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Predicting outcomes in therapy-related AML
Therapy-related acute myeloid leukemia (t-AML) occurs as a complication of chemotherapy and/or radiotherapy for previous cancer or for nonmalignant disorders, with an estimated prevalence of 10%-15% of all AML cases, according to Ram Vasudevan Nampoothiri, MD, and colleagues at the Princess Margaret Cancer Center, University of Toronto.
Dr. Nampoothiri and colleagues performed a retrospective study of 68 patients with t-AML who underwent hematopoietic stem cell transplantation (HSCT) at their institution. They found significant predictors of reduced overall survival, including chromosomal rearrangements, induction regimens, donor type, patient performance status, and the type of graft-versus-host disease (GVHD) prophylaxis the patients received, as reported in Hematology/Oncology and Stem Cell Therapy.
Some populations benefit
Among the 68 patients studied, a total of 59.9% were women; and the median age was 56.5 years. All patients were analyzed for prior malignancy, therapy, time to diagnosis of t-AML, transplant details, relapse-free survival, overall survival, and predictors of outcomes.
At 2 years, the cumulative incidence of relapse, nonrelapse mortality, relapse-free survival, and overall survival were 17.9%, 34.5%, 47.6%, and 49.3%, respectively. Overall, acute and chronic GVHD occurred in 39 (57.4%) and 23 (33.8%) patients, respectively, according to the researchers.
The significant predictors of reduced overall survival were the presence of the 11q23 chromosomal rearrangement (hazard ratio, 3.24), use of induction regimens other than fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor or 7 + 3 (HR, 3.65), use of haploidentical donors (HR, 3.48), an Eastern Cooperative Oncology Group performance status of 2 or higher (HR, 5.83), and use of cyclosporine A–methotrexate as GVHD prophylaxis (HR, 2.41).
The researchers also found that a significant decrease in survival was seen with an increasing number of any of these prognostic factors.
A growing need
The incidence of t-AML is increasing because of longer life expectancy of the general population and also because of the improved survival of patients treated with chemotherapy and/or radiation for prior malignancies, according to the researchers.
They concluded that, even with this increasing prevalence and normally poor prognosis, “patients of t-AML having good-risk karyotypes, good performance status, and having HLA-matched donors have favorable outcomes after allo-HSCT.”
The authors reported that they had no competing financial interests.
Therapy-related acute myeloid leukemia (t-AML) occurs as a complication of chemotherapy and/or radiotherapy for previous cancer or for nonmalignant disorders, with an estimated prevalence of 10%-15% of all AML cases, according to Ram Vasudevan Nampoothiri, MD, and colleagues at the Princess Margaret Cancer Center, University of Toronto.
Dr. Nampoothiri and colleagues performed a retrospective study of 68 patients with t-AML who underwent hematopoietic stem cell transplantation (HSCT) at their institution. They found significant predictors of reduced overall survival, including chromosomal rearrangements, induction regimens, donor type, patient performance status, and the type of graft-versus-host disease (GVHD) prophylaxis the patients received, as reported in Hematology/Oncology and Stem Cell Therapy.
Some populations benefit
Among the 68 patients studied, a total of 59.9% were women; and the median age was 56.5 years. All patients were analyzed for prior malignancy, therapy, time to diagnosis of t-AML, transplant details, relapse-free survival, overall survival, and predictors of outcomes.
At 2 years, the cumulative incidence of relapse, nonrelapse mortality, relapse-free survival, and overall survival were 17.9%, 34.5%, 47.6%, and 49.3%, respectively. Overall, acute and chronic GVHD occurred in 39 (57.4%) and 23 (33.8%) patients, respectively, according to the researchers.
The significant predictors of reduced overall survival were the presence of the 11q23 chromosomal rearrangement (hazard ratio, 3.24), use of induction regimens other than fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor or 7 + 3 (HR, 3.65), use of haploidentical donors (HR, 3.48), an Eastern Cooperative Oncology Group performance status of 2 or higher (HR, 5.83), and use of cyclosporine A–methotrexate as GVHD prophylaxis (HR, 2.41).
The researchers also found that a significant decrease in survival was seen with an increasing number of any of these prognostic factors.
A growing need
The incidence of t-AML is increasing because of longer life expectancy of the general population and also because of the improved survival of patients treated with chemotherapy and/or radiation for prior malignancies, according to the researchers.
They concluded that, even with this increasing prevalence and normally poor prognosis, “patients of t-AML having good-risk karyotypes, good performance status, and having HLA-matched donors have favorable outcomes after allo-HSCT.”
The authors reported that they had no competing financial interests.
Therapy-related acute myeloid leukemia (t-AML) occurs as a complication of chemotherapy and/or radiotherapy for previous cancer or for nonmalignant disorders, with an estimated prevalence of 10%-15% of all AML cases, according to Ram Vasudevan Nampoothiri, MD, and colleagues at the Princess Margaret Cancer Center, University of Toronto.
Dr. Nampoothiri and colleagues performed a retrospective study of 68 patients with t-AML who underwent hematopoietic stem cell transplantation (HSCT) at their institution. They found significant predictors of reduced overall survival, including chromosomal rearrangements, induction regimens, donor type, patient performance status, and the type of graft-versus-host disease (GVHD) prophylaxis the patients received, as reported in Hematology/Oncology and Stem Cell Therapy.
Some populations benefit
Among the 68 patients studied, a total of 59.9% were women; and the median age was 56.5 years. All patients were analyzed for prior malignancy, therapy, time to diagnosis of t-AML, transplant details, relapse-free survival, overall survival, and predictors of outcomes.
At 2 years, the cumulative incidence of relapse, nonrelapse mortality, relapse-free survival, and overall survival were 17.9%, 34.5%, 47.6%, and 49.3%, respectively. Overall, acute and chronic GVHD occurred in 39 (57.4%) and 23 (33.8%) patients, respectively, according to the researchers.
The significant predictors of reduced overall survival were the presence of the 11q23 chromosomal rearrangement (hazard ratio, 3.24), use of induction regimens other than fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor or 7 + 3 (HR, 3.65), use of haploidentical donors (HR, 3.48), an Eastern Cooperative Oncology Group performance status of 2 or higher (HR, 5.83), and use of cyclosporine A–methotrexate as GVHD prophylaxis (HR, 2.41).
The researchers also found that a significant decrease in survival was seen with an increasing number of any of these prognostic factors.
A growing need
The incidence of t-AML is increasing because of longer life expectancy of the general population and also because of the improved survival of patients treated with chemotherapy and/or radiation for prior malignancies, according to the researchers.
They concluded that, even with this increasing prevalence and normally poor prognosis, “patients of t-AML having good-risk karyotypes, good performance status, and having HLA-matched donors have favorable outcomes after allo-HSCT.”
The authors reported that they had no competing financial interests.
FROM HEMATOLOGY/ONCOLOGY AND STEM CELL THERAPY
Cell-free DNA improves response prediction in breast cancer
When the two techniques were in agreement, the accuracy of response prediction was 92.6% in the study, with a predictive value for complete response of 87.5% and a predictive value for absence of complete response of 94.7%, which was substantially better than either method alone.
“Our work identifies a new parameter that is easily combinable with MRI for a more accurate prediction of response following neoadjuvant treatment, with possible implications for current protocols for the evaluation of nodal residual disease,” researcher Francesco Ravera, MD, PhD, of the University of Genoa (Italy), said in a press release.
Dr. Ravera and colleagues presented their research in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB063).
Accurate response prediction is important because it guides subsequent surgical management, Dr. Ravera and colleagues noted. Pathological complete responders – generally about 25% of patients after neoadjuvant therapy – typically undergo a sentinel lymph node biopsy to ensure cancer hasn’t spread, while incomplete responders often have a complete axillary lymph node dissection.
Response is currently assessed by MRI, but accuracy is suboptimal, the researchers noted. A more accurate method might “allow the omission of sentinel lymph node biopsy in complete responders, which could be replaced by longitudinal radiologic monitoring. This would represent substantial progress in the pursuit of an effective, minimally invasive treatment,” Dr. Ravera said.
He and his colleagues turned to plasma cfDNA because it has shown potential for providing useful diagnostic, recurrence, and treatment response information in neoplastic patients.
When healthy cells die, they release similarly sized DNA fragments into the blood, but cancer cells release fragments of varying sizes. The heart of the research was using electrophoresis to assess the degree of fragmentation – called cfDNA integrity – in plasma samples from 38 patients after anthracycline/taxane-based regimens.
The researchers compared how well cfDNA, preoperative MRI, and the combination of the two methods predicted response according to surgical histology.
A total of 11 patients had pathological complete responses to neoadjuvant therapy.
The ratio of large 321-1,000 base pair sized fragments to smaller 150-220 base pair sized fragments, which the team dubbed the “cfDNA integrity index,” best predicted response. At a cutoff above 2.71, the index was 81.6% accurate in predicting pathological complete response, with a sensitivity of 81.8% and specificity of 81.5%.
The predictive power wasn’t much better than MRI, which was 77.1% accurate, with a sensitivity of 72.7% and a specificity of 81.5%.
The two techniques were concordant in their prediction in over two-thirds of patients. When the techniques agreed, accuracy was over 90%.
Prospective studies are needed to evaluate the cfDNA integrity index in combination with MRI, the researchers concluded.
The study was sponsored by the University of Genoa and others. Dr. Ravera disclosed no conflicts of interest.
When the two techniques were in agreement, the accuracy of response prediction was 92.6% in the study, with a predictive value for complete response of 87.5% and a predictive value for absence of complete response of 94.7%, which was substantially better than either method alone.
“Our work identifies a new parameter that is easily combinable with MRI for a more accurate prediction of response following neoadjuvant treatment, with possible implications for current protocols for the evaluation of nodal residual disease,” researcher Francesco Ravera, MD, PhD, of the University of Genoa (Italy), said in a press release.
Dr. Ravera and colleagues presented their research in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB063).
Accurate response prediction is important because it guides subsequent surgical management, Dr. Ravera and colleagues noted. Pathological complete responders – generally about 25% of patients after neoadjuvant therapy – typically undergo a sentinel lymph node biopsy to ensure cancer hasn’t spread, while incomplete responders often have a complete axillary lymph node dissection.
Response is currently assessed by MRI, but accuracy is suboptimal, the researchers noted. A more accurate method might “allow the omission of sentinel lymph node biopsy in complete responders, which could be replaced by longitudinal radiologic monitoring. This would represent substantial progress in the pursuit of an effective, minimally invasive treatment,” Dr. Ravera said.
He and his colleagues turned to plasma cfDNA because it has shown potential for providing useful diagnostic, recurrence, and treatment response information in neoplastic patients.
When healthy cells die, they release similarly sized DNA fragments into the blood, but cancer cells release fragments of varying sizes. The heart of the research was using electrophoresis to assess the degree of fragmentation – called cfDNA integrity – in plasma samples from 38 patients after anthracycline/taxane-based regimens.
The researchers compared how well cfDNA, preoperative MRI, and the combination of the two methods predicted response according to surgical histology.
A total of 11 patients had pathological complete responses to neoadjuvant therapy.
The ratio of large 321-1,000 base pair sized fragments to smaller 150-220 base pair sized fragments, which the team dubbed the “cfDNA integrity index,” best predicted response. At a cutoff above 2.71, the index was 81.6% accurate in predicting pathological complete response, with a sensitivity of 81.8% and specificity of 81.5%.
The predictive power wasn’t much better than MRI, which was 77.1% accurate, with a sensitivity of 72.7% and a specificity of 81.5%.
The two techniques were concordant in their prediction in over two-thirds of patients. When the techniques agreed, accuracy was over 90%.
Prospective studies are needed to evaluate the cfDNA integrity index in combination with MRI, the researchers concluded.
The study was sponsored by the University of Genoa and others. Dr. Ravera disclosed no conflicts of interest.
When the two techniques were in agreement, the accuracy of response prediction was 92.6% in the study, with a predictive value for complete response of 87.5% and a predictive value for absence of complete response of 94.7%, which was substantially better than either method alone.
“Our work identifies a new parameter that is easily combinable with MRI for a more accurate prediction of response following neoadjuvant treatment, with possible implications for current protocols for the evaluation of nodal residual disease,” researcher Francesco Ravera, MD, PhD, of the University of Genoa (Italy), said in a press release.
Dr. Ravera and colleagues presented their research in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB063).
Accurate response prediction is important because it guides subsequent surgical management, Dr. Ravera and colleagues noted. Pathological complete responders – generally about 25% of patients after neoadjuvant therapy – typically undergo a sentinel lymph node biopsy to ensure cancer hasn’t spread, while incomplete responders often have a complete axillary lymph node dissection.
Response is currently assessed by MRI, but accuracy is suboptimal, the researchers noted. A more accurate method might “allow the omission of sentinel lymph node biopsy in complete responders, which could be replaced by longitudinal radiologic monitoring. This would represent substantial progress in the pursuit of an effective, minimally invasive treatment,” Dr. Ravera said.
He and his colleagues turned to plasma cfDNA because it has shown potential for providing useful diagnostic, recurrence, and treatment response information in neoplastic patients.
When healthy cells die, they release similarly sized DNA fragments into the blood, but cancer cells release fragments of varying sizes. The heart of the research was using electrophoresis to assess the degree of fragmentation – called cfDNA integrity – in plasma samples from 38 patients after anthracycline/taxane-based regimens.
The researchers compared how well cfDNA, preoperative MRI, and the combination of the two methods predicted response according to surgical histology.
A total of 11 patients had pathological complete responses to neoadjuvant therapy.
