Neil Osterweil

After 5 years, the combination of lenalidomide and rituximab as first-line therapy for mantle cell lymphoma (MCL) continues to show durable responses with manageable toxicities, long-term results from a phase 2 clinical trial show.

After a median follow-up of 64 months, 21 of 33 patients with initial responses remained in durable, minimal residual disease (MRD)-negative remission following induction with lenalidomide and rituximab and maintenance with those same two agents for at least 3 years.

The patients with durable responses included five who opted to discontinue maintenance after 3 years, reported Jia Ruan, MD, PhD, of Cornell University, New York, and her colleagues.

“Our long-term data provide proof of concept that an outpatient-based induction and maintenance strategy free of conventional chemotherapy is effective, safe, and feasible as first-line therapy for MCL,” they wrote. Their report was published in Blood.

In the multicenter, phase 2 single-arm study, 38 patients with untreated MCL were enrolled and treated with lenalidomide 20 mg daily on days 1-21 of each 28-day cycle for 12 cycles during induction, followed by dose reduction to 15 mg during the maintenance phase. Patients also received standard dose rituximab 375 mg/m² weekly for 4 weeks during cycle 1, then once every other cycle.

Patients remained on treatment until disease progression, unacceptable toxicities, or study withdrawal. Patients who remained in remission after 3 years, based on routine surveillance CT scans, had the option to discontinue maintenance.

Of the original 38 patients enrolled, 36 were evaluable for response, including 23 with a complete response (CR) and 10 with a partial response.

At the 64-month median follow-up, neither the median progression-free survival (PFS) nor duration of response had been reached.

Overall, 21 of the 33 patients with responses (64%) had ongoing responses, including six patients with responses beyond 6 years.

Estimated 3-year and 5-year PFS rates were 80.3% and 63.9%, respectively. Respective estimated 3- and 5-year overall survival rates were 89.5% and 77.4%.

Mantle cell lymphoma international prognostic index (MIPI) scores were not associated with either response or PFS rates, but patients with high-risk MIPI scores were significantly more likely to have worse overall survival (P = .04).

Grade 3 or greater hematologic toxicities included neutropenia in 42% of patients in both induction and maintenance, anemia in 8% and 3%, thrombocytopenia in 11% and 5%, and febrile neutropenia in 3% and 5%.

Secondary primary malignancies occurred in six patients. These included five noninvasive skin cancers requiring only local therapy without the need for study interruption. Two patients, including one with a skin cancer, died from the secondary malignancies, including one from Merkel cell carcinoma and one from pancreatic cancer.

“The efficacy and survival outcome observed in our study compared favorably to those reported with lenalidomide either as single agent, or in combination with rituximab in relapsed and refractory setting, lending support for prioritizing novel agents such as lenalidomide early in the treatment sequence, to compare to conventional chemotherapy-based approach,” the investigators wrote.

The study was supported in part by Celgene Corporation, a Clinical Translational Science Center grant, and the Lymphoma Foundation. Dr. Ruan has received research support and been a consultant for Celgene, and other coauthors reported research support and consultant relationships with the company.

SOURCE: Ruan J et al. Blood. 2018 Sep 4. doi: 10.1182/blood-2018-07-859769.

After 5 years, the combination of lenalidomide and rituximab as first-line therapy for mantle cell lymphoma (MCL) continues to show durable responses with manageable toxicities, long-term results from a phase 2 clinical trial show.

After a median follow-up of 64 months, 21 of 33 patients with initial responses remained in durable, minimal residual disease (MRD)-negative remission following induction with lenalidomide and rituximab and maintenance with those same two agents for at least 3 years.

The patients with durable responses included five who opted to discontinue maintenance after 3 years, reported Jia Ruan, MD, PhD, of Cornell University, New York, and her colleagues.

“Our long-term data provide proof of concept that an outpatient-based induction and maintenance strategy free of conventional chemotherapy is effective, safe, and feasible as first-line therapy for MCL,” they wrote. Their report was published in Blood.

In the multicenter, phase 2 single-arm study, 38 patients with untreated MCL were enrolled and treated with lenalidomide 20 mg daily on days 1-21 of each 28-day cycle for 12 cycles during induction, followed by dose reduction to 15 mg during the maintenance phase. Patients also received standard dose rituximab 375 mg/m² weekly for 4 weeks during cycle 1, then once every other cycle.

Patients remained on treatment until disease progression, unacceptable toxicities, or study withdrawal. Patients who remained in remission after 3 years, based on routine surveillance CT scans, had the option to discontinue maintenance.

Of the original 38 patients enrolled, 36 were evaluable for response, including 23 with a complete response (CR) and 10 with a partial response.

At the 64-month median follow-up, neither the median progression-free survival (PFS) nor duration of response had been reached.

Overall, 21 of the 33 patients with responses (64%) had ongoing responses, including six patients with responses beyond 6 years.

Estimated 3-year and 5-year PFS rates were 80.3% and 63.9%, respectively. Respective estimated 3- and 5-year overall survival rates were 89.5% and 77.4%.

Mantle cell lymphoma international prognostic index (MIPI) scores were not associated with either response or PFS rates, but patients with high-risk MIPI scores were significantly more likely to have worse overall survival (P = .04).

Grade 3 or greater hematologic toxicities included neutropenia in 42% of patients in both induction and maintenance, anemia in 8% and 3%, thrombocytopenia in 11% and 5%, and febrile neutropenia in 3% and 5%.

Secondary primary malignancies occurred in six patients. These included five noninvasive skin cancers requiring only local therapy without the need for study interruption. Two patients, including one with a skin cancer, died from the secondary malignancies, including one from Merkel cell carcinoma and one from pancreatic cancer.

“The efficacy and survival outcome observed in our study compared favorably to those reported with lenalidomide either as single agent, or in combination with rituximab in relapsed and refractory setting, lending support for prioritizing novel agents such as lenalidomide early in the treatment sequence, to compare to conventional chemotherapy-based approach,” the investigators wrote.

The study was supported in part by Celgene Corporation, a Clinical Translational Science Center grant, and the Lymphoma Foundation. Dr. Ruan has received research support and been a consultant for Celgene, and other coauthors reported research support and consultant relationships with the company.

SOURCE: Ruan J et al. Blood. 2018 Sep 4. doi: 10.1182/blood-2018-07-859769.

After 5 years, the combination of lenalidomide and rituximab as first-line therapy for mantle cell lymphoma (MCL) continues to show durable responses with manageable toxicities, long-term results from a phase 2 clinical trial show.

After a median follow-up of 64 months, 21 of 33 patients with initial responses remained in durable, minimal residual disease (MRD)-negative remission following induction with lenalidomide and rituximab and maintenance with those same two agents for at least 3 years.

The patients with durable responses included five who opted to discontinue maintenance after 3 years, reported Jia Ruan, MD, PhD, of Cornell University, New York, and her colleagues.

“Our long-term data provide proof of concept that an outpatient-based induction and maintenance strategy free of conventional chemotherapy is effective, safe, and feasible as first-line therapy for MCL,” they wrote. Their report was published in Blood.

In the multicenter, phase 2 single-arm study, 38 patients with untreated MCL were enrolled and treated with lenalidomide 20 mg daily on days 1-21 of each 28-day cycle for 12 cycles during induction, followed by dose reduction to 15 mg during the maintenance phase. Patients also received standard dose rituximab 375 mg/m² weekly for 4 weeks during cycle 1, then once every other cycle.

Patients remained on treatment until disease progression, unacceptable toxicities, or study withdrawal. Patients who remained in remission after 3 years, based on routine surveillance CT scans, had the option to discontinue maintenance.

Of the original 38 patients enrolled, 36 were evaluable for response, including 23 with a complete response (CR) and 10 with a partial response.

At the 64-month median follow-up, neither the median progression-free survival (PFS) nor duration of response had been reached.

Overall, 21 of the 33 patients with responses (64%) had ongoing responses, including six patients with responses beyond 6 years.

Estimated 3-year and 5-year PFS rates were 80.3% and 63.9%, respectively. Respective estimated 3- and 5-year overall survival rates were 89.5% and 77.4%.

Mantle cell lymphoma international prognostic index (MIPI) scores were not associated with either response or PFS rates, but patients with high-risk MIPI scores were significantly more likely to have worse overall survival (P = .04).

Grade 3 or greater hematologic toxicities included neutropenia in 42% of patients in both induction and maintenance, anemia in 8% and 3%, thrombocytopenia in 11% and 5%, and febrile neutropenia in 3% and 5%.

Secondary primary malignancies occurred in six patients. These included five noninvasive skin cancers requiring only local therapy without the need for study interruption. Two patients, including one with a skin cancer, died from the secondary malignancies, including one from Merkel cell carcinoma and one from pancreatic cancer.

“The efficacy and survival outcome observed in our study compared favorably to those reported with lenalidomide either as single agent, or in combination with rituximab in relapsed and refractory setting, lending support for prioritizing novel agents such as lenalidomide early in the treatment sequence, to compare to conventional chemotherapy-based approach,” the investigators wrote.

The study was supported in part by Celgene Corporation, a Clinical Translational Science Center grant, and the Lymphoma Foundation. Dr. Ruan has received research support and been a consultant for Celgene, and other coauthors reported research support and consultant relationships with the company.

SOURCE: Ruan J et al. Blood. 2018 Sep 4. doi: 10.1182/blood-2018-07-859769.

The hematopoietic action of the thrombopoietin receptor (TPO-R) agonist eltrombopag (Promacta) occurs at the stem cell level through its effects on iron chelation that in turn leads to hematopoietic stem cell (HSC) stimulation and self-renewal, investigators report.

Studying the effects of eltrombopag treatment in mouse models and in bone marrow cells isolated from patients, Britta Will, PhD, from the Albert Einstein College of Medicine, New York, and her colleagues found that eltrombopag’s stimulatory effects on stem cell self-renewal were independent of the thrombopoietin receptor.

“The iron chelation–dependent mechanism of [eltrombopag] is very likely to confer clinical relevance in the context of enhancing TPO-R–dependent HSC stimulation and reinforcing stem cell identity through wide-ranging iron-dependent metabolic reprogramming, which increases healthy stem cells without causing their exhaustion in bone marrow failure syndromes, as well as aid in preserving functional HSCs under cellular stress (such as transplantation, cytotoxic treatment, or irradiation),” they wrote in Science Translational Medicine.

To gain insight into the effects of eltrombopag on the earliest stages of hematopoiesis, the investigators conducted a series of experiments, starting with an assessment of the effects of the agent on the functional hallmarks of primary human stem cells.

Using assays for differentiation, self-renewal, and cell proliferation in human bone marrow cell lines, they found that eltrombopag acts directly on multilineage hematopoiesis by fostering commitment to differentiation at the multipotent progenitor (MPP) cell level and by enhancing self-renewal of hematopoietic stem cells.

Next, they investigated whether eltrombopag promoted hematopoiesis by activating the TPO-R, or through a different mechanism, and found that its action was independent of the thrombopoietin receptor. Specifically, they found that eltrombopag “elicits gene expression alterations in HSCs consistent with a molecular response to reduced intracellular iron content, consisting of decreased glycolysis and enhanced lipid and protein catabolic pathway activation.”

