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CAR T-cell therapy ‘highly effective’ in high-risk CLL
A chimeric antigen receptor (CAR) T-cell therapy is “highly effective” in high-risk patients with chronic lymphocytic leukemia (CLL), according to researchers.
The CD19 CAR T-cell therapy, JCAR014, produced an overall response rate of 71% and a complete response (CR) rate of 17% in a phase 1/2 trial of patients with relapsed/refractory CLL.
Eighty-three percent of patients experienced cytokine release syndrome (CRS), and 33% developed neurotoxicity. One patient died of CRS/neurotoxicity.
Researchers reported these results in The Journal of Clinical Oncology.
The study was supported by Juno Therapeutics, Life Science Discovery Fund, the Bezos Family, the University of British Columbia Clinical Investigator Program, and grants from the National Cancer Institute and National Institute of Diabetes and Digestive and Kidney Diseases.
The trial included 24 patients with relapsed or refractory CLL. The patients’ median age was 61 (range, 40-73), and they had received a median of 5 prior therapies (range, 3-9). Nineteen patients had progressed while on ibrutinib, and 3 could not tolerate the drug.
“It was not known whether CAR T cells could be used to treat these high-risk CLL patients,” said study author Cameron Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.
“Our study shows that CD19 CAR T cells are a highly promising treatment for CLL patients who have failed ibrutinib.”
Treatment and safety
All 24 patients received lymphodepletion prior to JCAR014. Lymphodepleting regimens consisted of cyclophosphamide, fludarabine, or both.
Patients received JCAR014 at 1 of 3 dose levels—2 x 105, 2 x 106, or 2 x 107 CAR T cells/kg.
Twenty patients (83%) developed CRS—18 with grade 1/2, 1 with grade 4, and 1 with grade 5 CRS.
Eight patients (33%) developed neurotoxicity, all of whom also had CRS. Five patients had grade 3 neurotoxicity, and 1 had grade 5 (same patient with grade 5 CRS).
Initial response
The overall response rate, according to IWCLL criteria, was 71%. Seventeen patients responded, 4 with CRs and 13 with partial responses (PRs).
One of the patients who achieved a CR had received a second dose of JCAR014, without lymphodepletion, 14 days after the first dose.
One of the patients with a PR initially had stable disease (SD) at the 4-week assessment but was in PR 8 weeks later.
Twenty-one patients had a bone marrow evaluation 4 weeks after treatment with JCAR014. Seventeen of these patients (81%) had no residual disease according to high-resolution flow cytometry.
The researchers also performed IGH sequencing of bone marrow in 12 patients with no residual disease by flow cytometry. Seven of these patients (58%) had no detectable malignant IGH sequences 4 weeks after receiving JCAR014.
Second dose
Six patients who had persistent disease or who relapsed after receiving JCAR014 received a second cycle of lymphodepletion and JCAR014 at the same dose (n=1) or a 10-fold higher dose (n=5).
Four of these patients developed CRS (2 grade 3 or higher), and 1 developed reversible neurotoxicity (grade 3).
Two patients achieved a CR and had no residual disease by flow cytometry or IGH sequencing.
Survival
Responders had significantly superior progression-free survival (PFS) and overall survival (OS) compared to non-responders.
The median PFS was 9.8 months in patients who achieved a CR, was not reached in those with a PR, and was 1.1 months in patients with progressive disease (PD) or SD (P=0.0068 for CR/PR vs SD/PD).
The median OS was not reached in patients who achieved a CR or a PR, but it was 11.2 months in patients with SD or PD (P=0.0011 for CR/PR vs SD/PD).
The researchers also found that IGH sequencing revealed patients with durable PFS.
The median PFS was not reached in patients with no malignant IGH sequences, but it was 8.5 months in IGH-positive patients (P=0.253). The median OS was not reached in either group (P=0.25). 
A chimeric antigen receptor (CAR) T-cell therapy is “highly effective” in high-risk patients with chronic lymphocytic leukemia (CLL), according to researchers.
The CD19 CAR T-cell therapy, JCAR014, produced an overall response rate of 71% and a complete response (CR) rate of 17% in a phase 1/2 trial of patients with relapsed/refractory CLL.
