Will Pass

GENEVA – The TRK inhibitor larotrectinib is highly active in lung cancer patients with NTRK gene fusions, supporting routine screening for such fusions in cases of lung cancer, according to investigators.

Will Pass/MDedge News

Although NTRK fusions are relatively infrequent in lung cancer, lead author Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center, New York, suggested that their low frequency should not preclude testing in the current diagnostic setting.

“The frequency of TRK fusions in lung cancers in a prospective series that we put together was at the order of 0.23%, recognizing that the paradigm now for molecular profiling in lung cancer screens for many different drivers together, and not just single-gene testing,” Dr. Drilon said at the European Lung Cancer Conference. Dr. Drilon noted that larotrectinib is now approved by the Food and Drug Administration for the treatment of adult and pediatric patients with TRK fusion-positive cancers.

The present analysis involved 11 patients with metastatic lung adenocarcinoma and NTRK gene fusions from two previous clinical trials (NCT02122913 and NCT02576431); of these patients, 8 had NTRK1 fusions and 3 had NTRK3 fusions. Patients were given larotrectinib 100 mg twice daily on a continuous 28-day schedule until disease progression, unacceptable toxicity, or withdrawal. Almost all patients (10 out of 11) had a prior systemic therapy, and 5 patients had three or more prior therapies. The best response to previous therapies included four stable disease and one partial response. Out of 11 patients, 4 were ineligible for response analysis because of a treatment period of less than 1 month, leaving 7 evaluable patients; of these, 2 patients had stable disease, 4 had a partial response, and 1 had a complete response, translating to an overall response rate of 71%. On average, patients responded in just 1.8 months, with responses ranging from 7.4 months to 17.6 months, with the caveat that median duration of response has yet to be met. Treatment was generally well tolerated, with most adverse events being grade 1 or 2. Dr. Drilon cited a historical dose reduction rate of 9% and a discontinuation rate of less than 1% (out of 122 patients across cancer types).

Although most patients were heavily pretreated, Dr. Drilon highlighted one patient, a 76-year-old woman with non–small cell lung cancer, who had an NTRK1 gene fusion and multiple metastases to the brain and contralateral lung. This patient received larotrectinib as first-line therapy after refusing standard platinum doublet chemotherapy. The woman had a partial response, including “a near complete intracranial response with 95% volumetric shrinkage,” Dr. Drilon said at the meeting, presented by the European Society for Medical Oncology. “She remains on therapy as of six and a half months per the last data cutoff and is still doing well without any substantial toxicities from this drug.”

“In conclusion, larotrectinib is active in advanced lung cancers that harbor a TRK fusion,” Dr. Drilon said. “Of course, these [findings] underscore the utility of molecular profiling for TRK fusions when we look for drivers in patients with non–small cell lung cancer.”

When asked by the invited discussant if NTRK fusions should be tested up-front in all cases of non–small cell lung cancer, Dr. Drilon said, “I think the answer is absolutely yes.” He highlighted the fact that this study and other existing research has shown an overall response rate of about 70%, “which certainly beats the outcomes that we see with other systemic therapies, including, arguably, chemoimmunotherapy for this population. So I think that the paradigm here should be similar to the paradigm for EGFR and ALK, where we have an active target therapeutic that we can use up front, which would likely really improve outcomes for patients.”

Loxo Oncology Inc. and Bayer AG funded the study. The investigators reported financial relationships with Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, and others.

SOURCE: Drilon et al. ELCC 2019. Abstract 111O.

GENEVA – The TRK inhibitor larotrectinib is highly active in lung cancer patients with NTRK gene fusions, supporting routine screening for such fusions in cases of lung cancer, according to investigators.

Will Pass/MDedge News

Although NTRK fusions are relatively infrequent in lung cancer, lead author Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center, New York, suggested that their low frequency should not preclude testing in the current diagnostic setting.

“The frequency of TRK fusions in lung cancers in a prospective series that we put together was at the order of 0.23%, recognizing that the paradigm now for molecular profiling in lung cancer screens for many different drivers together, and not just single-gene testing,” Dr. Drilon said at the European Lung Cancer Conference. Dr. Drilon noted that larotrectinib is now approved by the Food and Drug Administration for the treatment of adult and pediatric patients with TRK fusion-positive cancers.

The present analysis involved 11 patients with metastatic lung adenocarcinoma and NTRK gene fusions from two previous clinical trials (NCT02122913 and NCT02576431); of these patients, 8 had NTRK1 fusions and 3 had NTRK3 fusions. Patients were given larotrectinib 100 mg twice daily on a continuous 28-day schedule until disease progression, unacceptable toxicity, or withdrawal. Almost all patients (10 out of 11) had a prior systemic therapy, and 5 patients had three or more prior therapies. The best response to previous therapies included four stable disease and one partial response. Out of 11 patients, 4 were ineligible for response analysis because of a treatment period of less than 1 month, leaving 7 evaluable patients; of these, 2 patients had stable disease, 4 had a partial response, and 1 had a complete response, translating to an overall response rate of 71%. On average, patients responded in just 1.8 months, with responses ranging from 7.4 months to 17.6 months, with the caveat that median duration of response has yet to be met. Treatment was generally well tolerated, with most adverse events being grade 1 or 2. Dr. Drilon cited a historical dose reduction rate of 9% and a discontinuation rate of less than 1% (out of 122 patients across cancer types).

Although most patients were heavily pretreated, Dr. Drilon highlighted one patient, a 76-year-old woman with non–small cell lung cancer, who had an NTRK1 gene fusion and multiple metastases to the brain and contralateral lung. This patient received larotrectinib as first-line therapy after refusing standard platinum doublet chemotherapy. The woman had a partial response, including “a near complete intracranial response with 95% volumetric shrinkage,” Dr. Drilon said at the meeting, presented by the European Society for Medical Oncology. “She remains on therapy as of six and a half months per the last data cutoff and is still doing well without any substantial toxicities from this drug.”

“In conclusion, larotrectinib is active in advanced lung cancers that harbor a TRK fusion,” Dr. Drilon said. “Of course, these [findings] underscore the utility of molecular profiling for TRK fusions when we look for drivers in patients with non–small cell lung cancer.”

When asked by the invited discussant if NTRK fusions should be tested up-front in all cases of non–small cell lung cancer, Dr. Drilon said, “I think the answer is absolutely yes.” He highlighted the fact that this study and other existing research has shown an overall response rate of about 70%, “which certainly beats the outcomes that we see with other systemic therapies, including, arguably, chemoimmunotherapy for this population. So I think that the paradigm here should be similar to the paradigm for EGFR and ALK, where we have an active target therapeutic that we can use up front, which would likely really improve outcomes for patients.”

Loxo Oncology Inc. and Bayer AG funded the study. The investigators reported financial relationships with Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, and others.

SOURCE: Drilon et al. ELCC 2019. Abstract 111O.

GENEVA – The TRK inhibitor larotrectinib is highly active in lung cancer patients with NTRK gene fusions, supporting routine screening for such fusions in cases of lung cancer, according to investigators.

Will Pass/MDedge News

Although NTRK fusions are relatively infrequent in lung cancer, lead author Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center, New York, suggested that their low frequency should not preclude testing in the current diagnostic setting.

“The frequency of TRK fusions in lung cancers in a prospective series that we put together was at the order of 0.23%, recognizing that the paradigm now for molecular profiling in lung cancer screens for many different drivers together, and not just single-gene testing,” Dr. Drilon said at the European Lung Cancer Conference. Dr. Drilon noted that larotrectinib is now approved by the Food and Drug Administration for the treatment of adult and pediatric patients with TRK fusion-positive cancers.

The present analysis involved 11 patients with metastatic lung adenocarcinoma and NTRK gene fusions from two previous clinical trials (NCT02122913 and NCT02576431); of these patients, 8 had NTRK1 fusions and 3 had NTRK3 fusions. Patients were given larotrectinib 100 mg twice daily on a continuous 28-day schedule until disease progression, unacceptable toxicity, or withdrawal. Almost all patients (10 out of 11) had a prior systemic therapy, and 5 patients had three or more prior therapies. The best response to previous therapies included four stable disease and one partial response. Out of 11 patients, 4 were ineligible for response analysis because of a treatment period of less than 1 month, leaving 7 evaluable patients; of these, 2 patients had stable disease, 4 had a partial response, and 1 had a complete response, translating to an overall response rate of 71%. On average, patients responded in just 1.8 months, with responses ranging from 7.4 months to 17.6 months, with the caveat that median duration of response has yet to be met. Treatment was generally well tolerated, with most adverse events being grade 1 or 2. Dr. Drilon cited a historical dose reduction rate of 9% and a discontinuation rate of less than 1% (out of 122 patients across cancer types).

Although most patients were heavily pretreated, Dr. Drilon highlighted one patient, a 76-year-old woman with non–small cell lung cancer, who had an NTRK1 gene fusion and multiple metastases to the brain and contralateral lung. This patient received larotrectinib as first-line therapy after refusing standard platinum doublet chemotherapy. The woman had a partial response, including “a near complete intracranial response with 95% volumetric shrinkage,” Dr. Drilon said at the meeting, presented by the European Society for Medical Oncology. “She remains on therapy as of six and a half months per the last data cutoff and is still doing well without any substantial toxicities from this drug.”

“In conclusion, larotrectinib is active in advanced lung cancers that harbor a TRK fusion,” Dr. Drilon said. “Of course, these [findings] underscore the utility of molecular profiling for TRK fusions when we look for drivers in patients with non–small cell lung cancer.”

When asked by the invited discussant if NTRK fusions should be tested up-front in all cases of non–small cell lung cancer, Dr. Drilon said, “I think the answer is absolutely yes.” He highlighted the fact that this study and other existing research has shown an overall response rate of about 70%, “which certainly beats the outcomes that we see with other systemic therapies, including, arguably, chemoimmunotherapy for this population. So I think that the paradigm here should be similar to the paradigm for EGFR and ALK, where we have an active target therapeutic that we can use up front, which would likely really improve outcomes for patients.”

Loxo Oncology Inc. and Bayer AG funded the study. The investigators reported financial relationships with Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, and others.

SOURCE: Drilon et al. ELCC 2019. Abstract 111O.

GENEVA – Pembrolizumab monotherapy is as safe and effective in elderly patients with non–small cell lung cancer (NSCLC) as it is younger patients, according to investigators.

Will Pass/MDedge News

They reached this conclusion after analyzing pooled data from 264 patients 75 years or older involved in the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 phase 3 trials, reported lead author Kaname Nosaki, MD, of the National Hospital Organization Kyushu Cancer Center in Fukuoka, Japan, and his colleagues.

“Approximately 70% of newly-diagnosed NSCLC cases occur in the elderly, and more than half are locally advanced or metastatic,” the investigators noted in their abstract. Despite this, patients aged 75 years or older are underrepresented in clinical trials, Dr. Nosaki said during a presentation at the European Lung Cancer Conference.

All patients in the three KEYNOTE trials had PD-L1 positive NSCLC, with variations between studies with respect to PD-L1 tumor proportion score (TPS) and dosing regimen. While KEYNOTE-010 and KEYNOTE-042 involved patients with a TPS of at least 1%, KEYNOTE-024 raised the minimum TPS threshold to 50%. KEYNOTE-010 pembrolizumab dose was set at 2 mg/kg or 10 mg/kg, compared with the other two studies, which set a consistent dose of the checkpoint inhibitor at 200 mg.

As with younger patients, higher TPS expression generally predicted better outcomes. Independent of treatment line, elderly patients with a TPS of at least 50% had a hazard ratio of 0.40 in favor of pembrolizumab over chemotherapy, compared with all PD-L1-positive elderly patients, who had a hazard ratio of 0.76.

Generally, adverse events were comparable between age groups, with 68% of elderly patients experiencing at least one treatment-related adverse event, compared with 65% of younger patients. Grade 3 or 4 adverse events were slightly more common among elderly patients than younger patients (23% vs. 16%), with a mild concomitant increase in adverse event–related treatment discontinuations (11% vs. 7%). The rate of immune-mediated adverse events and infusion reactions, however, held steady regardless of age group, occurring in one out of four patients (25%). In contrast with these similarities, almost all elderly patients receiving chemotherapy (94%) had adverse events, compared with two out of three elderly patients receiving pembrolizumab. Rates of grade 3 or 4 adverse events also favored pembrolizumab over chemotherapy (23% vs. 59%).

“These data support the use of pembrolizumab monotherapy in elderly patients more than 75 years old with advanced PD-L1-expressing NSCLC,” Dr. Nosaki concluded.

Invited discussant Sanjay Popat, PhD, of Imperial College London, described the knowledge gap addressed by this study. “If we look at U.S. statistics, we see that lung cancer is the leading cause of death for patients above the age of 80, both for males and females,” Dr. Popat said at the meeting, presented by the European Society for Medical Oncology. “The real question is should this group of patients be getting any form of checkpoint inhibitors at all, and if so, what is the benefit to risk ratio?

Will Pass/MDedge News

“Our patients are getting older, we’re all living slightly longer, and the burden of geriatric oncology is predicted to rise quite markedly with age, so it’s important to get a good feel for how we should be managing our senior population,” he added.

According to Dr. Popat, elderly patients naturally undergo immune senescence, meaning the immune system deteriorates with age, and this phenomenon could theoretically mitigate efficacy of immunotherapies; however, previous studies have not found decreased efficacy among elderly patients. Still, some “so-called elderly population subsets we’ve been analyzing are actually around the median age [of diagnosis with NSCLC],” Dr. Popat said, noting that among these studies, those with wider age ranges offer more reliable data.

“Today we looked at the novel cutoff, this 75-year group cutoff, which I very much welcome,” Dr. Popat said, “because this much more reflects what we see in routine clinical care.”

Regarding the results, Dr. Popat suggested that chemotherapy leads to an “excess of mortality” among elderly patients, “likely due to toxicities,” thereby explaining part of the relative advantage provided by pembrolizumab. Considering these findings in addition to previous experiences with pembrolizumab in the elderly, Dr. Popat said that “if you choose your patient population well, fit patients well enough to go to a trial, they don’t have an excess of toxicities regardless of their age.”

Taken as a whole, the present analysis supports the routine use of pembrolizumab in fit, elderly patients, Dr. Popat said.

The study was funded by MSD. The investigators reported financial relationships with AstraZeneca, Eli Lilly, Taiho, Chugai, and others.

SOURCE: Nosaki et al. ELCC 2019. Abstract 103O_PR.

GENEVA – Pembrolizumab monotherapy is as safe and effective in elderly patients with non–small cell lung cancer (NSCLC) as it is younger patients, according to investigators.