The ratio of large 321-1,000 base pair sized fragments to smaller 150-220 base pair sized fragments, which the team dubbed the “cfDNA integrity index,” best predicted response. At a cutoff above 2.71, the index was 81.6% accurate in predicting pathological complete response, with a sensitivity of 81.8% and specificity of 81.5%.
The predictive power wasn’t much better than MRI, which was 77.1% accurate, with a sensitivity of 72.7% and a specificity of 81.5%.
The two techniques were concordant in their prediction in over two-thirds of patients. When the techniques agreed, accuracy was over 90%.
Prospective studies are needed to evaluate the cfDNA integrity index in combination with MRI, the researchers concluded.
The study was sponsored by the University of Genoa and others. Dr. Ravera disclosed no conflicts of interest.
FROM AACR 2021
GENUINE improvements: Ublituximab plus ibrutinib for CLL
Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease associated with several known genetic abnormalities, including 17p deletion (del[17p]), 11q deletion (del[11q]), and TP53 gene mutations, which are adverse prognostic markers among patients treated with chemoimmunotherapy.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is approved for patients with untreated, relapsed, or refractory disease, including those with del(17p). Clinicians will soon have the chance to pair it with ublituximab, a next-generation, glycoengineered, type I, anti-CD20 monoclonal antibody that binds to a unique epitope on CD20, differentiating it from rituximab, ofatumumab, and obinutuzumab. Results from the phase 3 GENUINE trial, which were recently published in The Lancet Haematology, showed that ublituximab plus ibrutinib was superior to ibrutinib alone for patients with relapsed or refractory high-risk CLL.
This news organization spoke with Jennifer R. Brown, MD, PhD, director of the CLL Center and institute physician at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, about the GENUINE trial and its potential impact on treatment choices going forward.
What type of patients were treated in the GENUINE trial?
Dr. Brown: This is a trial among relapsed/refractory CLL patients with 17p or 11q deletion or TP53 mutation. Patients aged 18 years or older with CLL who warranted treatment, as defined by International Workshop on CLL criteria, were eligible if they had previously received at least two cycles of at least one standard treatment regimen, had an Eastern Cooperative Oncology Group performance status of 2 or lower, and had high-risk cytogenetics, defined as the presence of at least one of del(17p), del(11q), or TP53 mutation confirmed by a central laboratory with fluorescence in situ hybridization and/or next-generation sequencing.
What were the main outcomes of the trial?
Originally, the GENUINE trial had coprimary endpoints of progression-free survival (PFS) and overall response rate. Because of slow accrual, it was amended to have one primary endpoint of independent review committee (IRC)–assessed ORR.
IRC-assessed ORR was improved from 65% to 83% with the addition of ublituximab. PFS also improved significantly in the ublituximab group, with an even greater improvement when the analysis was limited to those with del(17p) or TP53 aberrancy, but this outcome was limited by the reduced sample size of the study as well as the relatively short PFS of the ibrutinib arm.
After a median follow-up of 41.6 months, the median IRC-assessed PFS in all treated patients was not reached in the ublituximab plus ibrutinib group after 15 PFS events but was 35.9 months in the ibrutinib group after 25 PFS events (hazard ratio, 0.46; 95% confidence interval, 0.24-0.87; P = .016).
Undetectable minimal residual disease was also seen in 42% of the combination arm, compared with 6% of the ibrutinib arm.
What types of adverse events were found in the trial?
The researchers found mostly mild and known side effects of ibrutinib. More atrial fibrillation and neutropenia were seen in the antibody group, but this was not marked.
Most adverse events were of grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and 7 [12%] in the ibrutinib group), anemia (5 [8%] and 5 [9%], respectively), and diarrhea (6 [10%] and 3 [5%], respectively).
What about serious adverse events?
Hospitalization from infection was seen, as expected. There were two cardiac arrests and an unexplained death, across both arms, which was concerning, given the known association of ibrutinib with ventricular arrhythmia and sudden death. There were also several hemorrhages, including one fatal one, which was again consistent with the known side effects of ibrutinib.
Are there treatments comparable with ublituximab plus ibrutinib that clinicians should perhaps first consider using?
In terms of other anti-CD20 antibodies, we have two randomized trials that have failed to show a benefit from adding rituximab to ibrutinib.
Obinutuzumab, like ublituximab, is also a next-generation glycoengineered antibody, and it is reasonably likely that it might lead to similar results. However, the only data we have on ibrutinib with obinutuzumab are from a single arm in a more heterogeneous, lower-risk patient population, and it is unlikely that a randomized comparison will ever be done.
On the basis of these trial results, how would you use the combination of ublituximab and ibrutinib for your patients?
I would consider the addition of ublituximab to a BTK inhibitor in high-risk patients (once ublituximab is approved). I already usually use a next-generation BTK inhibitor rather than ibrutinib.
Are there any other implications of the GENUINE trial?
I think this trial underscores the importance of studying genetic subgroups of patients separately. In this case, that was done in high-risk patients, but this observation likely also applies to low-risk patients.
Most trials to date have enrolled unselected patient populations, often without stratification, and their results therefore tend to obscure the outcomes in both the very high risk (as studied here) and in the low risk (patients with immunoglobulin heavy chain variable region gene mutations).
Dr. Brown has served as a consultant for AbbVie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys, and Novartis, and has received research funding from Gilead, Loxo/Lilly, TG Therapeutics, Verastem/SecuraBio.
A version of this article first appeared on Medscape.com.
Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease associated with several known genetic abnormalities, including 17p deletion (del[17p]), 11q deletion (del[11q]), and TP53 gene mutations, which are adverse prognostic markers among patients treated with chemoimmunotherapy.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is approved for patients with untreated, relapsed, or refractory disease, including those with del(17p). Clinicians will soon have the chance to pair it with ublituximab, a next-generation, glycoengineered, type I, anti-CD20 monoclonal antibody that binds to a unique epitope on CD20, differentiating it from rituximab, ofatumumab, and obinutuzumab. Results from the phase 3 GENUINE trial, which were recently published in The Lancet Haematology, showed that ublituximab plus ibrutinib was superior to ibrutinib alone for patients with relapsed or refractory high-risk CLL.
This news organization spoke with Jennifer R. Brown, MD, PhD, director of the CLL Center and institute physician at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, about the GENUINE trial and its potential impact on treatment choices going forward.
What type of patients were treated in the GENUINE trial?
Dr. Brown: This is a trial among relapsed/refractory CLL patients with 17p or 11q deletion or TP53 mutation. Patients aged 18 years or older with CLL who warranted treatment, as defined by International Workshop on CLL criteria, were eligible if they had previously received at least two cycles of at least one standard treatment regimen, had an Eastern Cooperative Oncology Group performance status of 2 or lower, and had high-risk cytogenetics, defined as the presence of at least one of del(17p), del(11q), or TP53 mutation confirmed by a central laboratory with fluorescence in situ hybridization and/or next-generation sequencing.
What were the main outcomes of the trial?
Originally, the GENUINE trial had coprimary endpoints of progression-free survival (PFS) and overall response rate. Because of slow accrual, it was amended to have one primary endpoint of independent review committee (IRC)–assessed ORR.
IRC-assessed ORR was improved from 65% to 83% with the addition of ublituximab. PFS also improved significantly in the ublituximab group, with an even greater improvement when the analysis was limited to those with del(17p) or TP53 aberrancy, but this outcome was limited by the reduced sample size of the study as well as the relatively short PFS of the ibrutinib arm.
After a median follow-up of 41.6 months, the median IRC-assessed PFS in all treated patients was not reached in the ublituximab plus ibrutinib group after 15 PFS events but was 35.9 months in the ibrutinib group after 25 PFS events (hazard ratio, 0.46; 95% confidence interval, 0.24-0.87; P = .016).
Undetectable minimal residual disease was also seen in 42% of the combination arm, compared with 6% of the ibrutinib arm.
What types of adverse events were found in the trial?
The researchers found mostly mild and known side effects of ibrutinib. More atrial fibrillation and neutropenia were seen in the antibody group, but this was not marked.
Most adverse events were of grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and 7 [12%] in the ibrutinib group), anemia (5 [8%] and 5 [9%], respectively), and diarrhea (6 [10%] and 3 [5%], respectively).
What about serious adverse events?
Hospitalization from infection was seen, as expected. There were two cardiac arrests and an unexplained death, across both arms, which was concerning, given the known association of ibrutinib with ventricular arrhythmia and sudden death. There were also several hemorrhages, including one fatal one, which was again consistent with the known side effects of ibrutinib.
Are there treatments comparable with ublituximab plus ibrutinib that clinicians should perhaps first consider using?
In terms of other anti-CD20 antibodies, we have two randomized trials that have failed to show a benefit from adding rituximab to ibrutinib.
Obinutuzumab, like ublituximab, is also a next-generation glycoengineered antibody, and it is reasonably likely that it might lead to similar results. However, the only data we have on ibrutinib with obinutuzumab are from a single arm in a more heterogeneous, lower-risk patient population, and it is unlikely that a randomized comparison will ever be done.
On the basis of these trial results, how would you use the combination of ublituximab and ibrutinib for your patients?
I would consider the addition of ublituximab to a BTK inhibitor in high-risk patients (once ublituximab is approved). I already usually use a next-generation BTK inhibitor rather than ibrutinib.
Are there any other implications of the GENUINE trial?
I think this trial underscores the importance of studying genetic subgroups of patients separately. In this case, that was done in high-risk patients, but this observation likely also applies to low-risk patients.
Most trials to date have enrolled unselected patient populations, often without stratification, and their results therefore tend to obscure the outcomes in both the very high risk (as studied here) and in the low risk (patients with immunoglobulin heavy chain variable region gene mutations).
Dr. Brown has served as a consultant for AbbVie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys, and Novartis, and has received research funding from Gilead, Loxo/Lilly, TG Therapeutics, Verastem/SecuraBio.
A version of this article first appeared on Medscape.com.
Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease associated with several known genetic abnormalities, including 17p deletion (del[17p]), 11q deletion (del[11q]), and TP53 gene mutations, which are adverse prognostic markers among patients treated with chemoimmunotherapy.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is approved for patients with untreated, relapsed, or refractory disease, including those with del(17p). Clinicians will soon have the chance to pair it with ublituximab, a next-generation, glycoengineered, type I, anti-CD20 monoclonal antibody that binds to a unique epitope on CD20, differentiating it from rituximab, ofatumumab, and obinutuzumab. Results from the phase 3 GENUINE trial, which were recently published in The Lancet Haematology, showed that ublituximab plus ibrutinib was superior to ibrutinib alone for patients with relapsed or refractory high-risk CLL.
This news organization spoke with Jennifer R. Brown, MD, PhD, director of the CLL Center and institute physician at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, about the GENUINE trial and its potential impact on treatment choices going forward.
What type of patients were treated in the GENUINE trial?
Dr. Brown: This is a trial among relapsed/refractory CLL patients with 17p or 11q deletion or TP53 mutation. Patients aged 18 years or older with CLL who warranted treatment, as defined by International Workshop on CLL criteria, were eligible if they had previously received at least two cycles of at least one standard treatment regimen, had an Eastern Cooperative Oncology Group performance status of 2 or lower, and had high-risk cytogenetics, defined as the presence of at least one of del(17p), del(11q), or TP53 mutation confirmed by a central laboratory with fluorescence in situ hybridization and/or next-generation sequencing.
What were the main outcomes of the trial?
Originally, the GENUINE trial had coprimary endpoints of progression-free survival (PFS) and overall response rate. Because of slow accrual, it was amended to have one primary endpoint of independent review committee (IRC)–assessed ORR.
IRC-assessed ORR was improved from 65% to 83% with the addition of ublituximab. PFS also improved significantly in the ublituximab group, with an even greater improvement when the analysis was limited to those with del(17p) or TP53 aberrancy, but this outcome was limited by the reduced sample size of the study as well as the relatively short PFS of the ibrutinib arm.
After a median follow-up of 41.6 months, the median IRC-assessed PFS in all treated patients was not reached in the ublituximab plus ibrutinib group after 15 PFS events but was 35.9 months in the ibrutinib group after 25 PFS events (hazard ratio, 0.46; 95% confidence interval, 0.24-0.87; P = .016).
Undetectable minimal residual disease was also seen in 42% of the combination arm, compared with 6% of the ibrutinib arm.
What types of adverse events were found in the trial?
The researchers found mostly mild and known side effects of ibrutinib. More atrial fibrillation and neutropenia were seen in the antibody group, but this was not marked.
Most adverse events were of grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and 7 [12%] in the ibrutinib group), anemia (5 [8%] and 5 [9%], respectively), and diarrhea (6 [10%] and 3 [5%], respectively).
What about serious adverse events?
Hospitalization from infection was seen, as expected. There were two cardiac arrests and an unexplained death, across both arms, which was concerning, given the known association of ibrutinib with ventricular arrhythmia and sudden death. There were also several hemorrhages, including one fatal one, which was again consistent with the known side effects of ibrutinib.
Are there treatments comparable with ublituximab plus ibrutinib that clinicians should perhaps first consider using?
In terms of other anti-CD20 antibodies, we have two randomized trials that have failed to show a benefit from adding rituximab to ibrutinib.
Obinutuzumab, like ublituximab, is also a next-generation glycoengineered antibody, and it is reasonably likely that it might lead to similar results. However, the only data we have on ibrutinib with obinutuzumab are from a single arm in a more heterogeneous, lower-risk patient population, and it is unlikely that a randomized comparison will ever be done.
On the basis of these trial results, how would you use the combination of ublituximab and ibrutinib for your patients?