Eighty-three percent of patients experienced cytokine release syndrome (CRS), and 33% developed neurotoxicity. One patient died of CRS/neurotoxicity.
Researchers reported these results in The Journal of Clinical Oncology.
The study was supported by Juno Therapeutics, Life Science Discovery Fund, the Bezos Family, the University of British Columbia Clinical Investigator Program, and grants from the National Cancer Institute and National Institute of Diabetes and Digestive and Kidney Diseases.
The trial included 24 patients with relapsed or refractory CLL. The patients’ median age was 61 (range, 40-73), and they had received a median of 5 prior therapies (range, 3-9). Nineteen patients had progressed while on ibrutinib, and 3 could not tolerate the drug.
“It was not known whether CAR T cells could be used to treat these high-risk CLL patients,” said study author Cameron Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.
“Our study shows that CD19 CAR T cells are a highly promising treatment for CLL patients who have failed ibrutinib.”
Treatment and safety
All 24 patients received lymphodepletion prior to JCAR014. Lymphodepleting regimens consisted of cyclophosphamide, fludarabine, or both.
Patients received JCAR014 at 1 of 3 dose levels—2 x 105, 2 x 106, or 2 x 107 CAR T cells/kg.
Twenty patients (83%) developed CRS—18 with grade 1/2, 1 with grade 4, and 1 with grade 5 CRS.
Eight patients (33%) developed neurotoxicity, all of whom also had CRS. Five patients had grade 3 neurotoxicity, and 1 had grade 5 (same patient with grade 5 CRS).
Initial response
The overall response rate, according to IWCLL criteria, was 71%. Seventeen patients responded, 4 with CRs and 13 with partial responses (PRs).
One of the patients who achieved a CR had received a second dose of JCAR014, without lymphodepletion, 14 days after the first dose.
One of the patients with a PR initially had stable disease (SD) at the 4-week assessment but was in PR 8 weeks later.
Twenty-one patients had a bone marrow evaluation 4 weeks after treatment with JCAR014. Seventeen of these patients (81%) had no residual disease according to high-resolution flow cytometry.
The researchers also performed IGH sequencing of bone marrow in 12 patients with no residual disease by flow cytometry. Seven of these patients (58%) had no detectable malignant IGH sequences 4 weeks after receiving JCAR014.
Second dose
Six patients who had persistent disease or who relapsed after receiving JCAR014 received a second cycle of lymphodepletion and JCAR014 at the same dose (n=1) or a 10-fold higher dose (n=5).
Four of these patients developed CRS (2 grade 3 or higher), and 1 developed reversible neurotoxicity (grade 3).
Two patients achieved a CR and had no residual disease by flow cytometry or IGH sequencing.
Survival
Responders had significantly superior progression-free survival (PFS) and overall survival (OS) compared to non-responders.
The median PFS was 9.8 months in patients who achieved a CR, was not reached in those with a PR, and was 1.1 months in patients with progressive disease (PD) or SD (P=0.0068 for CR/PR vs SD/PD).
The median OS was not reached in patients who achieved a CR or a PR, but it was 11.2 months in patients with SD or PD (P=0.0011 for CR/PR vs SD/PD).
The researchers also found that IGH sequencing revealed patients with durable PFS.
The median PFS was not reached in patients with no malignant IGH sequences, but it was 8.5 months in IGH-positive patients (P=0.253). The median OS was not reached in either group (P=0.25).
A chimeric antigen receptor (CAR) T-cell therapy is “highly effective” in high-risk patients with chronic lymphocytic leukemia (CLL), according to researchers.
The CD19 CAR T-cell therapy, JCAR014, produced an overall response rate of 71% and a complete response (CR) rate of 17% in a phase 1/2 trial of patients with relapsed/refractory CLL.
Eighty-three percent of patients experienced cytokine release syndrome (CRS), and 33% developed neurotoxicity. One patient died of CRS/neurotoxicity.
Researchers reported these results in The Journal of Clinical Oncology.
The study was supported by Juno Therapeutics, Life Science Discovery Fund, the Bezos Family, the University of British Columbia Clinical Investigator Program, and grants from the National Cancer Institute and National Institute of Diabetes and Digestive and Kidney Diseases.