To show that the effect was independent of TPO-R, they then turned to mouse models (eltrombopag is known to activate TPO-R signaling in primate cells, including in humans, but cannot do so in mice, they explained). They showed that in mice, eltrombopag is capable of stimulating HSCs even in the absence of action on the TPO-R.

They also demonstrated that HSCs from both humans and mice have evidence of changes in metabolism and in gene expression that were consistent with reduction of labile iron pools that stem cells rely on for maintenance. When they preloaded cells with iron, the stimulatory effects of eltrombopag were negated, further supporting the iron-chelating effects of the drug on HSC stimulation.

Finally, they looked at HSC function in bone marrow mononuclear cells from patients with immune thrombocytopenia who were being treated with eltrombopag and found a threefold greater increase in the number of functional HSCs, compared with samples from patients treated with the TPO-R agonist romiplostim (Nplate), which does not have iron-chelating properties.

“Together, our data demonstrate a TPO-R–independent stem cell stimulatory function of EP and suggest that free intracellular iron pools may serve as a rheostat for HSC maintenance,” the investigators wrote.

The study was supported by the New York State Department of Health. Dr. Will and two coauthors reported research support from GlaxoSmithKline and Novartis, and serving as consultants for Novartis. Two of the co-authors are employees of Novartis.

SOURCE: Kao YR et al. Sci Transl Med. 2018 Sep 12;10(458). doi: 10.1126/scitranslmed.aas9563.
 

The hematopoietic action of the thrombopoietin receptor (TPO-R) agonist eltrombopag (Promacta) occurs at the stem cell level through its effects on iron chelation that in turn leads to hematopoietic stem cell (HSC) stimulation and self-renewal, investigators report.

Studying the effects of eltrombopag treatment in mouse models and in bone marrow cells isolated from patients, Britta Will, PhD, from the Albert Einstein College of Medicine, New York, and her colleagues found that eltrombopag’s stimulatory effects on stem cell self-renewal were independent of the thrombopoietin receptor.

“The iron chelation–dependent mechanism of [eltrombopag] is very likely to confer clinical relevance in the context of enhancing TPO-R–dependent HSC stimulation and reinforcing stem cell identity through wide-ranging iron-dependent metabolic reprogramming, which increases healthy stem cells without causing their exhaustion in bone marrow failure syndromes, as well as aid in preserving functional HSCs under cellular stress (such as transplantation, cytotoxic treatment, or irradiation),” they wrote in Science Translational Medicine.

To gain insight into the effects of eltrombopag on the earliest stages of hematopoiesis, the investigators conducted a series of experiments, starting with an assessment of the effects of the agent on the functional hallmarks of primary human stem cells.

Using assays for differentiation, self-renewal, and cell proliferation in human bone marrow cell lines, they found that eltrombopag acts directly on multilineage hematopoiesis by fostering commitment to differentiation at the multipotent progenitor (MPP) cell level and by enhancing self-renewal of hematopoietic stem cells.

Next, they investigated whether eltrombopag promoted hematopoiesis by activating the TPO-R, or through a different mechanism, and found that its action was independent of the thrombopoietin receptor. Specifically, they found that eltrombopag “elicits gene expression alterations in HSCs consistent with a molecular response to reduced intracellular iron content, consisting of decreased glycolysis and enhanced lipid and protein catabolic pathway activation.”

To show that the effect was independent of TPO-R, they then turned to mouse models (eltrombopag is known to activate TPO-R signaling in primate cells, including in humans, but cannot do so in mice, they explained). They showed that in mice, eltrombopag is capable of stimulating HSCs even in the absence of action on the TPO-R.

They also demonstrated that HSCs from both humans and mice have evidence of changes in metabolism and in gene expression that were consistent with reduction of labile iron pools that stem cells rely on for maintenance. When they preloaded cells with iron, the stimulatory effects of eltrombopag were negated, further supporting the iron-chelating effects of the drug on HSC stimulation.

Finally, they looked at HSC function in bone marrow mononuclear cells from patients with immune thrombocytopenia who were being treated with eltrombopag and found a threefold greater increase in the number of functional HSCs, compared with samples from patients treated with the TPO-R agonist romiplostim (Nplate), which does not have iron-chelating properties.

“Together, our data demonstrate a TPO-R–independent stem cell stimulatory function of EP and suggest that free intracellular iron pools may serve as a rheostat for HSC maintenance,” the investigators wrote.

The study was supported by the New York State Department of Health. Dr. Will and two coauthors reported research support from GlaxoSmithKline and Novartis, and serving as consultants for Novartis. Two of the co-authors are employees of Novartis.

SOURCE: Kao YR et al. Sci Transl Med. 2018 Sep 12;10(458). doi: 10.1126/scitranslmed.aas9563.
 

The hematopoietic action of the thrombopoietin receptor (TPO-R) agonist eltrombopag (Promacta) occurs at the stem cell level through its effects on iron chelation that in turn leads to hematopoietic stem cell (HSC) stimulation and self-renewal, investigators report.

Studying the effects of eltrombopag treatment in mouse models and in bone marrow cells isolated from patients, Britta Will, PhD, from the Albert Einstein College of Medicine, New York, and her colleagues found that eltrombopag’s stimulatory effects on stem cell self-renewal were independent of the thrombopoietin receptor.

“The iron chelation–dependent mechanism of [eltrombopag] is very likely to confer clinical relevance in the context of enhancing TPO-R–dependent HSC stimulation and reinforcing stem cell identity through wide-ranging iron-dependent metabolic reprogramming, which increases healthy stem cells without causing their exhaustion in bone marrow failure syndromes, as well as aid in preserving functional HSCs under cellular stress (such as transplantation, cytotoxic treatment, or irradiation),” they wrote in Science Translational Medicine.

To gain insight into the effects of eltrombopag on the earliest stages of hematopoiesis, the investigators conducted a series of experiments, starting with an assessment of the effects of the agent on the functional hallmarks of primary human stem cells.

Using assays for differentiation, self-renewal, and cell proliferation in human bone marrow cell lines, they found that eltrombopag acts directly on multilineage hematopoiesis by fostering commitment to differentiation at the multipotent progenitor (MPP) cell level and by enhancing self-renewal of hematopoietic stem cells.

Next, they investigated whether eltrombopag promoted hematopoiesis by activating the TPO-R, or through a different mechanism, and found that its action was independent of the thrombopoietin receptor. Specifically, they found that eltrombopag “elicits gene expression alterations in HSCs consistent with a molecular response to reduced intracellular iron content, consisting of decreased glycolysis and enhanced lipid and protein catabolic pathway activation.”

To show that the effect was independent of TPO-R, they then turned to mouse models (eltrombopag is known to activate TPO-R signaling in primate cells, including in humans, but cannot do so in mice, they explained). They showed that in mice, eltrombopag is capable of stimulating HSCs even in the absence of action on the TPO-R.

They also demonstrated that HSCs from both humans and mice have evidence of changes in metabolism and in gene expression that were consistent with reduction of labile iron pools that stem cells rely on for maintenance. When they preloaded cells with iron, the stimulatory effects of eltrombopag were negated, further supporting the iron-chelating effects of the drug on HSC stimulation.

Finally, they looked at HSC function in bone marrow mononuclear cells from patients with immune thrombocytopenia who were being treated with eltrombopag and found a threefold greater increase in the number of functional HSCs, compared with samples from patients treated with the TPO-R agonist romiplostim (Nplate), which does not have iron-chelating properties.

“Together, our data demonstrate a TPO-R–independent stem cell stimulatory function of EP and suggest that free intracellular iron pools may serve as a rheostat for HSC maintenance,” the investigators wrote.

The study was supported by the New York State Department of Health. Dr. Will and two coauthors reported research support from GlaxoSmithKline and Novartis, and serving as consultants for Novartis. Two of the co-authors are employees of Novartis.

SOURCE: Kao YR et al. Sci Transl Med. 2018 Sep 12;10(458). doi: 10.1126/scitranslmed.aas9563.
 

Residual human papillomavirus DNA in plasma following chemoradiation for HPV-positive cervical cancer is not a good sign, investigators warn.

Among 19 women with HPV-positive cervical cancer who underwent definitive chemoradiation (CRT), detectable HPV DNA in plasma at the end of therapy was associated with a significantly lower rate of progression-free survival (PFS), reported Kathy Han, MD, of the Princess Margaret Cancer Center in Toronto, and her colleagues.

“This prospective multicenter study shows that plasma HPV DNA is detectable at end of CRT in a subset of patients with locally advanced cervical cancer and is associated with poor PFS,” they wrote in JCO Precision Oncology.

The investigators also found that HPV DNA testing 3 months after the end of therapy is more accurate than 3-month fluorodeoxyglucose positron emission tomography (FDG-PET) for detecting minimal residual disease.

In a prospective study, the investigators enrolled 23 women with International Federation of Gynecology and Obstetrics stage IB to IVA cervical adenosquamous, adenocarcinoma, or squamous cell carcinoma who were scheduled to undergo CRT. Three of the patients had no detectable HPV DNA on pretreatment cervical swab, and were excluded from the study, and one patient did not complete therapy, leaving 19 patients with detectable plasma HPV DNA for the analysis.

Of these patients, six had detectable DNA at the end of treatment, and of this group, three had metastatic disease at 3 months. In contrast, only 1 of the 13 patients with no detectable DNA at the end of therapy had developed recurrent disease by the data cutoff.

Six of the 13 patients without detectable DNA at the end of treatment had positive 3-month FDG-PET results, but no definite residual disease on either subsequent imaging or clinical exam. Of these six patients, four had undetectable plasma HPV DNA at 3 months.

The accuracy of 3-month plasma HPV DNA for predicting relapse at 18 months was 77%, compared with 60% for 3-month FDG-PET (P = .008).

PFS at 24 months was significantly better for women with undetectable HPV DNA at the end of therapy, at 92% vs. 50% for women with detectable post-treatment HPV DNA (P = .02).

The authors acknowledged that the study was limited by the small sample size and by an 18-month PFS rate (79%) that was higher than expected, which reduced the statistical power to detect significant associations between HPV DNA and outcomes.

“Additional studies are warranted to confirm the prognostic significance of plasma HPV DNA after CRT and to test the clinical utility of plasma HPV DNA for guiding adjuvant/salvage therapy,” they concluded.

SOURCE: Han K et al. JCO Precis Oncol. 2018 Sep 13. doi: 10.1200/PO.18.00152.

Residual human papillomavirus DNA in plasma following chemoradiation for HPV-positive cervical cancer is not a good sign, investigators warn.

Among 19 women with HPV-positive cervical cancer who underwent definitive chemoradiation (CRT), detectable HPV DNA in plasma at the end of therapy was associated with a significantly lower rate of progression-free survival (PFS), reported Kathy Han, MD, of the Princess Margaret Cancer Center in Toronto, and her colleagues.

“This prospective multicenter study shows that plasma HPV DNA is detectable at end of CRT in a subset of patients with locally advanced cervical cancer and is associated with poor PFS,” they wrote in JCO Precision Oncology.

The investigators also found that HPV DNA testing 3 months after the end of therapy is more accurate than 3-month fluorodeoxyglucose positron emission tomography (FDG-PET) for detecting minimal residual disease.