I would consider the addition of ublituximab to a BTK inhibitor in high-risk patients (once ublituximab is approved). I already usually use a next-generation BTK inhibitor rather than ibrutinib.
Are there any other implications of the GENUINE trial?
I think this trial underscores the importance of studying genetic subgroups of patients separately. In this case, that was done in high-risk patients, but this observation likely also applies to low-risk patients.
Most trials to date have enrolled unselected patient populations, often without stratification, and their results therefore tend to obscure the outcomes in both the very high risk (as studied here) and in the low risk (patients with immunoglobulin heavy chain variable region gene mutations).
Dr. Brown has served as a consultant for AbbVie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys, and Novartis, and has received research funding from Gilead, Loxo/Lilly, TG Therapeutics, Verastem/SecuraBio.
A version of this article first appeared on Medscape.com.
Hypothesis: Milk and beef ‘causally linked’ to colorectal cancer
Bovine meat and milk factors (BMMF), the recently discovered pathogenic agents found in milk products and beef, could play a role in the development of colorectal cancer, say German scientists.
The team was headed by Harald zur Hausen, MD, PhD, division of episomal-persistent DNA in cancer and chronic diseases, German Cancer Research Center, Heidelberg, who received the Nobel Prize in Physiology or Medicine in 2008 for his discovery of the role of human papillomaviruses in the development of cervical cancer.
The team has been researching the link between BMMF and colorectal cancer for some years, and the latest study was published in the Proceedings of the National Academy of Sciences.
“The results support our hypothesis that the consumption of milk and beef is causally linked to the development of colon cancer,” Dr. Hausen said in a related press statement.
Pathogenic agents, found in vicinity of tumors
BMMF are infectious agents that occur as circular single strands of DNA and have a notable similarity to the sequences of some bacterial plasmids.
A few years ago, Dr. Hausen and colleagues found these pathogenic agents in colon cancer patients, in the immediate vicinity of tumors.
They therefore put forward the hypothesis that BMMF could trigger chronic local inflammation, which in turn could cause genetic mutations via oxidative stress and lead to the development of cancer over the long term.
The German researchers were also able to show in in vitro models that BMMF multiply in human cells where the H1MSB.1 Rep protein, which is required for their replication, is synthesized.
In their latest study, the scientists analyzed tissue samples from colorectal cancer patients and from individuals without the disease.
The team found that BMMF could trigger chronic inflammation in the intestinal tissue of cancer patients, as demonstrated via the presence of proinflammatory macrophages.
The researchers also used anti-Rep antibodies to show that the Rep protein was present around and inside the macrophages. In cancer patients, 7.3% of all the intestinal cells in the tumor environment were positive for Rep versus just 1.7% of those in the control group.
In addition, the researchers reported increased levels of reactive oxygen species close to Rep-positive cells.
“These oxygen radicals promote the development of genetic changes,” Dr. Hausen said.
The inflammation was particularly localized to the immediate vicinity of the intestinal crypts, where the intestinal stem cells, which are responsible for the constant regeneration of the intestinal mucosa, are found.
“We therefore think of the BMMF as indirect carcinogens, some of which will probably have an impact on dividing cells in the intestinal mucosa for decades,” Dr. Hausen explained.
He assumes that infection with BMMF typically occurs early in life. This “opens up the possibility of early intervention,” he suggested.
The early detection of BMMF could allow the identification of individuals particularly at risk, and for these patients to be offered timely colon cancer screening.
The researchers stressed, however, that further study will be required to confirm the results.
They nevertheless believed that BMMF could help explain the link between the consumption of red meat and dairy products and other cancers and diseases, in particular breast, prostate, and lung cancers.
Finally, the pathogenic agents could partially explain the preventive effect of anti-inflammatory dugs such as aspirin and ibuprofen on the incidence of colon cancer and other cancers via the reduction of chronic inflammation.
This work was supported by an unrestricted grant from ORYX Alpha. One coauthor was supported by the EOS Foundation, the SFBTR-179 and 209, and a European Research Council consolidator grant. The other coauthors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Bovine meat and milk factors (BMMF), the recently discovered pathogenic agents found in milk products and beef, could play a role in the development of colorectal cancer, say German scientists.
The team was headed by Harald zur Hausen, MD, PhD, division of episomal-persistent DNA in cancer and chronic diseases, German Cancer Research Center, Heidelberg, who received the Nobel Prize in Physiology or Medicine in 2008 for his discovery of the role of human papillomaviruses in the development of cervical cancer.
The team has been researching the link between BMMF and colorectal cancer for some years, and the latest study was published in the Proceedings of the National Academy of Sciences.
“The results support our hypothesis that the consumption of milk and beef is causally linked to the development of colon cancer,” Dr. Hausen said in a related press statement.
Pathogenic agents, found in vicinity of tumors
BMMF are infectious agents that occur as circular single strands of DNA and have a notable similarity to the sequences of some bacterial plasmids.
A few years ago, Dr. Hausen and colleagues found these pathogenic agents in colon cancer patients, in the immediate vicinity of tumors.
They therefore put forward the hypothesis that BMMF could trigger chronic local inflammation, which in turn could cause genetic mutations via oxidative stress and lead to the development of cancer over the long term.
The German researchers were also able to show in in vitro models that BMMF multiply in human cells where the H1MSB.1 Rep protein, which is required for their replication, is synthesized.
In their latest study, the scientists analyzed tissue samples from colorectal cancer patients and from individuals without the disease.
The team found that BMMF could trigger chronic inflammation in the intestinal tissue of cancer patients, as demonstrated via the presence of proinflammatory macrophages.
The researchers also used anti-Rep antibodies to show that the Rep protein was present around and inside the macrophages. In cancer patients, 7.3% of all the intestinal cells in the tumor environment were positive for Rep versus just 1.7% of those in the control group.
In addition, the researchers reported increased levels of reactive oxygen species close to Rep-positive cells.
“These oxygen radicals promote the development of genetic changes,” Dr. Hausen said.
The inflammation was particularly localized to the immediate vicinity of the intestinal crypts, where the intestinal stem cells, which are responsible for the constant regeneration of the intestinal mucosa, are found.
“We therefore think of the BMMF as indirect carcinogens, some of which will probably have an impact on dividing cells in the intestinal mucosa for decades,” Dr. Hausen explained.
He assumes that infection with BMMF typically occurs early in life. This “opens up the possibility of early intervention,” he suggested.
The early detection of BMMF could allow the identification of individuals particularly at risk, and for these patients to be offered timely colon cancer screening.
The researchers stressed, however, that further study will be required to confirm the results.
They nevertheless believed that BMMF could help explain the link between the consumption of red meat and dairy products and other cancers and diseases, in particular breast, prostate, and lung cancers.
Finally, the pathogenic agents could partially explain the preventive effect of anti-inflammatory dugs such as aspirin and ibuprofen on the incidence of colon cancer and other cancers via the reduction of chronic inflammation.
This work was supported by an unrestricted grant from ORYX Alpha. One coauthor was supported by the EOS Foundation, the SFBTR-179 and 209, and a European Research Council consolidator grant. The other coauthors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Bovine meat and milk factors (BMMF), the recently discovered pathogenic agents found in milk products and beef, could play a role in the development of colorectal cancer, say German scientists.
The team was headed by Harald zur Hausen, MD, PhD, division of episomal-persistent DNA in cancer and chronic diseases, German Cancer Research Center, Heidelberg, who received the Nobel Prize in Physiology or Medicine in 2008 for his discovery of the role of human papillomaviruses in the development of cervical cancer.
The team has been researching the link between BMMF and colorectal cancer for some years, and the latest study was published in the Proceedings of the National Academy of Sciences.
“The results support our hypothesis that the consumption of milk and beef is causally linked to the development of colon cancer,” Dr. Hausen said in a related press statement.
Pathogenic agents, found in vicinity of tumors
BMMF are infectious agents that occur as circular single strands of DNA and have a notable similarity to the sequences of some bacterial plasmids.
A few years ago, Dr. Hausen and colleagues found these pathogenic agents in colon cancer patients, in the immediate vicinity of tumors.
They therefore put forward the hypothesis that BMMF could trigger chronic local inflammation, which in turn could cause genetic mutations via oxidative stress and lead to the development of cancer over the long term.
The German researchers were also able to show in in vitro models that BMMF multiply in human cells where the H1MSB.1 Rep protein, which is required for their replication, is synthesized.
In their latest study, the scientists analyzed tissue samples from colorectal cancer patients and from individuals without the disease.
The team found that BMMF could trigger chronic inflammation in the intestinal tissue of cancer patients, as demonstrated via the presence of proinflammatory macrophages.
The researchers also used anti-Rep antibodies to show that the Rep protein was present around and inside the macrophages. In cancer patients, 7.3% of all the intestinal cells in the tumor environment were positive for Rep versus just 1.7% of those in the control group.
In addition, the researchers reported increased levels of reactive oxygen species close to Rep-positive cells.
“These oxygen radicals promote the development of genetic changes,” Dr. Hausen said.
The inflammation was particularly localized to the immediate vicinity of the intestinal crypts, where the intestinal stem cells, which are responsible for the constant regeneration of the intestinal mucosa, are found.
“We therefore think of the BMMF as indirect carcinogens, some of which will probably have an impact on dividing cells in the intestinal mucosa for decades,” Dr. Hausen explained.
He assumes that infection with BMMF typically occurs early in life. This “opens up the possibility of early intervention,” he suggested.
The early detection of BMMF could allow the identification of individuals particularly at risk, and for these patients to be offered timely colon cancer screening.
The researchers stressed, however, that further study will be required to confirm the results.
They nevertheless believed that BMMF could help explain the link between the consumption of red meat and dairy products and other cancers and diseases, in particular breast, prostate, and lung cancers.
Finally, the pathogenic agents could partially explain the preventive effect of anti-inflammatory dugs such as aspirin and ibuprofen on the incidence of colon cancer and other cancers via the reduction of chronic inflammation.
This work was supported by an unrestricted grant from ORYX Alpha. One coauthor was supported by the EOS Foundation, the SFBTR-179 and 209, and a European Research Council consolidator grant. The other coauthors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Survey finds Mohs surgeons favor nicotinamide for chemoprevention
, in a survey of members of the American College of Mohs Surgeons.
Although nicotinamide, a vitamin B3 derivative, has been shown to reduce keratinocyte carcinoma (KC) in high-risk patients, it is not approved by the Food and Drug Administration for chemoprevention, and no safe upper limit has been established in clinical trials to date, wrote Sheena Desai of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues.
The investigators emailed an anonymous 12-question survey to 1,500 members of the American College of Mohs Surgeons. Of the 170 who responded, 10 were excluded for discordant responses, leaving 160 participants whose replies were included in a multiple logistic regression analysis. The respondents were mainly U.S. board-certified dermatologists and Mohs surgeons (99.4% for both); 86.9% were in clinical practice, including 78.8% in private practice, according to the report of the results, published in Dermatologic Surgery.
Overall, 76.9% of the respondents said they recommended nicotinamide for preventing KC, and 20% said they had recommended nicotinamide to more than 100 patients in the past year. In addition, 45% of respondents reported patients who had been taking nicotinamide for 2 years or more. Overall, 63.8% of the respondents expressed no concerns about long-term safety of nicotinamide, compared with 28.1% who said they were uncertain about long-term safety. Those who expressed concern or uncertainty about long-term safety were significantly less likely to recommend nicotinamide for KC prevention in the past year (odds ratio, 0.30; 95% confidence interval [CI] 0.13-0.71). Clinicians with more than 10 years in practice were significantly less likely to recommend nicotinamide for chemoprevention (OR, 0.20; 95% CI 0.05-0.82).
The study findings were limited by several factors, including the low number of responses and the potential lack of generalizability to clinicians other than Mohs surgeons, the researchers noted. “Additional studies on nicotinamide safety and use patterns, including cost-effectiveness analyses, are needed given the widespread use identified in this study,” they concluded.
Limited safety data highlight research gaps
The study is particularly important at this time because nicotinamide has been increasingly used for KC chemoprevention since a randomized, controlled trial published in 2015 in the New England Journal of Medicine showed benefits, corresponding author Rebecca I. Hartman, MD, of the department of dermatology, Brigham and Women’s Hospital and Harvard University, Boston, said in an interview. That study of high-risk patients found that nicotinamide, 500 mg twice a day, was safe and effective in lowering the rates of new nonmelanoma skin cancers and AKs after 12 months .
“However, because this is not a prescription medication, but rather an OTC vitamin supplement, data on its use are not available,” she said.
Dr. Hartman said she was not surprised that nicotinamide is being used frequently by a majority of the survey respondents. “Most are using this if someone has two KCs over 2 years, which is a quite common occurrence,” she noted. However, “I was a bit surprised that nearly two-thirds had no safety concerns with long-term use, even though this has not been well-studied,” she added.
“Like anything we recommend, we must consider the risks and benefits,” Dr. Hartman said of nicotinamide. “Unfortunately, we don’t know the risks well, since this hasn’t been well-characterized with regular long-term use in these doses,” and more research is needed, she said. “The risks are likely low, as this is a vitamin that has been used for years in various OTC supplements,” she added. “However, there are some data showing slightly increased all-cause mortality with similar doses of a related medicine, niacin, in cardiovascular patients. For this reason, I recommend the medication when a patient’s KCs are really becoming burdensome – several KCs in a year or two – or when they are high-risk due to immunosuppression,” she explained.