The trial included 24 patients with relapsed or refractory CLL. The patients’ median age was 61 (range, 40-73), and they had received a median of 5 prior therapies (range, 3-9). Nineteen patients had progressed while on ibrutinib, and 3 could not tolerate the drug.
“It was not known whether CAR T cells could be used to treat these high-risk CLL patients,” said study author Cameron Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.
“Our study shows that CD19 CAR T cells are a highly promising treatment for CLL patients who have failed ibrutinib.”
Treatment and safety
All 24 patients received lymphodepletion prior to JCAR014. Lymphodepleting regimens consisted of cyclophosphamide, fludarabine, or both.
Patients received JCAR014 at 1 of 3 dose levels—2 x 105, 2 x 106, or 2 x 107 CAR T cells/kg.
Twenty patients (83%) developed CRS—18 with grade 1/2, 1 with grade 4, and 1 with grade 5 CRS.
Eight patients (33%) developed neurotoxicity, all of whom also had CRS. Five patients had grade 3 neurotoxicity, and 1 had grade 5 (same patient with grade 5 CRS).
Initial response
The overall response rate, according to IWCLL criteria, was 71%. Seventeen patients responded, 4 with CRs and 13 with partial responses (PRs).
One of the patients who achieved a CR had received a second dose of JCAR014, without lymphodepletion, 14 days after the first dose.
One of the patients with a PR initially had stable disease (SD) at the 4-week assessment but was in PR 8 weeks later.
Twenty-one patients had a bone marrow evaluation 4 weeks after treatment with JCAR014. Seventeen of these patients (81%) had no residual disease according to high-resolution flow cytometry.
The researchers also performed IGH sequencing of bone marrow in 12 patients with no residual disease by flow cytometry. Seven of these patients (58%) had no detectable malignant IGH sequences 4 weeks after receiving JCAR014.
Second dose
Six patients who had persistent disease or who relapsed after receiving JCAR014 received a second cycle of lymphodepletion and JCAR014 at the same dose (n=1) or a 10-fold higher dose (n=5).
Four of these patients developed CRS (2 grade 3 or higher), and 1 developed reversible neurotoxicity (grade 3).
Two patients achieved a CR and had no residual disease by flow cytometry or IGH sequencing.
Survival
Responders had significantly superior progression-free survival (PFS) and overall survival (OS) compared to non-responders.
The median PFS was 9.8 months in patients who achieved a CR, was not reached in those with a PR, and was 1.1 months in patients with progressive disease (PD) or SD (P=0.0068 for CR/PR vs SD/PD).
The median OS was not reached in patients who achieved a CR or a PR, but it was 11.2 months in patients with SD or PD (P=0.0011 for CR/PR vs SD/PD).
The researchers also found that IGH sequencing revealed patients with durable PFS.
The median PFS was not reached in patients with no malignant IGH sequences, but it was 8.5 months in IGH-positive patients (P=0.253). The median OS was not reached in either group (P=0.25).
Death is most frequent major adverse outcome after VTE
BERLIN—Data from the GARFIELD-VTE registry showed that, in the first 6 months after a patient was diagnosed with venous thromboembolism (VTE), death was the most frequent major adverse outcome.
More than half of the deaths were related to cancer, with small percentages of patients dying from VTE complications and bleeding events.
GARFIELD-VTE is a prospective registry designed to provide insight into the management of VTE in everyday clinical practice.
Six-month results from the registry were presented in a poster at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress (PB 1196).
The GARFIELD-VTE registry has enrolled more than 10,000 patients with acute VTE—including deep vein thrombosis (DVT) and pulmonary embolism (PE)—from across 415 sites in 28 countries.
Alexander G. G. Turpie, MD, of McMaster University in Hamilton, Ontario, Canada, and his colleagues presented data on 10,315 patients with at least 6 months of follow-up.
Baseline characteristics
The patients’ median age was 60.2 (range, 46.2-71.7), and 49.9% were female. Most patients were white (69.3%), 19.6% were Asian, 4.4% were black, 0.6% were multiracial, 4.3% were classified as “other,” and 1.9% were of unknown race.
