Will Pass

MUNICH – Patients with HIV who are treated with nivolumab, a programmed death-1 (PD-1) inhibitor, appear to have similar safety and efficacy outcomes compared with HIV-negative patients treated with the same agent, investigators found.

The retrospective study also showed that viral load and CD4 status were largely unchanged by immunotherapy, lead author Aurélien Gobert, MD, of Groupe Hospitalier Pitié Salpêtrière, Paris, reported at the European Society for Medical Oncology Congress.

HIV increases risks of certain cancer types, Dr. Gobert said in a press release. “These patients are at higher risk for a number of cancers: AIDS-defining forms, the diagnosis of which results in the categorization of a person as suffering from AIDS, but also various other types that they are two to three times more likely to develop than in the general population, such as anal, skin, head and neck, and lung cancer,” he said.

Despite the increased risks, few studies have evaluated cancer treatments for patients with HIV due to exclusions from most clinical trials. As HIV is an immune-based disease, concerns have arisen surrounding the safety and efficacy of using anti-neoplastic immunotherapies for HIV-positive patients. Considering that millions of people worldwide are HIV positive, research in this area can have real-world consequences.

Dr. Gobert and his colleagues analyzed data from CANCERVIH, a French national database of patients with cancer and HIV. Since May 2014, nivolumab has been administered to 20 patients. Nineteen had metastatic non–small-cell lung cancer and 1 had metastatic melanoma. At diagnosis, the median CD4 count was 338.5 per cubic millimeter. Seventeen patients had undetectable viral load, two had fewer than 40 copies per millimeter, and one patient’s viral load was unknown. Dr. Gobert described the population as “demographically homogenous,” with “most patients being males around 60 years old.”

Analysis showed that nivolumab had little impact on CD4 count or viral load. One patient had a decreased CD4 count and an increased viral load, but this occurred during an interruption to antiretroviral therapy, which clouds potential associations with nivolumab. No immune-related adverse events or deaths due to drug toxicity occurred. Efficacy was assessed in 17 patients: Four (24%) showed a partial response, 2 (12%) had stable disease, and 11 (64%) had disease progression.

“Based on these preliminary data, treatment with anti-PD-1 ... seems to be feasible in people with HIV,” Dr. Gobert reported. He added that “antiretroviral therapy should not be interrupted.”

In a comment for ESMO, John Haanen, PhD, of the Netherlands Cancer Institute, Amsterdam, said that the results “confirm those of other, smaller cohorts in showing that while on antiretroviral therapy, cancer patients living with HIV can safely receive anti-PD-1 treatment. The efficacy data also suggests that the overall response rate of HIV-positive patients seems to be similar to that of other cancer patients. These promising results need to be confirmed in larger studies – ideally, in a prospective clinical trial.”

Principal investigator Jean-Philippe Spano, MD, PhD, disclosed relationships with Gilead, Roche, BMS, and others.

SOURCE: Gobert et al. ESMO 2018, Abstract 1213P_PR.

MUNICH – Patients with HIV who are treated with nivolumab, a programmed death-1 (PD-1) inhibitor, appear to have similar safety and efficacy outcomes compared with HIV-negative patients treated with the same agent, investigators found.

The retrospective study also showed that viral load and CD4 status were largely unchanged by immunotherapy, lead author Aurélien Gobert, MD, of Groupe Hospitalier Pitié Salpêtrière, Paris, reported at the European Society for Medical Oncology Congress.

HIV increases risks of certain cancer types, Dr. Gobert said in a press release. “These patients are at higher risk for a number of cancers: AIDS-defining forms, the diagnosis of which results in the categorization of a person as suffering from AIDS, but also various other types that they are two to three times more likely to develop than in the general population, such as anal, skin, head and neck, and lung cancer,” he said.

Despite the increased risks, few studies have evaluated cancer treatments for patients with HIV due to exclusions from most clinical trials. As HIV is an immune-based disease, concerns have arisen surrounding the safety and efficacy of using anti-neoplastic immunotherapies for HIV-positive patients. Considering that millions of people worldwide are HIV positive, research in this area can have real-world consequences.

Dr. Gobert and his colleagues analyzed data from CANCERVIH, a French national database of patients with cancer and HIV. Since May 2014, nivolumab has been administered to 20 patients. Nineteen had metastatic non–small-cell lung cancer and 1 had metastatic melanoma. At diagnosis, the median CD4 count was 338.5 per cubic millimeter. Seventeen patients had undetectable viral load, two had fewer than 40 copies per millimeter, and one patient’s viral load was unknown. Dr. Gobert described the population as “demographically homogenous,” with “most patients being males around 60 years old.”

Analysis showed that nivolumab had little impact on CD4 count or viral load. One patient had a decreased CD4 count and an increased viral load, but this occurred during an interruption to antiretroviral therapy, which clouds potential associations with nivolumab. No immune-related adverse events or deaths due to drug toxicity occurred. Efficacy was assessed in 17 patients: Four (24%) showed a partial response, 2 (12%) had stable disease, and 11 (64%) had disease progression.

“Based on these preliminary data, treatment with anti-PD-1 ... seems to be feasible in people with HIV,” Dr. Gobert reported. He added that “antiretroviral therapy should not be interrupted.”

In a comment for ESMO, John Haanen, PhD, of the Netherlands Cancer Institute, Amsterdam, said that the results “confirm those of other, smaller cohorts in showing that while on antiretroviral therapy, cancer patients living with HIV can safely receive anti-PD-1 treatment. The efficacy data also suggests that the overall response rate of HIV-positive patients seems to be similar to that of other cancer patients. These promising results need to be confirmed in larger studies – ideally, in a prospective clinical trial.”

Principal investigator Jean-Philippe Spano, MD, PhD, disclosed relationships with Gilead, Roche, BMS, and others.

SOURCE: Gobert et al. ESMO 2018, Abstract 1213P_PR.

MUNICH – Patients with HIV who are treated with nivolumab, a programmed death-1 (PD-1) inhibitor, appear to have similar safety and efficacy outcomes compared with HIV-negative patients treated with the same agent, investigators found.

The retrospective study also showed that viral load and CD4 status were largely unchanged by immunotherapy, lead author Aurélien Gobert, MD, of Groupe Hospitalier Pitié Salpêtrière, Paris, reported at the European Society for Medical Oncology Congress.

HIV increases risks of certain cancer types, Dr. Gobert said in a press release. “These patients are at higher risk for a number of cancers: AIDS-defining forms, the diagnosis of which results in the categorization of a person as suffering from AIDS, but also various other types that they are two to three times more likely to develop than in the general population, such as anal, skin, head and neck, and lung cancer,” he said.

Despite the increased risks, few studies have evaluated cancer treatments for patients with HIV due to exclusions from most clinical trials. As HIV is an immune-based disease, concerns have arisen surrounding the safety and efficacy of using anti-neoplastic immunotherapies for HIV-positive patients. Considering that millions of people worldwide are HIV positive, research in this area can have real-world consequences.

Dr. Gobert and his colleagues analyzed data from CANCERVIH, a French national database of patients with cancer and HIV. Since May 2014, nivolumab has been administered to 20 patients. Nineteen had metastatic non–small-cell lung cancer and 1 had metastatic melanoma. At diagnosis, the median CD4 count was 338.5 per cubic millimeter. Seventeen patients had undetectable viral load, two had fewer than 40 copies per millimeter, and one patient’s viral load was unknown. Dr. Gobert described the population as “demographically homogenous,” with “most patients being males around 60 years old.”

Analysis showed that nivolumab had little impact on CD4 count or viral load. One patient had a decreased CD4 count and an increased viral load, but this occurred during an interruption to antiretroviral therapy, which clouds potential associations with nivolumab. No immune-related adverse events or deaths due to drug toxicity occurred. Efficacy was assessed in 17 patients: Four (24%) showed a partial response, 2 (12%) had stable disease, and 11 (64%) had disease progression.

“Based on these preliminary data, treatment with anti-PD-1 ... seems to be feasible in people with HIV,” Dr. Gobert reported. He added that “antiretroviral therapy should not be interrupted.”

In a comment for ESMO, John Haanen, PhD, of the Netherlands Cancer Institute, Amsterdam, said that the results “confirm those of other, smaller cohorts in showing that while on antiretroviral therapy, cancer patients living with HIV can safely receive anti-PD-1 treatment. The efficacy data also suggests that the overall response rate of HIV-positive patients seems to be similar to that of other cancer patients. These promising results need to be confirmed in larger studies – ideally, in a prospective clinical trial.”

Principal investigator Jean-Philippe Spano, MD, PhD, disclosed relationships with Gilead, Roche, BMS, and others.

SOURCE: Gobert et al. ESMO 2018, Abstract 1213P_PR.

MUNICH – Olaparib maintenance therapy significantly reduces risk of disease progression or death in women with BRCA-mutated advanced ovarian cancer who respond to chemotherapy, according to results from the SOLO-1 trial.

Will Pass/MDedge News

The benefit from olaparib was compelling; compared with placebo, more than twice the number of women were alive and without disease progression after 3 years.

Current guidelines recommend olaparib for relapsed ovarian cancer, but the SOLO-1 results support first-line application, said lead author, Kathleen N. Moore, MD at the European Society for Medical Oncology Congress.

“We believe that the SOLO-1 data really prompts a change in the standard of care for women with advanced ovarian cancer who harbor a BRCA mutation,” said Dr. Moore of the Stephenson Cancer Center at the University of Oklahoma in Oklahoma City.

Olaparib (Lynparza) currently is approved for relapsed ovarian cancer regardless of mutation status, but poor outcomes suggest that this intervention is given too late – many patients relapse, and when they do, most do not survive.

“Although the majority of ... patients have no evidence of disease after [chemotherapy], approximately 70% have a relapse within the subsequent 3 years,” the investigators wrote in an article simultaneously published in the New England Journal of Medicine. “Recurrent ovarian cancer is typically incurable, with most patients receiving multiple additional lines of treatment before ultimately dying from the disease.”

Poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib, are well matched for BRCA-mutated tumors; they interfere with DNA repair, thereby exploiting repair deficits conferred by BRCA mutations. One in six women with advanced ovarian cancer exhibits a BRCA mutation, so eligible patients are relatively common.

The phase 3, placebo-controlled SOLO-1 trial involved 391 patients with advanced ovarian cancer who had a complete or partial response to platinum-based chemotherapy. Patients exhibited mutations in BRCA1, BRCA2, or both (BRCA1/BRCA2). After chemotherapy, patients were randomized to receive either olaparib 300 mg twice daily or placebo (in a 2:1 ratio).

The primary endpoint was progression-free survival (PFS) determined by imaging; MRI or CT was performed at baseline and every 3 months for up to 3 years, with 6-month intervals thereafter. Patients who had no disease progression at 2 years halted therapy, whereas patients with disease progression were allowed to continue olaparib if desired.

The 3-year follow-up period (median, 40.7 months) revealed a dramatic benefit from olaparib; the PFS rate was 60% for olaparib, compared with 27% for placebo (P less than .001). This represents a 70% reduction in risk of disease progression or death. Because of the magnitude of prolonged survival, median PFS could not be determined; however, estimates suggest that olaparib adds 3 years without disease progression.

Dr. Moore noted that these benefits were consistent regardless of stage or level of response to chemotherapy (partial vs. complete). “Everyone benefits,” she said. “It really looks like an all subgroup-beneficial regimen.”