Will Pass/MDedge News

They reached this conclusion after analyzing pooled data from 264 patients 75 years or older involved in the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 phase 3 trials, reported lead author Kaname Nosaki, MD, of the National Hospital Organization Kyushu Cancer Center in Fukuoka, Japan, and his colleagues.

“Approximately 70% of newly-diagnosed NSCLC cases occur in the elderly, and more than half are locally advanced or metastatic,” the investigators noted in their abstract. Despite this, patients aged 75 years or older are underrepresented in clinical trials, Dr. Nosaki said during a presentation at the European Lung Cancer Conference.

All patients in the three KEYNOTE trials had PD-L1 positive NSCLC, with variations between studies with respect to PD-L1 tumor proportion score (TPS) and dosing regimen. While KEYNOTE-010 and KEYNOTE-042 involved patients with a TPS of at least 1%, KEYNOTE-024 raised the minimum TPS threshold to 50%. KEYNOTE-010 pembrolizumab dose was set at 2 mg/kg or 10 mg/kg, compared with the other two studies, which set a consistent dose of the checkpoint inhibitor at 200 mg.

As with younger patients, higher TPS expression generally predicted better outcomes. Independent of treatment line, elderly patients with a TPS of at least 50% had a hazard ratio of 0.40 in favor of pembrolizumab over chemotherapy, compared with all PD-L1-positive elderly patients, who had a hazard ratio of 0.76.

Generally, adverse events were comparable between age groups, with 68% of elderly patients experiencing at least one treatment-related adverse event, compared with 65% of younger patients. Grade 3 or 4 adverse events were slightly more common among elderly patients than younger patients (23% vs. 16%), with a mild concomitant increase in adverse event–related treatment discontinuations (11% vs. 7%). The rate of immune-mediated adverse events and infusion reactions, however, held steady regardless of age group, occurring in one out of four patients (25%). In contrast with these similarities, almost all elderly patients receiving chemotherapy (94%) had adverse events, compared with two out of three elderly patients receiving pembrolizumab. Rates of grade 3 or 4 adverse events also favored pembrolizumab over chemotherapy (23% vs. 59%).

“These data support the use of pembrolizumab monotherapy in elderly patients more than 75 years old with advanced PD-L1-expressing NSCLC,” Dr. Nosaki concluded.

Invited discussant Sanjay Popat, PhD, of Imperial College London, described the knowledge gap addressed by this study. “If we look at U.S. statistics, we see that lung cancer is the leading cause of death for patients above the age of 80, both for males and females,” Dr. Popat said at the meeting, presented by the European Society for Medical Oncology. “The real question is should this group of patients be getting any form of checkpoint inhibitors at all, and if so, what is the benefit to risk ratio?

Will Pass/MDedge News

“Our patients are getting older, we’re all living slightly longer, and the burden of geriatric oncology is predicted to rise quite markedly with age, so it’s important to get a good feel for how we should be managing our senior population,” he added.

According to Dr. Popat, elderly patients naturally undergo immune senescence, meaning the immune system deteriorates with age, and this phenomenon could theoretically mitigate efficacy of immunotherapies; however, previous studies have not found decreased efficacy among elderly patients. Still, some “so-called elderly population subsets we’ve been analyzing are actually around the median age [of diagnosis with NSCLC],” Dr. Popat said, noting that among these studies, those with wider age ranges offer more reliable data.

“Today we looked at the novel cutoff, this 75-year group cutoff, which I very much welcome,” Dr. Popat said, “because this much more reflects what we see in routine clinical care.”

Regarding the results, Dr. Popat suggested that chemotherapy leads to an “excess of mortality” among elderly patients, “likely due to toxicities,” thereby explaining part of the relative advantage provided by pembrolizumab. Considering these findings in addition to previous experiences with pembrolizumab in the elderly, Dr. Popat said that “if you choose your patient population well, fit patients well enough to go to a trial, they don’t have an excess of toxicities regardless of their age.”

Taken as a whole, the present analysis supports the routine use of pembrolizumab in fit, elderly patients, Dr. Popat said.

The study was funded by MSD. The investigators reported financial relationships with AstraZeneca, Eli Lilly, Taiho, Chugai, and others.

SOURCE: Nosaki et al. ELCC 2019. Abstract 103O_PR.

GENEVA – Pembrolizumab monotherapy is as safe and effective in elderly patients with non–small cell lung cancer (NSCLC) as it is younger patients, according to investigators.

Will Pass/MDedge News

They reached this conclusion after analyzing pooled data from 264 patients 75 years or older involved in the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 phase 3 trials, reported lead author Kaname Nosaki, MD, of the National Hospital Organization Kyushu Cancer Center in Fukuoka, Japan, and his colleagues.

“Approximately 70% of newly-diagnosed NSCLC cases occur in the elderly, and more than half are locally advanced or metastatic,” the investigators noted in their abstract. Despite this, patients aged 75 years or older are underrepresented in clinical trials, Dr. Nosaki said during a presentation at the European Lung Cancer Conference.

All patients in the three KEYNOTE trials had PD-L1 positive NSCLC, with variations between studies with respect to PD-L1 tumor proportion score (TPS) and dosing regimen. While KEYNOTE-010 and KEYNOTE-042 involved patients with a TPS of at least 1%, KEYNOTE-024 raised the minimum TPS threshold to 50%. KEYNOTE-010 pembrolizumab dose was set at 2 mg/kg or 10 mg/kg, compared with the other two studies, which set a consistent dose of the checkpoint inhibitor at 200 mg.

As with younger patients, higher TPS expression generally predicted better outcomes. Independent of treatment line, elderly patients with a TPS of at least 50% had a hazard ratio of 0.40 in favor of pembrolizumab over chemotherapy, compared with all PD-L1-positive elderly patients, who had a hazard ratio of 0.76.

Generally, adverse events were comparable between age groups, with 68% of elderly patients experiencing at least one treatment-related adverse event, compared with 65% of younger patients. Grade 3 or 4 adverse events were slightly more common among elderly patients than younger patients (23% vs. 16%), with a mild concomitant increase in adverse event–related treatment discontinuations (11% vs. 7%). The rate of immune-mediated adverse events and infusion reactions, however, held steady regardless of age group, occurring in one out of four patients (25%). In contrast with these similarities, almost all elderly patients receiving chemotherapy (94%) had adverse events, compared with two out of three elderly patients receiving pembrolizumab. Rates of grade 3 or 4 adverse events also favored pembrolizumab over chemotherapy (23% vs. 59%).

“These data support the use of pembrolizumab monotherapy in elderly patients more than 75 years old with advanced PD-L1-expressing NSCLC,” Dr. Nosaki concluded.

Invited discussant Sanjay Popat, PhD, of Imperial College London, described the knowledge gap addressed by this study. “If we look at U.S. statistics, we see that lung cancer is the leading cause of death for patients above the age of 80, both for males and females,” Dr. Popat said at the meeting, presented by the European Society for Medical Oncology. “The real question is should this group of patients be getting any form of checkpoint inhibitors at all, and if so, what is the benefit to risk ratio?

Will Pass/MDedge News

“Our patients are getting older, we’re all living slightly longer, and the burden of geriatric oncology is predicted to rise quite markedly with age, so it’s important to get a good feel for how we should be managing our senior population,” he added.

According to Dr. Popat, elderly patients naturally undergo immune senescence, meaning the immune system deteriorates with age, and this phenomenon could theoretically mitigate efficacy of immunotherapies; however, previous studies have not found decreased efficacy among elderly patients. Still, some “so-called elderly population subsets we’ve been analyzing are actually around the median age [of diagnosis with NSCLC],” Dr. Popat said, noting that among these studies, those with wider age ranges offer more reliable data.

“Today we looked at the novel cutoff, this 75-year group cutoff, which I very much welcome,” Dr. Popat said, “because this much more reflects what we see in routine clinical care.”

Regarding the results, Dr. Popat suggested that chemotherapy leads to an “excess of mortality” among elderly patients, “likely due to toxicities,” thereby explaining part of the relative advantage provided by pembrolizumab. Considering these findings in addition to previous experiences with pembrolizumab in the elderly, Dr. Popat said that “if you choose your patient population well, fit patients well enough to go to a trial, they don’t have an excess of toxicities regardless of their age.”

Taken as a whole, the present analysis supports the routine use of pembrolizumab in fit, elderly patients, Dr. Popat said.

The study was funded by MSD. The investigators reported financial relationships with AstraZeneca, Eli Lilly, Taiho, Chugai, and others.

SOURCE: Nosaki et al. ELCC 2019. Abstract 103O_PR.

GENEVA – For patients with malignant pleural mesothelioma, adding tumor-treating fields (TTFields) to standard pemetrexed plus platinum compound chemotherapy could boost median overall survival by about 6 months, according to final results from the phase 2 STELLAR trial.

Will Pass/MDedge News

The survival benefit of TTFields was greatest among patients with epithelioid mesothelioma, reported lead author Giovanni Luca Ceresoli, MD, of Humanitas Gavazzeni in Bergamo, Italy. According to Dr. Ceresoli, who presented findings at the at the European Lung Cancer Conference, TTFields offer a safe way to improve mesothelioma outcomes without increasing the risk of serious adverse events.

“TTFields are a locoregional treatment comprising low-intensity alternating electric fields delivered through a portable medical device,” Dr. Ceresoli explained at the meeting, presented by the European Society for Medical Oncology. “Their main mode of action is an anti-mitotic mechanism.” He noted that TTFields are already approved by the Food and Drug Administration for newly diagnosed glioblastoma.

The STELLAR trial involved 80 patients with mesothelioma who were treated with TTFields in combination with standard first-line chemotherapy, a combination of pemetrexed with cisplatin or carboplatin. Patients were instructed to self-administer continuous 150 kHz TTFields for at least 18 hours a day. Eligibility required an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Both ECOG status and cancer-related pain were followed with a visual analog scale until disease progression. Median overall survival (OS) was the primary endpoint.

The patient population was predominantly male (84%), with median age of 67 years. About 44% of the patients had an ECOG performance status of 1 and 66% had epithelioid histology. Median treatment time per day was 16.3 hours.

After a minimum follow-up of 1 year, patients treated with TTFields in combination with standard chemotherapy had a median overall survival of 18.2 months, compared with 12.1 months for standard chemotherapy alone, which Dr. Ceresoli cited as the historical benchmark. The survival benefit was 3 months longer among patients with epithelioid mesothelioma, who had a median overall survival of 21.2 months.

In addition to survival benefits, the investigators found that median time to decreased performance status was just over 1 year (13.1 months), and that pain did not increase to a clinically significant degree (33%) until an average of 8.4 months. Although no device-related serious adverse events occurred, 37 patients (46%) experienced TTFields-related dermatitis; 4 of these patients had grade 3 dermatitis. Dr. Ceresoli noted that dermatitis was typically “easily managed” with topical application of a corticosteroid, while patients with severe dermatitis took short treatment breaks.

“In conclusion, in the STELLAR trial, TTFields in combination with standard chemotherapy were effective and safe for first-line treatment of unresectable malignant pleural mesothelioma, and median overall survival was significantly longer as compared to historical controls,” Dr. Ceresoli said, pointing out better survival than in recent trials MAPS and LUME-Meso.

When asked by the invited discussant about future research, Dr. Ceresoli described a narrower focus for upcoming TTFields studies for mesothelioma. “As you well know, most patients have epithelioid histology, and in our hands, the patients with epithelioid histology had better prognoses,” he said. “So, in the future, I think we will focus on epithelioid tumors.”

Dr. Ceresoli disclosed travel funding from Novocure.

SOURCE: Ceresoli et al. ELCC 2019. Abstract 55O.

GENEVA – For patients with malignant pleural mesothelioma, adding tumor-treating fields (TTFields) to standard pemetrexed plus platinum compound chemotherapy could boost median overall survival by about 6 months, according to final results from the phase 2 STELLAR trial.

Will Pass/MDedge News

The survival benefit of TTFields was greatest among patients with epithelioid mesothelioma, reported lead author Giovanni Luca Ceresoli, MD, of Humanitas Gavazzeni in Bergamo, Italy. According to Dr. Ceresoli, who presented findings at the at the European Lung Cancer Conference, TTFields offer a safe way to improve mesothelioma outcomes without increasing the risk of serious adverse events.

“TTFields are a locoregional treatment comprising low-intensity alternating electric fields delivered through a portable medical device,” Dr. Ceresoli explained at the meeting, presented by the European Society for Medical Oncology. “Their main mode of action is an anti-mitotic mechanism.” He noted that TTFields are already approved by the Food and Drug Administration for newly diagnosed glioblastoma.

The STELLAR trial involved 80 patients with mesothelioma who were treated with TTFields in combination with standard first-line chemotherapy, a combination of pemetrexed with cisplatin or carboplatin. Patients were instructed to self-administer continuous 150 kHz TTFields for at least 18 hours a day. Eligibility required an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Both ECOG status and cancer-related pain were followed with a visual analog scale until disease progression. Median overall survival (OS) was the primary endpoint.

The patient population was predominantly male (84%), with median age of 67 years. About 44% of the patients had an ECOG performance status of 1 and 66% had epithelioid histology. Median treatment time per day was 16.3 hours.

After a minimum follow-up of 1 year, patients treated with TTFields in combination with standard chemotherapy had a median overall survival of 18.2 months, compared with 12.1 months for standard chemotherapy alone, which Dr. Ceresoli cited as the historical benchmark. The survival benefit was 3 months longer among patients with epithelioid mesothelioma, who had a median overall survival of 21.2 months.

In addition to survival benefits, the investigators found that median time to decreased performance status was just over 1 year (13.1 months), and that pain did not increase to a clinically significant degree (33%) until an average of 8.4 months. Although no device-related serious adverse events occurred, 37 patients (46%) experienced TTFields-related dermatitis; 4 of these patients had grade 3 dermatitis. Dr. Ceresoli noted that dermatitis was typically “easily managed” with topical application of a corticosteroid, while patients with severe dermatitis took short treatment breaks.

“In conclusion, in the STELLAR trial, TTFields in combination with standard chemotherapy were effective and safe for first-line treatment of unresectable malignant pleural mesothelioma, and median overall survival was significantly longer as compared to historical controls,” Dr. Ceresoli said, pointing out better survival than in recent trials MAPS and LUME-Meso.

When asked by the invited discussant about future research, Dr. Ceresoli described a narrower focus for upcoming TTFields studies for mesothelioma. “As you well know, most patients have epithelioid histology, and in our hands, the patients with epithelioid histology had better prognoses,” he said. “So, in the future, I think we will focus on epithelioid tumors.”