Six percent of patients had a family history of VTE (first-degree relatives), 15.1% had a prior episode of DVT and/or PE themselves, and 37.5% had at least 1 provoking factor for VTE.
Most patients (61.8%) had DVT alone, but 38.3% had PE with or without DVT.
The registry included patients with active cancer (9.1%), a history of cancer (10.7%), thrombophilia (2.9%), chronic immobilization (5.6%), heart failure (3.2%), and renal insufficiency (3.5%).
Outcomes
Over 6 months of follow-up, the following events were reported:
- Any bleeding—622 total bleeds or 13.6 per 100 person-years
- All-cause mortality—460 total deaths or 9.7 per 100 person-years
- Recurrent VTE—169 events or 3.6 per 100 person-years
- Major bleeding—106 events or 2.2 per 100 person-years
- Myocardial infarction—42 events or 0.9 per 100 person-years
- Stroke/transient ischemic attack—38 events or 0.8 per 100 person-years.
Nearly 5% of patients died (4.5%, n=460). More than half (54.3%, n=250) of these deaths were cancer-related.
Other causes of death included:
- Cardiac death—7.0% (n=32)
- PE—3.5% (n=16)
- Bleeding—3.3% (n=15)
- VTE complications—1.3% (n=6)
- Stroke—1.1% (n=5)
- Other cause—17.8% (n=82)
- Unknown cause—11.7% (n=54).
Additional data from the GARFIELD-VTE registry were presented at ISTH 2017 as posters (PB 460 and PB 1188) and in an oral presentation (ASY 35.4). The next set of data from the registry is slated to be presented at the 2017 ASH Annual Meeting.
GARFIELD-VTE is supported by an unrestricted educational grant from Bayer AG. For further information on the registry, visit http://www.garfieldregistry.org.
BERLIN—Data from the GARFIELD-VTE registry showed that, in the first 6 months after a patient was diagnosed with venous thromboembolism (VTE), death was the most frequent major adverse outcome.
More than half of the deaths were related to cancer, with small percentages of patients dying from VTE complications and bleeding events.
GARFIELD-VTE is a prospective registry designed to provide insight into the management of VTE in everyday clinical practice.
Six-month results from the registry were presented in a poster at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress (PB 1196).
The GARFIELD-VTE registry has enrolled more than 10,000 patients with acute VTE—including deep vein thrombosis (DVT) and pulmonary embolism (PE)—from across 415 sites in 28 countries.
Alexander G. G. Turpie, MD, of McMaster University in Hamilton, Ontario, Canada, and his colleagues presented data on 10,315 patients with at least 6 months of follow-up.
Baseline characteristics
The patients’ median age was 60.2 (range, 46.2-71.7), and 49.9% were female. Most patients were white (69.3%), 19.6% were Asian, 4.4% were black, 0.6% were multiracial, 4.3% were classified as “other,” and 1.9% were of unknown race.
Six percent of patients had a family history of VTE (first-degree relatives), 15.1% had a prior episode of DVT and/or PE themselves, and 37.5% had at least 1 provoking factor for VTE.
Most patients (61.8%) had DVT alone, but 38.3% had PE with or without DVT.
The registry included patients with active cancer (9.1%), a history of cancer (10.7%), thrombophilia (2.9%), chronic immobilization (5.6%), heart failure (3.2%), and renal insufficiency (3.5%).
Outcomes
Over 6 months of follow-up, the following events were reported:
- Any bleeding—622 total bleeds or 13.6 per 100 person-years
- All-cause mortality—460 total deaths or 9.7 per 100 person-years
- Recurrent VTE—169 events or 3.6 per 100 person-years
- Major bleeding—106 events or 2.2 per 100 person-years
- Myocardial infarction—42 events or 0.9 per 100 person-years
- Stroke/transient ischemic attack—38 events or 0.8 per 100 person-years.
Nearly 5% of patients died (4.5%, n=460). More than half (54.3%, n=250) of these deaths were cancer-related.
Other causes of death included:
- Cardiac death—7.0% (n=32)
- PE—3.5% (n=16)
- Bleeding—3.3% (n=15)
- VTE complications—1.3% (n=6)
- Stroke—1.1% (n=5)
- Other cause—17.8% (n=82)
- Unknown cause—11.7% (n=54).