Still, questions of long-term benefit remain unanswered. “It’s too early to know what [the extended PFS] means long term,” Dr. Moore said. “We hope that it means we’ve converted a larger fraction of patients to cure, and that’s what you’re seeing with the flattening of the survival curve, but it took us 3 years just to get to this point, so how long will it take us to comment on overall survival? It’s a good problem to have, but it’s going to remain to be seen.”

As therapy was discontinued at 2 years, and yet patients remained progression free after 3 years, researchers also are left wondering about mechanisms of action. “Has olaparib eradicated all the disease?” asked Jonathan A. Ledermann, MD, member of the ESMO faculty and professor of medical oncology at University College London. “Or is something else happening, such as an immune response that’s taking over when you stop the drug? We don’t know the answer to that, but it’s an intriguing question and one that we need to follow up on.”

Safety data from SOLO-1 were comparable with previous olaparib trials. Overall, olaparib was well tolerated, with 21% of patients experiencing serious adverse events. The most common serious adverse event was neutropenia (7%).

SOLO-1 was sponsored by AstraZeneca and Merck. The authors reported financial affiliations with Clovis, Tesaro, Mateon, Merck, and others.
 

SOURCE: Moore et al. N Eng J Med. 2018 Oct 21. doi: 10.1056/NEJMoa1810858.

MUNICH – Olaparib maintenance therapy significantly reduces risk of disease progression or death in women with BRCA-mutated advanced ovarian cancer who respond to chemotherapy, according to results from the SOLO-1 trial.

Will Pass/MDedge News

The benefit from olaparib was compelling; compared with placebo, more than twice the number of women were alive and without disease progression after 3 years.

Current guidelines recommend olaparib for relapsed ovarian cancer, but the SOLO-1 results support first-line application, said lead author, Kathleen N. Moore, MD at the European Society for Medical Oncology Congress.

“We believe that the SOLO-1 data really prompts a change in the standard of care for women with advanced ovarian cancer who harbor a BRCA mutation,” said Dr. Moore of the Stephenson Cancer Center at the University of Oklahoma in Oklahoma City.

Olaparib (Lynparza) currently is approved for relapsed ovarian cancer regardless of mutation status, but poor outcomes suggest that this intervention is given too late – many patients relapse, and when they do, most do not survive.

“Although the majority of ... patients have no evidence of disease after [chemotherapy], approximately 70% have a relapse within the subsequent 3 years,” the investigators wrote in an article simultaneously published in the New England Journal of Medicine. “Recurrent ovarian cancer is typically incurable, with most patients receiving multiple additional lines of treatment before ultimately dying from the disease.”

Poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib, are well matched for BRCA-mutated tumors; they interfere with DNA repair, thereby exploiting repair deficits conferred by BRCA mutations. One in six women with advanced ovarian cancer exhibits a BRCA mutation, so eligible patients are relatively common.

The phase 3, placebo-controlled SOLO-1 trial involved 391 patients with advanced ovarian cancer who had a complete or partial response to platinum-based chemotherapy. Patients exhibited mutations in BRCA1, BRCA2, or both (BRCA1/BRCA2). After chemotherapy, patients were randomized to receive either olaparib 300 mg twice daily or placebo (in a 2:1 ratio).

The primary endpoint was progression-free survival (PFS) determined by imaging; MRI or CT was performed at baseline and every 3 months for up to 3 years, with 6-month intervals thereafter. Patients who had no disease progression at 2 years halted therapy, whereas patients with disease progression were allowed to continue olaparib if desired.

The 3-year follow-up period (median, 40.7 months) revealed a dramatic benefit from olaparib; the PFS rate was 60% for olaparib, compared with 27% for placebo (P less than .001). This represents a 70% reduction in risk of disease progression or death. Because of the magnitude of prolonged survival, median PFS could not be determined; however, estimates suggest that olaparib adds 3 years without disease progression.

Dr. Moore noted that these benefits were consistent regardless of stage or level of response to chemotherapy (partial vs. complete). “Everyone benefits,” she said. “It really looks like an all subgroup-beneficial regimen.”

Still, questions of long-term benefit remain unanswered. “It’s too early to know what [the extended PFS] means long term,” Dr. Moore said. “We hope that it means we’ve converted a larger fraction of patients to cure, and that’s what you’re seeing with the flattening of the survival curve, but it took us 3 years just to get to this point, so how long will it take us to comment on overall survival? It’s a good problem to have, but it’s going to remain to be seen.”

As therapy was discontinued at 2 years, and yet patients remained progression free after 3 years, researchers also are left wondering about mechanisms of action. “Has olaparib eradicated all the disease?” asked Jonathan A. Ledermann, MD, member of the ESMO faculty and professor of medical oncology at University College London. “Or is something else happening, such as an immune response that’s taking over when you stop the drug? We don’t know the answer to that, but it’s an intriguing question and one that we need to follow up on.”

Safety data from SOLO-1 were comparable with previous olaparib trials. Overall, olaparib was well tolerated, with 21% of patients experiencing serious adverse events. The most common serious adverse event was neutropenia (7%).

SOLO-1 was sponsored by AstraZeneca and Merck. The authors reported financial affiliations with Clovis, Tesaro, Mateon, Merck, and others.
 

SOURCE: Moore et al. N Eng J Med. 2018 Oct 21. doi: 10.1056/NEJMoa1810858.

MUNICH – Olaparib maintenance therapy significantly reduces risk of disease progression or death in women with BRCA-mutated advanced ovarian cancer who respond to chemotherapy, according to results from the SOLO-1 trial.

Will Pass/MDedge News

The benefit from olaparib was compelling; compared with placebo, more than twice the number of women were alive and without disease progression after 3 years.

Current guidelines recommend olaparib for relapsed ovarian cancer, but the SOLO-1 results support first-line application, said lead author, Kathleen N. Moore, MD at the European Society for Medical Oncology Congress.

“We believe that the SOLO-1 data really prompts a change in the standard of care for women with advanced ovarian cancer who harbor a BRCA mutation,” said Dr. Moore of the Stephenson Cancer Center at the University of Oklahoma in Oklahoma City.

Olaparib (Lynparza) currently is approved for relapsed ovarian cancer regardless of mutation status, but poor outcomes suggest that this intervention is given too late – many patients relapse, and when they do, most do not survive.

“Although the majority of ... patients have no evidence of disease after [chemotherapy], approximately 70% have a relapse within the subsequent 3 years,” the investigators wrote in an article simultaneously published in the New England Journal of Medicine. “Recurrent ovarian cancer is typically incurable, with most patients receiving multiple additional lines of treatment before ultimately dying from the disease.”

Poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib, are well matched for BRCA-mutated tumors; they interfere with DNA repair, thereby exploiting repair deficits conferred by BRCA mutations. One in six women with advanced ovarian cancer exhibits a BRCA mutation, so eligible patients are relatively common.

The phase 3, placebo-controlled SOLO-1 trial involved 391 patients with advanced ovarian cancer who had a complete or partial response to platinum-based chemotherapy. Patients exhibited mutations in BRCA1, BRCA2, or both (BRCA1/BRCA2). After chemotherapy, patients were randomized to receive either olaparib 300 mg twice daily or placebo (in a 2:1 ratio).

The primary endpoint was progression-free survival (PFS) determined by imaging; MRI or CT was performed at baseline and every 3 months for up to 3 years, with 6-month intervals thereafter. Patients who had no disease progression at 2 years halted therapy, whereas patients with disease progression were allowed to continue olaparib if desired.

The 3-year follow-up period (median, 40.7 months) revealed a dramatic benefit from olaparib; the PFS rate was 60% for olaparib, compared with 27% for placebo (P less than .001). This represents a 70% reduction in risk of disease progression or death. Because of the magnitude of prolonged survival, median PFS could not be determined; however, estimates suggest that olaparib adds 3 years without disease progression.

Dr. Moore noted that these benefits were consistent regardless of stage or level of response to chemotherapy (partial vs. complete). “Everyone benefits,” she said. “It really looks like an all subgroup-beneficial regimen.”

Still, questions of long-term benefit remain unanswered. “It’s too early to know what [the extended PFS] means long term,” Dr. Moore said. “We hope that it means we’ve converted a larger fraction of patients to cure, and that’s what you’re seeing with the flattening of the survival curve, but it took us 3 years just to get to this point, so how long will it take us to comment on overall survival? It’s a good problem to have, but it’s going to remain to be seen.”

As therapy was discontinued at 2 years, and yet patients remained progression free after 3 years, researchers also are left wondering about mechanisms of action. “Has olaparib eradicated all the disease?” asked Jonathan A. Ledermann, MD, member of the ESMO faculty and professor of medical oncology at University College London. “Or is something else happening, such as an immune response that’s taking over when you stop the drug? We don’t know the answer to that, but it’s an intriguing question and one that we need to follow up on.”

Safety data from SOLO-1 were comparable with previous olaparib trials. Overall, olaparib was well tolerated, with 21% of patients experiencing serious adverse events. The most common serious adverse event was neutropenia (7%).

SOLO-1 was sponsored by AstraZeneca and Merck. The authors reported financial affiliations with Clovis, Tesaro, Mateon, Merck, and others.
 

SOURCE: Moore et al. N Eng J Med. 2018 Oct 21. doi: 10.1056/NEJMoa1810858.

MUNICH – Neoadjuvant erlotinib for patients with stage IIIA (N2) non–small cell lung cancer (NSCLC) increased progression-free survival (PFS), compared with gemcitabine and cisplatin, according to results from the recent CTONG 1103 trial.

Will Pass/MDedge News

Despite beating chemotherapy, erlotinib, an epithelial growth factor receptor (EGFR)–mutant tyrosine kinase inhibitor (TKI), fell short of benchmarks set by adjuvant therapy, so it is unlikely that neoadjuvant erlotinib will see clinical use anytime soon.

Lead author Wen-Zhao Zhong, MD, PhD, of Guangdong Lung Cancer Institute and Guangdong General Hospital in Guangzhou, China, presenting at the European Society for Medical Oncology Congress, said that the recent findings support further investigation into biomarker-guided neoadjuvant therapy for stage IIIA (N2) NSCLC, as identifying patient subgroups could potentially improve outcomes.

Principal investigator Yi-Long Wu, MD, described the impetus for CTONG 1103 in an interview. “Recently, the CTONG 1104 trial showed for the first time that adjuvant EGFR-TKI gefitinib could improve disease-free survival ... compared to adjuvant chemotherapy ... in N1N2-resected NSCLC. This raises the possibility that EGFR-TKIs may play a beneficial role in the neoadjuvant setting for this subgroup,” he said.

CTONG 1103 is an ongoing, phase 2, open-label trial. Out of 386 patients screened, 72 were enrolled based on treatment naivety and EGFR mutation positivity (exon 19 or 21). Following randomization, patients received either erlotinib 150 mg daily for 42 days or gemcitabine 1,250 mg/m² (days 1 and 8) and cisplatin 75 mg/m2 (day 1) every 3 weeks for two cycles. After surgery, patients in the erlotinib group continued therapy for 1 year, while patients in the chemotherapy cohort received two more cycles of treatment.