In a prospective study, the investigators enrolled 23 women with International Federation of Gynecology and Obstetrics stage IB to IVA cervical adenosquamous, adenocarcinoma, or squamous cell carcinoma who were scheduled to undergo CRT. Three of the patients had no detectable HPV DNA on pretreatment cervical swab, and were excluded from the study, and one patient did not complete therapy, leaving 19 patients with detectable plasma HPV DNA for the analysis.

Of these patients, six had detectable DNA at the end of treatment, and of this group, three had metastatic disease at 3 months. In contrast, only 1 of the 13 patients with no detectable DNA at the end of therapy had developed recurrent disease by the data cutoff.

Six of the 13 patients without detectable DNA at the end of treatment had positive 3-month FDG-PET results, but no definite residual disease on either subsequent imaging or clinical exam. Of these six patients, four had undetectable plasma HPV DNA at 3 months.

The accuracy of 3-month plasma HPV DNA for predicting relapse at 18 months was 77%, compared with 60% for 3-month FDG-PET (P = .008).

PFS at 24 months was significantly better for women with undetectable HPV DNA at the end of therapy, at 92% vs. 50% for women with detectable post-treatment HPV DNA (P = .02).

The authors acknowledged that the study was limited by the small sample size and by an 18-month PFS rate (79%) that was higher than expected, which reduced the statistical power to detect significant associations between HPV DNA and outcomes.

“Additional studies are warranted to confirm the prognostic significance of plasma HPV DNA after CRT and to test the clinical utility of plasma HPV DNA for guiding adjuvant/salvage therapy,” they concluded.

SOURCE: Han K et al. JCO Precis Oncol. 2018 Sep 13. doi: 10.1200/PO.18.00152.

Residual human papillomavirus DNA in plasma following chemoradiation for HPV-positive cervical cancer is not a good sign, investigators warn.

Among 19 women with HPV-positive cervical cancer who underwent definitive chemoradiation (CRT), detectable HPV DNA in plasma at the end of therapy was associated with a significantly lower rate of progression-free survival (PFS), reported Kathy Han, MD, of the Princess Margaret Cancer Center in Toronto, and her colleagues.

“This prospective multicenter study shows that plasma HPV DNA is detectable at end of CRT in a subset of patients with locally advanced cervical cancer and is associated with poor PFS,” they wrote in JCO Precision Oncology.

The investigators also found that HPV DNA testing 3 months after the end of therapy is more accurate than 3-month fluorodeoxyglucose positron emission tomography (FDG-PET) for detecting minimal residual disease.

In a prospective study, the investigators enrolled 23 women with International Federation of Gynecology and Obstetrics stage IB to IVA cervical adenosquamous, adenocarcinoma, or squamous cell carcinoma who were scheduled to undergo CRT. Three of the patients had no detectable HPV DNA on pretreatment cervical swab, and were excluded from the study, and one patient did not complete therapy, leaving 19 patients with detectable plasma HPV DNA for the analysis.

Of these patients, six had detectable DNA at the end of treatment, and of this group, three had metastatic disease at 3 months. In contrast, only 1 of the 13 patients with no detectable DNA at the end of therapy had developed recurrent disease by the data cutoff.

Six of the 13 patients without detectable DNA at the end of treatment had positive 3-month FDG-PET results, but no definite residual disease on either subsequent imaging or clinical exam. Of these six patients, four had undetectable plasma HPV DNA at 3 months.

The accuracy of 3-month plasma HPV DNA for predicting relapse at 18 months was 77%, compared with 60% for 3-month FDG-PET (P = .008).

PFS at 24 months was significantly better for women with undetectable HPV DNA at the end of therapy, at 92% vs. 50% for women with detectable post-treatment HPV DNA (P = .02).

The authors acknowledged that the study was limited by the small sample size and by an 18-month PFS rate (79%) that was higher than expected, which reduced the statistical power to detect significant associations between HPV DNA and outcomes.

“Additional studies are warranted to confirm the prognostic significance of plasma HPV DNA after CRT and to test the clinical utility of plasma HPV DNA for guiding adjuvant/salvage therapy,” they concluded.

SOURCE: Han K et al. JCO Precis Oncol. 2018 Sep 13. doi: 10.1200/PO.18.00152.

Fatal adverse events are uncommon with immune checkpoint inhibitors (ICI), but they are not unknown, and it’s important to recognize rare, potentially lethal side effects with these agents, investigators say.

A systematic review and meta-analysis of records from academic medical centers and from a pharmacovigilance database found that fatal side adverse events varied in nature and severity according to the agent and immune checkpoint targeted, reported Daniel Y. Wang, MD, of Vanderbilt University Medical Center, Nashville, Tenn., and his colleagues.

“This study underscores that the risk of death associated with complications of ICI therapy is real, but within or well below fatality rates for common oncologic interventions,” they wrote in JAMA Oncology.

In their study, rates of fatal toxic effects associated with immune checkpoint inhibitors ranged from 0.3% to 1.3%. In contrast, the investigators noted, platinum doublet chemotherapy is associated with a 0.9% rate of fatal toxicities, targeted therapies with angiogenesis inhibitors or tyrosine kinase inhibitors have had fatal toxicity rates up to 4%, and allogeneic hematopoietic stem cell transplants are associated with a fatal adverse event rate of approximately 15%. In addition, the death rate associated with complex oncologic surgeries such as the Whipple procedure or esophagectomy ranges from 1% to 10%.

The authors queried the World Health Organization pharmacovigilance database, called Vigilyze, which contains data on more than 16 million adverse drug reactions; records from patients treated with checkpoint inhibitors in seven academic centers in the United States, Germany, and Australia; and published clinical trials.

They combed through the data to identify fatal toxic effects associated with the anti-programmed death 1/ligand-1 (PD-1/PD-L1) inhibitors nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi), and with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors ipilimumab (Yervoy) and tremelimumab (investigational).

They found in the Vigilyze data that of 193 deaths attributed to CTLA-4 inhibitors, 70% were from colitis, 16% from hepatitis, 8% from pneumonitis, and the remainder from other causes. In contrast, the most common fatal toxicities associated with PD-1/PD-L1 inhibitors were pneumonitis in 35%, hepatitis in 22%, colitis in 17%, and the remainder from other causes.

With the two classes of ICIs used in combination, primarily for treatment of malignant melanoma, colitis accounted for 37% of toxic fatal events, followed by myocarditis in 25%, hepatitis in 22%, pneumonitis in 14%, and others.

The events occurred early in the course of therapy, at a median of 14.5 days from the start of therapy for combination treatment, and 40 days each for anti-PD-1/PD-L1 and anti-CTLA-4 agents.

The complication with highest fatality rate was myocarditis, which killed 39.7% of affected patients. In contrast, endocrine events and colitis were fatal in only 2%-5% of cases. The fatality rates associated with toxic effects in other organ systems ranged from 10% to 17%.

A review of data on 3,545 patients treated with immune checkpoint inhibitors at the seven academic centers found a 0.6% fatality rate, with cardiac and neurologic events accounting for 43% of the deaths.

The investigators also conducted a meta-analysis of data from 112 clinical trials with a total of 19,217 patients treated with ICIs. In these studies, anti-PD-1 agents were associated with a 0.36% rate of fatal toxicities, anti-PD-L1 agents were associated with a 0.38% rate, anti-CTLA-4 agents were linked to a 1.08% rate, and combined PD-1/PD-L1 and CTLA-4 therapy was associated with a 1.23% fatal toxicity rate.

“Each database largely validated the patterns of death from distinct regimens with a few exceptions. Intriguingly, our retrospective analysis at large, experienced academic centers suggested that neurologic and cardiac toxic effects comprised nearly half of deaths. Thus, we surmise that more optimized treatment of these events is urgently needed. In addition, persistent deaths from colitis and pneumonitis, events with standardized treatment algorithms and clear symptoms, suggests that patient and physician education remains a critical objective,” the investigators wrote.

SOURCE: Wang DY et al. JAMA Oncol. 2018 Sept 13. doi: 10.1001/jamaoncol.2018.3923.

Fatal adverse events are uncommon with immune checkpoint inhibitors (ICI), but they are not unknown, and it’s important to recognize rare, potentially lethal side effects with these agents, investigators say.

A systematic review and meta-analysis of records from academic medical centers and from a pharmacovigilance database found that fatal side adverse events varied in nature and severity according to the agent and immune checkpoint targeted, reported Daniel Y. Wang, MD, of Vanderbilt University Medical Center, Nashville, Tenn., and his colleagues.

“This study underscores that the risk of death associated with complications of ICI therapy is real, but within or well below fatality rates for common oncologic interventions,” they wrote in JAMA Oncology.

In their study, rates of fatal toxic effects associated with immune checkpoint inhibitors ranged from 0.3% to 1.3%. In contrast, the investigators noted, platinum doublet chemotherapy is associated with a 0.9% rate of fatal toxicities, targeted therapies with angiogenesis inhibitors or tyrosine kinase inhibitors have had fatal toxicity rates up to 4%, and allogeneic hematopoietic stem cell transplants are associated with a fatal adverse event rate of approximately 15%. In addition, the death rate associated with complex oncologic surgeries such as the Whipple procedure or esophagectomy ranges from 1% to 10%.

The authors queried the World Health Organization pharmacovigilance database, called Vigilyze, which contains data on more than 16 million adverse drug reactions; records from patients treated with checkpoint inhibitors in seven academic centers in the United States, Germany, and Australia; and published clinical trials.

They combed through the data to identify fatal toxic effects associated with the anti-programmed death 1/ligand-1 (PD-1/PD-L1) inhibitors nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi), and with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors ipilimumab (Yervoy) and tremelimumab (investigational).

They found in the Vigilyze data that of 193 deaths attributed to CTLA-4 inhibitors, 70% were from colitis, 16% from hepatitis, 8% from pneumonitis, and the remainder from other causes. In contrast, the most common fatal toxicities associated with PD-1/PD-L1 inhibitors were pneumonitis in 35%, hepatitis in 22%, colitis in 17%, and the remainder from other causes.

With the two classes of ICIs used in combination, primarily for treatment of malignant melanoma, colitis accounted for 37% of toxic fatal events, followed by myocarditis in 25%, hepatitis in 22%, pneumonitis in 14%, and others.

The events occurred early in the course of therapy, at a median of 14.5 days from the start of therapy for combination treatment, and 40 days each for anti-PD-1/PD-L1 and anti-CTLA-4 agents.

The complication with highest fatality rate was myocarditis, which killed 39.7% of affected patients. In contrast, endocrine events and colitis were fatal in only 2%-5% of cases. The fatality rates associated with toxic effects in other organ systems ranged from 10% to 17%.

A review of data on 3,545 patients treated with immune checkpoint inhibitors at the seven academic centers found a 0.6% fatality rate, with cardiac and neurologic events accounting for 43% of the deaths.

The investigators also conducted a meta-analysis of data from 112 clinical trials with a total of 19,217 patients treated with ICIs. In these studies, anti-PD-1 agents were associated with a 0.36% rate of fatal toxicities, anti-PD-L1 agents were associated with a 0.38% rate, anti-CTLA-4 agents were linked to a 1.08% rate, and combined PD-1/PD-L1 and CTLA-4 therapy was associated with a 1.23% fatal toxicity rate.