Dr. Ceresoli disclosed travel funding from Novocure.

SOURCE: Ceresoli et al. ELCC 2019. Abstract 55O.

GENEVA – For patients with malignant pleural mesothelioma, adding tumor-treating fields (TTFields) to standard pemetrexed plus platinum compound chemotherapy could boost median overall survival by about 6 months, according to final results from the phase 2 STELLAR trial.

Will Pass/MDedge News

The survival benefit of TTFields was greatest among patients with epithelioid mesothelioma, reported lead author Giovanni Luca Ceresoli, MD, of Humanitas Gavazzeni in Bergamo, Italy. According to Dr. Ceresoli, who presented findings at the at the European Lung Cancer Conference, TTFields offer a safe way to improve mesothelioma outcomes without increasing the risk of serious adverse events.

“TTFields are a locoregional treatment comprising low-intensity alternating electric fields delivered through a portable medical device,” Dr. Ceresoli explained at the meeting, presented by the European Society for Medical Oncology. “Their main mode of action is an anti-mitotic mechanism.” He noted that TTFields are already approved by the Food and Drug Administration for newly diagnosed glioblastoma.

The STELLAR trial involved 80 patients with mesothelioma who were treated with TTFields in combination with standard first-line chemotherapy, a combination of pemetrexed with cisplatin or carboplatin. Patients were instructed to self-administer continuous 150 kHz TTFields for at least 18 hours a day. Eligibility required an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Both ECOG status and cancer-related pain were followed with a visual analog scale until disease progression. Median overall survival (OS) was the primary endpoint.

The patient population was predominantly male (84%), with median age of 67 years. About 44% of the patients had an ECOG performance status of 1 and 66% had epithelioid histology. Median treatment time per day was 16.3 hours.

After a minimum follow-up of 1 year, patients treated with TTFields in combination with standard chemotherapy had a median overall survival of 18.2 months, compared with 12.1 months for standard chemotherapy alone, which Dr. Ceresoli cited as the historical benchmark. The survival benefit was 3 months longer among patients with epithelioid mesothelioma, who had a median overall survival of 21.2 months.

In addition to survival benefits, the investigators found that median time to decreased performance status was just over 1 year (13.1 months), and that pain did not increase to a clinically significant degree (33%) until an average of 8.4 months. Although no device-related serious adverse events occurred, 37 patients (46%) experienced TTFields-related dermatitis; 4 of these patients had grade 3 dermatitis. Dr. Ceresoli noted that dermatitis was typically “easily managed” with topical application of a corticosteroid, while patients with severe dermatitis took short treatment breaks.

“In conclusion, in the STELLAR trial, TTFields in combination with standard chemotherapy were effective and safe for first-line treatment of unresectable malignant pleural mesothelioma, and median overall survival was significantly longer as compared to historical controls,” Dr. Ceresoli said, pointing out better survival than in recent trials MAPS and LUME-Meso.

When asked by the invited discussant about future research, Dr. Ceresoli described a narrower focus for upcoming TTFields studies for mesothelioma. “As you well know, most patients have epithelioid histology, and in our hands, the patients with epithelioid histology had better prognoses,” he said. “So, in the future, I think we will focus on epithelioid tumors.”

Dr. Ceresoli disclosed travel funding from Novocure.

SOURCE: Ceresoli et al. ELCC 2019. Abstract 55O.

GENEVA – Radiogenomic MRI signatures may be able to identify anaplastic lymphoma kinase (ALK)–positive brain metastases in non–small cell lung cancer (NSCLC), offering a minimally invasive option that could allow for initiation of treatment while waiting for molecular results, according to investigators.

Will Pass/MDedge News

In the future, artificial intelligence may be able to detect these imaging patterns, allowing for rapid and accurate mutation subtyping, reported lead author Shweta Wadhwa, MD, of Tata Memorial Centre in Mumbai, India, who presented the findings at the European Lung Cancer Conference.

“Radiogenomics is a concept used to associate genetic information with medical images,” Dr. Wadhwa explained at the meeting presented by the European Society for Medical Oncology. “It creates imaging biomarkers noninvasively without using biopsy. … The aim of my study was to analyze certain MRI data genomic parameters and correlate with the ALK mutation status.”

Dr. Wadhwa and her colleagues retrospectively analyzed data from 75 patients with ALK-positive NSCLC who underwent multiparametric MRI at the time of diagnosis. Univariate logistic regression analysis was conducted to look for associations between ALK mutation status and various clinical factors, including sex, age, smoking, histology, TNM stage, and imaging characteristics.

Out of 75 patients, 46 were ALK positive and 29 were ALK negative. Analysis showed that ALK positivity was associated with a variety of lesion morphology characteristics. ALK-positive lesions more often exhibited a fuzzy and infiltrative T2w border with hypointense peripheral solid rim, compared with ALK-negative lesions, which frequently had a well-defined T2w border with no solid rim (P less than .001). On T1w, most ALK-positive lesions were heterogeneous, whereas ALK-negative lesions were predominantly hypointense (P less than .001). Diffusion-weighted images showed that ALK-positive lesions often had peripheral restriction of the solid rim, compared with ALK-negative lesions, which were associated with central restriction (P = .001). MRI also revealed that about half of ALK-positive patients (54.3%) had meningeal involvement, compared with just 17.2% of ALK-negative patients (P = .02). ALK positivity was also associated with younger age and lack of smoking history. Considering these findings, Dr. Wadhwa concluded that “radiogenomics has a potential role in personalized management of ALK-positive NSCLC brain metastases.”

In an interview, Dr. Wadhwa provided more insight regarding the clinical need for this technology. “We have to wait for 10 days [for molecular diagnostic results], and ALK is usually aggressive disease, so if we wait for 10 days, patients can undergo rapid progression.”

Dr. Wadhwa noted that these results are similar to that of her colleague, Abhishek Mahajan, MD, who recently published results showing potential for radiogenomic detection of epidermal growth factor receptor (EGFR) status. According to Dr. Wadhwa, the two investigators plan to build on their collective findings in an effort to automate radiogenomic detection of NSCLC mutation subtypes.

“My upcoming project with my coinvestigator is to take a bigger sample,” Dr. Wadhwa said. “We will be further generalizing [this process] to all patients in a prospective study. We will also be sending this to the University of Pennsylvania for automatic brain segmentation.” Dr. Wadhwa estimated that adding automation will provide an accuracy rate of around 90%.

“We will train the computer accordingly,” Dr. Wadhwa said, “and then the computer will tell us, yes, this is ALK positive, this is EGFR positive.”

The investigators reported no external study funding and reported no conflicts of interest.

SOURCE: Wadhwa S et al. ELCC 2019, Abstract 55O.

GENEVA – Radiogenomic MRI signatures may be able to identify anaplastic lymphoma kinase (ALK)–positive brain metastases in non–small cell lung cancer (NSCLC), offering a minimally invasive option that could allow for initiation of treatment while waiting for molecular results, according to investigators.

Will Pass/MDedge News

In the future, artificial intelligence may be able to detect these imaging patterns, allowing for rapid and accurate mutation subtyping, reported lead author Shweta Wadhwa, MD, of Tata Memorial Centre in Mumbai, India, who presented the findings at the European Lung Cancer Conference.

“Radiogenomics is a concept used to associate genetic information with medical images,” Dr. Wadhwa explained at the meeting presented by the European Society for Medical Oncology. “It creates imaging biomarkers noninvasively without using biopsy. … The aim of my study was to analyze certain MRI data genomic parameters and correlate with the ALK mutation status.”

Dr. Wadhwa and her colleagues retrospectively analyzed data from 75 patients with ALK-positive NSCLC who underwent multiparametric MRI at the time of diagnosis. Univariate logistic regression analysis was conducted to look for associations between ALK mutation status and various clinical factors, including sex, age, smoking, histology, TNM stage, and imaging characteristics.

Out of 75 patients, 46 were ALK positive and 29 were ALK negative. Analysis showed that ALK positivity was associated with a variety of lesion morphology characteristics. ALK-positive lesions more often exhibited a fuzzy and infiltrative T2w border with hypointense peripheral solid rim, compared with ALK-negative lesions, which frequently had a well-defined T2w border with no solid rim (P less than .001). On T1w, most ALK-positive lesions were heterogeneous, whereas ALK-negative lesions were predominantly hypointense (P less than .001). Diffusion-weighted images showed that ALK-positive lesions often had peripheral restriction of the solid rim, compared with ALK-negative lesions, which were associated with central restriction (P = .001). MRI also revealed that about half of ALK-positive patients (54.3%) had meningeal involvement, compared with just 17.2% of ALK-negative patients (P = .02). ALK positivity was also associated with younger age and lack of smoking history. Considering these findings, Dr. Wadhwa concluded that “radiogenomics has a potential role in personalized management of ALK-positive NSCLC brain metastases.”

In an interview, Dr. Wadhwa provided more insight regarding the clinical need for this technology. “We have to wait for 10 days [for molecular diagnostic results], and ALK is usually aggressive disease, so if we wait for 10 days, patients can undergo rapid progression.”

Dr. Wadhwa noted that these results are similar to that of her colleague, Abhishek Mahajan, MD, who recently published results showing potential for radiogenomic detection of epidermal growth factor receptor (EGFR) status. According to Dr. Wadhwa, the two investigators plan to build on their collective findings in an effort to automate radiogenomic detection of NSCLC mutation subtypes.

“My upcoming project with my coinvestigator is to take a bigger sample,” Dr. Wadhwa said. “We will be further generalizing [this process] to all patients in a prospective study. We will also be sending this to the University of Pennsylvania for automatic brain segmentation.” Dr. Wadhwa estimated that adding automation will provide an accuracy rate of around 90%.

“We will train the computer accordingly,” Dr. Wadhwa said, “and then the computer will tell us, yes, this is ALK positive, this is EGFR positive.”

The investigators reported no external study funding and reported no conflicts of interest.

SOURCE: Wadhwa S et al. ELCC 2019, Abstract 55O.

GENEVA – Radiogenomic MRI signatures may be able to identify anaplastic lymphoma kinase (ALK)–positive brain metastases in non–small cell lung cancer (NSCLC), offering a minimally invasive option that could allow for initiation of treatment while waiting for molecular results, according to investigators.

Will Pass/MDedge News

In the future, artificial intelligence may be able to detect these imaging patterns, allowing for rapid and accurate mutation subtyping, reported lead author Shweta Wadhwa, MD, of Tata Memorial Centre in Mumbai, India, who presented the findings at the European Lung Cancer Conference.

“Radiogenomics is a concept used to associate genetic information with medical images,” Dr. Wadhwa explained at the meeting presented by the European Society for Medical Oncology. “It creates imaging biomarkers noninvasively without using biopsy. … The aim of my study was to analyze certain MRI data genomic parameters and correlate with the ALK mutation status.”

Dr. Wadhwa and her colleagues retrospectively analyzed data from 75 patients with ALK-positive NSCLC who underwent multiparametric MRI at the time of diagnosis. Univariate logistic regression analysis was conducted to look for associations between ALK mutation status and various clinical factors, including sex, age, smoking, histology, TNM stage, and imaging characteristics.

Out of 75 patients, 46 were ALK positive and 29 were ALK negative. Analysis showed that ALK positivity was associated with a variety of lesion morphology characteristics. ALK-positive lesions more often exhibited a fuzzy and infiltrative T2w border with hypointense peripheral solid rim, compared with ALK-negative lesions, which frequently had a well-defined T2w border with no solid rim (P less than .001). On T1w, most ALK-positive lesions were heterogeneous, whereas ALK-negative lesions were predominantly hypointense (P less than .001). Diffusion-weighted images showed that ALK-positive lesions often had peripheral restriction of the solid rim, compared with ALK-negative lesions, which were associated with central restriction (P = .001). MRI also revealed that about half of ALK-positive patients (54.3%) had meningeal involvement, compared with just 17.2% of ALK-negative patients (P = .02). ALK positivity was also associated with younger age and lack of smoking history. Considering these findings, Dr. Wadhwa concluded that “radiogenomics has a potential role in personalized management of ALK-positive NSCLC brain metastases.”

In an interview, Dr. Wadhwa provided more insight regarding the clinical need for this technology. “We have to wait for 10 days [for molecular diagnostic results], and ALK is usually aggressive disease, so if we wait for 10 days, patients can undergo rapid progression.”

Dr. Wadhwa noted that these results are similar to that of her colleague, Abhishek Mahajan, MD, who recently published results showing potential for radiogenomic detection of epidermal growth factor receptor (EGFR) status. According to Dr. Wadhwa, the two investigators plan to build on their collective findings in an effort to automate radiogenomic detection of NSCLC mutation subtypes.

“My upcoming project with my coinvestigator is to take a bigger sample,” Dr. Wadhwa said. “We will be further generalizing [this process] to all patients in a prospective study. We will also be sending this to the University of Pennsylvania for automatic brain segmentation.” Dr. Wadhwa estimated that adding automation will provide an accuracy rate of around 90%.

“We will train the computer accordingly,” Dr. Wadhwa said, “and then the computer will tell us, yes, this is ALK positive, this is EGFR positive.”

The investigators reported no external study funding and reported no conflicts of interest.

SOURCE: Wadhwa S et al. ELCC 2019, Abstract 55O.

GENEVA – For lung lesion biopsy, electromagnetic navigation bronchoscopy (ENB) offers high navigational success with a relatively low rate of pneumothorax, according to European data from the international NAVIGATE study.

Will Pass/MDedge News

In addition to lung lesion biopsy, ENB can facilitate concurrent lymph node sampling and fiducial placement during a single anesthetic event, reported lead author Kelvin Lau, MD, chief of thoracic surgery at Barts Thorax Centre in London, and his colleagues. According to Dr. Lau, who presented at the European Lung Cancer Conference, the findings from this European cohort add weight to previously published data from the NAVIGATE trial, which aims to demonstrate real-world use of ENB.

“The outcomes show that [ENB] is very safe in terms of pneumothorax rate, despite the fact that many of these patients were challenging and actually were turned down by the percutaneous radiologist before they came to us,” Dr. Lau said at the meeting, presented by the European Society for Medical Oncology.

Out of 1,200 patients enrolled in the NAVIGATE trial in the United States and Europe, the present 1-month interim analysis showed experiences with 175 patients treated at eight European centers. Anyone undergoing navigational bronchoscopy was eligible. The primary outcome was pneumothorax rate and the secondary outcome was diagnostic yield.