The primary endpoint was objective response rate, and secondary endpoints included PFS, pathological lymph node downstaging, overall survival, safety measures, and complete pathological response. The investigators also highlighted major pathological response (less than 10% viable cancer cells after preoperative therapy).

The results showed that about half of the patients receiving erlotinib had an objective response (54.1%), compared with approximately one-third in the chemotherapy group (34.3%); however, this difference was not statistically significant (P = .092). Erlotinib also provided a median PFS nearly twice that of chemotherapy (21.5 months vs. 11.9 months; P = .003) and more frequent lymph node downstaging (10.8% vs. 2.9%), but no patients achieved complete pathological response. The number of patients achieving major pathological response with erlotinib was limited but still more than chemotherapy (10.7% vs. 0%). The investigators are awaiting an overall survival rate.

Erlotinib showed similar adverse events to previous trials, most commonly, rash, diarrhea, cough, and oral ulcers, compared with chemotherapy, which was associated with GI issues, hematologic disturbances, and fatigue.

Will Pass/MDedge News

In response to these findings, Suresh S. Ramalingam, MD, invited discussant and deputy director of the Winship Cancer Institute of Emory University, Atlanta, first discussed relevant efficacy measures. “The best predictor of long-term outcomes in these patients is nodal downstaging,” Dr. Ramalingam said. In previous studies, “patients who had clearance of the nodes had the best outcomes, and that continues to be an important prognostic marker.”

While major pathological response is valuable, and previous studies have revealed prognostic value, evidence is too limited to suggest that this is equivalent with cure, and it should not be considered as significant as complete pathological response, he said.

Considering that “only 11% of the patients” treated with erlotinib had nodal downstaging and/or major pathological response, and none achieved complete pathological response, Dr. Ramalingam suggested that the results were modest at best.

“While erlotinib seems to be doing better than chemo, I feel that the chemo group here is underperforming, compared to historical controls,” Dr. Ramalingam said, noting higher benchmark objective response rates (61% vs. 34%) and complete pathological response rates (4% vs. 0%).

Instead of focusing on neoadjuvant studies, Dr. Ramalingam suggested that ongoing adjuvant trials (ALCHEMIST and ADAURA) hold more promise and are more likely to serve as inroads for TKIs like erlotinib.

“Adjuvant care has withstood the test of time,” Dr. Ramalingam said. “Neoadjuvant EGFR-TKI in N2 disease I don’t think is ready for center stage.”

CTONG 1103 was sponsored by CTONG and Roche. The authors reported financial affiliations with AstraZeneca, Pfizer, Roche, and others. Dr. Ramalingam reported compensation from Amgen, Bristol-Myers Squibb, Loxo Oncology, and others.

MUNICH – Neoadjuvant erlotinib for patients with stage IIIA (N2) non–small cell lung cancer (NSCLC) increased progression-free survival (PFS), compared with gemcitabine and cisplatin, according to results from the recent CTONG 1103 trial.

Will Pass/MDedge News

Despite beating chemotherapy, erlotinib, an epithelial growth factor receptor (EGFR)–mutant tyrosine kinase inhibitor (TKI), fell short of benchmarks set by adjuvant therapy, so it is unlikely that neoadjuvant erlotinib will see clinical use anytime soon.

Lead author Wen-Zhao Zhong, MD, PhD, of Guangdong Lung Cancer Institute and Guangdong General Hospital in Guangzhou, China, presenting at the European Society for Medical Oncology Congress, said that the recent findings support further investigation into biomarker-guided neoadjuvant therapy for stage IIIA (N2) NSCLC, as identifying patient subgroups could potentially improve outcomes.

Principal investigator Yi-Long Wu, MD, described the impetus for CTONG 1103 in an interview. “Recently, the CTONG 1104 trial showed for the first time that adjuvant EGFR-TKI gefitinib could improve disease-free survival ... compared to adjuvant chemotherapy ... in N1N2-resected NSCLC. This raises the possibility that EGFR-TKIs may play a beneficial role in the neoadjuvant setting for this subgroup,” he said.

CTONG 1103 is an ongoing, phase 2, open-label trial. Out of 386 patients screened, 72 were enrolled based on treatment naivety and EGFR mutation positivity (exon 19 or 21). Following randomization, patients received either erlotinib 150 mg daily for 42 days or gemcitabine 1,250 mg/m² (days 1 and 8) and cisplatin 75 mg/m2 (day 1) every 3 weeks for two cycles. After surgery, patients in the erlotinib group continued therapy for 1 year, while patients in the chemotherapy cohort received two more cycles of treatment.

The primary endpoint was objective response rate, and secondary endpoints included PFS, pathological lymph node downstaging, overall survival, safety measures, and complete pathological response. The investigators also highlighted major pathological response (less than 10% viable cancer cells after preoperative therapy).

The results showed that about half of the patients receiving erlotinib had an objective response (54.1%), compared with approximately one-third in the chemotherapy group (34.3%); however, this difference was not statistically significant (P = .092). Erlotinib also provided a median PFS nearly twice that of chemotherapy (21.5 months vs. 11.9 months; P = .003) and more frequent lymph node downstaging (10.8% vs. 2.9%), but no patients achieved complete pathological response. The number of patients achieving major pathological response with erlotinib was limited but still more than chemotherapy (10.7% vs. 0%). The investigators are awaiting an overall survival rate.

Erlotinib showed similar adverse events to previous trials, most commonly, rash, diarrhea, cough, and oral ulcers, compared with chemotherapy, which was associated with GI issues, hematologic disturbances, and fatigue.

Will Pass/MDedge News

In response to these findings, Suresh S. Ramalingam, MD, invited discussant and deputy director of the Winship Cancer Institute of Emory University, Atlanta, first discussed relevant efficacy measures. “The best predictor of long-term outcomes in these patients is nodal downstaging,” Dr. Ramalingam said. In previous studies, “patients who had clearance of the nodes had the best outcomes, and that continues to be an important prognostic marker.”

While major pathological response is valuable, and previous studies have revealed prognostic value, evidence is too limited to suggest that this is equivalent with cure, and it should not be considered as significant as complete pathological response, he said.

Considering that “only 11% of the patients” treated with erlotinib had nodal downstaging and/or major pathological response, and none achieved complete pathological response, Dr. Ramalingam suggested that the results were modest at best.

“While erlotinib seems to be doing better than chemo, I feel that the chemo group here is underperforming, compared to historical controls,” Dr. Ramalingam said, noting higher benchmark objective response rates (61% vs. 34%) and complete pathological response rates (4% vs. 0%).

Instead of focusing on neoadjuvant studies, Dr. Ramalingam suggested that ongoing adjuvant trials (ALCHEMIST and ADAURA) hold more promise and are more likely to serve as inroads for TKIs like erlotinib.

“Adjuvant care has withstood the test of time,” Dr. Ramalingam said. “Neoadjuvant EGFR-TKI in N2 disease I don’t think is ready for center stage.”

CTONG 1103 was sponsored by CTONG and Roche. The authors reported financial affiliations with AstraZeneca, Pfizer, Roche, and others. Dr. Ramalingam reported compensation from Amgen, Bristol-Myers Squibb, Loxo Oncology, and others.

MUNICH – Neoadjuvant erlotinib for patients with stage IIIA (N2) non–small cell lung cancer (NSCLC) increased progression-free survival (PFS), compared with gemcitabine and cisplatin, according to results from the recent CTONG 1103 trial.

Will Pass/MDedge News

Despite beating chemotherapy, erlotinib, an epithelial growth factor receptor (EGFR)–mutant tyrosine kinase inhibitor (TKI), fell short of benchmarks set by adjuvant therapy, so it is unlikely that neoadjuvant erlotinib will see clinical use anytime soon.

Lead author Wen-Zhao Zhong, MD, PhD, of Guangdong Lung Cancer Institute and Guangdong General Hospital in Guangzhou, China, presenting at the European Society for Medical Oncology Congress, said that the recent findings support further investigation into biomarker-guided neoadjuvant therapy for stage IIIA (N2) NSCLC, as identifying patient subgroups could potentially improve outcomes.

Principal investigator Yi-Long Wu, MD, described the impetus for CTONG 1103 in an interview. “Recently, the CTONG 1104 trial showed for the first time that adjuvant EGFR-TKI gefitinib could improve disease-free survival ... compared to adjuvant chemotherapy ... in N1N2-resected NSCLC. This raises the possibility that EGFR-TKIs may play a beneficial role in the neoadjuvant setting for this subgroup,” he said.

CTONG 1103 is an ongoing, phase 2, open-label trial. Out of 386 patients screened, 72 were enrolled based on treatment naivety and EGFR mutation positivity (exon 19 or 21). Following randomization, patients received either erlotinib 150 mg daily for 42 days or gemcitabine 1,250 mg/m² (days 1 and 8) and cisplatin 75 mg/m2 (day 1) every 3 weeks for two cycles. After surgery, patients in the erlotinib group continued therapy for 1 year, while patients in the chemotherapy cohort received two more cycles of treatment.

The primary endpoint was objective response rate, and secondary endpoints included PFS, pathological lymph node downstaging, overall survival, safety measures, and complete pathological response. The investigators also highlighted major pathological response (less than 10% viable cancer cells after preoperative therapy).

The results showed that about half of the patients receiving erlotinib had an objective response (54.1%), compared with approximately one-third in the chemotherapy group (34.3%); however, this difference was not statistically significant (P = .092). Erlotinib also provided a median PFS nearly twice that of chemotherapy (21.5 months vs. 11.9 months; P = .003) and more frequent lymph node downstaging (10.8% vs. 2.9%), but no patients achieved complete pathological response. The number of patients achieving major pathological response with erlotinib was limited but still more than chemotherapy (10.7% vs. 0%). The investigators are awaiting an overall survival rate.

Erlotinib showed similar adverse events to previous trials, most commonly, rash, diarrhea, cough, and oral ulcers, compared with chemotherapy, which was associated with GI issues, hematologic disturbances, and fatigue.

Will Pass/MDedge News

In response to these findings, Suresh S. Ramalingam, MD, invited discussant and deputy director of the Winship Cancer Institute of Emory University, Atlanta, first discussed relevant efficacy measures. “The best predictor of long-term outcomes in these patients is nodal downstaging,” Dr. Ramalingam said. In previous studies, “patients who had clearance of the nodes had the best outcomes, and that continues to be an important prognostic marker.”

While major pathological response is valuable, and previous studies have revealed prognostic value, evidence is too limited to suggest that this is equivalent with cure, and it should not be considered as significant as complete pathological response, he said.

Considering that “only 11% of the patients” treated with erlotinib had nodal downstaging and/or major pathological response, and none achieved complete pathological response, Dr. Ramalingam suggested that the results were modest at best.

“While erlotinib seems to be doing better than chemo, I feel that the chemo group here is underperforming, compared to historical controls,” Dr. Ramalingam said, noting higher benchmark objective response rates (61% vs. 34%) and complete pathological response rates (4% vs. 0%).

Instead of focusing on neoadjuvant studies, Dr. Ramalingam suggested that ongoing adjuvant trials (ALCHEMIST and ADAURA) hold more promise and are more likely to serve as inroads for TKIs like erlotinib.

“Adjuvant care has withstood the test of time,” Dr. Ramalingam said. “Neoadjuvant EGFR-TKI in N2 disease I don’t think is ready for center stage.”