“Each database largely validated the patterns of death from distinct regimens with a few exceptions. Intriguingly, our retrospective analysis at large, experienced academic centers suggested that neurologic and cardiac toxic effects comprised nearly half of deaths. Thus, we surmise that more optimized treatment of these events is urgently needed. In addition, persistent deaths from colitis and pneumonitis, events with standardized treatment algorithms and clear symptoms, suggests that patient and physician education remains a critical objective,” the investigators wrote.

SOURCE: Wang DY et al. JAMA Oncol. 2018 Sept 13. doi: 10.1001/jamaoncol.2018.3923.

Fatal adverse events are uncommon with immune checkpoint inhibitors (ICI), but they are not unknown, and it’s important to recognize rare, potentially lethal side effects with these agents, investigators say.

A systematic review and meta-analysis of records from academic medical centers and from a pharmacovigilance database found that fatal side adverse events varied in nature and severity according to the agent and immune checkpoint targeted, reported Daniel Y. Wang, MD, of Vanderbilt University Medical Center, Nashville, Tenn., and his colleagues.

“This study underscores that the risk of death associated with complications of ICI therapy is real, but within or well below fatality rates for common oncologic interventions,” they wrote in JAMA Oncology.

In their study, rates of fatal toxic effects associated with immune checkpoint inhibitors ranged from 0.3% to 1.3%. In contrast, the investigators noted, platinum doublet chemotherapy is associated with a 0.9% rate of fatal toxicities, targeted therapies with angiogenesis inhibitors or tyrosine kinase inhibitors have had fatal toxicity rates up to 4%, and allogeneic hematopoietic stem cell transplants are associated with a fatal adverse event rate of approximately 15%. In addition, the death rate associated with complex oncologic surgeries such as the Whipple procedure or esophagectomy ranges from 1% to 10%.

The authors queried the World Health Organization pharmacovigilance database, called Vigilyze, which contains data on more than 16 million adverse drug reactions; records from patients treated with checkpoint inhibitors in seven academic centers in the United States, Germany, and Australia; and published clinical trials.

They combed through the data to identify fatal toxic effects associated with the anti-programmed death 1/ligand-1 (PD-1/PD-L1) inhibitors nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi), and with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors ipilimumab (Yervoy) and tremelimumab (investigational).

They found in the Vigilyze data that of 193 deaths attributed to CTLA-4 inhibitors, 70% were from colitis, 16% from hepatitis, 8% from pneumonitis, and the remainder from other causes. In contrast, the most common fatal toxicities associated with PD-1/PD-L1 inhibitors were pneumonitis in 35%, hepatitis in 22%, colitis in 17%, and the remainder from other causes.

With the two classes of ICIs used in combination, primarily for treatment of malignant melanoma, colitis accounted for 37% of toxic fatal events, followed by myocarditis in 25%, hepatitis in 22%, pneumonitis in 14%, and others.

The events occurred early in the course of therapy, at a median of 14.5 days from the start of therapy for combination treatment, and 40 days each for anti-PD-1/PD-L1 and anti-CTLA-4 agents.

The complication with highest fatality rate was myocarditis, which killed 39.7% of affected patients. In contrast, endocrine events and colitis were fatal in only 2%-5% of cases. The fatality rates associated with toxic effects in other organ systems ranged from 10% to 17%.

A review of data on 3,545 patients treated with immune checkpoint inhibitors at the seven academic centers found a 0.6% fatality rate, with cardiac and neurologic events accounting for 43% of the deaths.

The investigators also conducted a meta-analysis of data from 112 clinical trials with a total of 19,217 patients treated with ICIs. In these studies, anti-PD-1 agents were associated with a 0.36% rate of fatal toxicities, anti-PD-L1 agents were associated with a 0.38% rate, anti-CTLA-4 agents were linked to a 1.08% rate, and combined PD-1/PD-L1 and CTLA-4 therapy was associated with a 1.23% fatal toxicity rate.

“Each database largely validated the patterns of death from distinct regimens with a few exceptions. Intriguingly, our retrospective analysis at large, experienced academic centers suggested that neurologic and cardiac toxic effects comprised nearly half of deaths. Thus, we surmise that more optimized treatment of these events is urgently needed. In addition, persistent deaths from colitis and pneumonitis, events with standardized treatment algorithms and clear symptoms, suggests that patient and physician education remains a critical objective,” the investigators wrote.

SOURCE: Wang DY et al. JAMA Oncol. 2018 Sept 13. doi: 10.1001/jamaoncol.2018.3923.

Micrograph showing MM

Preclinical research suggests an AKT inhibitor could be effective against multiple myeloma (MM).

The inhibitor, HS1793, is a derivative of the antioxidant compound resveratrol.

Investigators found that HS1793 decreased AKT signaling to induce mitochondria-mediated cell death in MM cells.

HS1793 was cytotoxic to MM cells in a mouse model of human metastatic myeloma and in human MM cells in vitro.

Jin Han, MD, PhD, of Inje University in Busan, South Korea, and colleagues reported these results in Cancer Letters.

“AKT is frequently activated in MM cells, and the incidence of AKT activation correlates positively with disease activity,” the authors noted.

They had screened 400 compounds and identified HS1793 as the most promising AKT inhibitor. Experiments suggested that HS1793 inhibits AKT activation by interfering with the interaction between AKT and its promoter, HSP90.

HS1793 exhibited antimyeloma activity in human MM cell lines. The investigators said this appeared to be from a dose-dependent effect that allowed for mitochondria-mediated programmed cell death.

In additional experiments, the team found that HS1793’s inhibition of AKT/HSP90 interaction results in cell death by suppressing NF-κB signaling. HS1793-induced cell death was caused by the direct inhibition of AKT that, in turn, suppressed NF-κB activation.

The investigators found that HS1793 “dramatically decreased” lytic skull and femur lesions in a mouse model of MM metastatic to bone. And mice that received HS1793 had superior survival, when compared to mice that received vehicle control.

The investigators also showed that HS1793 was cytotoxic to MM cells but not normal plasma cells isolated from patients with MM.

“Given that HS1793 treatment specifically induced the death of primary and relapsed MM cells, HS1793 offers excellent translational potential as a novel MM therapy,” the authors wrote.

This research was supported by grants from the Korean government. The investigators reported no potential conflicts of interest.

Micrograph showing MM

Preclinical research suggests an AKT inhibitor could be effective against multiple myeloma (MM).

The inhibitor, HS1793, is a derivative of the antioxidant compound resveratrol.

Investigators found that HS1793 decreased AKT signaling to induce mitochondria-mediated cell death in MM cells.

HS1793 was cytotoxic to MM cells in a mouse model of human metastatic myeloma and in human MM cells in vitro.

Jin Han, MD, PhD, of Inje University in Busan, South Korea, and colleagues reported these results in Cancer Letters.

“AKT is frequently activated in MM cells, and the incidence of AKT activation correlates positively with disease activity,” the authors noted.

They had screened 400 compounds and identified HS1793 as the most promising AKT inhibitor. Experiments suggested that HS1793 inhibits AKT activation by interfering with the interaction between AKT and its promoter, HSP90.

HS1793 exhibited antimyeloma activity in human MM cell lines. The investigators said this appeared to be from a dose-dependent effect that allowed for mitochondria-mediated programmed cell death.

In additional experiments, the team found that HS1793’s inhibition of AKT/HSP90 interaction results in cell death by suppressing NF-κB signaling. HS1793-induced cell death was caused by the direct inhibition of AKT that, in turn, suppressed NF-κB activation.

The investigators found that HS1793 “dramatically decreased” lytic skull and femur lesions in a mouse model of MM metastatic to bone. And mice that received HS1793 had superior survival, when compared to mice that received vehicle control.

The investigators also showed that HS1793 was cytotoxic to MM cells but not normal plasma cells isolated from patients with MM.

“Given that HS1793 treatment specifically induced the death of primary and relapsed MM cells, HS1793 offers excellent translational potential as a novel MM therapy,” the authors wrote.

This research was supported by grants from the Korean government. The investigators reported no potential conflicts of interest.

Micrograph showing MM

Preclinical research suggests an AKT inhibitor could be effective against multiple myeloma (MM).

The inhibitor, HS1793, is a derivative of the antioxidant compound resveratrol.

Investigators found that HS1793 decreased AKT signaling to induce mitochondria-mediated cell death in MM cells.

HS1793 was cytotoxic to MM cells in a mouse model of human metastatic myeloma and in human MM cells in vitro.

Jin Han, MD, PhD, of Inje University in Busan, South Korea, and colleagues reported these results in Cancer Letters.

“AKT is frequently activated in MM cells, and the incidence of AKT activation correlates positively with disease activity,” the authors noted.

They had screened 400 compounds and identified HS1793 as the most promising AKT inhibitor. Experiments suggested that HS1793 inhibits AKT activation by interfering with the interaction between AKT and its promoter, HSP90.

HS1793 exhibited antimyeloma activity in human MM cell lines. The investigators said this appeared to be from a dose-dependent effect that allowed for mitochondria-mediated programmed cell death.

In additional experiments, the team found that HS1793’s inhibition of AKT/HSP90 interaction results in cell death by suppressing NF-κB signaling. HS1793-induced cell death was caused by the direct inhibition of AKT that, in turn, suppressed NF-κB activation.

The investigators found that HS1793 “dramatically decreased” lytic skull and femur lesions in a mouse model of MM metastatic to bone. And mice that received HS1793 had superior survival, when compared to mice that received vehicle control.

The investigators also showed that HS1793 was cytotoxic to MM cells but not normal plasma cells isolated from patients with MM.

“Given that HS1793 treatment specifically induced the death of primary and relapsed MM cells, HS1793 offers excellent translational potential as a novel MM therapy,” the authors wrote.

This research was supported by grants from the Korean government. The investigators reported no potential conflicts of interest.

In patients with renal cell carcinoma, high levels of the inflammation marker C-reactive protein may signal the presence of an immunosuppressive tumor microenvironment, a feature associated with poor prognosis, investigators contend.

Among 111 patients with renal cell carcinoma (RCC) treated with either partial or radical nephrectomy, those with high C-reactive protein (CRP) levels had significantly worse cancer-specific survival (CSS) compared with patients with normal CRP levels, and CRP levels were significantly higher among patients whose tumors showed strong infiltration of immune-suppressor cells, reported Takayuki Nakayama, MD, of Tokyo Medical and Dental Graduate University in Japan, and his colleagues.

“We have found that CRP level is positively associated with the infiltration of Treg and M2 macrophage[s] in patients with RCC, indicating that CRP reflects an immunosuppressive microenvironment. However, further studies are required to confirm these findings and provide a better understanding of the association between host systemic inflammation and the immunosuppressive microenvironment,” they wrote in Clinical Genitourinary Cancer.

The investigators had previously proposed CRP as a biomarker for urologic malignancies, including RCC. The current study was designed to look at the association between CRP and the tumor microenvironment, and to determine whether serum CRP levels correlate with prognosis.

To do this, they performed immunohistochemistry studies of immune cells, including immunosuppressive M2 macrophages (CD4, CD8, and CD163 cells) and Foxp4 regulatory T cells (Tregs) on resected renal tissues from 111 patients with RCC treated in their center.

They found that 33 of the 111 patients (30%) had high CRP levels, defined as 0.5 mg/L or greater. These patients had a 5-year CSS rate of 51%, compared with 91% for patients with CRP levels below the 0.5 mg/L cutoff (P less than .001).