“We also must consider the individual patient. For a healthy younger patient who has a public-facing job and as a result is very averse to developing any KCs on his or her face and very motivated to try prevention, it may make sense to try nicotinamide,” Dr. Hartman said. But for an older patient with cardiovascular comorbidities who is not bothered by a KC on his or her back or extremities, “this medication may not have a favorable risk-benefit profile.”
To address safety concerns, “researchers need to examine whether there are any harms in long-term regular nicotinamide use for KC prevention,” Dr. Hartman said. “This is something we hope to do in our patients; however, it is challenging to study in a retrospective way since the harm is likely small and there are so many other features that influence mortality as an outcome,” she noted.
The study received no outside funding. The researchers had no financial conflicts to disclose.
, in a survey of members of the American College of Mohs Surgeons.
Although nicotinamide, a vitamin B3 derivative, has been shown to reduce keratinocyte carcinoma (KC) in high-risk patients, it is not approved by the Food and Drug Administration for chemoprevention, and no safe upper limit has been established in clinical trials to date, wrote Sheena Desai of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues.
The investigators emailed an anonymous 12-question survey to 1,500 members of the American College of Mohs Surgeons. Of the 170 who responded, 10 were excluded for discordant responses, leaving 160 participants whose replies were included in a multiple logistic regression analysis. The respondents were mainly U.S. board-certified dermatologists and Mohs surgeons (99.4% for both); 86.9% were in clinical practice, including 78.8% in private practice, according to the report of the results, published in Dermatologic Surgery.
Overall, 76.9% of the respondents said they recommended nicotinamide for preventing KC, and 20% said they had recommended nicotinamide to more than 100 patients in the past year. In addition, 45% of respondents reported patients who had been taking nicotinamide for 2 years or more. Overall, 63.8% of the respondents expressed no concerns about long-term safety of nicotinamide, compared with 28.1% who said they were uncertain about long-term safety. Those who expressed concern or uncertainty about long-term safety were significantly less likely to recommend nicotinamide for KC prevention in the past year (odds ratio, 0.30; 95% confidence interval [CI] 0.13-0.71). Clinicians with more than 10 years in practice were significantly less likely to recommend nicotinamide for chemoprevention (OR, 0.20; 95% CI 0.05-0.82).
The study findings were limited by several factors, including the low number of responses and the potential lack of generalizability to clinicians other than Mohs surgeons, the researchers noted. “Additional studies on nicotinamide safety and use patterns, including cost-effectiveness analyses, are needed given the widespread use identified in this study,” they concluded.
Limited safety data highlight research gaps
The study is particularly important at this time because nicotinamide has been increasingly used for KC chemoprevention since a randomized, controlled trial published in 2015 in the New England Journal of Medicine showed benefits, corresponding author Rebecca I. Hartman, MD, of the department of dermatology, Brigham and Women’s Hospital and Harvard University, Boston, said in an interview. That study of high-risk patients found that nicotinamide, 500 mg twice a day, was safe and effective in lowering the rates of new nonmelanoma skin cancers and AKs after 12 months .
“However, because this is not a prescription medication, but rather an OTC vitamin supplement, data on its use are not available,” she said.
Dr. Hartman said she was not surprised that nicotinamide is being used frequently by a majority of the survey respondents. “Most are using this if someone has two KCs over 2 years, which is a quite common occurrence,” she noted. However, “I was a bit surprised that nearly two-thirds had no safety concerns with long-term use, even though this has not been well-studied,” she added.
“Like anything we recommend, we must consider the risks and benefits,” Dr. Hartman said of nicotinamide. “Unfortunately, we don’t know the risks well, since this hasn’t been well-characterized with regular long-term use in these doses,” and more research is needed, she said. “The risks are likely low, as this is a vitamin that has been used for years in various OTC supplements,” she added. “However, there are some data showing slightly increased all-cause mortality with similar doses of a related medicine, niacin, in cardiovascular patients. For this reason, I recommend the medication when a patient’s KCs are really becoming burdensome – several KCs in a year or two – or when they are high-risk due to immunosuppression,” she explained.
“We also must consider the individual patient. For a healthy younger patient who has a public-facing job and as a result is very averse to developing any KCs on his or her face and very motivated to try prevention, it may make sense to try nicotinamide,” Dr. Hartman said. But for an older patient with cardiovascular comorbidities who is not bothered by a KC on his or her back or extremities, “this medication may not have a favorable risk-benefit profile.”
To address safety concerns, “researchers need to examine whether there are any harms in long-term regular nicotinamide use for KC prevention,” Dr. Hartman said. “This is something we hope to do in our patients; however, it is challenging to study in a retrospective way since the harm is likely small and there are so many other features that influence mortality as an outcome,” she noted.
The study received no outside funding. The researchers had no financial conflicts to disclose.
, in a survey of members of the American College of Mohs Surgeons.
Although nicotinamide, a vitamin B3 derivative, has been shown to reduce keratinocyte carcinoma (KC) in high-risk patients, it is not approved by the Food and Drug Administration for chemoprevention, and no safe upper limit has been established in clinical trials to date, wrote Sheena Desai of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues.
The investigators emailed an anonymous 12-question survey to 1,500 members of the American College of Mohs Surgeons. Of the 170 who responded, 10 were excluded for discordant responses, leaving 160 participants whose replies were included in a multiple logistic regression analysis. The respondents were mainly U.S. board-certified dermatologists and Mohs surgeons (99.4% for both); 86.9% were in clinical practice, including 78.8% in private practice, according to the report of the results, published in Dermatologic Surgery.
Overall, 76.9% of the respondents said they recommended nicotinamide for preventing KC, and 20% said they had recommended nicotinamide to more than 100 patients in the past year. In addition, 45% of respondents reported patients who had been taking nicotinamide for 2 years or more. Overall, 63.8% of the respondents expressed no concerns about long-term safety of nicotinamide, compared with 28.1% who said they were uncertain about long-term safety. Those who expressed concern or uncertainty about long-term safety were significantly less likely to recommend nicotinamide for KC prevention in the past year (odds ratio, 0.30; 95% confidence interval [CI] 0.13-0.71). Clinicians with more than 10 years in practice were significantly less likely to recommend nicotinamide for chemoprevention (OR, 0.20; 95% CI 0.05-0.82).
The study findings were limited by several factors, including the low number of responses and the potential lack of generalizability to clinicians other than Mohs surgeons, the researchers noted. “Additional studies on nicotinamide safety and use patterns, including cost-effectiveness analyses, are needed given the widespread use identified in this study,” they concluded.
Limited safety data highlight research gaps
The study is particularly important at this time because nicotinamide has been increasingly used for KC chemoprevention since a randomized, controlled trial published in 2015 in the New England Journal of Medicine showed benefits, corresponding author Rebecca I. Hartman, MD, of the department of dermatology, Brigham and Women’s Hospital and Harvard University, Boston, said in an interview. That study of high-risk patients found that nicotinamide, 500 mg twice a day, was safe and effective in lowering the rates of new nonmelanoma skin cancers and AKs after 12 months .
“However, because this is not a prescription medication, but rather an OTC vitamin supplement, data on its use are not available,” she said.
Dr. Hartman said she was not surprised that nicotinamide is being used frequently by a majority of the survey respondents. “Most are using this if someone has two KCs over 2 years, which is a quite common occurrence,” she noted. However, “I was a bit surprised that nearly two-thirds had no safety concerns with long-term use, even though this has not been well-studied,” she added.
“Like anything we recommend, we must consider the risks and benefits,” Dr. Hartman said of nicotinamide. “Unfortunately, we don’t know the risks well, since this hasn’t been well-characterized with regular long-term use in these doses,” and more research is needed, she said. “The risks are likely low, as this is a vitamin that has been used for years in various OTC supplements,” she added. “However, there are some data showing slightly increased all-cause mortality with similar doses of a related medicine, niacin, in cardiovascular patients. For this reason, I recommend the medication when a patient’s KCs are really becoming burdensome – several KCs in a year or two – or when they are high-risk due to immunosuppression,” she explained.
“We also must consider the individual patient. For a healthy younger patient who has a public-facing job and as a result is very averse to developing any KCs on his or her face and very motivated to try prevention, it may make sense to try nicotinamide,” Dr. Hartman said. But for an older patient with cardiovascular comorbidities who is not bothered by a KC on his or her back or extremities, “this medication may not have a favorable risk-benefit profile.”
To address safety concerns, “researchers need to examine whether there are any harms in long-term regular nicotinamide use for KC prevention,” Dr. Hartman said. “This is something we hope to do in our patients; however, it is challenging to study in a retrospective way since the harm is likely small and there are so many other features that influence mortality as an outcome,” she noted.
The study received no outside funding. The researchers had no financial conflicts to disclose.
FROM DERMATOLOGIC SURGERY
FDA approves frontline immunotherapy for gastric cancers
This is the first immunotherapy approved for the frontline treatment of gastric cancers, the agency says in a press release.
The approval comes after nivolumab received Priority Review and Orphan Drug designations for this indication. There are approximately 28,000 new diagnoses of gastric cancer annually in the United States, and overall survival is generally poor with currently available therapy, points out the FDA.
“Today’s approval is the first treatment in more than a decade to show a survival benefit for patients with advanced or metastatic gastric cancer who are being treated for the first time,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, states in an FDA press release.
Efficacy in the gastric cancer setting was demonstrated in the randomized, phase 3, open-label CheckMate 649 study of 1,518 untreated patients. Median survival was 13.8 months among those treated with nivolumab, compared with 11.6 months with chemotherapy alone (hazard ratio, 0.80; P = .0002).
Common side effects experienced by patients in the nivolumab group included peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain.
Nivolumab is also approved for numerous other cancers. Other known adverse effects include immune-mediated inflammation of the lungs, colon, liver, endocrine glands, and kidneys.
“Patients should tell their health care providers if they have immune system problems, lung or breathing problems, liver problems, have had an organ transplant, or are pregnant or plan to become pregnant before starting treatment,” the FDA states.
A version of this article first appeared on Medscape.com.
This is the first immunotherapy approved for the frontline treatment of gastric cancers, the agency says in a press release.
The approval comes after nivolumab received Priority Review and Orphan Drug designations for this indication. There are approximately 28,000 new diagnoses of gastric cancer annually in the United States, and overall survival is generally poor with currently available therapy, points out the FDA.
“Today’s approval is the first treatment in more than a decade to show a survival benefit for patients with advanced or metastatic gastric cancer who are being treated for the first time,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, states in an FDA press release.
Efficacy in the gastric cancer setting was demonstrated in the randomized, phase 3, open-label CheckMate 649 study of 1,518 untreated patients. Median survival was 13.8 months among those treated with nivolumab, compared with 11.6 months with chemotherapy alone (hazard ratio, 0.80; P = .0002).
Common side effects experienced by patients in the nivolumab group included peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain.
Nivolumab is also approved for numerous other cancers. Other known adverse effects include immune-mediated inflammation of the lungs, colon, liver, endocrine glands, and kidneys.
“Patients should tell their health care providers if they have immune system problems, lung or breathing problems, liver problems, have had an organ transplant, or are pregnant or plan to become pregnant before starting treatment,” the FDA states.
A version of this article first appeared on Medscape.com.
This is the first immunotherapy approved for the frontline treatment of gastric cancers, the agency says in a press release.
The approval comes after nivolumab received Priority Review and Orphan Drug designations for this indication. There are approximately 28,000 new diagnoses of gastric cancer annually in the United States, and overall survival is generally poor with currently available therapy, points out the FDA.
“Today’s approval is the first treatment in more than a decade to show a survival benefit for patients with advanced or metastatic gastric cancer who are being treated for the first time,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, states in an FDA press release.
Efficacy in the gastric cancer setting was demonstrated in the randomized, phase 3, open-label CheckMate 649 study of 1,518 untreated patients. Median survival was 13.8 months among those treated with nivolumab, compared with 11.6 months with chemotherapy alone (hazard ratio, 0.80; P = .0002).
Common side effects experienced by patients in the nivolumab group included peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain.
Nivolumab is also approved for numerous other cancers. Other known adverse effects include immune-mediated inflammation of the lungs, colon, liver, endocrine glands, and kidneys.
“Patients should tell their health care providers if they have immune system problems, lung or breathing problems, liver problems, have had an organ transplant, or are pregnant or plan to become pregnant before starting treatment,” the FDA states.
A version of this article first appeared on Medscape.com.
Unique oral drug candidate designed to overcome sickle cell disease
Progress is being made in the quest for an oral treatment for sickle cell disease. In preclinical trials, a new drug has shown the ability to induce blood cells to produce fetal hemoglobin at levels predicted to prevent sickling. The new small-molecule drug could be formulated into a convenient daily oral dosage, according to researchers who presented their results at the spring meeting of the American Chemical Society, which was held virtually.
The new drug candidate, designated FTX-6058 by Fulcrum Therapeutics, was developed using a proprietary small-molecule probe and CRISPR guide RNA libraries to screen “a disease-relevant cell model that allowed us to pinpoint a treatment target,” said Ivan V. Efremov, PhD, senior director, head of medicinal chemistry at the company, who presented the research.
Even though sickle cell patients carry genes leading to defective adult hemoglobin, they still carry stem cells in their bone marrow with the potential to produce fetal hemoglobin. FTX-6058 attaches to a protein inside these bone marrow stem cells destined to become mature red blood cells and reinstates their fetal hemoglobin expression, according to Dr. Efremov.
“What is really key is FTX-6058 upregulates fetal hemoglobin across all red blood cells, a pancellular distribution,” he explained, adding that if “some red blood cells did not express this, they could still sickle and cause disease symptoms.”
