positivity rate (OR, 1.59; P < .001), and those with severe comorbidity (vs. mild or moderate; OR, 9.77; P = .02).

Among COVID-19–positive patients, those prescribed ICIs did not have a significantly elevated risk for all-cause mortality (OR, 1.60; P = .71), but male sex and lower income were associated with an increased risk of death.

“We did not identify an increased risk of [COVID-19] diagnosis among patients prescribed ICIs compared to the controls,” Mr. Pahalyants said. “This information may assist patients and their providers in decision-making around continuation of therapy during this protracted pandemic. However, more research needs to be conducted to determine potential behavioral and testing factors that may have affected COVID-19 diagnosis susceptibility among patients included in the study.”

COVID-19 mortality with ICIs

For their study, Mr. Tyan and colleagues identified 25 cancer patients who had received ICIs in the year before a COVID-19 diagnosis between March 20, 2020, and June 3, 2020, at the Dana-Farber Cancer Institute and Mass General Brigham network. The researchers then matched each patient with a cancer patient having a COVID-19 diagnosis who had not received ICIs during the preceding year.

Overall, 28% of patients who had received ICIs before their COVID-19 diagnosis died from COVID-19, compared with 36% of those who had not received ICIs.

In multivariate analysis, ICI therapy did not predict COVID-19 mortality (OR, 0.36; P = .23). However, the risk of death from COVID-19 increased with age (OR, 1.14; P = .01) and for patients with chronic obstructive pulmonary disease (OR, 12.26; P = .01), and risk was lower for statin users (OR, 0.08; P = .02). Findings were similar in an analysis restricted to hospitalized patients in the ICI group and their matched controls.

Two ICI-treated patients with COVID-19 had persistent immune-related adverse events (hypophysitis in both cases), and one ICI-treated patient developed a new immune-related adverse event (hypothyroidism).

At COVID-19 presentation, relative to counterparts who had not received ICIs, patients who had received ICIs had higher platelet counts (P = .017) and higher D-dimer levels (P = .037). In the context of similar levels of other biomarkers, this finding is “of unclear significance, as all deaths in the cohort were due to respiratory failure as opposed to hypercoagulability,” Mr. Tyan said.

The patients treated with ICIs were more likely to die from COVID-19 if they had elevated troponin levels (P = .01), whereas no such association was seen for those not treated with ICIs.

“We found that ICI therapy is not associated with greater risk for COVID-19 mortality. Our period of follow-up was relatively short, but we did not observe a high incidence of new or persistent immune-related adverse events among our patients taking ICIs,” Mr. Tyan said.

“While larger prospective trials are needed to evaluate long-term safety in the context of COVID-19 infection, our findings support the continuation of ICI therapy during the pandemic as it does not appear to worsen outcomes for cancer patients,” he concluded.
 

ICI therapy can continue, with precautions

“The question of susceptibility to COVID-19 has been unclear as ICIs do not necessarily cause immunosuppression but certainly result in modulation of a patient’s immune system,” said Deborah Doroshow, MD, PhD, assistant professor at the Tisch Cancer Institute Icahn School of Medicine at Mount Sinai, New York. She was not involved in these studies.

“The findings of the study by Pahalyants and colleagues, which used a very large sample size, appear to convincingly demonstrate that ICI receipt is not associated with an increased susceptibility to COVID-19,” Dr. Doroshow said in an interview.

SOURCE: Pahalyants V et al. SITC 2020, Abstract 826. Tyan K et al. SITC 2020, Abstract 481.