CTONG 1103 was sponsored by CTONG and Roche. The authors reported financial affiliations with AstraZeneca, Pfizer, Roche, and others. Dr. Ramalingam reported compensation from Amgen, Bristol-Myers Squibb, Loxo Oncology, and others.

MUNICH – For patients with HR-positive (HR+) and human epidermal growth factor receptor 2 (HER2)–advanced breast cancer who have progressed after endocrine therapy, a combination of the oral histone deacetylase (HDAC) inhibitor chidamide and exemestane appears safe and more effective than exemestane alone, according to results from the phase 3 ACE trial.

Neil Osterweil/MDedge News

“This is the first phase 3 trial to demonstrate that an HDAC inhibitor plus endocrine blockade improves progression-free survival, compared to endocrine blockade alone in hormone receptor positive advanced breast cancer patients who have progressed after prior endocrine therapy,” said lead author, Zefei Jiang, MD, at the European Society for Medical Oncology Congress.

HDAC inhibitors have historically been used for psychiatric and neurologic applications, but interest in their antineoplastic potential has increased over the past decade. Chidamide is approved for T-cell lymphoma in China, but not in the United States, where three other HDAC inhibitors are labeled for T-cell lymphoma, and a fourth is approved for multiple myeloma.

Although no HDAC inhibitors are clinically available for breast cancer, the future may tell a different story. The HDAC inhibitor entinostat received a breakthrough therapy designation by the Food and Drug Administration after the phase 2 ENCORE 301 trial showed clinical benefit (also with exemestane for advanced breast cancer). Ongoing studies are also evaluating the potential for HDAC inhibitors in combination with immunotherapy.

“Histone modulation by HDACs is a very important mechanism for epigenetic regulation,” said Dr. Jiang, of the 307th Hospital of Chinese People’s Liberation Army in Beijing, highlighting associations with breast cancer drug resistance. HDAC inhibition may be able to overcome this obstacle by resensitizing tumors to estrogen modulator therapy.

ACE was a double-blind, placebo-controlled study involving 362 patients with HR+/HER2–advanced breast cancer who failed endocrine therapy. Patients had previously received no more than one round of chemotherapy for advanced disease, and no more than four therapies total. The treatment group received either chidamide 30 mg twice weekly with exemestane 25 mg daily (n = 241) or exemestane with placebo (n = 121). Tumor assessments were performed every 8 weeks, and the primary endpoint was progression-free survival (PFS).

The addition of chidamide nearly doubled PFS (7.4 months vs. 3.8 months) and provided a hazard ratio of .75 (P = .0336). Objective response and clinical benefit rates also were increased. At the time of presentation, data were too immature for an overall survival rate.

The most common grade 3 or higher adverse events were hematologic: neutropenia (50.8%), thrombocytopenia (27.5%), and leukopenia (18.8%), all considerably higher than 2.5% for each in the placebo group.

These tolerability issues were expected, however, based on previous chidamide findings.

Neil Osterweil/MDedge News

“Not surprisingly ... 33% of patients had their dose reduced, 50% their dose interrupted, and this is despite the biweekly schedule,” said invited discussant Rebecca Dent, MD, of the National Cancer Centre in Singapore. Despite these issues, Dr. Dent concluded that chidamide otherwise “appears to be quite well tolerated,” and showed meaningful results.

“We now have a second trial demonstrating ... clinical benefit from the addition of HDAC inhibitors to endocrine therapy in [HR+] advanced breast cancer,” Dr. Dent said. “HDAC inhibitors clearly warrant further investigation in earlier settings of [HR+] advanced breast cancer and ... yet to be defined ... subgroups, and obviously we anxiously await the phase 3 results of entinostat.”

In consideration of the future, Dr. Dent suggested that more studies are needed to develop subgroup-targeted therapies and optimize sequencing. “We’ve really underestimated the selective pressure of these treatments and how they impact our subsequent therapies,” she said.

Dr. Dent noted how these factors limit predictive relevance of study findings in clinical practice, in which patients with different treatment histories may have completely different responses to the same agent.

To overcome these obstacles, Dr. Dent encouraged development of biomarker-driven strategies that can identify unique patterns of drug resistance and sensitivity. “This will allow us to ... identify which patients, which drug, and at which time.”

The ACE trial was funded by Chipscreen Biosciences.

SOURCE: Jiang Z et al. ESMO 2018, Abstract 283O.

MUNICH – For patients with HR-positive (HR+) and human epidermal growth factor receptor 2 (HER2)–advanced breast cancer who have progressed after endocrine therapy, a combination of the oral histone deacetylase (HDAC) inhibitor chidamide and exemestane appears safe and more effective than exemestane alone, according to results from the phase 3 ACE trial.

Neil Osterweil/MDedge News

“This is the first phase 3 trial to demonstrate that an HDAC inhibitor plus endocrine blockade improves progression-free survival, compared to endocrine blockade alone in hormone receptor positive advanced breast cancer patients who have progressed after prior endocrine therapy,” said lead author, Zefei Jiang, MD, at the European Society for Medical Oncology Congress.

HDAC inhibitors have historically been used for psychiatric and neurologic applications, but interest in their antineoplastic potential has increased over the past decade. Chidamide is approved for T-cell lymphoma in China, but not in the United States, where three other HDAC inhibitors are labeled for T-cell lymphoma, and a fourth is approved for multiple myeloma.

Although no HDAC inhibitors are clinically available for breast cancer, the future may tell a different story. The HDAC inhibitor entinostat received a breakthrough therapy designation by the Food and Drug Administration after the phase 2 ENCORE 301 trial showed clinical benefit (also with exemestane for advanced breast cancer). Ongoing studies are also evaluating the potential for HDAC inhibitors in combination with immunotherapy.

“Histone modulation by HDACs is a very important mechanism for epigenetic regulation,” said Dr. Jiang, of the 307th Hospital of Chinese People’s Liberation Army in Beijing, highlighting associations with breast cancer drug resistance. HDAC inhibition may be able to overcome this obstacle by resensitizing tumors to estrogen modulator therapy.

ACE was a double-blind, placebo-controlled study involving 362 patients with HR+/HER2–advanced breast cancer who failed endocrine therapy. Patients had previously received no more than one round of chemotherapy for advanced disease, and no more than four therapies total. The treatment group received either chidamide 30 mg twice weekly with exemestane 25 mg daily (n = 241) or exemestane with placebo (n = 121). Tumor assessments were performed every 8 weeks, and the primary endpoint was progression-free survival (PFS).

The addition of chidamide nearly doubled PFS (7.4 months vs. 3.8 months) and provided a hazard ratio of .75 (P = .0336). Objective response and clinical benefit rates also were increased. At the time of presentation, data were too immature for an overall survival rate.

The most common grade 3 or higher adverse events were hematologic: neutropenia (50.8%), thrombocytopenia (27.5%), and leukopenia (18.8%), all considerably higher than 2.5% for each in the placebo group.

These tolerability issues were expected, however, based on previous chidamide findings.

Neil Osterweil/MDedge News

“Not surprisingly ... 33% of patients had their dose reduced, 50% their dose interrupted, and this is despite the biweekly schedule,” said invited discussant Rebecca Dent, MD, of the National Cancer Centre in Singapore. Despite these issues, Dr. Dent concluded that chidamide otherwise “appears to be quite well tolerated,” and showed meaningful results.

“We now have a second trial demonstrating ... clinical benefit from the addition of HDAC inhibitors to endocrine therapy in [HR+] advanced breast cancer,” Dr. Dent said. “HDAC inhibitors clearly warrant further investigation in earlier settings of [HR+] advanced breast cancer and ... yet to be defined ... subgroups, and obviously we anxiously await the phase 3 results of entinostat.”

In consideration of the future, Dr. Dent suggested that more studies are needed to develop subgroup-targeted therapies and optimize sequencing. “We’ve really underestimated the selective pressure of these treatments and how they impact our subsequent therapies,” she said.

Dr. Dent noted how these factors limit predictive relevance of study findings in clinical practice, in which patients with different treatment histories may have completely different responses to the same agent.

To overcome these obstacles, Dr. Dent encouraged development of biomarker-driven strategies that can identify unique patterns of drug resistance and sensitivity. “This will allow us to ... identify which patients, which drug, and at which time.”

The ACE trial was funded by Chipscreen Biosciences.

SOURCE: Jiang Z et al. ESMO 2018, Abstract 283O.

MUNICH – For patients with HR-positive (HR+) and human epidermal growth factor receptor 2 (HER2)–advanced breast cancer who have progressed after endocrine therapy, a combination of the oral histone deacetylase (HDAC) inhibitor chidamide and exemestane appears safe and more effective than exemestane alone, according to results from the phase 3 ACE trial.

Neil Osterweil/MDedge News

“This is the first phase 3 trial to demonstrate that an HDAC inhibitor plus endocrine blockade improves progression-free survival, compared to endocrine blockade alone in hormone receptor positive advanced breast cancer patients who have progressed after prior endocrine therapy,” said lead author, Zefei Jiang, MD, at the European Society for Medical Oncology Congress.

HDAC inhibitors have historically been used for psychiatric and neurologic applications, but interest in their antineoplastic potential has increased over the past decade. Chidamide is approved for T-cell lymphoma in China, but not in the United States, where three other HDAC inhibitors are labeled for T-cell lymphoma, and a fourth is approved for multiple myeloma.

Although no HDAC inhibitors are clinically available for breast cancer, the future may tell a different story. The HDAC inhibitor entinostat received a breakthrough therapy designation by the Food and Drug Administration after the phase 2 ENCORE 301 trial showed clinical benefit (also with exemestane for advanced breast cancer). Ongoing studies are also evaluating the potential for HDAC inhibitors in combination with immunotherapy.

“Histone modulation by HDACs is a very important mechanism for epigenetic regulation,” said Dr. Jiang, of the 307th Hospital of Chinese People’s Liberation Army in Beijing, highlighting associations with breast cancer drug resistance. HDAC inhibition may be able to overcome this obstacle by resensitizing tumors to estrogen modulator therapy.

ACE was a double-blind, placebo-controlled study involving 362 patients with HR+/HER2–advanced breast cancer who failed endocrine therapy. Patients had previously received no more than one round of chemotherapy for advanced disease, and no more than four therapies total. The treatment group received either chidamide 30 mg twice weekly with exemestane 25 mg daily (n = 241) or exemestane with placebo (n = 121). Tumor assessments were performed every 8 weeks, and the primary endpoint was progression-free survival (PFS).

The addition of chidamide nearly doubled PFS (7.4 months vs. 3.8 months) and provided a hazard ratio of .75 (P = .0336). Objective response and clinical benefit rates also were increased. At the time of presentation, data were too immature for an overall survival rate.

The most common grade 3 or higher adverse events were hematologic: neutropenia (50.8%), thrombocytopenia (27.5%), and leukopenia (18.8%), all considerably higher than 2.5% for each in the placebo group.

These tolerability issues were expected, however, based on previous chidamide findings.

Neil Osterweil/MDedge News

“Not surprisingly ... 33% of patients had their dose reduced, 50% their dose interrupted, and this is despite the biweekly schedule,” said invited discussant Rebecca Dent, MD, of the National Cancer Centre in Singapore. Despite these issues, Dr. Dent concluded that chidamide otherwise “appears to be quite well tolerated,” and showed meaningful results.