The premise behind the development of the drug evolved from the example of patients with sickle cell genes who also have a mutation that causes fetal hemoglobin production. The presence of fetal hemoglobin provides significant benefits to patients with sickle cell disease. At around 5%-10% levels of fetal hemoglobin expression, mortality is reduced. By 10%-25% levels of fetal hemoglobin, recurring events including vaso-occlusive crises, acute chest syndrome, and hospitalization are reduced. When fetal hemoglobin levels reaches around 25%-30%, enough red blood cell function is restored so that these patients become asymptomatic, Dr. Efremov said.
FTX-6058 was designed to mimic this effect.
FTX-6058 inhibits the action of the polycomb repressive complex 2 (PRC2) via binding to the EED subunit. PRC2 acts as a histone methyltransferase to control gene expression. Inhibition of PRC2 leads to significant fetal hemoglobin protein expression in both cell and mouse models. Other such inhibitors are under study for the suppression of cancer progression.
Preclinical experiments comparing FTX-6058 with the fetal hemoglobin booster, hydroxyurea, approved in the 1990s, showed the new drug candidate outperforms the current treatment, Christopher Moxham, PhD, chief scientific officer of Fulcrum Therapeutics, said in a company press release. The company began a phase 1 safety trial in healthy adult volunteers last year after preclinical experiments with FTX-6058 in human-derived cell assay systems and mouse models also showed an increase in fetal hemoglobin to meet the 25%-30% asymptomatic symptom threshold level.
Ongoing studies
The researchers plan to launch phase 2 clinical trial enrolling patients with sickle cell disease by end of 2021. In addition, further characterization of the therapeutic molecule is continuing, using genomics and additional cell assay systems to expand details FTX-6058’s mode of action.
The company also is looking to explore the use of FTX-6058 in patients with beta-thalassemia to supplement their reduced hemoglobin production.
The pharmacologic profile of FTX-6058 indicates that the drug has the potential to be administered as a once-a-day oral formulation, Dr. Efremov stated. Both the preclinical PK [pharmacokinetic] data and “the emerging PK from the human clinical study supports once-a-day oral administration, which obviously offers significant convenience to patients,” he added.
Fulcrum Therapeutics is funding the studies.
Progress is being made in the quest for an oral treatment for sickle cell disease. In preclinical trials, a new drug has shown the ability to induce blood cells to produce fetal hemoglobin at levels predicted to prevent sickling. The new small-molecule drug could be formulated into a convenient daily oral dosage, according to researchers who presented their results at the spring meeting of the American Chemical Society, which was held virtually.
The new drug candidate, designated FTX-6058 by Fulcrum Therapeutics, was developed using a proprietary small-molecule probe and CRISPR guide RNA libraries to screen “a disease-relevant cell model that allowed us to pinpoint a treatment target,” said Ivan V. Efremov, PhD, senior director, head of medicinal chemistry at the company, who presented the research.
Even though sickle cell patients carry genes leading to defective adult hemoglobin, they still carry stem cells in their bone marrow with the potential to produce fetal hemoglobin. FTX-6058 attaches to a protein inside these bone marrow stem cells destined to become mature red blood cells and reinstates their fetal hemoglobin expression, according to Dr. Efremov.
“What is really key is FTX-6058 upregulates fetal hemoglobin across all red blood cells, a pancellular distribution,” he explained, adding that if “some red blood cells did not express this, they could still sickle and cause disease symptoms.”
The premise behind the development of the drug evolved from the example of patients with sickle cell genes who also have a mutation that causes fetal hemoglobin production. The presence of fetal hemoglobin provides significant benefits to patients with sickle cell disease. At around 5%-10% levels of fetal hemoglobin expression, mortality is reduced. By 10%-25% levels of fetal hemoglobin, recurring events including vaso-occlusive crises, acute chest syndrome, and hospitalization are reduced. When fetal hemoglobin levels reaches around 25%-30%, enough red blood cell function is restored so that these patients become asymptomatic, Dr. Efremov said.
FTX-6058 was designed to mimic this effect.
FTX-6058 inhibits the action of the polycomb repressive complex 2 (PRC2) via binding to the EED subunit. PRC2 acts as a histone methyltransferase to control gene expression. Inhibition of PRC2 leads to significant fetal hemoglobin protein expression in both cell and mouse models. Other such inhibitors are under study for the suppression of cancer progression.
Preclinical experiments comparing FTX-6058 with the fetal hemoglobin booster, hydroxyurea, approved in the 1990s, showed the new drug candidate outperforms the current treatment, Christopher Moxham, PhD, chief scientific officer of Fulcrum Therapeutics, said in a company press release. The company began a phase 1 safety trial in healthy adult volunteers last year after preclinical experiments with FTX-6058 in human-derived cell assay systems and mouse models also showed an increase in fetal hemoglobin to meet the 25%-30% asymptomatic symptom threshold level.
Ongoing studies
The researchers plan to launch phase 2 clinical trial enrolling patients with sickle cell disease by end of 2021. In addition, further characterization of the therapeutic molecule is continuing, using genomics and additional cell assay systems to expand details FTX-6058’s mode of action.
The company also is looking to explore the use of FTX-6058 in patients with beta-thalassemia to supplement their reduced hemoglobin production.
The pharmacologic profile of FTX-6058 indicates that the drug has the potential to be administered as a once-a-day oral formulation, Dr. Efremov stated. Both the preclinical PK [pharmacokinetic] data and “the emerging PK from the human clinical study supports once-a-day oral administration, which obviously offers significant convenience to patients,” he added.
Fulcrum Therapeutics is funding the studies.
Progress is being made in the quest for an oral treatment for sickle cell disease. In preclinical trials, a new drug has shown the ability to induce blood cells to produce fetal hemoglobin at levels predicted to prevent sickling. The new small-molecule drug could be formulated into a convenient daily oral dosage, according to researchers who presented their results at the spring meeting of the American Chemical Society, which was held virtually.
The new drug candidate, designated FTX-6058 by Fulcrum Therapeutics, was developed using a proprietary small-molecule probe and CRISPR guide RNA libraries to screen “a disease-relevant cell model that allowed us to pinpoint a treatment target,” said Ivan V. Efremov, PhD, senior director, head of medicinal chemistry at the company, who presented the research.
Even though sickle cell patients carry genes leading to defective adult hemoglobin, they still carry stem cells in their bone marrow with the potential to produce fetal hemoglobin. FTX-6058 attaches to a protein inside these bone marrow stem cells destined to become mature red blood cells and reinstates their fetal hemoglobin expression, according to Dr. Efremov.
“What is really key is FTX-6058 upregulates fetal hemoglobin across all red blood cells, a pancellular distribution,” he explained, adding that if “some red blood cells did not express this, they could still sickle and cause disease symptoms.”
The premise behind the development of the drug evolved from the example of patients with sickle cell genes who also have a mutation that causes fetal hemoglobin production. The presence of fetal hemoglobin provides significant benefits to patients with sickle cell disease. At around 5%-10% levels of fetal hemoglobin expression, mortality is reduced. By 10%-25% levels of fetal hemoglobin, recurring events including vaso-occlusive crises, acute chest syndrome, and hospitalization are reduced. When fetal hemoglobin levels reaches around 25%-30%, enough red blood cell function is restored so that these patients become asymptomatic, Dr. Efremov said.
FTX-6058 was designed to mimic this effect.
FTX-6058 inhibits the action of the polycomb repressive complex 2 (PRC2) via binding to the EED subunit. PRC2 acts as a histone methyltransferase to control gene expression. Inhibition of PRC2 leads to significant fetal hemoglobin protein expression in both cell and mouse models. Other such inhibitors are under study for the suppression of cancer progression.
Preclinical experiments comparing FTX-6058 with the fetal hemoglobin booster, hydroxyurea, approved in the 1990s, showed the new drug candidate outperforms the current treatment, Christopher Moxham, PhD, chief scientific officer of Fulcrum Therapeutics, said in a company press release. The company began a phase 1 safety trial in healthy adult volunteers last year after preclinical experiments with FTX-6058 in human-derived cell assay systems and mouse models also showed an increase in fetal hemoglobin to meet the 25%-30% asymptomatic symptom threshold level.
Ongoing studies
The researchers plan to launch phase 2 clinical trial enrolling patients with sickle cell disease by end of 2021. In addition, further characterization of the therapeutic molecule is continuing, using genomics and additional cell assay systems to expand details FTX-6058’s mode of action.
The company also is looking to explore the use of FTX-6058 in patients with beta-thalassemia to supplement their reduced hemoglobin production.
The pharmacologic profile of FTX-6058 indicates that the drug has the potential to be administered as a once-a-day oral formulation, Dr. Efremov stated. Both the preclinical PK [pharmacokinetic] data and “the emerging PK from the human clinical study supports once-a-day oral administration, which obviously offers significant convenience to patients,” he added.
Fulcrum Therapeutics is funding the studies.
Leveraging the microbiome to enhance cancer treatment
Andrea Facciabene, PhD, of the University of Pennsylvania, Philadelphia, and colleagues conducted a preclinical study in which vancomycin enhanced the efficacy of radiotherapy against melanoma and lung cancer. Now, researchers are conducting a clinical trial to determine if vancomycin can have the same effect in patients with non–small cell lung cancer.
Dr. Facciabene reviewed this research at the AACR Virtual Special Conference: Radiation Science and Medicine.
According to Dr. Facciabene, “gut microbiota” includes the more than 1,000 different strains of bacteria living in human intestines. He indicated that the average human has 10 times more bacteria than cells in the body and 150 times more genes in the gut microbiome than in the human genome.
In healthy individuals, the gut microbiota play a key role in intestinal function and digestive processes, modulation of hormones and vitamin secretion, energy extraction from food, and development and maintenance of a balanced immune system.
“Dysbiosis” is the term applied to a change in the composition, diversity, or metabolites of the microbiome from a healthy pattern to one associated with disease. Antibiotic therapy is a classic cause of dysbiosis, and dysbiosis has been implicated in a variety of inflammatory diseases.
The mechanisms by which the gut microbiome could influence systemic immunity is not known but is relevant to cancer therapy response. Augmenting the frequency and durability of response to immune-targeted treatments – potentially by manipulating the influence of gut microbiota on the immune system – could be highly impactful.
Gut microbiota and radiation-induced cell death
Immunogenic cell death – a process by which tumors die and release their intracellular molecular contents – is one of the mechanisms by which radiotherapy kills cancer cells.
Tumor cells succumbing to immunogenic cell death stimulate antigen presenting cells, such as dendritic cells, that engulf tumor antigens and cross-present them to CD8+ cytotoxic T lymphocytes. This process culminates in the generation of a specific immune response capable of killing the malignant cells in the irradiated area, but it also impacts distant nonirradiated tumors – an abscopal effect.
Dr. Facciabene and colleagues hypothesized that alterations of the gut microbiota could have an impact on the effect of radiotherapy. To investigate this, they studied mouse models of melanoma.
The team allowed B16-OVA tumors to grow for 9-12 days, then delivered a single dose of radiotherapy (21 Gy) to one – but not all – tumors. Simultaneously with the delivery of radiotherapy, the investigators started some animals on oral vancomycin. The team chose vancomycin because its effects are localized and impact the gut microbiota directly, without any known systemic effects.
Results showed that vancomycin significantly augmented the impact of radiotherapy in the irradiated area and was associated with regression of remote tumors.
The effects of the combination treatment on tumor volume were significantly greater than the effects of either treatment alone. Since manipulation of the gut microbiome potentiated radiotherapy effects both locally and distantly, the investigators concluded that immunogenic cell death may be involved in both the local and abscopal effects of radiotherapy.
When the experiment was repeated with a lung tumor model, similar findings were observed.
Involvement of cytotoxic T cells and interferon-gamma
Dr. Facciabene and colleagues found that the irradiated and unirradiated B16 OVA melanoma tumors treated with the radiotherapy-vancomycin combination were infiltrated by CD3+ and CD8+ T cells.
The investigators selectively depleted CD8+ T cells by pretreating the mice with an anti-CD8 monoclonal antibody. Depletion of CD8+ cells prior to administering radiotherapy plus vancomycin abrogated the antitumor effects of the combination treatment, demonstrating that the CD8+ T cells were required.
To characterize the antigen specificity of the tumor-infiltrating CD8+ T cells, Dr. Facciabene and colleagues used OVA MHC class 1 tetramer. Tumors from mice treated with vancomycin alone, radiotherapy alone, or the combination were dissected. Individual dendritic cells were assayed for OVA tetramer by flow cytometry.
The investigators found that tumors from mice treated with radiotherapy plus vancomycin had a significantly higher number of OVA-specific CD8+ T cells, in comparison with untreated tumors or tumors treated with either vancomycin alone or radiotherapy alone. Since antibody that impaired recognition of MHC class I peptides by T cells ablated the effect, it was clear that antigen recognition was vital.
Interferon-gamma (IFN-gamma) is known to play a critical role in both differentiation and effector functions of CD8+ cytolytic T cells in the antitumor immune response. To determine whether IFN-gamma is involved in the antitumor effects of the radiotherapy-vancomycin combination, the investigators measured intratumoral expression of IFN-gamma in the tumors 5 days after radiotherapy.
IFN-gamma messenger RNA expression levels were significantly elevated in the combination treatment group when compared with either treatment alone. In B16-OVA melanoma–challenged knockout mice, the enhancement of the radiotherapy effects by vancomycin was ablated.
The investigators concluded that vancomycin remodels the tumor microenvironment and increases the functionality of tumor-infiltrating, tumor-specific, CD8+ T cells. Furthermore, IFN-gamma is required to augment the radiotherapy-induced immune effect against the tumor.