They also found that tumors with strong infiltration of M2 macrophages had significantly worse disease and poorer prognoses. For example, patients with strong infiltration of CD163-positive cells had higher tumor and nodal stages, as well as higher rates of distant metastases and higher Fuhrman nuclear grade (respective P values less than .001, = .003, less than .001, and = .008).

CRP levels were significantly higher among patients with strong infiltration of CD8-positive cells (P = .041), Foxp3-positive cells (P = .001), or CD163-positive (P = .035). These patients also had significantly worse CSS compared with patients with weak tumor infiltration of the respective cells (P = .040, P = .026, and P less than .001, respectively).

Independent prognostic factors for CSS in multivariate analysis included strong CD163-positive cell infiltration (P =.001), pathologic stage T3 (P = .036), lymph-node involvement (P = .007), distant metastasis (P less than .001), and Fuhrman nuclear grade 4 (P = .003).

The authors acknowledged that the study was limited by its retrospective design, small sample size, and limited analysis of components of the tumor microenvironment.

The study was supported by the Japan Society for the Promotion of Science. The authors reported having no conflicts of interest to disclose.

SOURCE: Nakayama T et al. Clin Genitourin Cancer. 2018 Aug 11. doi: 10.1016/j.clgc.2018.07.027.

In patients with renal cell carcinoma, high levels of the inflammation marker C-reactive protein may signal the presence of an immunosuppressive tumor microenvironment, a feature associated with poor prognosis, investigators contend.

Among 111 patients with renal cell carcinoma (RCC) treated with either partial or radical nephrectomy, those with high C-reactive protein (CRP) levels had significantly worse cancer-specific survival (CSS) compared with patients with normal CRP levels, and CRP levels were significantly higher among patients whose tumors showed strong infiltration of immune-suppressor cells, reported Takayuki Nakayama, MD, of Tokyo Medical and Dental Graduate University in Japan, and his colleagues.

“We have found that CRP level is positively associated with the infiltration of Treg and M2 macrophage[s] in patients with RCC, indicating that CRP reflects an immunosuppressive microenvironment. However, further studies are required to confirm these findings and provide a better understanding of the association between host systemic inflammation and the immunosuppressive microenvironment,” they wrote in Clinical Genitourinary Cancer.

The investigators had previously proposed CRP as a biomarker for urologic malignancies, including RCC. The current study was designed to look at the association between CRP and the tumor microenvironment, and to determine whether serum CRP levels correlate with prognosis.

To do this, they performed immunohistochemistry studies of immune cells, including immunosuppressive M2 macrophages (CD4, CD8, and CD163 cells) and Foxp4 regulatory T cells (Tregs) on resected renal tissues from 111 patients with RCC treated in their center.

They found that 33 of the 111 patients (30%) had high CRP levels, defined as 0.5 mg/L or greater. These patients had a 5-year CSS rate of 51%, compared with 91% for patients with CRP levels below the 0.5 mg/L cutoff (P less than .001).

They also found that tumors with strong infiltration of M2 macrophages had significantly worse disease and poorer prognoses. For example, patients with strong infiltration of CD163-positive cells had higher tumor and nodal stages, as well as higher rates of distant metastases and higher Fuhrman nuclear grade (respective P values less than .001, = .003, less than .001, and = .008).

CRP levels were significantly higher among patients with strong infiltration of CD8-positive cells (P = .041), Foxp3-positive cells (P = .001), or CD163-positive (P = .035). These patients also had significantly worse CSS compared with patients with weak tumor infiltration of the respective cells (P = .040, P = .026, and P less than .001, respectively).

Independent prognostic factors for CSS in multivariate analysis included strong CD163-positive cell infiltration (P =.001), pathologic stage T3 (P = .036), lymph-node involvement (P = .007), distant metastasis (P less than .001), and Fuhrman nuclear grade 4 (P = .003).

The authors acknowledged that the study was limited by its retrospective design, small sample size, and limited analysis of components of the tumor microenvironment.

The study was supported by the Japan Society for the Promotion of Science. The authors reported having no conflicts of interest to disclose.

SOURCE: Nakayama T et al. Clin Genitourin Cancer. 2018 Aug 11. doi: 10.1016/j.clgc.2018.07.027.

In patients with renal cell carcinoma, high levels of the inflammation marker C-reactive protein may signal the presence of an immunosuppressive tumor microenvironment, a feature associated with poor prognosis, investigators contend.

Among 111 patients with renal cell carcinoma (RCC) treated with either partial or radical nephrectomy, those with high C-reactive protein (CRP) levels had significantly worse cancer-specific survival (CSS) compared with patients with normal CRP levels, and CRP levels were significantly higher among patients whose tumors showed strong infiltration of immune-suppressor cells, reported Takayuki Nakayama, MD, of Tokyo Medical and Dental Graduate University in Japan, and his colleagues.

“We have found that CRP level is positively associated with the infiltration of Treg and M2 macrophage[s] in patients with RCC, indicating that CRP reflects an immunosuppressive microenvironment. However, further studies are required to confirm these findings and provide a better understanding of the association between host systemic inflammation and the immunosuppressive microenvironment,” they wrote in Clinical Genitourinary Cancer.

The investigators had previously proposed CRP as a biomarker for urologic malignancies, including RCC. The current study was designed to look at the association between CRP and the tumor microenvironment, and to determine whether serum CRP levels correlate with prognosis.

To do this, they performed immunohistochemistry studies of immune cells, including immunosuppressive M2 macrophages (CD4, CD8, and CD163 cells) and Foxp4 regulatory T cells (Tregs) on resected renal tissues from 111 patients with RCC treated in their center.

They found that 33 of the 111 patients (30%) had high CRP levels, defined as 0.5 mg/L or greater. These patients had a 5-year CSS rate of 51%, compared with 91% for patients with CRP levels below the 0.5 mg/L cutoff (P less than .001).

They also found that tumors with strong infiltration of M2 macrophages had significantly worse disease and poorer prognoses. For example, patients with strong infiltration of CD163-positive cells had higher tumor and nodal stages, as well as higher rates of distant metastases and higher Fuhrman nuclear grade (respective P values less than .001, = .003, less than .001, and = .008).

CRP levels were significantly higher among patients with strong infiltration of CD8-positive cells (P = .041), Foxp3-positive cells (P = .001), or CD163-positive (P = .035). These patients also had significantly worse CSS compared with patients with weak tumor infiltration of the respective cells (P = .040, P = .026, and P less than .001, respectively).

Independent prognostic factors for CSS in multivariate analysis included strong CD163-positive cell infiltration (P =.001), pathologic stage T3 (P = .036), lymph-node involvement (P = .007), distant metastasis (P less than .001), and Fuhrman nuclear grade 4 (P = .003).

The authors acknowledged that the study was limited by its retrospective design, small sample size, and limited analysis of components of the tumor microenvironment.

The study was supported by the Japan Society for the Promotion of Science. The authors reported having no conflicts of interest to disclose.

SOURCE: Nakayama T et al. Clin Genitourin Cancer. 2018 Aug 11. doi: 10.1016/j.clgc.2018.07.027.

Photo by Chad McNeeley

Gene sequencing early after transplant may provide important prognostic information in patients with myelodysplastic syndromes (MDS), according to a new study.

Patients who had disease-associated mutations in the bone marrow 30 days after hematopoietic stem cell transplant (HSCT) were significantly more likely to experience disease progression and have lower rates of progression-free survival (PFS) at 1 year.

“Using our sequencing method, we’re identifying residual tumor cells before a pathologist could see them under the microscope and before a patient develops symptoms,” said Matthew J. Walter, MD, of Washington University in St. Louis, Mo.

“At that moment, there may be time to intervene in ways that could delay the cancer from coming back or potentially prevent it completely.”

Dr. Walter and his colleagues described results with their sequencing method in The New England Journal of Medicine.

The researchers sequenced bone marrow and skin (control) samples from 90 adults with MDS who underwent allogeneic HSCT.

The team used enhanced exome sequencing to detect mutations before HSCT and evaluated mutation clearance using error-corrected sequencing to genotype mutations in bone marrow samples collected 30 days after HSCT.

The researchers detected at least one validated somatic mutation in the pre-HSCT samples from 86 of 90 patients.

Of the 86 patients, 32 had at least one mutation with a maximum variant allele frequency of at least 0.5% detected 30 days after HSCT. The frequency is equivalent to 1 heterozygous mutant cell per 100 cells, the researchers explained.

Patients who experienced disease progression had mutations with a median maximum variant allele frequency of 0.9%, compared with 0% for patients who did not progress (P<0.001).

Progression occurred in 53.1% of patients who had one or more mutations with a variant allele frequency of at least 0.5% at 30 days, whereas progression occurred in 13% of patients who did not have such mutations. After adjusting for conditioning regimen, the hazard ratio (HR) for disease progression in the patients with mutations was 3.86 (P<0.001).

The 1-year PFS rate was 31.3% in patients who had one or more mutations with a variant allele frequency of at least 0.5% at 30 days and 59.3% in patients who did not have the mutations. After adjusting for conditioning, the HR for progression or death was 2.22 (P=0.005).

The researchers noted that PFS was lower in patients who had received reduced-intensity conditioning and had at least one persistent mutation with a variant allele frequency of at least 0.5% at day 30 (P≤0.001), when compared to other combinations of conditioning regimen and mutation status.

In multivariable analyses, the presence of a mutation with at least 0.5% variant allele frequency was associated with a more than four-fold risk of progression (HR, 4.48; P<0.001) and a more than two-fold risk of progression or death (HR, 2.39; P=0.002).

“Now that we have detected mutations early and shown that it predicts a higher risk of recurrence, we want to determine the best course of action for those high-risk patients,” Dr. Walter said.

He and his colleagues acknowledged that the high-coverage exome sequencing technique used for this study is not routinely available in the clinic. Therefore, the researchers also analyzed samples using a subset of genes that are usually included in gene sequencing panels for MDS and acute myeloid leukemia.

The researchers noted that this 40-gene panel revealed fewer patients (n=68; 79%) with mutations, but “the prognostic value of detection of measurable residual disease was still highly clinically significant.”

With this approach, the presence of at least one mutation with a variant allele frequency of at least 0.5% 30 days after HSCT was associated with a higher risk of disease progression at 1 year (HR, 3.39; P=0.001) and a higher risk of progression or death at 1 year (HR, 2.09; P=0.02).

This study was supported by grants from the Leukemia and Lymphoma Society and other groups.

Photo by Chad McNeeley

Gene sequencing early after transplant may provide important prognostic information in patients with myelodysplastic syndromes (MDS), according to a new study.

Patients who had disease-associated mutations in the bone marrow 30 days after hematopoietic stem cell transplant (HSCT) were significantly more likely to experience disease progression and have lower rates of progression-free survival (PFS) at 1 year.

“Using our sequencing method, we’re identifying residual tumor cells before a pathologist could see them under the microscope and before a patient develops symptoms,” said Matthew J. Walter, MD, of Washington University in St. Louis, Mo.

“At that moment, there may be time to intervene in ways that could delay the cancer from coming back or potentially prevent it completely.”

Dr. Walter and his colleagues described results with their sequencing method in The New England Journal of Medicine.