Data analysis showed that lesions were most frequently in the upper lobe (62.6%) and in the peripheral third of the lung (72.7%), the latter of which is beyond the reach of a conventional bronchoscope. In two out of three patients (66.8%), a bronchus sign was present, which “means that the bronchoscope runs straight into the lesion, and theoretically means it’s easier to access,” Dr. Lau said. Almost all patients had ENB for lung biopsy (99.4%), while in a small minority (8.0%), ENB was used for fiducial marking. The median total procedure time was 43.5 minutes, of which 32.9 minutes were spent navigating and sampling with ENB.

The ENB-related pneumothorax rate was 7.4%, although a slightly lower percentage, 5.1%, required intervention or hospitalization. According to the ENB-related Common Terminology Criteria for Adverse Events, 2.3% of patients had grade 2 or higher bronchopulmonary hemorrhage and 0.6% of patients had grade 4 or higher respiratory failure. Although the secondary endpoint, diagnostic yield, was not met because of inadequate follow-up time, the navigational success rate, defined as access to the intended lung lesion, was 96.6%, which offers some sense of efficacy.

“The purpose of this study is to show that [ENB] is very safe,” Dr. Lau said in an interview. “And the numbers are significantly better than historic CT-guided biopsy data.”

Considering the choice between ENB and CT-guided biopsy, invited discussant Anne-Marie Dingemans, MD, of Maastricht University, the Netherlands, offered a different viewpoint.

Will Pass/MDedge News

“CT-guided biopsies are low cost ... and the sensitivity is very, very high,” Dr. Dingemans said. “In good hands, with a good radiologist, you have a high chance that you will have a good diagnosis of the nodules.” She also noted that a bronchus sign does not impact efficacy.

“I’m very into CT-guided biopsies,” Dr. Dingemans continued, noting that the radiologist at her treatment center takes biopsies with a 10-gauge large-core needle. With this technique, Dr. Dingemans reported a 5.7% pneumothorax rate, which is comparable with the present NAVIGATE data.

However, Dr. Lau contested this figure.

“The pneumothorax rates [for CT-guided biopsy] in larger studies have always been about 20% to 40%,” Dr. Lau said. “You can’t compare large overall practice in a pragmatic study capturing everyone versus one single center. The truth is, most centers will have a 20% pneumothorax rate.”

Dr. Lau added that patient experiences are likely to be better with ENB than with CT-guided percutaneous biopsy.

“To me, patient comfort for biopsy is essential,” Dr. Lau said. “Having a needle stuck into your chest – it’s very uncomfortable. I’ve had patients who’ve come to me after they had a percutaneous biopsy and who for some reason needed a re-biopsy ... those patients almost always wish they had navigational bronchoscopy the first time because there would be no pain for them.”

When asked about capital cost concerns surrounding ENB, Dr. Lau suggested that the benefits outweigh the costs.

“The most expensive procedure is the one you have to do again,” Dr. Lau said. “So what we do is put a brush in, and a needle, and a biopsy, and hopefully, one of those three, if not all three, gets tissue, and we can do that with navigational bronchoscopy because there is one channel down. You can’t repeatedly stick needles into patients. By definition, you can’t throw three needle jabs, because you will get a 90% pneumothorax rate. And that’s the beauty of navigational bronchoscopy as well, because in the NAVIGATE series, a number of patients, about 10%, had multiple lesions biopsied.” Furthermore, Dr. Lau noted, percutaneous biopsy is “almost never” performed bilaterally, for fear of collapsing both lungs, but this is not the case with ENB. “We’ve done it on patients who have one lung,” he said.

Dr. Lau predicted that costs of ENB will come down with time. “Because of the number of products increasing, the price will drop,” he said.

Concluding the interview, Dr. Lau offered a summarizing message: “If you want to give the patient the safe option, you should do [ENB], and when it becomes more popular, the price will fall,” he said.

Medtronic funded the study. The investigators reported financial relationships with Olympus, Ambu, PulmonX, Boston Scientific, and others.

SOURCE: Lau et al. ELCC 2019. Abstract 68O.

GENEVA – For lung lesion biopsy, electromagnetic navigation bronchoscopy (ENB) offers high navigational success with a relatively low rate of pneumothorax, according to European data from the international NAVIGATE study.

Will Pass/MDedge News

In addition to lung lesion biopsy, ENB can facilitate concurrent lymph node sampling and fiducial placement during a single anesthetic event, reported lead author Kelvin Lau, MD, chief of thoracic surgery at Barts Thorax Centre in London, and his colleagues. According to Dr. Lau, who presented at the European Lung Cancer Conference, the findings from this European cohort add weight to previously published data from the NAVIGATE trial, which aims to demonstrate real-world use of ENB.

“The outcomes show that [ENB] is very safe in terms of pneumothorax rate, despite the fact that many of these patients were challenging and actually were turned down by the percutaneous radiologist before they came to us,” Dr. Lau said at the meeting, presented by the European Society for Medical Oncology.

Out of 1,200 patients enrolled in the NAVIGATE trial in the United States and Europe, the present 1-month interim analysis showed experiences with 175 patients treated at eight European centers. Anyone undergoing navigational bronchoscopy was eligible. The primary outcome was pneumothorax rate and the secondary outcome was diagnostic yield.

Data analysis showed that lesions were most frequently in the upper lobe (62.6%) and in the peripheral third of the lung (72.7%), the latter of which is beyond the reach of a conventional bronchoscope. In two out of three patients (66.8%), a bronchus sign was present, which “means that the bronchoscope runs straight into the lesion, and theoretically means it’s easier to access,” Dr. Lau said. Almost all patients had ENB for lung biopsy (99.4%), while in a small minority (8.0%), ENB was used for fiducial marking. The median total procedure time was 43.5 minutes, of which 32.9 minutes were spent navigating and sampling with ENB.

The ENB-related pneumothorax rate was 7.4%, although a slightly lower percentage, 5.1%, required intervention or hospitalization. According to the ENB-related Common Terminology Criteria for Adverse Events, 2.3% of patients had grade 2 or higher bronchopulmonary hemorrhage and 0.6% of patients had grade 4 or higher respiratory failure. Although the secondary endpoint, diagnostic yield, was not met because of inadequate follow-up time, the navigational success rate, defined as access to the intended lung lesion, was 96.6%, which offers some sense of efficacy.

“The purpose of this study is to show that [ENB] is very safe,” Dr. Lau said in an interview. “And the numbers are significantly better than historic CT-guided biopsy data.”

Considering the choice between ENB and CT-guided biopsy, invited discussant Anne-Marie Dingemans, MD, of Maastricht University, the Netherlands, offered a different viewpoint.

Will Pass/MDedge News

“CT-guided biopsies are low cost ... and the sensitivity is very, very high,” Dr. Dingemans said. “In good hands, with a good radiologist, you have a high chance that you will have a good diagnosis of the nodules.” She also noted that a bronchus sign does not impact efficacy.

“I’m very into CT-guided biopsies,” Dr. Dingemans continued, noting that the radiologist at her treatment center takes biopsies with a 10-gauge large-core needle. With this technique, Dr. Dingemans reported a 5.7% pneumothorax rate, which is comparable with the present NAVIGATE data.

However, Dr. Lau contested this figure.

“The pneumothorax rates [for CT-guided biopsy] in larger studies have always been about 20% to 40%,” Dr. Lau said. “You can’t compare large overall practice in a pragmatic study capturing everyone versus one single center. The truth is, most centers will have a 20% pneumothorax rate.”

Dr. Lau added that patient experiences are likely to be better with ENB than with CT-guided percutaneous biopsy.

“To me, patient comfort for biopsy is essential,” Dr. Lau said. “Having a needle stuck into your chest – it’s very uncomfortable. I’ve had patients who’ve come to me after they had a percutaneous biopsy and who for some reason needed a re-biopsy ... those patients almost always wish they had navigational bronchoscopy the first time because there would be no pain for them.”

When asked about capital cost concerns surrounding ENB, Dr. Lau suggested that the benefits outweigh the costs.

“The most expensive procedure is the one you have to do again,” Dr. Lau said. “So what we do is put a brush in, and a needle, and a biopsy, and hopefully, one of those three, if not all three, gets tissue, and we can do that with navigational bronchoscopy because there is one channel down. You can’t repeatedly stick needles into patients. By definition, you can’t throw three needle jabs, because you will get a 90% pneumothorax rate. And that’s the beauty of navigational bronchoscopy as well, because in the NAVIGATE series, a number of patients, about 10%, had multiple lesions biopsied.” Furthermore, Dr. Lau noted, percutaneous biopsy is “almost never” performed bilaterally, for fear of collapsing both lungs, but this is not the case with ENB. “We’ve done it on patients who have one lung,” he said.

Dr. Lau predicted that costs of ENB will come down with time. “Because of the number of products increasing, the price will drop,” he said.

Concluding the interview, Dr. Lau offered a summarizing message: “If you want to give the patient the safe option, you should do [ENB], and when it becomes more popular, the price will fall,” he said.

Medtronic funded the study. The investigators reported financial relationships with Olympus, Ambu, PulmonX, Boston Scientific, and others.

SOURCE: Lau et al. ELCC 2019. Abstract 68O.

GENEVA – For lung lesion biopsy, electromagnetic navigation bronchoscopy (ENB) offers high navigational success with a relatively low rate of pneumothorax, according to European data from the international NAVIGATE study.

Will Pass/MDedge News

In addition to lung lesion biopsy, ENB can facilitate concurrent lymph node sampling and fiducial placement during a single anesthetic event, reported lead author Kelvin Lau, MD, chief of thoracic surgery at Barts Thorax Centre in London, and his colleagues. According to Dr. Lau, who presented at the European Lung Cancer Conference, the findings from this European cohort add weight to previously published data from the NAVIGATE trial, which aims to demonstrate real-world use of ENB.

“The outcomes show that [ENB] is very safe in terms of pneumothorax rate, despite the fact that many of these patients were challenging and actually were turned down by the percutaneous radiologist before they came to us,” Dr. Lau said at the meeting, presented by the European Society for Medical Oncology.

Out of 1,200 patients enrolled in the NAVIGATE trial in the United States and Europe, the present 1-month interim analysis showed experiences with 175 patients treated at eight European centers. Anyone undergoing navigational bronchoscopy was eligible. The primary outcome was pneumothorax rate and the secondary outcome was diagnostic yield.

Data analysis showed that lesions were most frequently in the upper lobe (62.6%) and in the peripheral third of the lung (72.7%), the latter of which is beyond the reach of a conventional bronchoscope. In two out of three patients (66.8%), a bronchus sign was present, which “means that the bronchoscope runs straight into the lesion, and theoretically means it’s easier to access,” Dr. Lau said. Almost all patients had ENB for lung biopsy (99.4%), while in a small minority (8.0%), ENB was used for fiducial marking. The median total procedure time was 43.5 minutes, of which 32.9 minutes were spent navigating and sampling with ENB.

The ENB-related pneumothorax rate was 7.4%, although a slightly lower percentage, 5.1%, required intervention or hospitalization. According to the ENB-related Common Terminology Criteria for Adverse Events, 2.3% of patients had grade 2 or higher bronchopulmonary hemorrhage and 0.6% of patients had grade 4 or higher respiratory failure. Although the secondary endpoint, diagnostic yield, was not met because of inadequate follow-up time, the navigational success rate, defined as access to the intended lung lesion, was 96.6%, which offers some sense of efficacy.

“The purpose of this study is to show that [ENB] is very safe,” Dr. Lau said in an interview. “And the numbers are significantly better than historic CT-guided biopsy data.”

Considering the choice between ENB and CT-guided biopsy, invited discussant Anne-Marie Dingemans, MD, of Maastricht University, the Netherlands, offered a different viewpoint.

Will Pass/MDedge News

“CT-guided biopsies are low cost ... and the sensitivity is very, very high,” Dr. Dingemans said. “In good hands, with a good radiologist, you have a high chance that you will have a good diagnosis of the nodules.” She also noted that a bronchus sign does not impact efficacy.

“I’m very into CT-guided biopsies,” Dr. Dingemans continued, noting that the radiologist at her treatment center takes biopsies with a 10-gauge large-core needle. With this technique, Dr. Dingemans reported a 5.7% pneumothorax rate, which is comparable with the present NAVIGATE data.

However, Dr. Lau contested this figure.

“The pneumothorax rates [for CT-guided biopsy] in larger studies have always been about 20% to 40%,” Dr. Lau said. “You can’t compare large overall practice in a pragmatic study capturing everyone versus one single center. The truth is, most centers will have a 20% pneumothorax rate.”

Dr. Lau added that patient experiences are likely to be better with ENB than with CT-guided percutaneous biopsy.

“To me, patient comfort for biopsy is essential,” Dr. Lau said. “Having a needle stuck into your chest – it’s very uncomfortable. I’ve had patients who’ve come to me after they had a percutaneous biopsy and who for some reason needed a re-biopsy ... those patients almost always wish they had navigational bronchoscopy the first time because there would be no pain for them.”

When asked about capital cost concerns surrounding ENB, Dr. Lau suggested that the benefits outweigh the costs.

“The most expensive procedure is the one you have to do again,” Dr. Lau said. “So what we do is put a brush in, and a needle, and a biopsy, and hopefully, one of those three, if not all three, gets tissue, and we can do that with navigational bronchoscopy because there is one channel down. You can’t repeatedly stick needles into patients. By definition, you can’t throw three needle jabs, because you will get a 90% pneumothorax rate. And that’s the beauty of navigational bronchoscopy as well, because in the NAVIGATE series, a number of patients, about 10%, had multiple lesions biopsied.” Furthermore, Dr. Lau noted, percutaneous biopsy is “almost never” performed bilaterally, for fear of collapsing both lungs, but this is not the case with ENB. “We’ve done it on patients who have one lung,” he said.

Dr. Lau predicted that costs of ENB will come down with time. “Because of the number of products increasing, the price will drop,” he said.

Concluding the interview, Dr. Lau offered a summarizing message: “If you want to give the patient the safe option, you should do [ENB], and when it becomes more popular, the price will fall,” he said.

Medtronic funded the study. The investigators reported financial relationships with Olympus, Ambu, PulmonX, Boston Scientific, and others.

SOURCE: Lau et al. ELCC 2019. Abstract 68O.

Individuals who are younger when diagnosed with type 2 diabetes are at greater risk of cardiovascular disease and death, compared with those diagnosed at an older age, according to a retrospective study involving almost 2 million people.