Potential biochemical mediators of immune effects
The gut microbiota aid host digestion and generate a large repertoire of metabolites after defermentation of fiber. Short-chain fatty acids (SCFAs) constitute the major products of bacterial fermentation.
Acetic acid, propionic acid, and butyric acid represent 95% of total SCFAs present in the intestine. SCFAs are known to directly modulate cytokine production and dendritic cell function.
In their study, Dr. Facciabene and colleagues focused on butyric acid. Using mass spectroscopy, they demonstrated that vancomycin treatment reduces butyrate concentrations in tumor and tumor-draining lymph nodes by eradicating the major families of SCFA-producing Clostridia species.
To test whether supplementing butyrate could influence the synergy of the radiotherapy-vancomycin combination in vivo, the investigators added sodium butyrate to the mice’s drinking water when starting vancomycin treatment. The team then challenged the mice with B16-OVA tumors and treated them with radiotherapy.
In agreement with the group’s prior findings, vancomycin enhanced the tumor-inhibitory effects of radiotherapy, but dietary butyrate inhibited the benefit. The investigators found a significant decrease in the population of B16-OVA–presenting dendritic cells in the lymph nodes of mice receiving the supplemental butyrate.
Dr. Facciabene said these findings were supported by a recent publication. The authors observed that butyrate inhibited type I IFN expression in dendritic cells and radiotherapy-induced, tumor-specific cytotoxic T-cell immune responses without directly protecting tumor cells from the cytotoxic effects of radiotherapy.
Wide-ranging implications
Overall, Dr. Facciabene’s research has shown that:
- Vancomycin significantly enhances the tumor inhibitory effect of targeted radiation, including abscopal effects.
- The synergistic effects are dependent upon IFN-gamma and CD8+ cells.
- Depletion of some gut microbiome species increases antigen presentation by dendritic cells. This is mediated by SCFAs produced by certain bacterial families.
- There are promising new strategies to improve responses to radiotherapy, including targeting gut microbiota.
A clinical trial (NCT03546829) of vancomycin plus stereotactic body radiation in patients with locally advanced non–small cell lung cancer has been launched to investigate these findings further. Early data analysis has shown a significant impact of vancomycin on several species of gut microbiota, according to Dr. Facciabene.
Revolutionary results from immune-targeted therapy in the recent past have highlighted the important role the immune system can play in fighting cancer. Still, up to one-third of cancer patients fail to respond to overtly immune-targeted therapy.
The ability to inhibit cancer cells from evading immune surveillance by using new adjuvants – including those acting on non-traditional targets like gut microbiota – could herald the next major advances in cancer therapy. During his presentation, Dr. Facciabene gave participants an enticing hint of what could be coming for cancer patients in the years ahead.
Dr. Facciabene reported having no relevant disclosures.
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.
Andrea Facciabene, PhD, of the University of Pennsylvania, Philadelphia, and colleagues conducted a preclinical study in which vancomycin enhanced the efficacy of radiotherapy against melanoma and lung cancer. Now, researchers are conducting a clinical trial to determine if vancomycin can have the same effect in patients with non–small cell lung cancer.
Dr. Facciabene reviewed this research at the AACR Virtual Special Conference: Radiation Science and Medicine.
According to Dr. Facciabene, “gut microbiota” includes the more than 1,000 different strains of bacteria living in human intestines. He indicated that the average human has 10 times more bacteria than cells in the body and 150 times more genes in the gut microbiome than in the human genome.
In healthy individuals, the gut microbiota play a key role in intestinal function and digestive processes, modulation of hormones and vitamin secretion, energy extraction from food, and development and maintenance of a balanced immune system.
“Dysbiosis” is the term applied to a change in the composition, diversity, or metabolites of the microbiome from a healthy pattern to one associated with disease. Antibiotic therapy is a classic cause of dysbiosis, and dysbiosis has been implicated in a variety of inflammatory diseases.
The mechanisms by which the gut microbiome could influence systemic immunity is not known but is relevant to cancer therapy response. Augmenting the frequency and durability of response to immune-targeted treatments – potentially by manipulating the influence of gut microbiota on the immune system – could be highly impactful.
Gut microbiota and radiation-induced cell death
Immunogenic cell death – a process by which tumors die and release their intracellular molecular contents – is one of the mechanisms by which radiotherapy kills cancer cells.
Tumor cells succumbing to immunogenic cell death stimulate antigen presenting cells, such as dendritic cells, that engulf tumor antigens and cross-present them to CD8+ cytotoxic T lymphocytes. This process culminates in the generation of a specific immune response capable of killing the malignant cells in the irradiated area, but it also impacts distant nonirradiated tumors – an abscopal effect.
Dr. Facciabene and colleagues hypothesized that alterations of the gut microbiota could have an impact on the effect of radiotherapy. To investigate this, they studied mouse models of melanoma.
The team allowed B16-OVA tumors to grow for 9-12 days, then delivered a single dose of radiotherapy (21 Gy) to one – but not all – tumors. Simultaneously with the delivery of radiotherapy, the investigators started some animals on oral vancomycin. The team chose vancomycin because its effects are localized and impact the gut microbiota directly, without any known systemic effects.
Results showed that vancomycin significantly augmented the impact of radiotherapy in the irradiated area and was associated with regression of remote tumors.
The effects of the combination treatment on tumor volume were significantly greater than the effects of either treatment alone. Since manipulation of the gut microbiome potentiated radiotherapy effects both locally and distantly, the investigators concluded that immunogenic cell death may be involved in both the local and abscopal effects of radiotherapy.
When the experiment was repeated with a lung tumor model, similar findings were observed.
Involvement of cytotoxic T cells and interferon-gamma
Dr. Facciabene and colleagues found that the irradiated and unirradiated B16 OVA melanoma tumors treated with the radiotherapy-vancomycin combination were infiltrated by CD3+ and CD8+ T cells.
The investigators selectively depleted CD8+ T cells by pretreating the mice with an anti-CD8 monoclonal antibody. Depletion of CD8+ cells prior to administering radiotherapy plus vancomycin abrogated the antitumor effects of the combination treatment, demonstrating that the CD8+ T cells were required.
To characterize the antigen specificity of the tumor-infiltrating CD8+ T cells, Dr. Facciabene and colleagues used OVA MHC class 1 tetramer. Tumors from mice treated with vancomycin alone, radiotherapy alone, or the combination were dissected. Individual dendritic cells were assayed for OVA tetramer by flow cytometry.
The investigators found that tumors from mice treated with radiotherapy plus vancomycin had a significantly higher number of OVA-specific CD8+ T cells, in comparison with untreated tumors or tumors treated with either vancomycin alone or radiotherapy alone. Since antibody that impaired recognition of MHC class I peptides by T cells ablated the effect, it was clear that antigen recognition was vital.
Interferon-gamma (IFN-gamma) is known to play a critical role in both differentiation and effector functions of CD8+ cytolytic T cells in the antitumor immune response. To determine whether IFN-gamma is involved in the antitumor effects of the radiotherapy-vancomycin combination, the investigators measured intratumoral expression of IFN-gamma in the tumors 5 days after radiotherapy.
IFN-gamma messenger RNA expression levels were significantly elevated in the combination treatment group when compared with either treatment alone. In B16-OVA melanoma–challenged knockout mice, the enhancement of the radiotherapy effects by vancomycin was ablated.
The investigators concluded that vancomycin remodels the tumor microenvironment and increases the functionality of tumor-infiltrating, tumor-specific, CD8+ T cells. Furthermore, IFN-gamma is required to augment the radiotherapy-induced immune effect against the tumor.
Potential biochemical mediators of immune effects
The gut microbiota aid host digestion and generate a large repertoire of metabolites after defermentation of fiber. Short-chain fatty acids (SCFAs) constitute the major products of bacterial fermentation.
Acetic acid, propionic acid, and butyric acid represent 95% of total SCFAs present in the intestine. SCFAs are known to directly modulate cytokine production and dendritic cell function.
In their study, Dr. Facciabene and colleagues focused on butyric acid. Using mass spectroscopy, they demonstrated that vancomycin treatment reduces butyrate concentrations in tumor and tumor-draining lymph nodes by eradicating the major families of SCFA-producing Clostridia species.
To test whether supplementing butyrate could influence the synergy of the radiotherapy-vancomycin combination in vivo, the investigators added sodium butyrate to the mice’s drinking water when starting vancomycin treatment. The team then challenged the mice with B16-OVA tumors and treated them with radiotherapy.
In agreement with the group’s prior findings, vancomycin enhanced the tumor-inhibitory effects of radiotherapy, but dietary butyrate inhibited the benefit. The investigators found a significant decrease in the population of B16-OVA–presenting dendritic cells in the lymph nodes of mice receiving the supplemental butyrate.
Dr. Facciabene said these findings were supported by a recent publication. The authors observed that butyrate inhibited type I IFN expression in dendritic cells and radiotherapy-induced, tumor-specific cytotoxic T-cell immune responses without directly protecting tumor cells from the cytotoxic effects of radiotherapy.
Wide-ranging implications
Overall, Dr. Facciabene’s research has shown that:
- Vancomycin significantly enhances the tumor inhibitory effect of targeted radiation, including abscopal effects.
- The synergistic effects are dependent upon IFN-gamma and CD8+ cells.
- Depletion of some gut microbiome species increases antigen presentation by dendritic cells. This is mediated by SCFAs produced by certain bacterial families.
- There are promising new strategies to improve responses to radiotherapy, including targeting gut microbiota.
A clinical trial (NCT03546829) of vancomycin plus stereotactic body radiation in patients with locally advanced non–small cell lung cancer has been launched to investigate these findings further. Early data analysis has shown a significant impact of vancomycin on several species of gut microbiota, according to Dr. Facciabene.
Revolutionary results from immune-targeted therapy in the recent past have highlighted the important role the immune system can play in fighting cancer. Still, up to one-third of cancer patients fail to respond to overtly immune-targeted therapy.
The ability to inhibit cancer cells from evading immune surveillance by using new adjuvants – including those acting on non-traditional targets like gut microbiota – could herald the next major advances in cancer therapy. During his presentation, Dr. Facciabene gave participants an enticing hint of what could be coming for cancer patients in the years ahead.
Dr. Facciabene reported having no relevant disclosures.
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.
Andrea Facciabene, PhD, of the University of Pennsylvania, Philadelphia, and colleagues conducted a preclinical study in which vancomycin enhanced the efficacy of radiotherapy against melanoma and lung cancer. Now, researchers are conducting a clinical trial to determine if vancomycin can have the same effect in patients with non–small cell lung cancer.
Dr. Facciabene reviewed this research at the AACR Virtual Special Conference: Radiation Science and Medicine.
According to Dr. Facciabene, “gut microbiota” includes the more than 1,000 different strains of bacteria living in human intestines. He indicated that the average human has 10 times more bacteria than cells in the body and 150 times more genes in the gut microbiome than in the human genome.
In healthy individuals, the gut microbiota play a key role in intestinal function and digestive processes, modulation of hormones and vitamin secretion, energy extraction from food, and development and maintenance of a balanced immune system.
“Dysbiosis” is the term applied to a change in the composition, diversity, or metabolites of the microbiome from a healthy pattern to one associated with disease. Antibiotic therapy is a classic cause of dysbiosis, and dysbiosis has been implicated in a variety of inflammatory diseases.
The mechanisms by which the gut microbiome could influence systemic immunity is not known but is relevant to cancer therapy response. Augmenting the frequency and durability of response to immune-targeted treatments – potentially by manipulating the influence of gut microbiota on the immune system – could be highly impactful.
Gut microbiota and radiation-induced cell death
Immunogenic cell death – a process by which tumors die and release their intracellular molecular contents – is one of the mechanisms by which radiotherapy kills cancer cells.
Tumor cells succumbing to immunogenic cell death stimulate antigen presenting cells, such as dendritic cells, that engulf tumor antigens and cross-present them to CD8+ cytotoxic T lymphocytes. This process culminates in the generation of a specific immune response capable of killing the malignant cells in the irradiated area, but it also impacts distant nonirradiated tumors – an abscopal effect.
Dr. Facciabene and colleagues hypothesized that alterations of the gut microbiota could have an impact on the effect of radiotherapy. To investigate this, they studied mouse models of melanoma.
The team allowed B16-OVA tumors to grow for 9-12 days, then delivered a single dose of radiotherapy (21 Gy) to one – but not all – tumors. Simultaneously with the delivery of radiotherapy, the investigators started some animals on oral vancomycin. The team chose vancomycin because its effects are localized and impact the gut microbiota directly, without any known systemic effects.
Results showed that vancomycin significantly augmented the impact of radiotherapy in the irradiated area and was associated with regression of remote tumors.
The effects of the combination treatment on tumor volume were significantly greater than the effects of either treatment alone. Since manipulation of the gut microbiome potentiated radiotherapy effects both locally and distantly, the investigators concluded that immunogenic cell death may be involved in both the local and abscopal effects of radiotherapy.
When the experiment was repeated with a lung tumor model, similar findings were observed.
Involvement of cytotoxic T cells and interferon-gamma
Dr. Facciabene and colleagues found that the irradiated and unirradiated B16 OVA melanoma tumors treated with the radiotherapy-vancomycin combination were infiltrated by CD3+ and CD8+ T cells.
The investigators selectively depleted CD8+ T cells by pretreating the mice with an anti-CD8 monoclonal antibody. Depletion of CD8+ cells prior to administering radiotherapy plus vancomycin abrogated the antitumor effects of the combination treatment, demonstrating that the CD8+ T cells were required.