The researchers sequenced bone marrow and skin (control) samples from 90 adults with MDS who underwent allogeneic HSCT.

The team used enhanced exome sequencing to detect mutations before HSCT and evaluated mutation clearance using error-corrected sequencing to genotype mutations in bone marrow samples collected 30 days after HSCT.

The researchers detected at least one validated somatic mutation in the pre-HSCT samples from 86 of 90 patients.

Of the 86 patients, 32 had at least one mutation with a maximum variant allele frequency of at least 0.5% detected 30 days after HSCT. The frequency is equivalent to 1 heterozygous mutant cell per 100 cells, the researchers explained.

Patients who experienced disease progression had mutations with a median maximum variant allele frequency of 0.9%, compared with 0% for patients who did not progress (P<0.001).

Progression occurred in 53.1% of patients who had one or more mutations with a variant allele frequency of at least 0.5% at 30 days, whereas progression occurred in 13% of patients who did not have such mutations. After adjusting for conditioning regimen, the hazard ratio (HR) for disease progression in the patients with mutations was 3.86 (P<0.001).

The 1-year PFS rate was 31.3% in patients who had one or more mutations with a variant allele frequency of at least 0.5% at 30 days and 59.3% in patients who did not have the mutations. After adjusting for conditioning, the HR for progression or death was 2.22 (P=0.005).

The researchers noted that PFS was lower in patients who had received reduced-intensity conditioning and had at least one persistent mutation with a variant allele frequency of at least 0.5% at day 30 (P≤0.001), when compared to other combinations of conditioning regimen and mutation status.

In multivariable analyses, the presence of a mutation with at least 0.5% variant allele frequency was associated with a more than four-fold risk of progression (HR, 4.48; P<0.001) and a more than two-fold risk of progression or death (HR, 2.39; P=0.002).

“Now that we have detected mutations early and shown that it predicts a higher risk of recurrence, we want to determine the best course of action for those high-risk patients,” Dr. Walter said.

He and his colleagues acknowledged that the high-coverage exome sequencing technique used for this study is not routinely available in the clinic. Therefore, the researchers also analyzed samples using a subset of genes that are usually included in gene sequencing panels for MDS and acute myeloid leukemia.

The researchers noted that this 40-gene panel revealed fewer patients (n=68; 79%) with mutations, but “the prognostic value of detection of measurable residual disease was still highly clinically significant.”

With this approach, the presence of at least one mutation with a variant allele frequency of at least 0.5% 30 days after HSCT was associated with a higher risk of disease progression at 1 year (HR, 3.39; P=0.001) and a higher risk of progression or death at 1 year (HR, 2.09; P=0.02).

This study was supported by grants from the Leukemia and Lymphoma Society and other groups.

Photo by Chad McNeeley

Gene sequencing early after transplant may provide important prognostic information in patients with myelodysplastic syndromes (MDS), according to a new study.

Patients who had disease-associated mutations in the bone marrow 30 days after hematopoietic stem cell transplant (HSCT) were significantly more likely to experience disease progression and have lower rates of progression-free survival (PFS) at 1 year.

“Using our sequencing method, we’re identifying residual tumor cells before a pathologist could see them under the microscope and before a patient develops symptoms,” said Matthew J. Walter, MD, of Washington University in St. Louis, Mo.

“At that moment, there may be time to intervene in ways that could delay the cancer from coming back or potentially prevent it completely.”

Dr. Walter and his colleagues described results with their sequencing method in The New England Journal of Medicine.

The researchers sequenced bone marrow and skin (control) samples from 90 adults with MDS who underwent allogeneic HSCT.

The team used enhanced exome sequencing to detect mutations before HSCT and evaluated mutation clearance using error-corrected sequencing to genotype mutations in bone marrow samples collected 30 days after HSCT.

The researchers detected at least one validated somatic mutation in the pre-HSCT samples from 86 of 90 patients.

Of the 86 patients, 32 had at least one mutation with a maximum variant allele frequency of at least 0.5% detected 30 days after HSCT. The frequency is equivalent to 1 heterozygous mutant cell per 100 cells, the researchers explained.

Patients who experienced disease progression had mutations with a median maximum variant allele frequency of 0.9%, compared with 0% for patients who did not progress (P<0.001).

Progression occurred in 53.1% of patients who had one or more mutations with a variant allele frequency of at least 0.5% at 30 days, whereas progression occurred in 13% of patients who did not have such mutations. After adjusting for conditioning regimen, the hazard ratio (HR) for disease progression in the patients with mutations was 3.86 (P<0.001).

The 1-year PFS rate was 31.3% in patients who had one or more mutations with a variant allele frequency of at least 0.5% at 30 days and 59.3% in patients who did not have the mutations. After adjusting for conditioning, the HR for progression or death was 2.22 (P=0.005).

The researchers noted that PFS was lower in patients who had received reduced-intensity conditioning and had at least one persistent mutation with a variant allele frequency of at least 0.5% at day 30 (P≤0.001), when compared to other combinations of conditioning regimen and mutation status.

In multivariable analyses, the presence of a mutation with at least 0.5% variant allele frequency was associated with a more than four-fold risk of progression (HR, 4.48; P<0.001) and a more than two-fold risk of progression or death (HR, 2.39; P=0.002).

“Now that we have detected mutations early and shown that it predicts a higher risk of recurrence, we want to determine the best course of action for those high-risk patients,” Dr. Walter said.

He and his colleagues acknowledged that the high-coverage exome sequencing technique used for this study is not routinely available in the clinic. Therefore, the researchers also analyzed samples using a subset of genes that are usually included in gene sequencing panels for MDS and acute myeloid leukemia.

The researchers noted that this 40-gene panel revealed fewer patients (n=68; 79%) with mutations, but “the prognostic value of detection of measurable residual disease was still highly clinically significant.”

With this approach, the presence of at least one mutation with a variant allele frequency of at least 0.5% 30 days after HSCT was associated with a higher risk of disease progression at 1 year (HR, 3.39; P=0.001) and a higher risk of progression or death at 1 year (HR, 2.09; P=0.02).

This study was supported by grants from the Leukemia and Lymphoma Society and other groups.

The combination of a targeted antiangiogenic agent and denosumab (Xgeva) appears to significantly increase the risk for osteonecrosis of the jaw in patients with metastatic renal cell carcinoma (mRCC), French investigators cautioned.

Among 41 patients with RCC metastatic to bone treated with an antiangiogenic agent and denosumab, 7 (17%) developed osteonecrosis of the jaw (ONJ). All seven received the combination in the first line, reported Aline Guillot, MD, from the Institut de cancérologie Lucien Neuwirth in Saint-Priest-en-Jarez, France, and her colleagues.

“The incidence of ONJ was high in this real-life population of patients with mRCC treated with antiangiogenic therapies combined with denosumab. This toxicity signal should warn physicians about this combination in the mRCC population,” they wrote in Clinical Genitourinary Cancer.

Previous studies have shown that the combination of another bone-targeted therapy – zoledronic acid – with antiangiogenic tyrosine kinase inhibitors (TKIs) such as sunitinib (Sutent) is associated with increased risk for ONJ. In addition, ONJ with the combination of denosumab and antiangiogenic therapies “has been noticed but never estimated,” the authors noted.

To evaluate the incidence of hypocalcemia and ONJ in patients with RCC metastatic to bone treated with denosumab and a TKI or mammalian target of rapamycin inhibitor, the investigators gathered data retrospectively from 10 French centers.

They identified 25 men and 16 women with a median age of 62 years (range, 54-68 years). Of this group, 40 received denosumab in the first line in combination with either sunitinib (31 patients), pazopanib (6), everolimus (Afinitor and generics; 2), and temsirolimus (Torisel and generics; 1). The median duration of first-line therapy was 12 months.

Denosumab was given in the second line with axitinib (Inlyta) to nine patients, with everolimus to nine, and with sunitinib to three patients. The median duration of second-line therapy was 3 months.

Skeletal-related events occurred in 41% of patients prior to receiving denosumab and in 61% (25 patients) after denosumab. The events included clinical fracture, bone pain requiring radiation, and spinal compression.

Of the seven patients who developed ONJ, six received denosumab and sunitinib in the first line and one received denosumab plus temsirolimus, with a median duration of treatment of 11.8 months. Three of these patients also received denosumab in the second line with either axitinib, everolimus, or sunitinib, with a median duration of 9.8 months. Data on second-line therapy for the remaining four patients with ONJ were not available.

The investigators noted that the 17% incidence of ONJ was higher than the 10% rate seen in a study of patients with mRCC treated with a TKI and a bisphosphonate (Acta Clin Belg. 2018 Apr;73(2):100-9), and the 1.8% incidence seen in an analysis of three phase 3 trials in cancer patients with bone metastases (Ann Oncol. 2012 May;23(5):1341-7).

Although the etiology of ONJ is unknown, patient education and oral hygiene may reduce the risk in patients treated with denosumab and a TKI.

“The benefit of denosumab in this setting in regard [to] toxicity needs to be demonstrated in a prospective trial,” they wrote.

No conflicts of interest or disclosures were reported.

SOURCE: Guillot A et al. Clin Genitourin Cancer. 2018 Sep 6. doi: 10.1016/j.clgc.2018.08.006.

The combination of a targeted antiangiogenic agent and denosumab (Xgeva) appears to significantly increase the risk for osteonecrosis of the jaw in patients with metastatic renal cell carcinoma (mRCC), French investigators cautioned.

Among 41 patients with RCC metastatic to bone treated with an antiangiogenic agent and denosumab, 7 (17%) developed osteonecrosis of the jaw (ONJ). All seven received the combination in the first line, reported Aline Guillot, MD, from the Institut de cancérologie Lucien Neuwirth in Saint-Priest-en-Jarez, France, and her colleagues.

“The incidence of ONJ was high in this real-life population of patients with mRCC treated with antiangiogenic therapies combined with denosumab. This toxicity signal should warn physicians about this combination in the mRCC population,” they wrote in Clinical Genitourinary Cancer.

Previous studies have shown that the combination of another bone-targeted therapy – zoledronic acid – with antiangiogenic tyrosine kinase inhibitors (TKIs) such as sunitinib (Sutent) is associated with increased risk for ONJ. In addition, ONJ with the combination of denosumab and antiangiogenic therapies “has been noticed but never estimated,” the authors noted.

To evaluate the incidence of hypocalcemia and ONJ in patients with RCC metastatic to bone treated with denosumab and a TKI or mammalian target of rapamycin inhibitor, the investigators gathered data retrospectively from 10 French centers.

They identified 25 men and 16 women with a median age of 62 years (range, 54-68 years). Of this group, 40 received denosumab in the first line in combination with either sunitinib (31 patients), pazopanib (6), everolimus (Afinitor and generics; 2), and temsirolimus (Torisel and generics; 1). The median duration of first-line therapy was 12 months.

Denosumab was given in the second line with axitinib (Inlyta) to nine patients, with everolimus to nine, and with sunitinib to three patients. The median duration of second-line therapy was 3 months.

Skeletal-related events occurred in 41% of patients prior to receiving denosumab and in 61% (25 patients) after denosumab. The events included clinical fracture, bone pain requiring radiation, and spinal compression.