People diagnosed with type 2 diabetes at age 40 or younger were at greatest risk of most outcomes, reported lead author Naveed Sattar, MD, PhD, professor of metabolic medicine, University of Glasgow, Scotland, and his colleagues. “Treatment target recommendations in regards to the risk factor control may need to be more aggressive in people developing diabetes at younger ages,” they wrote in Circulation. 

In contrast, developing type 2 diabetes over the age of 80 years had little impact on risks.

“[R]eassessment of treatment goals in elderly might be useful,” the investigators wrote. “Diabetes screening needs for the elderly (above 80) should also be reevaluated.”

The study involved 318,083 patients with type 2 diabetes registered  in the Swedish National Diabetes Registry between 1998 and 2012. Each patient was matched with 5 individuals from the general population based on sex, age, and country of residence, providing a control population of 1,575,108. Outcomes assessed included non-cardiovascular mortality, cardiovascular mortality, all causemortality, hospitalization for heart failure, coronary heart disease, stroke, atrial fibrillation, and acute myocardial infarction. Patients were followed for cardiovascular outcomes from 1998 to December 2013, while mortality surveillance continued through 2014.

In comparison with controls, patients 40 years or less had the highest excess risk of the most outcomes. *Excess risk of heart failure was elevated almost 5-fold (hazard ratio (HR), R 4.77), and risk of coronary heart disease wasn’t far behind (HR, 4.33). Risks of acute MI (HR, 3.41), stroke (HR, 3.58), and atrial fibrillation (HR, 1.95) were also elevated. Cardiovascular-related mortality was increased almost 3-fold (HR, 2.72), while total mortality (HR, 2.05) and non-cardiovascular mortality (HR, 1.95) were raised to a lesser degree.

“Thereafter, incremental risks generally declined with each higher decade age at diagnosis” of type 2 diabetes,” the investigators wrote.

After 80 years of age, all relative mortality risk factors dropped to less than 1, indicating lower risk than controls. Although non-fatal outcomes were still greater than 1 in this age group, these risks were “substantially attenuated compared with relative incremental risks in those diagnosed with T2DM at younger ages,” the investigators wrote.

The study was funded by the Swedish Association of Local Authorities Regions, the Swedish Heart and Lung Foundation, and the Swedish Research Council.

The investigators disclosed financial relationships with Amgen, AstraZeneca, Eli Lilly, and other pharmaceutical companies.

SOURCE: Sattar et al. Circulation. 2019 Apr 8. doi:10.1161/CIRCULATIONAHA.118.037885.

Individuals who are younger when diagnosed with type 2 diabetes are at greater risk of cardiovascular disease and death, compared with those diagnosed at an older age, according to a retrospective study involving almost 2 million people.

People diagnosed with type 2 diabetes at age 40 or younger were at greatest risk of most outcomes, reported lead author Naveed Sattar, MD, PhD, professor of metabolic medicine, University of Glasgow, Scotland, and his colleagues. “Treatment target recommendations in regards to the risk factor control may need to be more aggressive in people developing diabetes at younger ages,” they wrote in Circulation. 

In contrast, developing type 2 diabetes over the age of 80 years had little impact on risks.

“[R]eassessment of treatment goals in elderly might be useful,” the investigators wrote. “Diabetes screening needs for the elderly (above 80) should also be reevaluated.”

The study involved 318,083 patients with type 2 diabetes registered  in the Swedish National Diabetes Registry between 1998 and 2012. Each patient was matched with 5 individuals from the general population based on sex, age, and country of residence, providing a control population of 1,575,108. Outcomes assessed included non-cardiovascular mortality, cardiovascular mortality, all causemortality, hospitalization for heart failure, coronary heart disease, stroke, atrial fibrillation, and acute myocardial infarction. Patients were followed for cardiovascular outcomes from 1998 to December 2013, while mortality surveillance continued through 2014.

In comparison with controls, patients 40 years or less had the highest excess risk of the most outcomes. *Excess risk of heart failure was elevated almost 5-fold (hazard ratio (HR), R 4.77), and risk of coronary heart disease wasn’t far behind (HR, 4.33). Risks of acute MI (HR, 3.41), stroke (HR, 3.58), and atrial fibrillation (HR, 1.95) were also elevated. Cardiovascular-related mortality was increased almost 3-fold (HR, 2.72), while total mortality (HR, 2.05) and non-cardiovascular mortality (HR, 1.95) were raised to a lesser degree.

“Thereafter, incremental risks generally declined with each higher decade age at diagnosis” of type 2 diabetes,” the investigators wrote.

After 80 years of age, all relative mortality risk factors dropped to less than 1, indicating lower risk than controls. Although non-fatal outcomes were still greater than 1 in this age group, these risks were “substantially attenuated compared with relative incremental risks in those diagnosed with T2DM at younger ages,” the investigators wrote.

The study was funded by the Swedish Association of Local Authorities Regions, the Swedish Heart and Lung Foundation, and the Swedish Research Council.

The investigators disclosed financial relationships with Amgen, AstraZeneca, Eli Lilly, and other pharmaceutical companies.

SOURCE: Sattar et al. Circulation. 2019 Apr 8. doi:10.1161/CIRCULATIONAHA.118.037885.

Individuals who are younger when diagnosed with type 2 diabetes are at greater risk of cardiovascular disease and death, compared with those diagnosed at an older age, according to a retrospective study involving almost 2 million people.

People diagnosed with type 2 diabetes at age 40 or younger were at greatest risk of most outcomes, reported lead author Naveed Sattar, MD, PhD, professor of metabolic medicine, University of Glasgow, Scotland, and his colleagues. “Treatment target recommendations in regards to the risk factor control may need to be more aggressive in people developing diabetes at younger ages,” they wrote in Circulation. 

In contrast, developing type 2 diabetes over the age of 80 years had little impact on risks.

“[R]eassessment of treatment goals in elderly might be useful,” the investigators wrote. “Diabetes screening needs for the elderly (above 80) should also be reevaluated.”

The study involved 318,083 patients with type 2 diabetes registered  in the Swedish National Diabetes Registry between 1998 and 2012. Each patient was matched with 5 individuals from the general population based on sex, age, and country of residence, providing a control population of 1,575,108. Outcomes assessed included non-cardiovascular mortality, cardiovascular mortality, all causemortality, hospitalization for heart failure, coronary heart disease, stroke, atrial fibrillation, and acute myocardial infarction. Patients were followed for cardiovascular outcomes from 1998 to December 2013, while mortality surveillance continued through 2014.

In comparison with controls, patients 40 years or less had the highest excess risk of the most outcomes. *Excess risk of heart failure was elevated almost 5-fold (hazard ratio (HR), R 4.77), and risk of coronary heart disease wasn’t far behind (HR, 4.33). Risks of acute MI (HR, 3.41), stroke (HR, 3.58), and atrial fibrillation (HR, 1.95) were also elevated. Cardiovascular-related mortality was increased almost 3-fold (HR, 2.72), while total mortality (HR, 2.05) and non-cardiovascular mortality (HR, 1.95) were raised to a lesser degree.

“Thereafter, incremental risks generally declined with each higher decade age at diagnosis” of type 2 diabetes,” the investigators wrote.

After 80 years of age, all relative mortality risk factors dropped to less than 1, indicating lower risk than controls. Although non-fatal outcomes were still greater than 1 in this age group, these risks were “substantially attenuated compared with relative incremental risks in those diagnosed with T2DM at younger ages,” the investigators wrote.

The study was funded by the Swedish Association of Local Authorities Regions, the Swedish Heart and Lung Foundation, and the Swedish Research Council.

The investigators disclosed financial relationships with Amgen, AstraZeneca, Eli Lilly, and other pharmaceutical companies.

SOURCE: Sattar et al. Circulation. 2019 Apr 8. doi:10.1161/CIRCULATIONAHA.118.037885.

GLASGOW – Targeting circulating parasitic histones may hold promise for patients with cerebral malaria (CM), according to investigators.

A retrospective study, involving over 300 individuals, compared parasitic histone concentrations among patients with various forms of malaria and non-malarial illnesses, in addition to healthy controls, finding that elevated histone levels were associated with malarial disease severity and death, reported Simon Abrams, PhD, of the University of Liverpool, UK, a coauthor of the study. He noted that this research could guide the development of treatment strategies for hundreds of thousands of patients each year, particularly children.

“Cerebral malaria is the most severe form of Plasmodium falciparum infection, and despite effective anti-malarial therapy, between 10% and 20% of children that develop cerebral malaria die,” Dr. Abrams said during his presentation at the annual meeting of the British Society for Haematology. “This accounts for a huge amount of deaths per annum. Around 400,000 malarial deaths are in children in subSaharan Africa, and death typically occurs within 24 hours of hospital admission.”

In CM, the blood-brain barrier deteriorates, leading to brain swelling, hemorrhaging, clot formation, and in many cases, death, Dr. Abrams said. CM patients with the worst outcomes typically have retinal abnormalities on fundic exam, granting the disease subtype “retinopathy-positive.”

Aided by colleagues in Malawi, the investigators gathered over 300 patient samples for analysis. They found that patients with retinopathy-positive CM had higher mean extracellular histone levels than retinopathy-negative CM patients and healthy controls (22.6 mcg/ml, 6.31 mcg/ml, and 0.33 mcg/ml, respectively). In addition, retinopathy-positive CM patients who died had significantly higher levels of circulating histones, compared with similar patients who survived (35.7 mcg/ml vs. 21.6 mcg/ml).

These findings translated to predictive capability, as the investigators showed that patients with CM who had elevated histones when admitted to the hospital were at a higher risk of death than those with normal histone levels (P = .04). Unlike patients with CM, patients with uncomplicated malaria had relatively low histone levels (0.57 mcg/ml), as did patients with mild non-malarial febrile illness (1.73 mcg/ml) and non-malarial coma (1.73 mcg/ml).

During his presentation, Dr. Abrams elaborated on the origins of these histones and how they contribute to poor outcomes in patients.

“Histones are small positively charged proteins that bind to negatively charged DNA,” Dr. Abrams said. “Typically, they are found within the cell nucleus, where they are involved in the packaging of DNA. However, during cell death and cell damage, histones are released from the nucleus, extracellularly, and we find that they are very much elevated in critically ill patients that have undergone huge amounts of cell death and damage.”

Once in circulation, histones can make a bad situation even worse.

“Work by ourselves and others around the globe have found that when circulating histones are elevated in these critically ill patients, they’re extremely toxic,” Dr. Abrams said. “Histones can induce endothelial damage and vascular permeability.” In addition, he pointed out that histones are pro-inflammatory and pro-coagulant. “If you bring all of these phenomena together,” he pointed out, “histones induce organ injury and mortality in critically ill patients.”

“The current hypothesis is that if you’re treating patients with these antimalarials, and it’s killing off the parasite, it may cause the histones to be released, which is actually worse for certain patients,” Dr. Abrams explained.

Based on this hypothesis, the investigators developed an anti-histone therapy.

“We’ve got a small peptide that we use to bind to the histones that reduces their toxicity,” Dr. Abrams said. “If we coincubate the serum of [CM] patients with our anti-histone reagent and then put this onto a monolayer of endothelial cells, we see that this toxicity is inhibited. Therefore, this is suggestive that a major toxic factor within these patients are the extracellular histones.”

Providing additional support for the role of histones in cerebral toxicity, postmortem brain tissue from patients with CM showed localization of histones to the endothelium, which has been tied with increased permeability of vascular tissue. In addition, “we are seeing co-localization between the histones and the sequestration of the malarial parasite itself,” Dr. Abrams said. 

Concluding his presentation, he looked to the future.

“It’s difficult to get an animal model for malaria,” but he and his associates are currently working with other investigators to develop one. Once developed, the investigators plan on testing concurrent administration of anti-malarial therapy with antihistone therapy.

“What we’re hoping is that sometime in the future, maybe we’d be able to target circulating histones in this patient cohort to improve the survival of these patients,” Dr. Abrams said.

The investigators declared no conflicts of interest.

SOURCE: Moxon et al. BSH 2019. Abstract OR-034.

GLASGOW – Targeting circulating parasitic histones may hold promise for patients with cerebral malaria (CM), according to investigators.

A retrospective study, involving over 300 individuals, compared parasitic histone concentrations among patients with various forms of malaria and non-malarial illnesses, in addition to healthy controls, finding that elevated histone levels were associated with malarial disease severity and death, reported Simon Abrams, PhD, of the University of Liverpool, UK, a coauthor of the study. He noted that this research could guide the development of treatment strategies for hundreds of thousands of patients each year, particularly children.

“Cerebral malaria is the most severe form of Plasmodium falciparum infection, and despite effective anti-malarial therapy, between 10% and 20% of children that develop cerebral malaria die,” Dr. Abrams said during his presentation at the annual meeting of the British Society for Haematology. “This accounts for a huge amount of deaths per annum. Around 400,000 malarial deaths are in children in subSaharan Africa, and death typically occurs within 24 hours of hospital admission.”

In CM, the blood-brain barrier deteriorates, leading to brain swelling, hemorrhaging, clot formation, and in many cases, death, Dr. Abrams said. CM patients with the worst outcomes typically have retinal abnormalities on fundic exam, granting the disease subtype “retinopathy-positive.”

Aided by colleagues in Malawi, the investigators gathered over 300 patient samples for analysis. They found that patients with retinopathy-positive CM had higher mean extracellular histone levels than retinopathy-negative CM patients and healthy controls (22.6 mcg/ml, 6.31 mcg/ml, and 0.33 mcg/ml, respectively). In addition, retinopathy-positive CM patients who died had significantly higher levels of circulating histones, compared with similar patients who survived (35.7 mcg/ml vs. 21.6 mcg/ml).

These findings translated to predictive capability, as the investigators showed that patients with CM who had elevated histones when admitted to the hospital were at a higher risk of death than those with normal histone levels (P = .04). Unlike patients with CM, patients with uncomplicated malaria had relatively low histone levels (0.57 mcg/ml), as did patients with mild non-malarial febrile illness (1.73 mcg/ml) and non-malarial coma (1.73 mcg/ml).

During his presentation, Dr. Abrams elaborated on the origins of these histones and how they contribute to poor outcomes in patients.

“Histones are small positively charged proteins that bind to negatively charged DNA,” Dr. Abrams said. “Typically, they are found within the cell nucleus, where they are involved in the packaging of DNA. However, during cell death and cell damage, histones are released from the nucleus, extracellularly, and we find that they are very much elevated in critically ill patients that have undergone huge amounts of cell death and damage.”

Once in circulation, histones can make a bad situation even worse.