“We now have a second trial demonstrating ... clinical benefit from the addition of HDAC inhibitors to endocrine therapy in [HR+] advanced breast cancer,” Dr. Dent said. “HDAC inhibitors clearly warrant further investigation in earlier settings of [HR+] advanced breast cancer and ... yet to be defined ... subgroups, and obviously we anxiously await the phase 3 results of entinostat.”

In consideration of the future, Dr. Dent suggested that more studies are needed to develop subgroup-targeted therapies and optimize sequencing. “We’ve really underestimated the selective pressure of these treatments and how they impact our subsequent therapies,” she said.

Dr. Dent noted how these factors limit predictive relevance of study findings in clinical practice, in which patients with different treatment histories may have completely different responses to the same agent.

To overcome these obstacles, Dr. Dent encouraged development of biomarker-driven strategies that can identify unique patterns of drug resistance and sensitivity. “This will allow us to ... identify which patients, which drug, and at which time.”

The ACE trial was funded by Chipscreen Biosciences.

SOURCE: Jiang Z et al. ESMO 2018, Abstract 283O.

Moderate hypofractionation is preferred over conventional fractionation in treatment of patients with localized prostate cancer who are candidates for external beam radiotherapy (EBRT), according to new a clinical practice guideline.

A meta-analysis of randomized clinical trials showed that moderate fractionation delivered the same efficacy as did conventional fractionation with a mild increase in gastrointestinal toxicity, reported lead author Scott C. Morgan, MD of OSF Medical Group in Bloomington, Illinois, and his colleagues. The drawback of toxicity is outweighed by distinct advantages in resource utilization and patient convenience, which make moderate hypofractionation the winning choice.

For many types of cancer, a shift toward fewer fractions of higher radiation is ongoing, driven largely by technological advances in radiation planning and delivery.

“Technical advances have permitted more precise and conformal delivery of escalated doses of radiation to the prostate, thereby improving the therapeutic ratio,” the authors wrote in the Journal of Clinical Oncology.

Fractionation is typically limited by adjacent tissue sensitivity, but prostate tumors are more sensitive to radiation than the rectum, allowing for higher doses of radiation without damaging healthy tissue. While conventional fractionation doses are between 180 and 200 cGy, moderate hypofractionation delivers doses of 240-340 cGy. Ultrahypofractionation is defined by doses equal to or greater than 500 cGy (the upper limit of the linear-quadratic model of cell survival).

The present guideline was developed through a 2-year, collaborative effort between the American Society of Radiation Oncology, the Society of Clinical Oncology, and the American Urological Association. Task force members included urologic surgeons and oncologists, medical physicists, and radiation oncologists from academic and nonacademic settings. A patient representative and radiation oncology resident also were involved. After completing a systematic literature review, the team developed recommendations with varying degrees of strength. Supporting evidence quality and level of consensus also were described.

Of note, the guideline calls for moderate hypofractionation for patients with localized prostate cancer regardless of urinary function, anatomy, comorbidity, or age, with or without radiation to the seminal vesicles. Along with this recommendation, clinicians should discuss with patients the small increased risk of acute gastrointestinal toxicity, compared with conventional fractionation and the limited follow-up time in most relevant clinical trials (often less than 5 years).

The guideline conveyed more skepticism regarding ultrahypofractionation because of a lack of supporting evidence and comparative trials. As such, the authors conditionally recommended ultrahypofractionation for low-risk and intermediate patients, the latter of whom should be encouraged to enter clinical trials.

“The conditional recommendations regarding ultrahypofractionation underscore the importance of shared decision making between clinicians and patients in this setting,” the authors wrote. “The decision to use ultrahypofractionated EBRT at this time should follow a detailed discussion of the existing uncertainties in the risk-benefit balance associated with this treatment approach and should be informed at all stages by the patient’s values and preferences.”

The authors reported financial affiliations with Amgen, GlaxoSmithKline, Bristol-Myers Squibb, and others.

SOURCE: Morgan et al. J Clin Oncol. 2018 Oct 11. doi: 10.1200/JCO.18.01097.

Moderate hypofractionation is preferred over conventional fractionation in treatment of patients with localized prostate cancer who are candidates for external beam radiotherapy (EBRT), according to new a clinical practice guideline.

A meta-analysis of randomized clinical trials showed that moderate fractionation delivered the same efficacy as did conventional fractionation with a mild increase in gastrointestinal toxicity, reported lead author Scott C. Morgan, MD of OSF Medical Group in Bloomington, Illinois, and his colleagues. The drawback of toxicity is outweighed by distinct advantages in resource utilization and patient convenience, which make moderate hypofractionation the winning choice.

For many types of cancer, a shift toward fewer fractions of higher radiation is ongoing, driven largely by technological advances in radiation planning and delivery.

“Technical advances have permitted more precise and conformal delivery of escalated doses of radiation to the prostate, thereby improving the therapeutic ratio,” the authors wrote in the Journal of Clinical Oncology.

Fractionation is typically limited by adjacent tissue sensitivity, but prostate tumors are more sensitive to radiation than the rectum, allowing for higher doses of radiation without damaging healthy tissue. While conventional fractionation doses are between 180 and 200 cGy, moderate hypofractionation delivers doses of 240-340 cGy. Ultrahypofractionation is defined by doses equal to or greater than 500 cGy (the upper limit of the linear-quadratic model of cell survival).

The present guideline was developed through a 2-year, collaborative effort between the American Society of Radiation Oncology, the Society of Clinical Oncology, and the American Urological Association. Task force members included urologic surgeons and oncologists, medical physicists, and radiation oncologists from academic and nonacademic settings. A patient representative and radiation oncology resident also were involved. After completing a systematic literature review, the team developed recommendations with varying degrees of strength. Supporting evidence quality and level of consensus also were described.

Of note, the guideline calls for moderate hypofractionation for patients with localized prostate cancer regardless of urinary function, anatomy, comorbidity, or age, with or without radiation to the seminal vesicles. Along with this recommendation, clinicians should discuss with patients the small increased risk of acute gastrointestinal toxicity, compared with conventional fractionation and the limited follow-up time in most relevant clinical trials (often less than 5 years).

The guideline conveyed more skepticism regarding ultrahypofractionation because of a lack of supporting evidence and comparative trials. As such, the authors conditionally recommended ultrahypofractionation for low-risk and intermediate patients, the latter of whom should be encouraged to enter clinical trials.

“The conditional recommendations regarding ultrahypofractionation underscore the importance of shared decision making between clinicians and patients in this setting,” the authors wrote. “The decision to use ultrahypofractionated EBRT at this time should follow a detailed discussion of the existing uncertainties in the risk-benefit balance associated with this treatment approach and should be informed at all stages by the patient’s values and preferences.”

The authors reported financial affiliations with Amgen, GlaxoSmithKline, Bristol-Myers Squibb, and others.

SOURCE: Morgan et al. J Clin Oncol. 2018 Oct 11. doi: 10.1200/JCO.18.01097.

Moderate hypofractionation is preferred over conventional fractionation in treatment of patients with localized prostate cancer who are candidates for external beam radiotherapy (EBRT), according to new a clinical practice guideline.

A meta-analysis of randomized clinical trials showed that moderate fractionation delivered the same efficacy as did conventional fractionation with a mild increase in gastrointestinal toxicity, reported lead author Scott C. Morgan, MD of OSF Medical Group in Bloomington, Illinois, and his colleagues. The drawback of toxicity is outweighed by distinct advantages in resource utilization and patient convenience, which make moderate hypofractionation the winning choice.

For many types of cancer, a shift toward fewer fractions of higher radiation is ongoing, driven largely by technological advances in radiation planning and delivery.

“Technical advances have permitted more precise and conformal delivery of escalated doses of radiation to the prostate, thereby improving the therapeutic ratio,” the authors wrote in the Journal of Clinical Oncology.

Fractionation is typically limited by adjacent tissue sensitivity, but prostate tumors are more sensitive to radiation than the rectum, allowing for higher doses of radiation without damaging healthy tissue. While conventional fractionation doses are between 180 and 200 cGy, moderate hypofractionation delivers doses of 240-340 cGy. Ultrahypofractionation is defined by doses equal to or greater than 500 cGy (the upper limit of the linear-quadratic model of cell survival).

The present guideline was developed through a 2-year, collaborative effort between the American Society of Radiation Oncology, the Society of Clinical Oncology, and the American Urological Association. Task force members included urologic surgeons and oncologists, medical physicists, and radiation oncologists from academic and nonacademic settings. A patient representative and radiation oncology resident also were involved. After completing a systematic literature review, the team developed recommendations with varying degrees of strength. Supporting evidence quality and level of consensus also were described.

Of note, the guideline calls for moderate hypofractionation for patients with localized prostate cancer regardless of urinary function, anatomy, comorbidity, or age, with or without radiation to the seminal vesicles. Along with this recommendation, clinicians should discuss with patients the small increased risk of acute gastrointestinal toxicity, compared with conventional fractionation and the limited follow-up time in most relevant clinical trials (often less than 5 years).

The guideline conveyed more skepticism regarding ultrahypofractionation because of a lack of supporting evidence and comparative trials. As such, the authors conditionally recommended ultrahypofractionation for low-risk and intermediate patients, the latter of whom should be encouraged to enter clinical trials.

“The conditional recommendations regarding ultrahypofractionation underscore the importance of shared decision making between clinicians and patients in this setting,” the authors wrote. “The decision to use ultrahypofractionated EBRT at this time should follow a detailed discussion of the existing uncertainties in the risk-benefit balance associated with this treatment approach and should be informed at all stages by the patient’s values and preferences.”

The authors reported financial affiliations with Amgen, GlaxoSmithKline, Bristol-Myers Squibb, and others.

SOURCE: Morgan et al. J Clin Oncol. 2018 Oct 11. doi: 10.1200/JCO.18.01097.

Image by Betty Pace

Crizanlizumab can reduce vaso-occlusive crises (VOCs) across subgroups of patients with sickle cell disease (SCD), according to a post-hoc analysis of the phase 2 SUSTAIN trial.

Researchers found crizanlizumab was more effective than placebo at delaying time to first VOC and eliminating crises in patients who had numerous previous crises, exhibited the HbSS genotype, or were taking concomitant hydroxyurea.

Abdullah Kutlar, MD, of the Medical College of Georgia in Augusta, and his colleagues reported these findings in the American Journal of Hematology.

The phase 2 SUSTAIN trial previously showed that crizanlizumab—a humanized, anti–P-selectin monoclonal antibody—reduced the frequency of VOCs by 45% and delayed time to first crisis by about 3 months.

Additionally, a subgroup analysis showed there was a lower frequency of VOCs with crizanlizumab at 5 mg/kg, compared with placebo, regardless of the number of prior VOCs, concomitant hydroxyurea use, or the SCD genotype.

The present post-hoc analysis took a deeper look at these observations across the same subgroups. Specifically, the investigators assessed elimination of VOCs, time to first crisis, and adverse events in 132 patients.

Crizanlizumab eliminated VOCs about seven times more frequently than did placebo in patients who had a high frequency of VOCs before the study (5 to 10 VOCs in the year prior)—28.0% and 4.2%, respectively.

Crizanlizumab eliminated VOCs about twice as often as placebo in patients with the HbSS genotype—31.9% and 17.0%, respectively—and in patients who were using concomitant hydroxyurea—33.3% and 17.5%, respectively.