Of the seven patients who developed ONJ, six received denosumab and sunitinib in the first line and one received denosumab plus temsirolimus, with a median duration of treatment of 11.8 months. Three of these patients also received denosumab in the second line with either axitinib, everolimus, or sunitinib, with a median duration of 9.8 months. Data on second-line therapy for the remaining four patients with ONJ were not available.

The investigators noted that the 17% incidence of ONJ was higher than the 10% rate seen in a study of patients with mRCC treated with a TKI and a bisphosphonate (Acta Clin Belg. 2018 Apr;73(2):100-9), and the 1.8% incidence seen in an analysis of three phase 3 trials in cancer patients with bone metastases (Ann Oncol. 2012 May;23(5):1341-7).

Although the etiology of ONJ is unknown, patient education and oral hygiene may reduce the risk in patients treated with denosumab and a TKI.

“The benefit of denosumab in this setting in regard [to] toxicity needs to be demonstrated in a prospective trial,” they wrote.

No conflicts of interest or disclosures were reported.

SOURCE: Guillot A et al. Clin Genitourin Cancer. 2018 Sep 6. doi: 10.1016/j.clgc.2018.08.006.

The combination of a targeted antiangiogenic agent and denosumab (Xgeva) appears to significantly increase the risk for osteonecrosis of the jaw in patients with metastatic renal cell carcinoma (mRCC), French investigators cautioned.

Among 41 patients with RCC metastatic to bone treated with an antiangiogenic agent and denosumab, 7 (17%) developed osteonecrosis of the jaw (ONJ). All seven received the combination in the first line, reported Aline Guillot, MD, from the Institut de cancérologie Lucien Neuwirth in Saint-Priest-en-Jarez, France, and her colleagues.

“The incidence of ONJ was high in this real-life population of patients with mRCC treated with antiangiogenic therapies combined with denosumab. This toxicity signal should warn physicians about this combination in the mRCC population,” they wrote in Clinical Genitourinary Cancer.

Previous studies have shown that the combination of another bone-targeted therapy – zoledronic acid – with antiangiogenic tyrosine kinase inhibitors (TKIs) such as sunitinib (Sutent) is associated with increased risk for ONJ. In addition, ONJ with the combination of denosumab and antiangiogenic therapies “has been noticed but never estimated,” the authors noted.

To evaluate the incidence of hypocalcemia and ONJ in patients with RCC metastatic to bone treated with denosumab and a TKI or mammalian target of rapamycin inhibitor, the investigators gathered data retrospectively from 10 French centers.

They identified 25 men and 16 women with a median age of 62 years (range, 54-68 years). Of this group, 40 received denosumab in the first line in combination with either sunitinib (31 patients), pazopanib (6), everolimus (Afinitor and generics; 2), and temsirolimus (Torisel and generics; 1). The median duration of first-line therapy was 12 months.

Denosumab was given in the second line with axitinib (Inlyta) to nine patients, with everolimus to nine, and with sunitinib to three patients. The median duration of second-line therapy was 3 months.

Skeletal-related events occurred in 41% of patients prior to receiving denosumab and in 61% (25 patients) after denosumab. The events included clinical fracture, bone pain requiring radiation, and spinal compression.

Of the seven patients who developed ONJ, six received denosumab and sunitinib in the first line and one received denosumab plus temsirolimus, with a median duration of treatment of 11.8 months. Three of these patients also received denosumab in the second line with either axitinib, everolimus, or sunitinib, with a median duration of 9.8 months. Data on second-line therapy for the remaining four patients with ONJ were not available.

The investigators noted that the 17% incidence of ONJ was higher than the 10% rate seen in a study of patients with mRCC treated with a TKI and a bisphosphonate (Acta Clin Belg. 2018 Apr;73(2):100-9), and the 1.8% incidence seen in an analysis of three phase 3 trials in cancer patients with bone metastases (Ann Oncol. 2012 May;23(5):1341-7).

Although the etiology of ONJ is unknown, patient education and oral hygiene may reduce the risk in patients treated with denosumab and a TKI.

“The benefit of denosumab in this setting in regard [to] toxicity needs to be demonstrated in a prospective trial,” they wrote.

No conflicts of interest or disclosures were reported.

SOURCE: Guillot A et al. Clin Genitourin Cancer. 2018 Sep 6. doi: 10.1016/j.clgc.2018.08.006.

Signs of efficacy of anti-cancer therapies may be only skin deep, results of a retrospective review indicate.

Cutaneous toxicities such as vitiligo, rash, alopecia, and nail toxicities may be early signs of efficacy of targeted therapies, immunotherapy, or cytotoxic chemotherapy, according to Alexandra K. Rzepecki, of the University of Michigan, and her coauthors from Albert Einstein Medical College in the Bronx, New York.

“Because cutaneous toxicities are a clinically visible parameter, they may alert clinicians to the possibility of treatment success or failure in a rapid, cost-effective, and noninvasive manner,” they wrote. The report is in the Journal of the American Academy of Dermatology.

The investigators reviewed the medical literature for clinical studies of three major classes of anti-cancer therapies that included data on associations between cutaneous toxicities and clinical outcomes such progression-free survival (PFS) overall survival (OS).

The drug classes and their associations with cutaneous toxicities and clinical outcomes were as follows:

• Targeted therapies, including tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR) such as cetuximab (Erbitux) and erlotinib (Tarceva), and multikinase targeted agents such as sorafenib (Nexavar) and sunitinib (Sutent). Toxicities associated with clinical benefit from EGFR inhibitors include rash, xerosis, leukocytoclastic vasculitis, paronychia, and pruritus, whereas skin toxicities associated with the multikinase inhibitors trended toward the hand-foot syndrome and hand-foot skin reaction.
• Immunotherapies included blockers of cytotoxic T-lymphocyte associated protein 4 (CTLA4) such as ipilimumab (Yervoy) and inhibitors of programmed death 1 protein (PD-1) and its ligand 1 (PD-L1) such as nivolumab (Opdivo), pembrolizumab (Keytruda), and atezolizumab (Tecentriq). In studies of pembrolizumab for various malignancies, rash or vitiligo was an independent prognostic factor for longer OS, a higher proportion of objective responses, and longer PFS. Similar associations were seen with nivolumab, with the additional association of hair repigmentation among patients with non–small-cell lung cancer being associated with stable disease responses or better. Among patients with melanoma treated with ipilimumab, hair depigmentation correlated with durable responses.
• Cytotoxic chemotherapy agents included the anthracycline doxorubicin, taxanes such as paclitaxel and docetaxel, platinum agents (cisplatin and carboplatin), and fluoropyrimidines such as capecitabine. Patients treated for various cancers with doxorubicin who had alopecia were significantly more likely to have clinical remissions than were patients who did not lose their hair, and patients treated with this agent who developed hand-foot syndrome had significantly longer PFS. For patients treated with docetaxel, severity of nail changes and/or development of nail alterations were associated with both improved OS and PFS. Patients treated with the combination of paclitaxel and a platinum agent who developed grade 2 or greater alopecia up to cycle 3 had significantly longer OS than did patients who had hair loss later in the course of therapy. Patients treated with capecitabine who developed had hand-foot skin reactions had improved progression-free and disease-free survival.

“Although further studies are needed to better evaluate these promising associations, vigilant monitoring of cutaneous toxicities should be a priority, as their development may indicate a favorable response to treatment. Dermatologists have a unique opportunity to collaborate with oncologists to help identify and manage these toxicities, thereby allowing patients to receive life-prolonging anticancer therapy while minimizing dose reduction or interruption of their treatment,” the authors wrote.

They reported no study funding source and no conflicts of interest.

SOURCE: Rzepecki A, et al. J Am Acad Dermatol. 2018;79:545-555.

Signs of efficacy of anti-cancer therapies may be only skin deep, results of a retrospective review indicate.

Cutaneous toxicities such as vitiligo, rash, alopecia, and nail toxicities may be early signs of efficacy of targeted therapies, immunotherapy, or cytotoxic chemotherapy, according to Alexandra K. Rzepecki, of the University of Michigan, and her coauthors from Albert Einstein Medical College in the Bronx, New York.

“Because cutaneous toxicities are a clinically visible parameter, they may alert clinicians to the possibility of treatment success or failure in a rapid, cost-effective, and noninvasive manner,” they wrote. The report is in the Journal of the American Academy of Dermatology.

The investigators reviewed the medical literature for clinical studies of three major classes of anti-cancer therapies that included data on associations between cutaneous toxicities and clinical outcomes such progression-free survival (PFS) overall survival (OS).

The drug classes and their associations with cutaneous toxicities and clinical outcomes were as follows:

• Targeted therapies, including tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR) such as cetuximab (Erbitux) and erlotinib (Tarceva), and multikinase targeted agents such as sorafenib (Nexavar) and sunitinib (Sutent). Toxicities associated with clinical benefit from EGFR inhibitors include rash, xerosis, leukocytoclastic vasculitis, paronychia, and pruritus, whereas skin toxicities associated with the multikinase inhibitors trended toward the hand-foot syndrome and hand-foot skin reaction.
• Immunotherapies included blockers of cytotoxic T-lymphocyte associated protein 4 (CTLA4) such as ipilimumab (Yervoy) and inhibitors of programmed death 1 protein (PD-1) and its ligand 1 (PD-L1) such as nivolumab (Opdivo), pembrolizumab (Keytruda), and atezolizumab (Tecentriq). In studies of pembrolizumab for various malignancies, rash or vitiligo was an independent prognostic factor for longer OS, a higher proportion of objective responses, and longer PFS. Similar associations were seen with nivolumab, with the additional association of hair repigmentation among patients with non–small-cell lung cancer being associated with stable disease responses or better. Among patients with melanoma treated with ipilimumab, hair depigmentation correlated with durable responses.
• Cytotoxic chemotherapy agents included the anthracycline doxorubicin, taxanes such as paclitaxel and docetaxel, platinum agents (cisplatin and carboplatin), and fluoropyrimidines such as capecitabine. Patients treated for various cancers with doxorubicin who had alopecia were significantly more likely to have clinical remissions than were patients who did not lose their hair, and patients treated with this agent who developed hand-foot syndrome had significantly longer PFS. For patients treated with docetaxel, severity of nail changes and/or development of nail alterations were associated with both improved OS and PFS. Patients treated with the combination of paclitaxel and a platinum agent who developed grade 2 or greater alopecia up to cycle 3 had significantly longer OS than did patients who had hair loss later in the course of therapy. Patients treated with capecitabine who developed had hand-foot skin reactions had improved progression-free and disease-free survival.

“Although further studies are needed to better evaluate these promising associations, vigilant monitoring of cutaneous toxicities should be a priority, as their development may indicate a favorable response to treatment. Dermatologists have a unique opportunity to collaborate with oncologists to help identify and manage these toxicities, thereby allowing patients to receive life-prolonging anticancer therapy while minimizing dose reduction or interruption of their treatment,” the authors wrote.

They reported no study funding source and no conflicts of interest.

SOURCE: Rzepecki A, et al. J Am Acad Dermatol. 2018;79:545-555.

Signs of efficacy of anti-cancer therapies may be only skin deep, results of a retrospective review indicate.