“Work by ourselves and others around the globe have found that when circulating histones are elevated in these critically ill patients, they’re extremely toxic,” Dr. Abrams said. “Histones can induce endothelial damage and vascular permeability.” In addition, he pointed out that histones are pro-inflammatory and pro-coagulant. “If you bring all of these phenomena together,” he pointed out, “histones induce organ injury and mortality in critically ill patients.”

“The current hypothesis is that if you’re treating patients with these antimalarials, and it’s killing off the parasite, it may cause the histones to be released, which is actually worse for certain patients,” Dr. Abrams explained.

Based on this hypothesis, the investigators developed an anti-histone therapy.

“We’ve got a small peptide that we use to bind to the histones that reduces their toxicity,” Dr. Abrams said. “If we coincubate the serum of [CM] patients with our anti-histone reagent and then put this onto a monolayer of endothelial cells, we see that this toxicity is inhibited. Therefore, this is suggestive that a major toxic factor within these patients are the extracellular histones.”

Providing additional support for the role of histones in cerebral toxicity, postmortem brain tissue from patients with CM showed localization of histones to the endothelium, which has been tied with increased permeability of vascular tissue. In addition, “we are seeing co-localization between the histones and the sequestration of the malarial parasite itself,” Dr. Abrams said. 

Concluding his presentation, he looked to the future.

“It’s difficult to get an animal model for malaria,” but he and his associates are currently working with other investigators to develop one. Once developed, the investigators plan on testing concurrent administration of anti-malarial therapy with antihistone therapy.

“What we’re hoping is that sometime in the future, maybe we’d be able to target circulating histones in this patient cohort to improve the survival of these patients,” Dr. Abrams said.

The investigators declared no conflicts of interest.

SOURCE: Moxon et al. BSH 2019. Abstract OR-034.

GLASGOW – Targeting circulating parasitic histones may hold promise for patients with cerebral malaria (CM), according to investigators.

A retrospective study, involving over 300 individuals, compared parasitic histone concentrations among patients with various forms of malaria and non-malarial illnesses, in addition to healthy controls, finding that elevated histone levels were associated with malarial disease severity and death, reported Simon Abrams, PhD, of the University of Liverpool, UK, a coauthor of the study. He noted that this research could guide the development of treatment strategies for hundreds of thousands of patients each year, particularly children.

“Cerebral malaria is the most severe form of Plasmodium falciparum infection, and despite effective anti-malarial therapy, between 10% and 20% of children that develop cerebral malaria die,” Dr. Abrams said during his presentation at the annual meeting of the British Society for Haematology. “This accounts for a huge amount of deaths per annum. Around 400,000 malarial deaths are in children in subSaharan Africa, and death typically occurs within 24 hours of hospital admission.”

In CM, the blood-brain barrier deteriorates, leading to brain swelling, hemorrhaging, clot formation, and in many cases, death, Dr. Abrams said. CM patients with the worst outcomes typically have retinal abnormalities on fundic exam, granting the disease subtype “retinopathy-positive.”

Aided by colleagues in Malawi, the investigators gathered over 300 patient samples for analysis. They found that patients with retinopathy-positive CM had higher mean extracellular histone levels than retinopathy-negative CM patients and healthy controls (22.6 mcg/ml, 6.31 mcg/ml, and 0.33 mcg/ml, respectively). In addition, retinopathy-positive CM patients who died had significantly higher levels of circulating histones, compared with similar patients who survived (35.7 mcg/ml vs. 21.6 mcg/ml).

These findings translated to predictive capability, as the investigators showed that patients with CM who had elevated histones when admitted to the hospital were at a higher risk of death than those with normal histone levels (P = .04). Unlike patients with CM, patients with uncomplicated malaria had relatively low histone levels (0.57 mcg/ml), as did patients with mild non-malarial febrile illness (1.73 mcg/ml) and non-malarial coma (1.73 mcg/ml).

During his presentation, Dr. Abrams elaborated on the origins of these histones and how they contribute to poor outcomes in patients.

“Histones are small positively charged proteins that bind to negatively charged DNA,” Dr. Abrams said. “Typically, they are found within the cell nucleus, where they are involved in the packaging of DNA. However, during cell death and cell damage, histones are released from the nucleus, extracellularly, and we find that they are very much elevated in critically ill patients that have undergone huge amounts of cell death and damage.”

Once in circulation, histones can make a bad situation even worse.

“Work by ourselves and others around the globe have found that when circulating histones are elevated in these critically ill patients, they’re extremely toxic,” Dr. Abrams said. “Histones can induce endothelial damage and vascular permeability.” In addition, he pointed out that histones are pro-inflammatory and pro-coagulant. “If you bring all of these phenomena together,” he pointed out, “histones induce organ injury and mortality in critically ill patients.”

“The current hypothesis is that if you’re treating patients with these antimalarials, and it’s killing off the parasite, it may cause the histones to be released, which is actually worse for certain patients,” Dr. Abrams explained.

Based on this hypothesis, the investigators developed an anti-histone therapy.

“We’ve got a small peptide that we use to bind to the histones that reduces their toxicity,” Dr. Abrams said. “If we coincubate the serum of [CM] patients with our anti-histone reagent and then put this onto a monolayer of endothelial cells, we see that this toxicity is inhibited. Therefore, this is suggestive that a major toxic factor within these patients are the extracellular histones.”

Providing additional support for the role of histones in cerebral toxicity, postmortem brain tissue from patients with CM showed localization of histones to the endothelium, which has been tied with increased permeability of vascular tissue. In addition, “we are seeing co-localization between the histones and the sequestration of the malarial parasite itself,” Dr. Abrams said. 

Concluding his presentation, he looked to the future.

“It’s difficult to get an animal model for malaria,” but he and his associates are currently working with other investigators to develop one. Once developed, the investigators plan on testing concurrent administration of anti-malarial therapy with antihistone therapy.

“What we’re hoping is that sometime in the future, maybe we’d be able to target circulating histones in this patient cohort to improve the survival of these patients,” Dr. Abrams said.

The investigators declared no conflicts of interest.

SOURCE: Moxon et al. BSH 2019. Abstract OR-034.

GLASGOW – Patients with relapsed or refractory mantle cell lymphoma (MCL) who experience disease progression on a Bruton’s tyrosine kinase inhibitor (BTKi) may respond best to a combination of rituximab, bendamustine, and cytarabine (R-BAC), based on early results from an ongoing retrospective study.

Will Pass/MDedge News

Findings from the study, which were presented at the annual meeting of the British Society for Haematology, showed that R-BAC after BTKi failure had an overall response rate (ORR) of 90.5%.

This is a “remarkable response rate” according to the investigators, who cited previously reported response rates for other treatments ranging from 29% to 53%.

Treatment of relapsed/refractory MCL patients in the post-BTKi setting is an area of unmet clinical need, said senior author Simon Rule, MD, of the University of Plymouth, England. He noted that there is currently no consensus regarding best treatment strategy for this patient population.

Dr. Rule said that he and his colleagues have collected data on 30 patients so far, of which 22 were included in this early data release.

All patients received R-BAC between 2016 and 2018 at treatment centers in Italy and the United Kingdom. Treatment consisted of rituximab (375 mg/m² or 500 mg) on day 1, bendamustine 70 mg/m² on days 1 and 2, and cytarabine 500 mg/m² on days 1 through 3, given in a 28-day cycle.

Patients received R-BAC immediately after BTKi failure. Data were drawn from hospital records.

Analysis showed that the median patient age was 65 years, with a range from 43 to 79 years. Most patients were men (81.8%), 55.0% were high risk based on the Mantle Cell Lymphoma International Prognostic Index, and 22.7% had blastoid morphology.

Patients had a median of two prior systemic therapies, with a range from one to six lines. First-line therapies included rituximab in combination with HDAC (high-dose cytarabine containing regimen), CHOP, CVP, or ibrutinib. Nine patients (42.9%) had allogeneic stem cell transplantation (ASCT) after induction treatment.

For BTKi therapy, most patients received ibrutinib (n = 18), while the remainder received acalabrutinib, tirabrutinib or M7583. Most patients discontinued BTKi therapy because of disease progression (90.9%); two patients stopped because of a lack of response (9.1%).

The median number of R-BAC cycles received was four. Two patients started with attenuated doses and seven patients reduced doses after the first cycle. More than 70% of patients completed R-BAC treatment.

The estimated median progression-free survival was 7.3 months and estimated median overall survival was 11.2 months.

Although the investigators reported a complete response rate of 57.1%, they noted that this figure “may be exaggerated” because of a lack of bone marrow biopsy; however, they suggested that the overall response rate (90.5%) “should be accurate.”

During the course of treatment, 31.8% of patients required inpatient admission, 22.7% developed neutropenic fever, and 77.8% required transfusion support. No treatment-related deaths occurred.

“This population, enriched for patients with high risk features, showed remarkable response rates to R-BAC,” the investigators wrote. “The treatment had acceptable toxicity, maintained efficacy at attenuated doses, and was used successfully as a bridge to ASCT in over 20% of patients.”

The investigators suggested that R-BAC should be considered a new standard of care in the United Kingdom for bendamustine-naive patients who are unable to be enrolled in clinical trials. “The high response rate makes it particularly appealing for patients considered candidates for consolidation ASCT,” they wrote.

In an interview, Dr. Rule added perspective to these findings.

“There’s been an obsession with venetoclax, that that’s the answer, but it really isn’t,” Dr. Rule said. “So people are looking for a new drug. I guess what I do differently to most people is I use CHOP frontline rather than bendamustine. To me, that’s the best way of sequencing the therapies, whereas if you use [bendamustine and rituximab] up front, which a lot of people do, particularly in the [United] States, your R-BAC might not be so effective.”

However, Dr. Rule said that first-line therapies appear to have minimal impact on R-BAC efficacy. “Even if you’ve had bendamustine, even if you’ve had high-dose cytarabine, even if you’ve had an allogeneic stem cell transplant, [R-BAC] still works,” he said.

Where patients have issues with tolerability, Dr. Rule noted that dose reductions are possible without sacrificing efficacy.

He offered an example of such a scenario. “My oldest patient was about 80 with blastoid disease, relapsing,” Dr. Rule said. “After ibrutinib, I gave him just a single dose of bendamustine at 70 mg, a single dose of cytarabine at 500 mg, just 1 day, and he had that six times, probably 3 weeks apart. He’s been in complete remission for over a year.”

With data on 30 patients collected, Dr. Rule said that he and his colleagues plan to present more extensive findings at the European Hematology Association Congress, held June 13-16 in Amsterdam.

The investigators reported having no conflicts of interest.
 

GLASGOW – Patients with relapsed or refractory mantle cell lymphoma (MCL) who experience disease progression on a Bruton’s tyrosine kinase inhibitor (BTKi) may respond best to a combination of rituximab, bendamustine, and cytarabine (R-BAC), based on early results from an ongoing retrospective study.

Will Pass/MDedge News

Findings from the study, which were presented at the annual meeting of the British Society for Haematology, showed that R-BAC after BTKi failure had an overall response rate (ORR) of 90.5%.

This is a “remarkable response rate” according to the investigators, who cited previously reported response rates for other treatments ranging from 29% to 53%.

Treatment of relapsed/refractory MCL patients in the post-BTKi setting is an area of unmet clinical need, said senior author Simon Rule, MD, of the University of Plymouth, England. He noted that there is currently no consensus regarding best treatment strategy for this patient population.

Dr. Rule said that he and his colleagues have collected data on 30 patients so far, of which 22 were included in this early data release.

All patients received R-BAC between 2016 and 2018 at treatment centers in Italy and the United Kingdom. Treatment consisted of rituximab (375 mg/m² or 500 mg) on day 1, bendamustine 70 mg/m² on days 1 and 2, and cytarabine 500 mg/m² on days 1 through 3, given in a 28-day cycle.

Patients received R-BAC immediately after BTKi failure. Data were drawn from hospital records.

Analysis showed that the median patient age was 65 years, with a range from 43 to 79 years. Most patients were men (81.8%), 55.0% were high risk based on the Mantle Cell Lymphoma International Prognostic Index, and 22.7% had blastoid morphology.

Patients had a median of two prior systemic therapies, with a range from one to six lines. First-line therapies included rituximab in combination with HDAC (high-dose cytarabine containing regimen), CHOP, CVP, or ibrutinib. Nine patients (42.9%) had allogeneic stem cell transplantation (ASCT) after induction treatment.

For BTKi therapy, most patients received ibrutinib (n = 18), while the remainder received acalabrutinib, tirabrutinib or M7583. Most patients discontinued BTKi therapy because of disease progression (90.9%); two patients stopped because of a lack of response (9.1%).

The median number of R-BAC cycles received was four. Two patients started with attenuated doses and seven patients reduced doses after the first cycle. More than 70% of patients completed R-BAC treatment.

The estimated median progression-free survival was 7.3 months and estimated median overall survival was 11.2 months.

Although the investigators reported a complete response rate of 57.1%, they noted that this figure “may be exaggerated” because of a lack of bone marrow biopsy; however, they suggested that the overall response rate (90.5%) “should be accurate.”

During the course of treatment, 31.8% of patients required inpatient admission, 22.7% developed neutropenic fever, and 77.8% required transfusion support. No treatment-related deaths occurred.

“This population, enriched for patients with high risk features, showed remarkable response rates to R-BAC,” the investigators wrote. “The treatment had acceptable toxicity, maintained efficacy at attenuated doses, and was used successfully as a bridge to ASCT in over 20% of patients.”

The investigators suggested that R-BAC should be considered a new standard of care in the United Kingdom for bendamustine-naive patients who are unable to be enrolled in clinical trials. “The high response rate makes it particularly appealing for patients considered candidates for consolidation ASCT,” they wrote.

In an interview, Dr. Rule added perspective to these findings.

“There’s been an obsession with venetoclax, that that’s the answer, but it really isn’t,” Dr. Rule said. “So people are looking for a new drug. I guess what I do differently to most people is I use CHOP frontline rather than bendamustine. To me, that’s the best way of sequencing the therapies, whereas if you use [bendamustine and rituximab] up front, which a lot of people do, particularly in the [United] States, your R-BAC might not be so effective.”

However, Dr. Rule said that first-line therapies appear to have minimal impact on R-BAC efficacy. “Even if you’ve had bendamustine, even if you’ve had high-dose cytarabine, even if you’ve had an allogeneic stem cell transplant, [R-BAC] still works,” he said.

Where patients have issues with tolerability, Dr. Rule noted that dose reductions are possible without sacrificing efficacy.