Further analysis showed that crizanlizumab delayed time to first VOC across all subgroups.

In patients with the HbSS genotype, the time to first VOC was 4.07 months with crizanlizumab and 1.12 months with placebo.

In patients with a higher frequency of previous VOCs, the time to first on-study VOC was 2.43 months with crizanlizumab and 1.03 months with placebo.

In patients taking hydroxyurea, the time to first VOC was 2.43 months with crizanlizumab and 1.45 months with placebo.

Safety was comparable across subgroups.

This study was sponsored by Novartis. The authors reported financial relationships with Novartis, Bluebird Bio, AstraZeneca, and others.

Image by Betty Pace

Crizanlizumab can reduce vaso-occlusive crises (VOCs) across subgroups of patients with sickle cell disease (SCD), according to a post-hoc analysis of the phase 2 SUSTAIN trial.

Researchers found crizanlizumab was more effective than placebo at delaying time to first VOC and eliminating crises in patients who had numerous previous crises, exhibited the HbSS genotype, or were taking concomitant hydroxyurea.

Abdullah Kutlar, MD, of the Medical College of Georgia in Augusta, and his colleagues reported these findings in the American Journal of Hematology.

The phase 2 SUSTAIN trial previously showed that crizanlizumab—a humanized, anti–P-selectin monoclonal antibody—reduced the frequency of VOCs by 45% and delayed time to first crisis by about 3 months.

Additionally, a subgroup analysis showed there was a lower frequency of VOCs with crizanlizumab at 5 mg/kg, compared with placebo, regardless of the number of prior VOCs, concomitant hydroxyurea use, or the SCD genotype.

The present post-hoc analysis took a deeper look at these observations across the same subgroups. Specifically, the investigators assessed elimination of VOCs, time to first crisis, and adverse events in 132 patients.

Crizanlizumab eliminated VOCs about seven times more frequently than did placebo in patients who had a high frequency of VOCs before the study (5 to 10 VOCs in the year prior)—28.0% and 4.2%, respectively.

Crizanlizumab eliminated VOCs about twice as often as placebo in patients with the HbSS genotype—31.9% and 17.0%, respectively—and in patients who were using concomitant hydroxyurea—33.3% and 17.5%, respectively.

Further analysis showed that crizanlizumab delayed time to first VOC across all subgroups.

In patients with the HbSS genotype, the time to first VOC was 4.07 months with crizanlizumab and 1.12 months with placebo.

In patients with a higher frequency of previous VOCs, the time to first on-study VOC was 2.43 months with crizanlizumab and 1.03 months with placebo.

In patients taking hydroxyurea, the time to first VOC was 2.43 months with crizanlizumab and 1.45 months with placebo.

Safety was comparable across subgroups.

This study was sponsored by Novartis. The authors reported financial relationships with Novartis, Bluebird Bio, AstraZeneca, and others.

Image by Betty Pace

Crizanlizumab can reduce vaso-occlusive crises (VOCs) across subgroups of patients with sickle cell disease (SCD), according to a post-hoc analysis of the phase 2 SUSTAIN trial.

Researchers found crizanlizumab was more effective than placebo at delaying time to first VOC and eliminating crises in patients who had numerous previous crises, exhibited the HbSS genotype, or were taking concomitant hydroxyurea.

Abdullah Kutlar, MD, of the Medical College of Georgia in Augusta, and his colleagues reported these findings in the American Journal of Hematology.

The phase 2 SUSTAIN trial previously showed that crizanlizumab—a humanized, anti–P-selectin monoclonal antibody—reduced the frequency of VOCs by 45% and delayed time to first crisis by about 3 months.

Additionally, a subgroup analysis showed there was a lower frequency of VOCs with crizanlizumab at 5 mg/kg, compared with placebo, regardless of the number of prior VOCs, concomitant hydroxyurea use, or the SCD genotype.

The present post-hoc analysis took a deeper look at these observations across the same subgroups. Specifically, the investigators assessed elimination of VOCs, time to first crisis, and adverse events in 132 patients.

Crizanlizumab eliminated VOCs about seven times more frequently than did placebo in patients who had a high frequency of VOCs before the study (5 to 10 VOCs in the year prior)—28.0% and 4.2%, respectively.

Crizanlizumab eliminated VOCs about twice as often as placebo in patients with the HbSS genotype—31.9% and 17.0%, respectively—and in patients who were using concomitant hydroxyurea—33.3% and 17.5%, respectively.

Further analysis showed that crizanlizumab delayed time to first VOC across all subgroups.

In patients with the HbSS genotype, the time to first VOC was 4.07 months with crizanlizumab and 1.12 months with placebo.

In patients with a higher frequency of previous VOCs, the time to first on-study VOC was 2.43 months with crizanlizumab and 1.03 months with placebo.

In patients taking hydroxyurea, the time to first VOC was 2.43 months with crizanlizumab and 1.45 months with placebo.

Safety was comparable across subgroups.

This study was sponsored by Novartis. The authors reported financial relationships with Novartis, Bluebird Bio, AstraZeneca, and others.

Crizanlizumab effectively reduced vaso-occlusive crises among patients with sickle cell disease (SCD) who have numerous crises, exhibit the HbSS genotype, and take concomitant hydroxyurea, according to investigators.

CDC/Janice Haney Carr

Across subgroups, crizanlizumab was safe and more effective than placebo at delaying time to first vaso-occlusive crisis (VOC) and eliminating crises, reported lead author Abdullah Kutlar, MD, of the Sickle Cell Center at the Medical College of Georgia, Augusta, and his colleagues.

The phase 2 SUSTAIN trial recently showed that crizanlizumab – a humanized, anti–P-selectin monoclonal antibody – reduced the frequency of VOCs by 45% and delayed time to first crisis by about 3 months (N Engl J Med. 2017;376:429-39).

Additionally, a subgroup analysis showed that there was a lower frequency of pain crises with crizanlizumab 5 mg/kg, compared with placebo, regardless of the number of prior VOCs, concomitant hydroxyurea use, or the SCD genotype.

The present post hoc analysis took a deeper look at these observations across the same subgroups; specifically, the investigators assessed elimination of VOCs, time to first crisis, and adverse events. They reported the findings in the American Journal of Hematology.

Crizanlizumab eliminated pain crises about seven times more frequently than did placebo in patients who had a high frequency of VOCs before the study (28.0% vs. 4.2%), and about twice as often in patients with the HbSS genotype (31.9% vs. 17.0%), and patients who were using concomitant hydroxyurea (33.3% vs. 17.5%).

Further analysis showed that crizanlizumab delayed time to first pain crisis across all subgroups, most dramatically in patients with the HbSS genotype (4.07 months for crizanlizumab vs. 1.12 months for placebo). Safety was comparable across subgroups.

“These findings provide supportive evidence that crizanlizumab provides a clinically meaningful treatment benefit when used alone or in combination with hydroxyurea for the prevention of VOCs,” the investigators wrote.

An ongoing phase 2 pharmacokinetic/pharmacodynamic study is evaluating a higher dose of crizanlizumab (7.5 mg/kg), and another trial seeks to evaluate pediatric doses of the drug.

The study was sponsored by Novartis. The authors reported financial relationships with Novartis, Bluebird Bio, AstraZeneca, and others.

SOURCE: Kutlar A et al. Am J Hematol. 2018 Oct 8. doi: 10.1002/ajh.25308.

Crizanlizumab effectively reduced vaso-occlusive crises among patients with sickle cell disease (SCD) who have numerous crises, exhibit the HbSS genotype, and take concomitant hydroxyurea, according to investigators.

CDC/Janice Haney Carr

Across subgroups, crizanlizumab was safe and more effective than placebo at delaying time to first vaso-occlusive crisis (VOC) and eliminating crises, reported lead author Abdullah Kutlar, MD, of the Sickle Cell Center at the Medical College of Georgia, Augusta, and his colleagues.

The phase 2 SUSTAIN trial recently showed that crizanlizumab – a humanized, anti–P-selectin monoclonal antibody – reduced the frequency of VOCs by 45% and delayed time to first crisis by about 3 months (N Engl J Med. 2017;376:429-39).

Additionally, a subgroup analysis showed that there was a lower frequency of pain crises with crizanlizumab 5 mg/kg, compared with placebo, regardless of the number of prior VOCs, concomitant hydroxyurea use, or the SCD genotype.

The present post hoc analysis took a deeper look at these observations across the same subgroups; specifically, the investigators assessed elimination of VOCs, time to first crisis, and adverse events. They reported the findings in the American Journal of Hematology.

Crizanlizumab eliminated pain crises about seven times more frequently than did placebo in patients who had a high frequency of VOCs before the study (28.0% vs. 4.2%), and about twice as often in patients with the HbSS genotype (31.9% vs. 17.0%), and patients who were using concomitant hydroxyurea (33.3% vs. 17.5%).

Further analysis showed that crizanlizumab delayed time to first pain crisis across all subgroups, most dramatically in patients with the HbSS genotype (4.07 months for crizanlizumab vs. 1.12 months for placebo). Safety was comparable across subgroups.

“These findings provide supportive evidence that crizanlizumab provides a clinically meaningful treatment benefit when used alone or in combination with hydroxyurea for the prevention of VOCs,” the investigators wrote.

An ongoing phase 2 pharmacokinetic/pharmacodynamic study is evaluating a higher dose of crizanlizumab (7.5 mg/kg), and another trial seeks to evaluate pediatric doses of the drug.

The study was sponsored by Novartis. The authors reported financial relationships with Novartis, Bluebird Bio, AstraZeneca, and others.

SOURCE: Kutlar A et al. Am J Hematol. 2018 Oct 8. doi: 10.1002/ajh.25308.

Crizanlizumab effectively reduced vaso-occlusive crises among patients with sickle cell disease (SCD) who have numerous crises, exhibit the HbSS genotype, and take concomitant hydroxyurea, according to investigators.

CDC/Janice Haney Carr

Across subgroups, crizanlizumab was safe and more effective than placebo at delaying time to first vaso-occlusive crisis (VOC) and eliminating crises, reported lead author Abdullah Kutlar, MD, of the Sickle Cell Center at the Medical College of Georgia, Augusta, and his colleagues.

The phase 2 SUSTAIN trial recently showed that crizanlizumab – a humanized, anti–P-selectin monoclonal antibody – reduced the frequency of VOCs by 45% and delayed time to first crisis by about 3 months (N Engl J Med. 2017;376:429-39).

Additionally, a subgroup analysis showed that there was a lower frequency of pain crises with crizanlizumab 5 mg/kg, compared with placebo, regardless of the number of prior VOCs, concomitant hydroxyurea use, or the SCD genotype.

The present post hoc analysis took a deeper look at these observations across the same subgroups; specifically, the investigators assessed elimination of VOCs, time to first crisis, and adverse events. They reported the findings in the American Journal of Hematology.

Crizanlizumab eliminated pain crises about seven times more frequently than did placebo in patients who had a high frequency of VOCs before the study (28.0% vs. 4.2%), and about twice as often in patients with the HbSS genotype (31.9% vs. 17.0%), and patients who were using concomitant hydroxyurea (33.3% vs. 17.5%).

Further analysis showed that crizanlizumab delayed time to first pain crisis across all subgroups, most dramatically in patients with the HbSS genotype (4.07 months for crizanlizumab vs. 1.12 months for placebo). Safety was comparable across subgroups.