To characterize the antigen specificity of the tumor-infiltrating CD8+ T cells, Dr. Facciabene and colleagues used OVA MHC class 1 tetramer. Tumors from mice treated with vancomycin alone, radiotherapy alone, or the combination were dissected. Individual dendritic cells were assayed for OVA tetramer by flow cytometry.
The investigators found that tumors from mice treated with radiotherapy plus vancomycin had a significantly higher number of OVA-specific CD8+ T cells, in comparison with untreated tumors or tumors treated with either vancomycin alone or radiotherapy alone. Since antibody that impaired recognition of MHC class I peptides by T cells ablated the effect, it was clear that antigen recognition was vital.
Interferon-gamma (IFN-gamma) is known to play a critical role in both differentiation and effector functions of CD8+ cytolytic T cells in the antitumor immune response. To determine whether IFN-gamma is involved in the antitumor effects of the radiotherapy-vancomycin combination, the investigators measured intratumoral expression of IFN-gamma in the tumors 5 days after radiotherapy.
IFN-gamma messenger RNA expression levels were significantly elevated in the combination treatment group when compared with either treatment alone. In B16-OVA melanoma–challenged knockout mice, the enhancement of the radiotherapy effects by vancomycin was ablated.
The investigators concluded that vancomycin remodels the tumor microenvironment and increases the functionality of tumor-infiltrating, tumor-specific, CD8+ T cells. Furthermore, IFN-gamma is required to augment the radiotherapy-induced immune effect against the tumor.
Potential biochemical mediators of immune effects
The gut microbiota aid host digestion and generate a large repertoire of metabolites after defermentation of fiber. Short-chain fatty acids (SCFAs) constitute the major products of bacterial fermentation.
Acetic acid, propionic acid, and butyric acid represent 95% of total SCFAs present in the intestine. SCFAs are known to directly modulate cytokine production and dendritic cell function.
In their study, Dr. Facciabene and colleagues focused on butyric acid. Using mass spectroscopy, they demonstrated that vancomycin treatment reduces butyrate concentrations in tumor and tumor-draining lymph nodes by eradicating the major families of SCFA-producing Clostridia species.
To test whether supplementing butyrate could influence the synergy of the radiotherapy-vancomycin combination in vivo, the investigators added sodium butyrate to the mice’s drinking water when starting vancomycin treatment. The team then challenged the mice with B16-OVA tumors and treated them with radiotherapy.
In agreement with the group’s prior findings, vancomycin enhanced the tumor-inhibitory effects of radiotherapy, but dietary butyrate inhibited the benefit. The investigators found a significant decrease in the population of B16-OVA–presenting dendritic cells in the lymph nodes of mice receiving the supplemental butyrate.
Dr. Facciabene said these findings were supported by a recent publication. The authors observed that butyrate inhibited type I IFN expression in dendritic cells and radiotherapy-induced, tumor-specific cytotoxic T-cell immune responses without directly protecting tumor cells from the cytotoxic effects of radiotherapy.
Wide-ranging implications
Overall, Dr. Facciabene’s research has shown that:
- Vancomycin significantly enhances the tumor inhibitory effect of targeted radiation, including abscopal effects.
- The synergistic effects are dependent upon IFN-gamma and CD8+ cells.
- Depletion of some gut microbiome species increases antigen presentation by dendritic cells. This is mediated by SCFAs produced by certain bacterial families.
- There are promising new strategies to improve responses to radiotherapy, including targeting gut microbiota.
A clinical trial (NCT03546829) of vancomycin plus stereotactic body radiation in patients with locally advanced non–small cell lung cancer has been launched to investigate these findings further. Early data analysis has shown a significant impact of vancomycin on several species of gut microbiota, according to Dr. Facciabene.
Revolutionary results from immune-targeted therapy in the recent past have highlighted the important role the immune system can play in fighting cancer. Still, up to one-third of cancer patients fail to respond to overtly immune-targeted therapy.
The ability to inhibit cancer cells from evading immune surveillance by using new adjuvants – including those acting on non-traditional targets like gut microbiota – could herald the next major advances in cancer therapy. During his presentation, Dr. Facciabene gave participants an enticing hint of what could be coming for cancer patients in the years ahead.
Dr. Facciabene reported having no relevant disclosures.
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.
FROM AACR: RADIATION SCIENCE AND MEDICINE
Blacks and Hispanics have higher inpatient use for mycosis fungoides
according to an analysis of the 2012-2017 National Inpatient Sample (NIS).
The findings are consistent with prior studies implicating earlier and more severe disease in Black and Hispanic patients, and reinforce the importance of accurate diagnosis and early treatment.
Dermatologists should maintain “a higher index of suspicion for MF in patients with skin of color, as early diagnosis may help mitigate the downstream costs of management,” Justin Choi, BA, a medical student at the University of Illinois at Chicago, said at the annual Skin of Color Society symposium.
Mr. Choi and coinvestigators, led by Shawn Kwatra, MD, of Johns Hopkins University, Baltimore, identified hospital admissions for MF in the NIS for 10,790 White patients, 4,020 Black patients, and 1,615 Hispanic patients over the 5-year period. The inpatient prevalence of MF – the most common variant of primary cutaneous T-cell lymphoma – was highest in these groups.
Black and Hispanic patients who were hospitalized for MF were significantly younger than White patients, with a mean age of 51.7 years and 48.5 years, respectively, compared with 59.9 years (P < .001 in each case). They also had longer lengths of stay: 8.34 days on average for Black patients and 8.88 for Hispanic patients, compared with 6.66 days for White patients (P < .001 and P = .001, respectively).
Hispanic patients accrued the highest costs of care (a mean of $107,242 vs. $64,049, P =.003) and underwent more procedures (a mean of 2.43 vs. 1.93, P = .004) than White patients. Black patients similarly had higher costs associated with their hospital stay (a mean of $75,053 vs. $64,049, P =.042).
In a multivariate linear regression adjusted for age, sex and insurance type, Black race remained significantly associated with a longer LOS than White race, and Hispanic ethnicity with a longer LOS, increased costs, and more procedures than White race.
The NIS is a publicly available, all-payer inpatient care database developed for the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project.
Mr. Choi is a dermatology research fellow working under the guidance of Dr. Kwatra.
according to an analysis of the 2012-2017 National Inpatient Sample (NIS).
The findings are consistent with prior studies implicating earlier and more severe disease in Black and Hispanic patients, and reinforce the importance of accurate diagnosis and early treatment.
Dermatologists should maintain “a higher index of suspicion for MF in patients with skin of color, as early diagnosis may help mitigate the downstream costs of management,” Justin Choi, BA, a medical student at the University of Illinois at Chicago, said at the annual Skin of Color Society symposium.
Mr. Choi and coinvestigators, led by Shawn Kwatra, MD, of Johns Hopkins University, Baltimore, identified hospital admissions for MF in the NIS for 10,790 White patients, 4,020 Black patients, and 1,615 Hispanic patients over the 5-year period. The inpatient prevalence of MF – the most common variant of primary cutaneous T-cell lymphoma – was highest in these groups.
Black and Hispanic patients who were hospitalized for MF were significantly younger than White patients, with a mean age of 51.7 years and 48.5 years, respectively, compared with 59.9 years (P < .001 in each case). They also had longer lengths of stay: 8.34 days on average for Black patients and 8.88 for Hispanic patients, compared with 6.66 days for White patients (P < .001 and P = .001, respectively).
Hispanic patients accrued the highest costs of care (a mean of $107,242 vs. $64,049, P =.003) and underwent more procedures (a mean of 2.43 vs. 1.93, P = .004) than White patients. Black patients similarly had higher costs associated with their hospital stay (a mean of $75,053 vs. $64,049, P =.042).
In a multivariate linear regression adjusted for age, sex and insurance type, Black race remained significantly associated with a longer LOS than White race, and Hispanic ethnicity with a longer LOS, increased costs, and more procedures than White race.
The NIS is a publicly available, all-payer inpatient care database developed for the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project.
Mr. Choi is a dermatology research fellow working under the guidance of Dr. Kwatra.
according to an analysis of the 2012-2017 National Inpatient Sample (NIS).
The findings are consistent with prior studies implicating earlier and more severe disease in Black and Hispanic patients, and reinforce the importance of accurate diagnosis and early treatment.
Dermatologists should maintain “a higher index of suspicion for MF in patients with skin of color, as early diagnosis may help mitigate the downstream costs of management,” Justin Choi, BA, a medical student at the University of Illinois at Chicago, said at the annual Skin of Color Society symposium.
Mr. Choi and coinvestigators, led by Shawn Kwatra, MD, of Johns Hopkins University, Baltimore, identified hospital admissions for MF in the NIS for 10,790 White patients, 4,020 Black patients, and 1,615 Hispanic patients over the 5-year period. The inpatient prevalence of MF – the most common variant of primary cutaneous T-cell lymphoma – was highest in these groups.
Black and Hispanic patients who were hospitalized for MF were significantly younger than White patients, with a mean age of 51.7 years and 48.5 years, respectively, compared with 59.9 years (P < .001 in each case). They also had longer lengths of stay: 8.34 days on average for Black patients and 8.88 for Hispanic patients, compared with 6.66 days for White patients (P < .001 and P = .001, respectively).
Hispanic patients accrued the highest costs of care (a mean of $107,242 vs. $64,049, P =.003) and underwent more procedures (a mean of 2.43 vs. 1.93, P = .004) than White patients. Black patients similarly had higher costs associated with their hospital stay (a mean of $75,053 vs. $64,049, P =.042).
In a multivariate linear regression adjusted for age, sex and insurance type, Black race remained significantly associated with a longer LOS than White race, and Hispanic ethnicity with a longer LOS, increased costs, and more procedures than White race.
The NIS is a publicly available, all-payer inpatient care database developed for the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project.
Mr. Choi is a dermatology research fellow working under the guidance of Dr. Kwatra.
FROM SOC SOCIETY 2021
Adverse reactions to immunotherapy can appear after a year
Clinicians should be on the lookout for immune-related adverse events (irAEs) even after patients have been receiving anti-PD-1 immunotherapy for a year or longer, according to team of international investigators.
They reported that, among melanoma patients, the incidence of new-onset reactions that occurred 1 year or longer after anti-PD-1 treatment was 5.3%.
In a review of 118 patients, the investigators found that irAEs are often “high grade, difficult to manage, and can lead to death.”
Reactions are more likely to occur in those for whom treatment with an anti-PD-1 checkpoint inhibitor – primarily pembrolizumab and nivolumab – continued for longer than a year, and patients can present “long after stopping” the treatment, the investigators noted.
The findings were published online in Annals of Oncology.
“We do not yet understand why some patients have no side effects for months or years, then develop toxicities so late in their course,” said one of the coauthors, Douglas Johnson, MD, assistant professor of hematology/oncology at Vanderbilt University, Nashville, Tenn.
“Physicians should continue to monitor patients for side effects, even if they have been on anti-PD-1 therapy for some time, since delayed side effects may cause morbidity and even death,” Dr. Johnson said.
Patients and clinicians need “to be aware of these risks when making decisions regarding therapy continuation” and need “to consider irAE as a possible diagnosis in any presentation where there is a history of checkpoint inhibitor treatment, regardless of the time frame, to enable early recognition and appropriate treatment,” Dr. Johnson and colleagues concluded.
Largest series to document delayed reactions
Immunotherapies have revolutionized cancer treatment of many types of tumors, but they carry a well known risk for autoimmune toxicity, which typically occurs within the first 4-6 months, the authors wrote.
Delayed reactions have been reported but are not as well described. The new study is the largest to date on this question, and Dr. Johnson said the findings likely apply across indications, not simply in regard to melanoma patients.
An expert not involved in the study agrees.
“We are definitely seeing delayed reactions to immunotherapy in our practice” in several organ systems, including the skin, said Jennifer Choi, MD, chief of oncodermatology at Northwestern University’s Comprehensive Cancer Center, Chicago.
“Some of these side effects can take months to resolve and may require systemic treatment, such as steroids, nonsteroidal immunosuppressants, or biologics. Clinicians must be on high alert of any possible side effect for a patient on immunotherapy throughout their entire course, and even after they have completed treatment,” Dr. Choi said in an interview.
Anti-PD-1 therapy doesn’t “follow the typical drug hypersensitivity laws and rules with respect to timing,” said Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington.
Median onset was 16 months
The investigators reported in detail on 118 patients. A total of 140 delayed irAEs that occurred 1 year or longer after treatment were identified in 20 centers around the world.
The median onset of delayed irAE was 16 months after start of treatment. Most occurred in conjunction with stand-alone anti-PD-1 therapy, but in the case of 20 patients, a combination of an anti-PD-1 drug and the anti-CTLA-4 drug ipilimumab was used.
In 39% of patients (n = 55), the adverse reaction was of grade 3 or worse. These included two deaths: one case of fatal encephalitis with concurrent anti-PD-1 use, and a death from immune-related multiple organ failure 11 months after anti-PD-1 discontinuation.
Most of the patients (n = 87; 74%) were receiving anti-PD-1 therapy at the time of onset of the adverse reaction; 15 patients (12%) were within 3 months of their last dose, and 16 (14%) were 3 months past their last dose.
Among the subgroup who developed an irAE after discontinuation of treatment was a patient with grade 4 colitis that required colectomy 26 months afterward, although Dr. Johnson noted it’s difficult to be sure that the colitis was related to the immunotherapy, because it occurred so long after treatment had ended.
An early warning system
The most common reactions were colitis, pneumonitis, and rash.