He offered an example of such a scenario. “My oldest patient was about 80 with blastoid disease, relapsing,” Dr. Rule said. “After ibrutinib, I gave him just a single dose of bendamustine at 70 mg, a single dose of cytarabine at 500 mg, just 1 day, and he had that six times, probably 3 weeks apart. He’s been in complete remission for over a year.”

With data on 30 patients collected, Dr. Rule said that he and his colleagues plan to present more extensive findings at the European Hematology Association Congress, held June 13-16 in Amsterdam.

The investigators reported having no conflicts of interest.
 

GLASGOW – Patients with relapsed or refractory mantle cell lymphoma (MCL) who experience disease progression on a Bruton’s tyrosine kinase inhibitor (BTKi) may respond best to a combination of rituximab, bendamustine, and cytarabine (R-BAC), based on early results from an ongoing retrospective study.

Will Pass/MDedge News

Findings from the study, which were presented at the annual meeting of the British Society for Haematology, showed that R-BAC after BTKi failure had an overall response rate (ORR) of 90.5%.

This is a “remarkable response rate” according to the investigators, who cited previously reported response rates for other treatments ranging from 29% to 53%.

Treatment of relapsed/refractory MCL patients in the post-BTKi setting is an area of unmet clinical need, said senior author Simon Rule, MD, of the University of Plymouth, England. He noted that there is currently no consensus regarding best treatment strategy for this patient population.

Dr. Rule said that he and his colleagues have collected data on 30 patients so far, of which 22 were included in this early data release.

All patients received R-BAC between 2016 and 2018 at treatment centers in Italy and the United Kingdom. Treatment consisted of rituximab (375 mg/m² or 500 mg) on day 1, bendamustine 70 mg/m² on days 1 and 2, and cytarabine 500 mg/m² on days 1 through 3, given in a 28-day cycle.

Patients received R-BAC immediately after BTKi failure. Data were drawn from hospital records.

Analysis showed that the median patient age was 65 years, with a range from 43 to 79 years. Most patients were men (81.8%), 55.0% were high risk based on the Mantle Cell Lymphoma International Prognostic Index, and 22.7% had blastoid morphology.

Patients had a median of two prior systemic therapies, with a range from one to six lines. First-line therapies included rituximab in combination with HDAC (high-dose cytarabine containing regimen), CHOP, CVP, or ibrutinib. Nine patients (42.9%) had allogeneic stem cell transplantation (ASCT) after induction treatment.

For BTKi therapy, most patients received ibrutinib (n = 18), while the remainder received acalabrutinib, tirabrutinib or M7583. Most patients discontinued BTKi therapy because of disease progression (90.9%); two patients stopped because of a lack of response (9.1%).

The median number of R-BAC cycles received was four. Two patients started with attenuated doses and seven patients reduced doses after the first cycle. More than 70% of patients completed R-BAC treatment.

The estimated median progression-free survival was 7.3 months and estimated median overall survival was 11.2 months.

Although the investigators reported a complete response rate of 57.1%, they noted that this figure “may be exaggerated” because of a lack of bone marrow biopsy; however, they suggested that the overall response rate (90.5%) “should be accurate.”

During the course of treatment, 31.8% of patients required inpatient admission, 22.7% developed neutropenic fever, and 77.8% required transfusion support. No treatment-related deaths occurred.

“This population, enriched for patients with high risk features, showed remarkable response rates to R-BAC,” the investigators wrote. “The treatment had acceptable toxicity, maintained efficacy at attenuated doses, and was used successfully as a bridge to ASCT in over 20% of patients.”

The investigators suggested that R-BAC should be considered a new standard of care in the United Kingdom for bendamustine-naive patients who are unable to be enrolled in clinical trials. “The high response rate makes it particularly appealing for patients considered candidates for consolidation ASCT,” they wrote.

In an interview, Dr. Rule added perspective to these findings.

“There’s been an obsession with venetoclax, that that’s the answer, but it really isn’t,” Dr. Rule said. “So people are looking for a new drug. I guess what I do differently to most people is I use CHOP frontline rather than bendamustine. To me, that’s the best way of sequencing the therapies, whereas if you use [bendamustine and rituximab] up front, which a lot of people do, particularly in the [United] States, your R-BAC might not be so effective.”

However, Dr. Rule said that first-line therapies appear to have minimal impact on R-BAC efficacy. “Even if you’ve had bendamustine, even if you’ve had high-dose cytarabine, even if you’ve had an allogeneic stem cell transplant, [R-BAC] still works,” he said.

Where patients have issues with tolerability, Dr. Rule noted that dose reductions are possible without sacrificing efficacy.

He offered an example of such a scenario. “My oldest patient was about 80 with blastoid disease, relapsing,” Dr. Rule said. “After ibrutinib, I gave him just a single dose of bendamustine at 70 mg, a single dose of cytarabine at 500 mg, just 1 day, and he had that six times, probably 3 weeks apart. He’s been in complete remission for over a year.”

With data on 30 patients collected, Dr. Rule said that he and his colleagues plan to present more extensive findings at the European Hematology Association Congress, held June 13-16 in Amsterdam.

The investigators reported having no conflicts of interest.
 

High-cost hospital stays among elderly patients with cancer are associated with major procedures, more comorbid conditions, hematologic cancer, and metastatic cancer, according to a retrospective analysis of more than 570,000 inpatient visits.

Patients involved in the top 10% most expensive cancer-related hospital visits were more likely to have five or more comorbidities, or receive chemotherapy, reported lead author Jaqueline Avila, PhD candidate at the University of Texas Medical Branch in Galveston, and her colleagues.

“A small fraction (approximately 10%) of patients account for more than half of the overall health care costs incurred annually,” the investigators wrote. The report is in the Journal of Oncology Practice.

“[S]imilar to the general population, a small population of patients with cancer (the top 5% to 10% of patients with highest costs) accounts for more than 80% of the total cancer costs,” the investigators wrote. “However, we lack a detailed understanding of the characteristics of these high-cost and high-risk elderly patients with cancer.”

To gain insight, the investigators analyzed 574,367 cancer-related inpatient visits of patients aged 65 years or older, using data from the 2014 National Inpatient Sample. Visits were divided based on cost, with the top 10% most expensive visits in one group (n = 57,437) and the lower 90% of visits in another group (n = 516,930). The investigators then compared these groups based on a variety of patient factor covariates, including race, sex, age, type of cancer, comorbidities, treatments received, and hospital characteristics, such as private or public ownership and location.

The overall median cost of the top 10% of inpatient visits was $38,194 (interquartile range, $31,405-$51,802), compared with $8,257 in the lower-cost group (interquartile range, $5,032-$13,335). This was partly attributed to comorbidities. In the high-cost group, 38.4% of patients had five or more comorbidities, compared with 26.2% in the lower-cost group (P less than .001).

Procedures also factored into cost. The high-cost group had more procedures than did the lower-cost group (mean, 5.48 vs. 2.36; P less than .001), and expensive stays more often entailed major procedures (67.1% vs. 24.3%; P less than .001). Hematologic cancer and metastatic cancer were also more common in the high-cost group than in the lower-cost group, with rates of 23.5% versus 14.6% and 16.5% versus 11.8%, respectively. Among all cancer types, lymphoma, leukemia, and myeloma were the most expensive. The investigators noted that 97.9% of stem-cell or bone marrow transplants were received by patients with hematologic cancer.

Cost did not increase directly with age, as patients aged 65-84 years were more likely to have high-cost inpatient visits than were those who were aged 85 years or older.

The investigators suggested that complications of chronic diseases were likely at the root of this difference, particularly among patients in the 65- to 72-year range. “The difference in costs could also be because caregivers and clinicians may choose to provide only necessary and often less intensive procedures and care to the oldest patients,” the investigators wrote.

A variety of other factors were associated with high-cost visits, although to a lesser degree, including male sex, treatment at a metropolitan teaching hospital, higher median household income, radiation therapy, and large bed size.

The investigators stated that more research is needed to determine relationships between costs and medical necessity, and to develop strategies for reducing costs.

“Although we evaluated the drivers of hospital costs, we could not assess whether additional costs incurred by the high-cost group were medically necessary or could be prevented or whether these excess costs resulted in better outcomes,” the investigators wrote. “Additional research is needed to measure outcomes such as survival and quality of life in this high-cost group and also evaluate whether the excess cost is spent on medically necessary services.

“Future studies should address how implementation of models such as the integrative care model and hospice care may affect the distribution of high-cost and low-cost visits,” the investigators suggested.

Novartis funded the study. Dr. Chavez-MacGregor reported financial relationships with Pfizer and Genentech.

SOURCE: Avila et al. JOP. 2019 Apr 4. doi:10.1200/JOP.18.00706.

High-cost hospital stays among elderly patients with cancer are associated with major procedures, more comorbid conditions, hematologic cancer, and metastatic cancer, according to a retrospective analysis of more than 570,000 inpatient visits.

Patients involved in the top 10% most expensive cancer-related hospital visits were more likely to have five or more comorbidities, or receive chemotherapy, reported lead author Jaqueline Avila, PhD candidate at the University of Texas Medical Branch in Galveston, and her colleagues.

“A small fraction (approximately 10%) of patients account for more than half of the overall health care costs incurred annually,” the investigators wrote. The report is in the Journal of Oncology Practice.

“[S]imilar to the general population, a small population of patients with cancer (the top 5% to 10% of patients with highest costs) accounts for more than 80% of the total cancer costs,” the investigators wrote. “However, we lack a detailed understanding of the characteristics of these high-cost and high-risk elderly patients with cancer.”

To gain insight, the investigators analyzed 574,367 cancer-related inpatient visits of patients aged 65 years or older, using data from the 2014 National Inpatient Sample. Visits were divided based on cost, with the top 10% most expensive visits in one group (n = 57,437) and the lower 90% of visits in another group (n = 516,930). The investigators then compared these groups based on a variety of patient factor covariates, including race, sex, age, type of cancer, comorbidities, treatments received, and hospital characteristics, such as private or public ownership and location.

The overall median cost of the top 10% of inpatient visits was $38,194 (interquartile range, $31,405-$51,802), compared with $8,257 in the lower-cost group (interquartile range, $5,032-$13,335). This was partly attributed to comorbidities. In the high-cost group, 38.4% of patients had five or more comorbidities, compared with 26.2% in the lower-cost group (P less than .001).

Procedures also factored into cost. The high-cost group had more procedures than did the lower-cost group (mean, 5.48 vs. 2.36; P less than .001), and expensive stays more often entailed major procedures (67.1% vs. 24.3%; P less than .001). Hematologic cancer and metastatic cancer were also more common in the high-cost group than in the lower-cost group, with rates of 23.5% versus 14.6% and 16.5% versus 11.8%, respectively. Among all cancer types, lymphoma, leukemia, and myeloma were the most expensive. The investigators noted that 97.9% of stem-cell or bone marrow transplants were received by patients with hematologic cancer.

Cost did not increase directly with age, as patients aged 65-84 years were more likely to have high-cost inpatient visits than were those who were aged 85 years or older.

The investigators suggested that complications of chronic diseases were likely at the root of this difference, particularly among patients in the 65- to 72-year range. “The difference in costs could also be because caregivers and clinicians may choose to provide only necessary and often less intensive procedures and care to the oldest patients,” the investigators wrote.

A variety of other factors were associated with high-cost visits, although to a lesser degree, including male sex, treatment at a metropolitan teaching hospital, higher median household income, radiation therapy, and large bed size.

The investigators stated that more research is needed to determine relationships between costs and medical necessity, and to develop strategies for reducing costs.

“Although we evaluated the drivers of hospital costs, we could not assess whether additional costs incurred by the high-cost group were medically necessary or could be prevented or whether these excess costs resulted in better outcomes,” the investigators wrote. “Additional research is needed to measure outcomes such as survival and quality of life in this high-cost group and also evaluate whether the excess cost is spent on medically necessary services.

“Future studies should address how implementation of models such as the integrative care model and hospice care may affect the distribution of high-cost and low-cost visits,” the investigators suggested.

Novartis funded the study. Dr. Chavez-MacGregor reported financial relationships with Pfizer and Genentech.

SOURCE: Avila et al. JOP. 2019 Apr 4. doi:10.1200/JOP.18.00706.

High-cost hospital stays among elderly patients with cancer are associated with major procedures, more comorbid conditions, hematologic cancer, and metastatic cancer, according to a retrospective analysis of more than 570,000 inpatient visits.

Patients involved in the top 10% most expensive cancer-related hospital visits were more likely to have five or more comorbidities, or receive chemotherapy, reported lead author Jaqueline Avila, PhD candidate at the University of Texas Medical Branch in Galveston, and her colleagues.

“A small fraction (approximately 10%) of patients account for more than half of the overall health care costs incurred annually,” the investigators wrote. The report is in the Journal of Oncology Practice.

“[S]imilar to the general population, a small population of patients with cancer (the top 5% to 10% of patients with highest costs) accounts for more than 80% of the total cancer costs,” the investigators wrote. “However, we lack a detailed understanding of the characteristics of these high-cost and high-risk elderly patients with cancer.”

To gain insight, the investigators analyzed 574,367 cancer-related inpatient visits of patients aged 65 years or older, using data from the 2014 National Inpatient Sample. Visits were divided based on cost, with the top 10% most expensive visits in one group (n = 57,437) and the lower 90% of visits in another group (n = 516,930). The investigators then compared these groups based on a variety of patient factor covariates, including race, sex, age, type of cancer, comorbidities, treatments received, and hospital characteristics, such as private or public ownership and location.

The overall median cost of the top 10% of inpatient visits was $38,194 (interquartile range, $31,405-$51,802), compared with $8,257 in the lower-cost group (interquartile range, $5,032-$13,335). This was partly attributed to comorbidities. In the high-cost group, 38.4% of patients had five or more comorbidities, compared with 26.2% in the lower-cost group (P less than .001).

Procedures also factored into cost. The high-cost group had more procedures than did the lower-cost group (mean, 5.48 vs. 2.36; P less than .001), and expensive stays more often entailed major procedures (67.1% vs. 24.3%; P less than .001). Hematologic cancer and metastatic cancer were also more common in the high-cost group than in the lower-cost group, with rates of 23.5% versus 14.6% and 16.5% versus 11.8%, respectively. Among all cancer types, lymphoma, leukemia, and myeloma were the most expensive. The investigators noted that 97.9% of stem-cell or bone marrow transplants were received by patients with hematologic cancer.

Cost did not increase directly with age, as patients aged 65-84 years were more likely to have high-cost inpatient visits than were those who were aged 85 years or older.