“These findings provide supportive evidence that crizanlizumab provides a clinically meaningful treatment benefit when used alone or in combination with hydroxyurea for the prevention of VOCs,” the investigators wrote.

An ongoing phase 2 pharmacokinetic/pharmacodynamic study is evaluating a higher dose of crizanlizumab (7.5 mg/kg), and another trial seeks to evaluate pediatric doses of the drug.

The study was sponsored by Novartis. The authors reported financial relationships with Novartis, Bluebird Bio, AstraZeneca, and others.

SOURCE: Kutlar A et al. Am J Hematol. 2018 Oct 8. doi: 10.1002/ajh.25308.

Essential thrombocythemia

New research suggests genomic characteristics of patients with myeloproliferative neoplasms (MPNs) can predict clinical outcomes.

Investigators defined eight genomic subgroups of MPNs, each with distinct clinical features, including event-free survival, risk of leukemic transformation, and blood counts.

Jacob Grinfeld, MD, of the University of Cambridge in the U.K., and his colleagues described these findings in The New England Journal of Medicine.

This study included 2,035 patients with MPNs, including essential thrombocythemia, polycythemia vera, myelofibrosis, and other diagnoses.

The investigators performed targeted sequencing for the full coding sequence of 69 genes and genome-wide copy number information in 1,887 patients. Whole-exome sequencing was performed in another 148 patients.

By sequencing coding exons from 69 myeloid cancer genes, the investigators were able to survey the diversity of mutations across MPN patients and identify mutation-associated clinical outcomes.

The results showed that slightly less than half (45%) of the patients had a solitary abnormality in CALR, MPL, or JAK2, while the remaining patients had additional driver mutations.

In some instances, additional mutations were numerous, particularly in older patients with advanced disease. In at least five cases, 33 genes had driver mutations.

Further analysis revealed eight genomic subgroups that could predict clinical outcomes based on shared chromosomal abnormalities and mutations.

For example, one subgroup included patients with TP53 mutations. These individuals had a “dismal prognosis” and were 15.5 times more likely to transform to acute myeloid leukemia, compared with the JAK2-heterozygous subgroup (P<0.001).

Because prognosis is “a key determinant” of MPN treatment, genomic subgrouping may one day guide clinical decision-making, the investigators concluded.

To further this cause, they have made available an online calculator of individualized patient outcomes, which can be accessed at https://cancer.sanger.ac.uk/mpn-multistage/.

This study was funded by the Wellcome Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Cancer Research UK, and others. Some study authors reported fees from Celgene, Novartis, Gilead, Shire, and others outside of the study.

Essential thrombocythemia

New research suggests genomic characteristics of patients with myeloproliferative neoplasms (MPNs) can predict clinical outcomes.

Investigators defined eight genomic subgroups of MPNs, each with distinct clinical features, including event-free survival, risk of leukemic transformation, and blood counts.

Jacob Grinfeld, MD, of the University of Cambridge in the U.K., and his colleagues described these findings in The New England Journal of Medicine.

This study included 2,035 patients with MPNs, including essential thrombocythemia, polycythemia vera, myelofibrosis, and other diagnoses.

The investigators performed targeted sequencing for the full coding sequence of 69 genes and genome-wide copy number information in 1,887 patients. Whole-exome sequencing was performed in another 148 patients.

By sequencing coding exons from 69 myeloid cancer genes, the investigators were able to survey the diversity of mutations across MPN patients and identify mutation-associated clinical outcomes.

The results showed that slightly less than half (45%) of the patients had a solitary abnormality in CALR, MPL, or JAK2, while the remaining patients had additional driver mutations.

In some instances, additional mutations were numerous, particularly in older patients with advanced disease. In at least five cases, 33 genes had driver mutations.

Further analysis revealed eight genomic subgroups that could predict clinical outcomes based on shared chromosomal abnormalities and mutations.

For example, one subgroup included patients with TP53 mutations. These individuals had a “dismal prognosis” and were 15.5 times more likely to transform to acute myeloid leukemia, compared with the JAK2-heterozygous subgroup (P<0.001).

Because prognosis is “a key determinant” of MPN treatment, genomic subgrouping may one day guide clinical decision-making, the investigators concluded.

To further this cause, they have made available an online calculator of individualized patient outcomes, which can be accessed at https://cancer.sanger.ac.uk/mpn-multistage/.

This study was funded by the Wellcome Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Cancer Research UK, and others. Some study authors reported fees from Celgene, Novartis, Gilead, Shire, and others outside of the study.

Essential thrombocythemia

New research suggests genomic characteristics of patients with myeloproliferative neoplasms (MPNs) can predict clinical outcomes.

Investigators defined eight genomic subgroups of MPNs, each with distinct clinical features, including event-free survival, risk of leukemic transformation, and blood counts.

Jacob Grinfeld, MD, of the University of Cambridge in the U.K., and his colleagues described these findings in The New England Journal of Medicine.

This study included 2,035 patients with MPNs, including essential thrombocythemia, polycythemia vera, myelofibrosis, and other diagnoses.

The investigators performed targeted sequencing for the full coding sequence of 69 genes and genome-wide copy number information in 1,887 patients. Whole-exome sequencing was performed in another 148 patients.

By sequencing coding exons from 69 myeloid cancer genes, the investigators were able to survey the diversity of mutations across MPN patients and identify mutation-associated clinical outcomes.

The results showed that slightly less than half (45%) of the patients had a solitary abnormality in CALR, MPL, or JAK2, while the remaining patients had additional driver mutations.

In some instances, additional mutations were numerous, particularly in older patients with advanced disease. In at least five cases, 33 genes had driver mutations.

Further analysis revealed eight genomic subgroups that could predict clinical outcomes based on shared chromosomal abnormalities and mutations.

For example, one subgroup included patients with TP53 mutations. These individuals had a “dismal prognosis” and were 15.5 times more likely to transform to acute myeloid leukemia, compared with the JAK2-heterozygous subgroup (P<0.001).

Because prognosis is “a key determinant” of MPN treatment, genomic subgrouping may one day guide clinical decision-making, the investigators concluded.

To further this cause, they have made available an online calculator of individualized patient outcomes, which can be accessed at https://cancer.sanger.ac.uk/mpn-multistage/.

This study was funded by the Wellcome Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Cancer Research UK, and others. Some study authors reported fees from Celgene, Novartis, Gilead, Shire, and others outside of the study.

Infusion of allogeneic BK virus–specific T cells may be an effective treatment for patients with progressive multifocal leukoencephalopathy (PML), according to investigators from the University of Texas MD Anderson Cancer Center, Houston.

The infusion cleared JC virus from the cerebrospinal fluid (CSF) of two patients and reduced viral load in the third, reported lead author Muharrem Muftuoglu, MD, of MD Anderson’s department of stem cell transplantation and cellular therapy and colleagues. One of the patients completely recovered and returned to work.

Jochen Sand/Thinkstock

“Several approaches for the treatment of PML, including the use of antiviral medications and mirtazapine, have been tested, with poor results,” the investigators wrote in the New England Journal of Medicine. Although virus-specific T-cell infusion is a novel approach to treating PML, this method has been used for other conditions.

“Several groups, including ours, have successfully used viral-specific T cells to treat BK virus infection after stem-cell transplantation,” the investigators wrote. “Because BK virus and JC virus are genetically similar to one another and share a number of immunogenic proteins with a substantial degree of sequence homology ... we hypothesized that T cells developed against BK virus may also be effective against JC virus infection.”

This hypothesis proved accurate. The investigators infused three PML patients with “cryopreserved, third-party–produced, viral-specific T cells that had been designed for the treatment of patients with BK virus infection after stem-cell transplantation.” Each patient presented with a different condition and PML-precipitating therapy. The first patient was a 32-year-old woman with high-risk acute myeloid leukemia who had received a cord-blood transplantation, the second a 73-year-old woman with JAK2-positive myeloproliferative neoplasia on ruxolitinib (Jakafi) therapy, and the third a 35-year-old man with HIV who had received highly active antiretroviral therapy.

T-cell infusions cleared JC virus from the CSF of the woman with leukemia (three infusions) and the man with HIV (four infusions). These patients recovered to different degrees: The woman had full resolution of symptoms, while the man had slurred speech and walked with a cane. Treatment reduced JC viral load in the elderly woman with myeloproliferative neoplasia (two infusions), but she did not clear the virus and died about 8 months later.

No adverse events occurred, but two patients developed immune reconstitution inflammatory syndrome. This was likely caused by the T-cell infusion, since absolute T-cell counts remained steady and white matter enhancement was detected on MRI within 4 weeks of treatment. Still, the investigators were optimistic about future potential.

“Third-party–produced, ‘off-the-shelf,’ partially HLA-matched, BK virus–specific T cells may serve as therapy for PML,” the investigators concluded. “Further study in a larger group of patients is required to determine the success rate, durability, and longer-term adverse events associated with this treatment.”

The study was funded by the MD Anderson Cancer Center Moon Shots Program and the National Institutes of Health.

SOURCE: Muftuoglu M et al. N Engl J Med. 2018 Oct 11;379:1443-51

This article was updated 3/22/19.

Infusion of allogeneic BK virus–specific T cells may be an effective treatment for patients with progressive multifocal leukoencephalopathy (PML), according to investigators from the University of Texas MD Anderson Cancer Center, Houston.

The infusion cleared JC virus from the cerebrospinal fluid (CSF) of two patients and reduced viral load in the third, reported lead author Muharrem Muftuoglu, MD, of MD Anderson’s department of stem cell transplantation and cellular therapy and colleagues. One of the patients completely recovered and returned to work.

Jochen Sand/Thinkstock

“Several approaches for the treatment of PML, including the use of antiviral medications and mirtazapine, have been tested, with poor results,” the investigators wrote in the New England Journal of Medicine. Although virus-specific T-cell infusion is a novel approach to treating PML, this method has been used for other conditions.

“Several groups, including ours, have successfully used viral-specific T cells to treat BK virus infection after stem-cell transplantation,” the investigators wrote. “Because BK virus and JC virus are genetically similar to one another and share a number of immunogenic proteins with a substantial degree of sequence homology ... we hypothesized that T cells developed against BK virus may also be effective against JC virus infection.”

This hypothesis proved accurate. The investigators infused three PML patients with “cryopreserved, third-party–produced, viral-specific T cells that had been designed for the treatment of patients with BK virus infection after stem-cell transplantation.” Each patient presented with a different condition and PML-precipitating therapy. The first patient was a 32-year-old woman with high-risk acute myeloid leukemia who had received a cord-blood transplantation, the second a 73-year-old woman with JAK2-positive myeloproliferative neoplasia on ruxolitinib (Jakafi) therapy, and the third a 35-year-old man with HIV who had received highly active antiretroviral therapy.

T-cell infusions cleared JC virus from the CSF of the woman with leukemia (three infusions) and the man with HIV (four infusions). These patients recovered to different degrees: The woman had full resolution of symptoms, while the man had slurred speech and walked with a cane. Treatment reduced JC viral load in the elderly woman with myeloproliferative neoplasia (two infusions), but she did not clear the virus and died about 8 months later.

No adverse events occurred, but two patients developed immune reconstitution inflammatory syndrome. This was likely caused by the T-cell infusion, since absolute T-cell counts remained steady and white matter enhancement was detected on MRI within 4 weeks of treatment. Still, the investigators were optimistic about future potential.