Cutaneous toxicities such as vitiligo, rash, alopecia, and nail toxicities may be early signs of efficacy of targeted therapies, immunotherapy, or cytotoxic chemotherapy, according to Alexandra K. Rzepecki, of the University of Michigan, and her coauthors from Albert Einstein Medical College in the Bronx, New York.

“Because cutaneous toxicities are a clinically visible parameter, they may alert clinicians to the possibility of treatment success or failure in a rapid, cost-effective, and noninvasive manner,” they wrote. The report is in the Journal of the American Academy of Dermatology.

The investigators reviewed the medical literature for clinical studies of three major classes of anti-cancer therapies that included data on associations between cutaneous toxicities and clinical outcomes such progression-free survival (PFS) overall survival (OS).

The drug classes and their associations with cutaneous toxicities and clinical outcomes were as follows:

• Targeted therapies, including tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR) such as cetuximab (Erbitux) and erlotinib (Tarceva), and multikinase targeted agents such as sorafenib (Nexavar) and sunitinib (Sutent). Toxicities associated with clinical benefit from EGFR inhibitors include rash, xerosis, leukocytoclastic vasculitis, paronychia, and pruritus, whereas skin toxicities associated with the multikinase inhibitors trended toward the hand-foot syndrome and hand-foot skin reaction.
• Immunotherapies included blockers of cytotoxic T-lymphocyte associated protein 4 (CTLA4) such as ipilimumab (Yervoy) and inhibitors of programmed death 1 protein (PD-1) and its ligand 1 (PD-L1) such as nivolumab (Opdivo), pembrolizumab (Keytruda), and atezolizumab (Tecentriq). In studies of pembrolizumab for various malignancies, rash or vitiligo was an independent prognostic factor for longer OS, a higher proportion of objective responses, and longer PFS. Similar associations were seen with nivolumab, with the additional association of hair repigmentation among patients with non–small-cell lung cancer being associated with stable disease responses or better. Among patients with melanoma treated with ipilimumab, hair depigmentation correlated with durable responses.
• Cytotoxic chemotherapy agents included the anthracycline doxorubicin, taxanes such as paclitaxel and docetaxel, platinum agents (cisplatin and carboplatin), and fluoropyrimidines such as capecitabine. Patients treated for various cancers with doxorubicin who had alopecia were significantly more likely to have clinical remissions than were patients who did not lose their hair, and patients treated with this agent who developed hand-foot syndrome had significantly longer PFS. For patients treated with docetaxel, severity of nail changes and/or development of nail alterations were associated with both improved OS and PFS. Patients treated with the combination of paclitaxel and a platinum agent who developed grade 2 or greater alopecia up to cycle 3 had significantly longer OS than did patients who had hair loss later in the course of therapy. Patients treated with capecitabine who developed had hand-foot skin reactions had improved progression-free and disease-free survival.

“Although further studies are needed to better evaluate these promising associations, vigilant monitoring of cutaneous toxicities should be a priority, as their development may indicate a favorable response to treatment. Dermatologists have a unique opportunity to collaborate with oncologists to help identify and manage these toxicities, thereby allowing patients to receive life-prolonging anticancer therapy while minimizing dose reduction or interruption of their treatment,” the authors wrote.

They reported no study funding source and no conflicts of interest.

SOURCE: Rzepecki A, et al. J Am Acad Dermatol. 2018;79:545-555.

A novel inhibitor of AKT pathway signaling showed significant cytotoxic activity in mouse models and in human cells isolated from patients with primary or relapsed multiple myeloma (MM), investigators reported.

Peter Anderson/ Pathology Education Informational Resource Digital Library/copyright University of Alabama at Birmingham, Department of Pathology

The experimental agent, labeled HS1793, is a derivative of the naturally occurring antioxidant compound resveratrol. In preclinical studies, HS1793 was shown to offer “great promise in eliminating MM cells and improving therapeutic responses in primary and relapsed/refractory MM patients,” according to Jin Han, MD, PhD, of Inje University in Busan, South Korea, and colleagues.

In a series of experiments, described in the journal Cancer Letters, the investigators demonstrated that HS1793 decreased AKT signaling to induce mitochondria-mediated cell death in multiple myeloma cells, and was cytotoxic and specific for myeloma cells in a mouse model of human metastatic myeloma, and in samples of human multiple myeloma cells.

When activated, AKT promotes oncogenesis by in turn activating other downstream pathways involved in proliferation or survival of malignant cells.

“AKT is frequently activated in MM cells and the incidence of AKT activation correlates positively with disease activity,” the authors noted.

They first screened 400 compounds, and narrowed in on resveratrol analogs, eventually choosing HS1793 as the most promising candidate.

This first experiment found evidence that suggested that the compound inhibits AKT activation by interfering with the interaction between AKT and its promoter HSP90.

They then showed in human MM cell lines that the antimyeloma action of HS1793 appeared to be from a dose-dependent effect that allowed for mitochondria-mediated programmed cell death.

In a separate series of experiments, they found that the inhibition by HS1793 of AKT/HSP90 interaction results in cell death by suppressing nuclear factor kappa–B (NF-KB) pathway signaling. The investigators had previously reported that a different compound, an inhibitor of spindle protein kinesin, induced MM cell death via inhibition of NF-KB signaling.

Next, the investigators showed that HS1793-induced cell death was caused by the direct inhibition of AKT that in turn suppressed NF-KB activation.

Finally, they showed in a mouse model of multiple myeloma metastatic to bone that HS1793 “dramatically decreased” lytic skull and femur lesions in treated mice, compared with mice treated with a vehicle placebo, and increased survival of the mice that received the AKT inhibitor.

They also showed that HS1793 was cytotoxic to multiple myeloma cells but not to normal plasma cells isolated from patients with MM.

“Given that HS1793 treatment specifically induced the death of primary and relapsed MM cells, HS1793 offers excellent translational potential as a novel MM therapy,” they wrote.

The study was supported by grants from the Korean government. The researchers reported having no potential conflicts of interest.

SOURCE: Song IS et al. Cancer Lett. 2018;432:205-15.

A novel inhibitor of AKT pathway signaling showed significant cytotoxic activity in mouse models and in human cells isolated from patients with primary or relapsed multiple myeloma (MM), investigators reported.

Peter Anderson/ Pathology Education Informational Resource Digital Library/copyright University of Alabama at Birmingham, Department of Pathology

The experimental agent, labeled HS1793, is a derivative of the naturally occurring antioxidant compound resveratrol. In preclinical studies, HS1793 was shown to offer “great promise in eliminating MM cells and improving therapeutic responses in primary and relapsed/refractory MM patients,” according to Jin Han, MD, PhD, of Inje University in Busan, South Korea, and colleagues.

In a series of experiments, described in the journal Cancer Letters, the investigators demonstrated that HS1793 decreased AKT signaling to induce mitochondria-mediated cell death in multiple myeloma cells, and was cytotoxic and specific for myeloma cells in a mouse model of human metastatic myeloma, and in samples of human multiple myeloma cells.

When activated, AKT promotes oncogenesis by in turn activating other downstream pathways involved in proliferation or survival of malignant cells.

“AKT is frequently activated in MM cells and the incidence of AKT activation correlates positively with disease activity,” the authors noted.

They first screened 400 compounds, and narrowed in on resveratrol analogs, eventually choosing HS1793 as the most promising candidate.

This first experiment found evidence that suggested that the compound inhibits AKT activation by interfering with the interaction between AKT and its promoter HSP90.

They then showed in human MM cell lines that the antimyeloma action of HS1793 appeared to be from a dose-dependent effect that allowed for mitochondria-mediated programmed cell death.

In a separate series of experiments, they found that the inhibition by HS1793 of AKT/HSP90 interaction results in cell death by suppressing nuclear factor kappa–B (NF-KB) pathway signaling. The investigators had previously reported that a different compound, an inhibitor of spindle protein kinesin, induced MM cell death via inhibition of NF-KB signaling.

Next, the investigators showed that HS1793-induced cell death was caused by the direct inhibition of AKT that in turn suppressed NF-KB activation.

Finally, they showed in a mouse model of multiple myeloma metastatic to bone that HS1793 “dramatically decreased” lytic skull and femur lesions in treated mice, compared with mice treated with a vehicle placebo, and increased survival of the mice that received the AKT inhibitor.

They also showed that HS1793 was cytotoxic to multiple myeloma cells but not to normal plasma cells isolated from patients with MM.

“Given that HS1793 treatment specifically induced the death of primary and relapsed MM cells, HS1793 offers excellent translational potential as a novel MM therapy,” they wrote.

The study was supported by grants from the Korean government. The researchers reported having no potential conflicts of interest.

SOURCE: Song IS et al. Cancer Lett. 2018;432:205-15.

A novel inhibitor of AKT pathway signaling showed significant cytotoxic activity in mouse models and in human cells isolated from patients with primary or relapsed multiple myeloma (MM), investigators reported.

Peter Anderson/ Pathology Education Informational Resource Digital Library/copyright University of Alabama at Birmingham, Department of Pathology

The experimental agent, labeled HS1793, is a derivative of the naturally occurring antioxidant compound resveratrol. In preclinical studies, HS1793 was shown to offer “great promise in eliminating MM cells and improving therapeutic responses in primary and relapsed/refractory MM patients,” according to Jin Han, MD, PhD, of Inje University in Busan, South Korea, and colleagues.

In a series of experiments, described in the journal Cancer Letters, the investigators demonstrated that HS1793 decreased AKT signaling to induce mitochondria-mediated cell death in multiple myeloma cells, and was cytotoxic and specific for myeloma cells in a mouse model of human metastatic myeloma, and in samples of human multiple myeloma cells.

When activated, AKT promotes oncogenesis by in turn activating other downstream pathways involved in proliferation or survival of malignant cells.

“AKT is frequently activated in MM cells and the incidence of AKT activation correlates positively with disease activity,” the authors noted.

They first screened 400 compounds, and narrowed in on resveratrol analogs, eventually choosing HS1793 as the most promising candidate.

This first experiment found evidence that suggested that the compound inhibits AKT activation by interfering with the interaction between AKT and its promoter HSP90.

They then showed in human MM cell lines that the antimyeloma action of HS1793 appeared to be from a dose-dependent effect that allowed for mitochondria-mediated programmed cell death.

In a separate series of experiments, they found that the inhibition by HS1793 of AKT/HSP90 interaction results in cell death by suppressing nuclear factor kappa–B (NF-KB) pathway signaling. The investigators had previously reported that a different compound, an inhibitor of spindle protein kinesin, induced MM cell death via inhibition of NF-KB signaling.

Next, the investigators showed that HS1793-induced cell death was caused by the direct inhibition of AKT that in turn suppressed NF-KB activation.

Finally, they showed in a mouse model of multiple myeloma metastatic to bone that HS1793 “dramatically decreased” lytic skull and femur lesions in treated mice, compared with mice treated with a vehicle placebo, and increased survival of the mice that received the AKT inhibitor.

They also showed that HS1793 was cytotoxic to multiple myeloma cells but not to normal plasma cells isolated from patients with MM.

“Given that HS1793 treatment specifically induced the death of primary and relapsed MM cells, HS1793 offers excellent translational potential as a novel MM therapy,” they wrote.

The study was supported by grants from the Korean government. The researchers reported having no potential conflicts of interest.

SOURCE: Song IS et al. Cancer Lett. 2018;432:205-15.