The investigators suggested that complications of chronic diseases were likely at the root of this difference, particularly among patients in the 65- to 72-year range. “The difference in costs could also be because caregivers and clinicians may choose to provide only necessary and often less intensive procedures and care to the oldest patients,” the investigators wrote.

A variety of other factors were associated with high-cost visits, although to a lesser degree, including male sex, treatment at a metropolitan teaching hospital, higher median household income, radiation therapy, and large bed size.

The investigators stated that more research is needed to determine relationships between costs and medical necessity, and to develop strategies for reducing costs.

“Although we evaluated the drivers of hospital costs, we could not assess whether additional costs incurred by the high-cost group were medically necessary or could be prevented or whether these excess costs resulted in better outcomes,” the investigators wrote. “Additional research is needed to measure outcomes such as survival and quality of life in this high-cost group and also evaluate whether the excess cost is spent on medically necessary services.

“Future studies should address how implementation of models such as the integrative care model and hospice care may affect the distribution of high-cost and low-cost visits,” the investigators suggested.

Novartis funded the study. Dr. Chavez-MacGregor reported financial relationships with Pfizer and Genentech.

SOURCE: Avila et al. JOP. 2019 Apr 4. doi:10.1200/JOP.18.00706.

Glasgow – Patients with relapsed or refractory multiple myeloma (RRMM) who were treated with a combination of the oral protease inhibitor ixazomib with lenalidomide and dexamethasone (IRd) in routine clinical practice had similar responses to clinical trial patients, according to a global observational study.

Will Pass/MDedge News

Real-world progression-free survival (PFS) and overall response (OR) rates closely approximated data from the TOURMALINE‑MM1 trial, reported lead author Gordon Cook, MB ChB, PhD, clinical director of hematology at the University of Leeds (England).

Tolerability appeared slightly higher in routine clinical practice, and in agreement with previous real-world studies for RRMM, patients who received IRd in earlier lines of therapy had better outcomes than did those who received IRd in later lines of therapy. “The translation of clinical trial data into the real world is really important because we practice in the real world,” Dr. Cook said at the annual meeting of the British Society for Haematology. “We know that trials are really important for establishing efficacy and safety of drugs so they can get licensed and market access, but [clinical trials] often don’t tell us about the true effectiveness of the drugs and tolerability because the populations in trials are often different from [patients in] the real world.”

This situation leads to an evidence gap, which the present trial, dubbed INSIGHT MM aims to fill. INSIGHT is the largest global, prospective, observational trial for multiple myeloma conducted to date, with ongoing enrollment of about 4,200 patients from 15 countries with newly diagnosed or refractory/relapsed multiple myeloma. Dr. Cook estimated that recruitment would be complete by June of 2019.

“The aim of [INSIGHT MM] is to evaluate real-world treatment and outcomes [in multiple myeloma] over 5 years and beyond,” Dr. Cook said.

In combination with interim data from INSIGHT MM (n = 50), Dr. Cook reported patient outcomes from the Czech Registry of Monoclonal Gammopathies (n = 113), a similar database. Unlike INSIGHT MM, which includes patients treated with between one and three prior lines of therapy, the Czech registry does not cap the number of prior therapies. Overall, in the data presented by Dr. Cook, nine countries were represented; about 90% of which were European, although approximately 10% of patients were treated in the United States and about 1% were treated in Taiwan.

The median age of diagnosis was 67 years, with about 14% of patients over the age of 75 years. Median time from diagnosis to initiation of IRd was about 3.5 years (42.6 months), at which point 71% of patients had an Eastern Cooperative Oncology Group performance status of at least 1.

About two-thirds of the patients (65%) had IgG multiple myeloma, and 14% had extramedullary disease. The most common prior therapy was bortezomib (89%), followed by transplant (61%), thalidomide (42%), lenalidomide (21%), carfilzomib (11%), daratumumab (3%), and pomalidomide (2%).

Half of the patients received IRd as second-line therapy, while the other half received the treatment third-line (30%), or fourth-line or later (20%). Median duration of therapy was just over 1 year (14 months), with 62% of patients still receiving therapy at data cutoff.

Dr. Cook cautioned that with a median follow-up of 9.3 months, data are still immature. However, the results so far suggest strong similarities in tolerability and efficacy when comparing real-world and clinical trial administration of IRd.

Routine clinical use was associated with an overall response rate of 74%, compared with 78% in the TOURMALINE‑MM1 trial. Again, showing high similarity, median PFS rates were 20.9 months and 20.6 months for the present data set and the TOURMALINE‑MM1 trial, respectively.

Just 4% of patients permanently discontinued ixazomib in the real-world study, compared with 17% in the clinical trial, suggesting that IRd may be better tolerated in routine clinical practice than the trial data indicated.

“IRd is effective in this setting,” Dr. Cook said. “Bear in mind that patients in the real-world database were further down the line in terms of the treatment pathway, they had prior heavier exposure to bortezomib and lenalidomide, and their performance status was slightly less impressive than it was in [TOURMALINE‑MM1]; therefore, to see this level of response in the real world is very pleasing.”

When asked by an attendee if clinical trials should push for inclusion of patients more representative of real-world populations, Dr. Cook said no. “I think the way we conduct phase 3 clinical trials, in particular, has to be the way it is in order for us to ensure that we can actually get the absolute efficacy and the safety, and that has to be done by a refined population, I’m afraid,” he said.

However, Dr. Cook supported efforts to improve reliability of data for clinicians at the time of drug licensing.

“We should be running real-world exposure in parallel with phase 3 studies, which is harder to do but just requires a bit of imagination,” Dr. Cook said.

The study was funded by Takeda. The investigators reported financial relationships with Takeda and other companies.

SOURCE: Cook G et al. BSH 2019, Abstract OR-018.

Glasgow – Patients with relapsed or refractory multiple myeloma (RRMM) who were treated with a combination of the oral protease inhibitor ixazomib with lenalidomide and dexamethasone (IRd) in routine clinical practice had similar responses to clinical trial patients, according to a global observational study.

Will Pass/MDedge News

Real-world progression-free survival (PFS) and overall response (OR) rates closely approximated data from the TOURMALINE‑MM1 trial, reported lead author Gordon Cook, MB ChB, PhD, clinical director of hematology at the University of Leeds (England).

Tolerability appeared slightly higher in routine clinical practice, and in agreement with previous real-world studies for RRMM, patients who received IRd in earlier lines of therapy had better outcomes than did those who received IRd in later lines of therapy. “The translation of clinical trial data into the real world is really important because we practice in the real world,” Dr. Cook said at the annual meeting of the British Society for Haematology. “We know that trials are really important for establishing efficacy and safety of drugs so they can get licensed and market access, but [clinical trials] often don’t tell us about the true effectiveness of the drugs and tolerability because the populations in trials are often different from [patients in] the real world.”

This situation leads to an evidence gap, which the present trial, dubbed INSIGHT MM aims to fill. INSIGHT is the largest global, prospective, observational trial for multiple myeloma conducted to date, with ongoing enrollment of about 4,200 patients from 15 countries with newly diagnosed or refractory/relapsed multiple myeloma. Dr. Cook estimated that recruitment would be complete by June of 2019.

“The aim of [INSIGHT MM] is to evaluate real-world treatment and outcomes [in multiple myeloma] over 5 years and beyond,” Dr. Cook said.

In combination with interim data from INSIGHT MM (n = 50), Dr. Cook reported patient outcomes from the Czech Registry of Monoclonal Gammopathies (n = 113), a similar database. Unlike INSIGHT MM, which includes patients treated with between one and three prior lines of therapy, the Czech registry does not cap the number of prior therapies. Overall, in the data presented by Dr. Cook, nine countries were represented; about 90% of which were European, although approximately 10% of patients were treated in the United States and about 1% were treated in Taiwan.

The median age of diagnosis was 67 years, with about 14% of patients over the age of 75 years. Median time from diagnosis to initiation of IRd was about 3.5 years (42.6 months), at which point 71% of patients had an Eastern Cooperative Oncology Group performance status of at least 1.

About two-thirds of the patients (65%) had IgG multiple myeloma, and 14% had extramedullary disease. The most common prior therapy was bortezomib (89%), followed by transplant (61%), thalidomide (42%), lenalidomide (21%), carfilzomib (11%), daratumumab (3%), and pomalidomide (2%).

Half of the patients received IRd as second-line therapy, while the other half received the treatment third-line (30%), or fourth-line or later (20%). Median duration of therapy was just over 1 year (14 months), with 62% of patients still receiving therapy at data cutoff.

Dr. Cook cautioned that with a median follow-up of 9.3 months, data are still immature. However, the results so far suggest strong similarities in tolerability and efficacy when comparing real-world and clinical trial administration of IRd.

Routine clinical use was associated with an overall response rate of 74%, compared with 78% in the TOURMALINE‑MM1 trial. Again, showing high similarity, median PFS rates were 20.9 months and 20.6 months for the present data set and the TOURMALINE‑MM1 trial, respectively.

Just 4% of patients permanently discontinued ixazomib in the real-world study, compared with 17% in the clinical trial, suggesting that IRd may be better tolerated in routine clinical practice than the trial data indicated.

“IRd is effective in this setting,” Dr. Cook said. “Bear in mind that patients in the real-world database were further down the line in terms of the treatment pathway, they had prior heavier exposure to bortezomib and lenalidomide, and their performance status was slightly less impressive than it was in [TOURMALINE‑MM1]; therefore, to see this level of response in the real world is very pleasing.”

When asked by an attendee if clinical trials should push for inclusion of patients more representative of real-world populations, Dr. Cook said no. “I think the way we conduct phase 3 clinical trials, in particular, has to be the way it is in order for us to ensure that we can actually get the absolute efficacy and the safety, and that has to be done by a refined population, I’m afraid,” he said.

However, Dr. Cook supported efforts to improve reliability of data for clinicians at the time of drug licensing.

“We should be running real-world exposure in parallel with phase 3 studies, which is harder to do but just requires a bit of imagination,” Dr. Cook said.

The study was funded by Takeda. The investigators reported financial relationships with Takeda and other companies.

SOURCE: Cook G et al. BSH 2019, Abstract OR-018.

Glasgow – Patients with relapsed or refractory multiple myeloma (RRMM) who were treated with a combination of the oral protease inhibitor ixazomib with lenalidomide and dexamethasone (IRd) in routine clinical practice had similar responses to clinical trial patients, according to a global observational study.

Will Pass/MDedge News

Real-world progression-free survival (PFS) and overall response (OR) rates closely approximated data from the TOURMALINE‑MM1 trial, reported lead author Gordon Cook, MB ChB, PhD, clinical director of hematology at the University of Leeds (England).

Tolerability appeared slightly higher in routine clinical practice, and in agreement with previous real-world studies for RRMM, patients who received IRd in earlier lines of therapy had better outcomes than did those who received IRd in later lines of therapy. “The translation of clinical trial data into the real world is really important because we practice in the real world,” Dr. Cook said at the annual meeting of the British Society for Haematology. “We know that trials are really important for establishing efficacy and safety of drugs so they can get licensed and market access, but [clinical trials] often don’t tell us about the true effectiveness of the drugs and tolerability because the populations in trials are often different from [patients in] the real world.”

This situation leads to an evidence gap, which the present trial, dubbed INSIGHT MM aims to fill. INSIGHT is the largest global, prospective, observational trial for multiple myeloma conducted to date, with ongoing enrollment of about 4,200 patients from 15 countries with newly diagnosed or refractory/relapsed multiple myeloma. Dr. Cook estimated that recruitment would be complete by June of 2019.

“The aim of [INSIGHT MM] is to evaluate real-world treatment and outcomes [in multiple myeloma] over 5 years and beyond,” Dr. Cook said.

In combination with interim data from INSIGHT MM (n = 50), Dr. Cook reported patient outcomes from the Czech Registry of Monoclonal Gammopathies (n = 113), a similar database. Unlike INSIGHT MM, which includes patients treated with between one and three prior lines of therapy, the Czech registry does not cap the number of prior therapies. Overall, in the data presented by Dr. Cook, nine countries were represented; about 90% of which were European, although approximately 10% of patients were treated in the United States and about 1% were treated in Taiwan.

The median age of diagnosis was 67 years, with about 14% of patients over the age of 75 years. Median time from diagnosis to initiation of IRd was about 3.5 years (42.6 months), at which point 71% of patients had an Eastern Cooperative Oncology Group performance status of at least 1.

About two-thirds of the patients (65%) had IgG multiple myeloma, and 14% had extramedullary disease. The most common prior therapy was bortezomib (89%), followed by transplant (61%), thalidomide (42%), lenalidomide (21%), carfilzomib (11%), daratumumab (3%), and pomalidomide (2%).

Half of the patients received IRd as second-line therapy, while the other half received the treatment third-line (30%), or fourth-line or later (20%). Median duration of therapy was just over 1 year (14 months), with 62% of patients still receiving therapy at data cutoff.

Dr. Cook cautioned that with a median follow-up of 9.3 months, data are still immature. However, the results so far suggest strong similarities in tolerability and efficacy when comparing real-world and clinical trial administration of IRd.

Routine clinical use was associated with an overall response rate of 74%, compared with 78% in the TOURMALINE‑MM1 trial. Again, showing high similarity, median PFS rates were 20.9 months and 20.6 months for the present data set and the TOURMALINE‑MM1 trial, respectively.

Just 4% of patients permanently discontinued ixazomib in the real-world study, compared with 17% in the clinical trial, suggesting that IRd may be better tolerated in routine clinical practice than the trial data indicated.

“IRd is effective in this setting,” Dr. Cook said. “Bear in mind that patients in the real-world database were further down the line in terms of the treatment pathway, they had prior heavier exposure to bortezomib and lenalidomide, and their performance status was slightly less impressive than it was in [TOURMALINE‑MM1]; therefore, to see this level of response in the real world is very pleasing.”

When asked by an attendee if clinical trials should push for inclusion of patients more representative of real-world populations, Dr. Cook said no. “I think the way we conduct phase 3 clinical trials, in particular, has to be the way it is in order for us to ensure that we can actually get the absolute efficacy and the safety, and that has to be done by a refined population, I’m afraid,” he said.

However, Dr. Cook supported efforts to improve reliability of data for clinicians at the time of drug licensing.

“We should be running real-world exposure in parallel with phase 3 studies, which is harder to do but just requires a bit of imagination,” Dr. Cook said.

The study was funded by Takeda. The investigators reported financial relationships with Takeda and other companies.

SOURCE: Cook G et al. BSH 2019, Abstract OR-018.