“Third-party–produced, ‘off-the-shelf,’ partially HLA-matched, BK virus–specific T cells may serve as therapy for PML,” the investigators concluded. “Further study in a larger group of patients is required to determine the success rate, durability, and longer-term adverse events associated with this treatment.”

The study was funded by the MD Anderson Cancer Center Moon Shots Program and the National Institutes of Health.

SOURCE: Muftuoglu M et al. N Engl J Med. 2018 Oct 11;379:1443-51

This article was updated 3/22/19.

Infusion of allogeneic BK virus–specific T cells may be an effective treatment for patients with progressive multifocal leukoencephalopathy (PML), according to investigators from the University of Texas MD Anderson Cancer Center, Houston.

The infusion cleared JC virus from the cerebrospinal fluid (CSF) of two patients and reduced viral load in the third, reported lead author Muharrem Muftuoglu, MD, of MD Anderson’s department of stem cell transplantation and cellular therapy and colleagues. One of the patients completely recovered and returned to work.

Jochen Sand/Thinkstock

“Several approaches for the treatment of PML, including the use of antiviral medications and mirtazapine, have been tested, with poor results,” the investigators wrote in the New England Journal of Medicine. Although virus-specific T-cell infusion is a novel approach to treating PML, this method has been used for other conditions.

“Several groups, including ours, have successfully used viral-specific T cells to treat BK virus infection after stem-cell transplantation,” the investigators wrote. “Because BK virus and JC virus are genetically similar to one another and share a number of immunogenic proteins with a substantial degree of sequence homology ... we hypothesized that T cells developed against BK virus may also be effective against JC virus infection.”

This hypothesis proved accurate. The investigators infused three PML patients with “cryopreserved, third-party–produced, viral-specific T cells that had been designed for the treatment of patients with BK virus infection after stem-cell transplantation.” Each patient presented with a different condition and PML-precipitating therapy. The first patient was a 32-year-old woman with high-risk acute myeloid leukemia who had received a cord-blood transplantation, the second a 73-year-old woman with JAK2-positive myeloproliferative neoplasia on ruxolitinib (Jakafi) therapy, and the third a 35-year-old man with HIV who had received highly active antiretroviral therapy.

T-cell infusions cleared JC virus from the CSF of the woman with leukemia (three infusions) and the man with HIV (four infusions). These patients recovered to different degrees: The woman had full resolution of symptoms, while the man had slurred speech and walked with a cane. Treatment reduced JC viral load in the elderly woman with myeloproliferative neoplasia (two infusions), but she did not clear the virus and died about 8 months later.

No adverse events occurred, but two patients developed immune reconstitution inflammatory syndrome. This was likely caused by the T-cell infusion, since absolute T-cell counts remained steady and white matter enhancement was detected on MRI within 4 weeks of treatment. Still, the investigators were optimistic about future potential.

“Third-party–produced, ‘off-the-shelf,’ partially HLA-matched, BK virus–specific T cells may serve as therapy for PML,” the investigators concluded. “Further study in a larger group of patients is required to determine the success rate, durability, and longer-term adverse events associated with this treatment.”

The study was funded by the MD Anderson Cancer Center Moon Shots Program and the National Institutes of Health.

SOURCE: Muftuoglu M et al. N Engl J Med. 2018 Oct 11;379:1443-51

This article was updated 3/22/19.

Genomic characteristics of patients with myeloproliferative neoplasms (MPN) can predict clinical outcomes, a recent study found.

Gio_tto/Thinkstock

Eight genomic subgroups of MPN were recognized, each with distinct clinical features, including event-free survival, risk of leukemic transformation, and blood counts, according to Jacob Grinfeld, MD, of the Wellcome-MRC Cambridge (England) Stem Cell Institute and Cambridge Institute for Medical Research and his colleagues.

“Current classification schemes distinguish among the subtypes of myeloproliferative neoplasms according to clinical and laboratory features, but uncertainty clouds where and how to draw dividing lines among them,” the investigators wrote in the New England Journal of Medicine. “In blood cancers, a progressive shift is under way, from clinical and morphologic classification schemes to those that are based on genomics.”

MPNs are often driven by mutations in CALR, MPL, or JAK2 genes, but classification is not confined to just three genomic types; many patients have additional driver mutations throughout a variety of cancer genes, and it is these additional mutations that are responsible for the wide range of disease phenotypes and clinical outcomes.

This study included 2,035 patients with MPNs, including essential thrombocythemia, polycythemia vera, myelofibrosis, and other MPN diagnoses. The investigators performed targeted sequencing for the full coding sequence of 69 genes and genomewide copy-number information in 1,887 patients. Another 148 patients underwent whole-exome sequencing.

By sequencing coding exons from 69 myeloid cancer genes, the investigators were able to survey the diversity of mutations across a population of patients with MPNs and identify mutation-associated clinical outcomes.

The results showed that slightly less than half (45%) of the patients had a solitary abnormality in CALR, MPL, or JAK2, while the remaining patients had additional driver mutations. In some instances, additional mutations were numerous, particularly in older patients with advanced disease. In at least five cases, 33 genes had driver mutations.

Further analysis identified eight genomic subgroups that could predict clinical outcomes based on shared chromosomal abnormalities and mutations. For example, one subgroup included patients with TP53 mutations; these individuals had a “dismal prognosis” and were 15.5 times more likely to transform to acute myeloid leukemia (AML), compared with the JAK2-heterozygous subgroup (P less than .001).

Because prognosis is “a key determinant of the treatment of patients with MPNs,” genomic subgrouping may one day guide clinical decision making, the investigators concluded.

To further this cause, the investigators have made available an online calculator of individualized patient outcomes, which can be accessed at https://cancer.sanger.ac.uk/mpn-multistage/.

The study was funded by the Wellcome Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Cancer Research UK, and others. Some study authors reported fees from Celgene, Novartis, Gilead, Shire, and others outside of the study.

SOURCE: Grinfeld J et al. N Engl J Med. 2018;379:1416-30.

Genomic characteristics of patients with myeloproliferative neoplasms (MPN) can predict clinical outcomes, a recent study found.

Gio_tto/Thinkstock

Eight genomic subgroups of MPN were recognized, each with distinct clinical features, including event-free survival, risk of leukemic transformation, and blood counts, according to Jacob Grinfeld, MD, of the Wellcome-MRC Cambridge (England) Stem Cell Institute and Cambridge Institute for Medical Research and his colleagues.

“Current classification schemes distinguish among the subtypes of myeloproliferative neoplasms according to clinical and laboratory features, but uncertainty clouds where and how to draw dividing lines among them,” the investigators wrote in the New England Journal of Medicine. “In blood cancers, a progressive shift is under way, from clinical and morphologic classification schemes to those that are based on genomics.”

MPNs are often driven by mutations in CALR, MPL, or JAK2 genes, but classification is not confined to just three genomic types; many patients have additional driver mutations throughout a variety of cancer genes, and it is these additional mutations that are responsible for the wide range of disease phenotypes and clinical outcomes.

This study included 2,035 patients with MPNs, including essential thrombocythemia, polycythemia vera, myelofibrosis, and other MPN diagnoses. The investigators performed targeted sequencing for the full coding sequence of 69 genes and genomewide copy-number information in 1,887 patients. Another 148 patients underwent whole-exome sequencing.

By sequencing coding exons from 69 myeloid cancer genes, the investigators were able to survey the diversity of mutations across a population of patients with MPNs and identify mutation-associated clinical outcomes.

The results showed that slightly less than half (45%) of the patients had a solitary abnormality in CALR, MPL, or JAK2, while the remaining patients had additional driver mutations. In some instances, additional mutations were numerous, particularly in older patients with advanced disease. In at least five cases, 33 genes had driver mutations.

Further analysis identified eight genomic subgroups that could predict clinical outcomes based on shared chromosomal abnormalities and mutations. For example, one subgroup included patients with TP53 mutations; these individuals had a “dismal prognosis” and were 15.5 times more likely to transform to acute myeloid leukemia (AML), compared with the JAK2-heterozygous subgroup (P less than .001).

Because prognosis is “a key determinant of the treatment of patients with MPNs,” genomic subgrouping may one day guide clinical decision making, the investigators concluded.

To further this cause, the investigators have made available an online calculator of individualized patient outcomes, which can be accessed at https://cancer.sanger.ac.uk/mpn-multistage/.

The study was funded by the Wellcome Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Cancer Research UK, and others. Some study authors reported fees from Celgene, Novartis, Gilead, Shire, and others outside of the study.

SOURCE: Grinfeld J et al. N Engl J Med. 2018;379:1416-30.

Genomic characteristics of patients with myeloproliferative neoplasms (MPN) can predict clinical outcomes, a recent study found.

Gio_tto/Thinkstock

Eight genomic subgroups of MPN were recognized, each with distinct clinical features, including event-free survival, risk of leukemic transformation, and blood counts, according to Jacob Grinfeld, MD, of the Wellcome-MRC Cambridge (England) Stem Cell Institute and Cambridge Institute for Medical Research and his colleagues.

“Current classification schemes distinguish among the subtypes of myeloproliferative neoplasms according to clinical and laboratory features, but uncertainty clouds where and how to draw dividing lines among them,” the investigators wrote in the New England Journal of Medicine. “In blood cancers, a progressive shift is under way, from clinical and morphologic classification schemes to those that are based on genomics.”

MPNs are often driven by mutations in CALR, MPL, or JAK2 genes, but classification is not confined to just three genomic types; many patients have additional driver mutations throughout a variety of cancer genes, and it is these additional mutations that are responsible for the wide range of disease phenotypes and clinical outcomes.

This study included 2,035 patients with MPNs, including essential thrombocythemia, polycythemia vera, myelofibrosis, and other MPN diagnoses. The investigators performed targeted sequencing for the full coding sequence of 69 genes and genomewide copy-number information in 1,887 patients. Another 148 patients underwent whole-exome sequencing.

By sequencing coding exons from 69 myeloid cancer genes, the investigators were able to survey the diversity of mutations across a population of patients with MPNs and identify mutation-associated clinical outcomes.

The results showed that slightly less than half (45%) of the patients had a solitary abnormality in CALR, MPL, or JAK2, while the remaining patients had additional driver mutations. In some instances, additional mutations were numerous, particularly in older patients with advanced disease. In at least five cases, 33 genes had driver mutations.

Further analysis identified eight genomic subgroups that could predict clinical outcomes based on shared chromosomal abnormalities and mutations. For example, one subgroup included patients with TP53 mutations; these individuals had a “dismal prognosis” and were 15.5 times more likely to transform to acute myeloid leukemia (AML), compared with the JAK2-heterozygous subgroup (P less than .001).

Because prognosis is “a key determinant of the treatment of patients with MPNs,” genomic subgrouping may one day guide clinical decision making, the investigators concluded.

To further this cause, the investigators have made available an online calculator of individualized patient outcomes, which can be accessed at https://cancer.sanger.ac.uk/mpn-multistage/.

The study was funded by the Wellcome Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Cancer Research UK, and others. Some study authors reported fees from Celgene, Novartis, Gilead, Shire, and others outside of the study.

SOURCE: Grinfeld J et al. N Engl J Med. 2018;379:1416-30.