The reactions were often tough to manage, the authors reported. Eighty patients (68%) required steroids, and 27 (23%) required steroids plus additional immunosuppressives, such as tumor necrosis factor blockers, particularly for colitis and renal, rheumatologic, and neurologic complications. Rheumatologic events required a median corticosteroid course of 15 months plus additional immunosuppression in half of cases and often left patients with ongoing morbidity.
“Often, the skin is one of the first and most easily visible immune-related adverse event that develops,” said Bernice Kwong, MD, director of the supportive dermato-oncology program at Stanford (Calif.) University, who was not involved in the study and was approached for comment.
Presentations can range from small itchy plaques to total body dermatitis. It is something to be aware of, because the skin can act as an early warning system to catch internal organ damage earlier, she said.
On a positive note, the investigators found no indication that the effect of immunotherapy was diminished by delayed reactions and their treatment.
Managing events “gets a little complicated” when anti-PD-1 drugs are still being administered, but “we have successfully utilized systemic steroid pulses for several weeks without impeding the efficacy of the therapy. For the lichenoid and psoriasiform dermatitis, topical steroids and oral retinoids have been useful and can be used concurrently with immunotherapy,” Dr. Friedman said.
Question on treatment duration
No obvious factors were predictive of delayed events, including previous autoimmune disease or earlier reactions, which usually affected different organs, the authors said.
The findings raise a question about the appropriate duration of anti-PD-1 therapy, at least for melanoma.
The standard duration of adjuvant therapy was empirically determined to be 1 year for melanoma, and trials support anti-PD-1 therapy for up to 2 years for metastatic disease.
However, the authors suggest that “shorter treatment duration may reduce the risk of delayed irAE” and may be sufficient for patients who have a complete response.
“This should be considered when making decisions regarding therapy continuation in responding patients,” they wrote.
Ongoing clinical trials are investigating the optimal duration of therapy, they wrote.
No outside funding was reported. Dr. Johnson has been an adviser for Array Biopharma, BMS, Iovance, Jansen, Merck, and Novartis and has received research funding from BMS and Incyte. Other investigators reported similar ties. Dr. Choi, Dr. Kwong, and Dr. Friedman have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Clinicians should be on the lookout for immune-related adverse events (irAEs) even after patients have been receiving anti-PD-1 immunotherapy for a year or longer, according to team of international investigators.
They reported that, among melanoma patients, the incidence of new-onset reactions that occurred 1 year or longer after anti-PD-1 treatment was 5.3%.
In a review of 118 patients, the investigators found that irAEs are often “high grade, difficult to manage, and can lead to death.”
Reactions are more likely to occur in those for whom treatment with an anti-PD-1 checkpoint inhibitor – primarily pembrolizumab and nivolumab – continued for longer than a year, and patients can present “long after stopping” the treatment, the investigators noted.
The findings were published online in Annals of Oncology.
“We do not yet understand why some patients have no side effects for months or years, then develop toxicities so late in their course,” said one of the coauthors, Douglas Johnson, MD, assistant professor of hematology/oncology at Vanderbilt University, Nashville, Tenn.
“Physicians should continue to monitor patients for side effects, even if they have been on anti-PD-1 therapy for some time, since delayed side effects may cause morbidity and even death,” Dr. Johnson said.
Patients and clinicians need “to be aware of these risks when making decisions regarding therapy continuation” and need “to consider irAE as a possible diagnosis in any presentation where there is a history of checkpoint inhibitor treatment, regardless of the time frame, to enable early recognition and appropriate treatment,” Dr. Johnson and colleagues concluded.
Largest series to document delayed reactions
Immunotherapies have revolutionized cancer treatment of many types of tumors, but they carry a well known risk for autoimmune toxicity, which typically occurs within the first 4-6 months, the authors wrote.
Delayed reactions have been reported but are not as well described. The new study is the largest to date on this question, and Dr. Johnson said the findings likely apply across indications, not simply in regard to melanoma patients.
An expert not involved in the study agrees.
“We are definitely seeing delayed reactions to immunotherapy in our practice” in several organ systems, including the skin, said Jennifer Choi, MD, chief of oncodermatology at Northwestern University’s Comprehensive Cancer Center, Chicago.
“Some of these side effects can take months to resolve and may require systemic treatment, such as steroids, nonsteroidal immunosuppressants, or biologics. Clinicians must be on high alert of any possible side effect for a patient on immunotherapy throughout their entire course, and even after they have completed treatment,” Dr. Choi said in an interview.
Anti-PD-1 therapy doesn’t “follow the typical drug hypersensitivity laws and rules with respect to timing,” said Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington.
Median onset was 16 months
The investigators reported in detail on 118 patients. A total of 140 delayed irAEs that occurred 1 year or longer after treatment were identified in 20 centers around the world.
The median onset of delayed irAE was 16 months after start of treatment. Most occurred in conjunction with stand-alone anti-PD-1 therapy, but in the case of 20 patients, a combination of an anti-PD-1 drug and the anti-CTLA-4 drug ipilimumab was used.
In 39% of patients (n = 55), the adverse reaction was of grade 3 or worse. These included two deaths: one case of fatal encephalitis with concurrent anti-PD-1 use, and a death from immune-related multiple organ failure 11 months after anti-PD-1 discontinuation.
Most of the patients (n = 87; 74%) were receiving anti-PD-1 therapy at the time of onset of the adverse reaction; 15 patients (12%) were within 3 months of their last dose, and 16 (14%) were 3 months past their last dose.
Among the subgroup who developed an irAE after discontinuation of treatment was a patient with grade 4 colitis that required colectomy 26 months afterward, although Dr. Johnson noted it’s difficult to be sure that the colitis was related to the immunotherapy, because it occurred so long after treatment had ended.
An early warning system
The most common reactions were colitis, pneumonitis, and rash.
The reactions were often tough to manage, the authors reported. Eighty patients (68%) required steroids, and 27 (23%) required steroids plus additional immunosuppressives, such as tumor necrosis factor blockers, particularly for colitis and renal, rheumatologic, and neurologic complications. Rheumatologic events required a median corticosteroid course of 15 months plus additional immunosuppression in half of cases and often left patients with ongoing morbidity.
“Often, the skin is one of the first and most easily visible immune-related adverse event that develops,” said Bernice Kwong, MD, director of the supportive dermato-oncology program at Stanford (Calif.) University, who was not involved in the study and was approached for comment.
Presentations can range from small itchy plaques to total body dermatitis. It is something to be aware of, because the skin can act as an early warning system to catch internal organ damage earlier, she said.
On a positive note, the investigators found no indication that the effect of immunotherapy was diminished by delayed reactions and their treatment.
Managing events “gets a little complicated” when anti-PD-1 drugs are still being administered, but “we have successfully utilized systemic steroid pulses for several weeks without impeding the efficacy of the therapy. For the lichenoid and psoriasiform dermatitis, topical steroids and oral retinoids have been useful and can be used concurrently with immunotherapy,” Dr. Friedman said.
Question on treatment duration
No obvious factors were predictive of delayed events, including previous autoimmune disease or earlier reactions, which usually affected different organs, the authors said.
The findings raise a question about the appropriate duration of anti-PD-1 therapy, at least for melanoma.
The standard duration of adjuvant therapy was empirically determined to be 1 year for melanoma, and trials support anti-PD-1 therapy for up to 2 years for metastatic disease.
However, the authors suggest that “shorter treatment duration may reduce the risk of delayed irAE” and may be sufficient for patients who have a complete response.
“This should be considered when making decisions regarding therapy continuation in responding patients,” they wrote.
Ongoing clinical trials are investigating the optimal duration of therapy, they wrote.
No outside funding was reported. Dr. Johnson has been an adviser for Array Biopharma, BMS, Iovance, Jansen, Merck, and Novartis and has received research funding from BMS and Incyte. Other investigators reported similar ties. Dr. Choi, Dr. Kwong, and Dr. Friedman have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Clinicians should be on the lookout for immune-related adverse events (irAEs) even after patients have been receiving anti-PD-1 immunotherapy for a year or longer, according to team of international investigators.
They reported that, among melanoma patients, the incidence of new-onset reactions that occurred 1 year or longer after anti-PD-1 treatment was 5.3%.
In a review of 118 patients, the investigators found that irAEs are often “high grade, difficult to manage, and can lead to death.”
Reactions are more likely to occur in those for whom treatment with an anti-PD-1 checkpoint inhibitor – primarily pembrolizumab and nivolumab – continued for longer than a year, and patients can present “long after stopping” the treatment, the investigators noted.
The findings were published online in Annals of Oncology.
“We do not yet understand why some patients have no side effects for months or years, then develop toxicities so late in their course,” said one of the coauthors, Douglas Johnson, MD, assistant professor of hematology/oncology at Vanderbilt University, Nashville, Tenn.
“Physicians should continue to monitor patients for side effects, even if they have been on anti-PD-1 therapy for some time, since delayed side effects may cause morbidity and even death,” Dr. Johnson said.
Patients and clinicians need “to be aware of these risks when making decisions regarding therapy continuation” and need “to consider irAE as a possible diagnosis in any presentation where there is a history of checkpoint inhibitor treatment, regardless of the time frame, to enable early recognition and appropriate treatment,” Dr. Johnson and colleagues concluded.
Largest series to document delayed reactions
Immunotherapies have revolutionized cancer treatment of many types of tumors, but they carry a well known risk for autoimmune toxicity, which typically occurs within the first 4-6 months, the authors wrote.
Delayed reactions have been reported but are not as well described. The new study is the largest to date on this question, and Dr. Johnson said the findings likely apply across indications, not simply in regard to melanoma patients.
An expert not involved in the study agrees.
“We are definitely seeing delayed reactions to immunotherapy in our practice” in several organ systems, including the skin, said Jennifer Choi, MD, chief of oncodermatology at Northwestern University’s Comprehensive Cancer Center, Chicago.
“Some of these side effects can take months to resolve and may require systemic treatment, such as steroids, nonsteroidal immunosuppressants, or biologics. Clinicians must be on high alert of any possible side effect for a patient on immunotherapy throughout their entire course, and even after they have completed treatment,” Dr. Choi said in an interview.
Anti-PD-1 therapy doesn’t “follow the typical drug hypersensitivity laws and rules with respect to timing,” said Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington.
Median onset was 16 months
The investigators reported in detail on 118 patients. A total of 140 delayed irAEs that occurred 1 year or longer after treatment were identified in 20 centers around the world.
The median onset of delayed irAE was 16 months after start of treatment. Most occurred in conjunction with stand-alone anti-PD-1 therapy, but in the case of 20 patients, a combination of an anti-PD-1 drug and the anti-CTLA-4 drug ipilimumab was used.
In 39% of patients (n = 55), the adverse reaction was of grade 3 or worse. These included two deaths: one case of fatal encephalitis with concurrent anti-PD-1 use, and a death from immune-related multiple organ failure 11 months after anti-PD-1 discontinuation.
Most of the patients (n = 87; 74%) were receiving anti-PD-1 therapy at the time of onset of the adverse reaction; 15 patients (12%) were within 3 months of their last dose, and 16 (14%) were 3 months past their last dose.
Among the subgroup who developed an irAE after discontinuation of treatment was a patient with grade 4 colitis that required colectomy 26 months afterward, although Dr. Johnson noted it’s difficult to be sure that the colitis was related to the immunotherapy, because it occurred so long after treatment had ended.
An early warning system
The most common reactions were colitis, pneumonitis, and rash.
The reactions were often tough to manage, the authors reported. Eighty patients (68%) required steroids, and 27 (23%) required steroids plus additional immunosuppressives, such as tumor necrosis factor blockers, particularly for colitis and renal, rheumatologic, and neurologic complications. Rheumatologic events required a median corticosteroid course of 15 months plus additional immunosuppression in half of cases and often left patients with ongoing morbidity.
“Often, the skin is one of the first and most easily visible immune-related adverse event that develops,” said Bernice Kwong, MD, director of the supportive dermato-oncology program at Stanford (Calif.) University, who was not involved in the study and was approached for comment.
Presentations can range from small itchy plaques to total body dermatitis. It is something to be aware of, because the skin can act as an early warning system to catch internal organ damage earlier, she said.
On a positive note, the investigators found no indication that the effect of immunotherapy was diminished by delayed reactions and their treatment.
Managing events “gets a little complicated” when anti-PD-1 drugs are still being administered, but “we have successfully utilized systemic steroid pulses for several weeks without impeding the efficacy of the therapy. For the lichenoid and psoriasiform dermatitis, topical steroids and oral retinoids have been useful and can be used concurrently with immunotherapy,” Dr. Friedman said.
Question on treatment duration
No obvious factors were predictive of delayed events, including previous autoimmune disease or earlier reactions, which usually affected different organs, the authors said.
The findings raise a question about the appropriate duration of anti-PD-1 therapy, at least for melanoma.
The standard duration of adjuvant therapy was empirically determined to be 1 year for melanoma, and trials support anti-PD-1 therapy for up to 2 years for metastatic disease.
However, the authors suggest that “shorter treatment duration may reduce the risk of delayed irAE” and may be sufficient for patients who have a complete response.
“This should be considered when making decisions regarding therapy continuation in responding patients,” they wrote.
Ongoing clinical trials are investigating the optimal duration of therapy, they wrote.
No outside funding was reported. Dr. Johnson has been an adviser for Array Biopharma, BMS, Iovance, Jansen, Merck, and Novartis and has received research funding from BMS and Incyte. Other investigators reported similar ties. Dr. Choi, Dr. Kwong, and Dr. Friedman have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.