Additional data from the GARFIELD-VTE registry were presented at ISTH 2017 as posters (PB 460 and PB 1188) and in an oral presentation (ASY 35.4). The next set of data from the registry is slated to be presented at the 2017 ASH Annual Meeting.
GARFIELD-VTE is supported by an unrestricted educational grant from Bayer AG. For further information on the registry, visit http://www.garfieldregistry.org.
BERLIN—Data from the GARFIELD-VTE registry showed that, in the first 6 months after a patient was diagnosed with venous thromboembolism (VTE), death was the most frequent major adverse outcome.
More than half of the deaths were related to cancer, with small percentages of patients dying from VTE complications and bleeding events.
GARFIELD-VTE is a prospective registry designed to provide insight into the management of VTE in everyday clinical practice.
Six-month results from the registry were presented in a poster at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress (PB 1196).
The GARFIELD-VTE registry has enrolled more than 10,000 patients with acute VTE—including deep vein thrombosis (DVT) and pulmonary embolism (PE)—from across 415 sites in 28 countries.
Alexander G. G. Turpie, MD, of McMaster University in Hamilton, Ontario, Canada, and his colleagues presented data on 10,315 patients with at least 6 months of follow-up.
Baseline characteristics
The patients’ median age was 60.2 (range, 46.2-71.7), and 49.9% were female. Most patients were white (69.3%), 19.6% were Asian, 4.4% were black, 0.6% were multiracial, 4.3% were classified as “other,” and 1.9% were of unknown race.
Six percent of patients had a family history of VTE (first-degree relatives), 15.1% had a prior episode of DVT and/or PE themselves, and 37.5% had at least 1 provoking factor for VTE.
Most patients (61.8%) had DVT alone, but 38.3% had PE with or without DVT.
The registry included patients with active cancer (9.1%), a history of cancer (10.7%), thrombophilia (2.9%), chronic immobilization (5.6%), heart failure (3.2%), and renal insufficiency (3.5%).
Outcomes
Over 6 months of follow-up, the following events were reported:
- Any bleeding—622 total bleeds or 13.6 per 100 person-years
- All-cause mortality—460 total deaths or 9.7 per 100 person-years
- Recurrent VTE—169 events or 3.6 per 100 person-years
- Major bleeding—106 events or 2.2 per 100 person-years
- Myocardial infarction—42 events or 0.9 per 100 person-years
- Stroke/transient ischemic attack—38 events or 0.8 per 100 person-years.
Nearly 5% of patients died (4.5%, n=460). More than half (54.3%, n=250) of these deaths were cancer-related.
Other causes of death included:
- Cardiac death—7.0% (n=32)
- PE—3.5% (n=16)
- Bleeding—3.3% (n=15)
- VTE complications—1.3% (n=6)
- Stroke—1.1% (n=5)
- Other cause—17.8% (n=82)
- Unknown cause—11.7% (n=54).
Additional data from the GARFIELD-VTE registry were presented at ISTH 2017 as posters (PB 460 and PB 1188) and in an oral presentation (ASY 35.4). The next set of data from the registry is slated to be presented at the 2017 ASH Annual Meeting.
GARFIELD-VTE is supported by an unrestricted educational grant from Bayer AG. For further information on the registry, visit http://www.garfieldregistry.org.
Combo may be option for elderly patients with untreated AML
MADRID—The combination of venetoclax and low-dose cytarabine (VEN+LDAC) appears to be a feasible treatment option for elderly patients with untreated acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy.
In a phase 1/2 study of such patients, VEN+LDAC was considered well-tolerated, conferring moderate myelosuppression and largely low-grade non-hematologic toxicities.
In addition, the combination produced “rapid and durable” responses, and early death rates were low, according to Andrew H. Wei, MBBS, PhD, of Monash University in Melbourne, Victoria, Australia.
However, nearly three-quarters of patients ultimately discontinued the treatment, many due to disease progression.
Dr Wei presented these results at the 22nd Congress of the European Hematology Association (EHA) as abstract S473. AbbVie and Genentech, the companies developing and marketing venetoclax, provided financial support for this study.
“Expression of pro-survival proteins is an established mechanism of chemoresistance in diverse cancers,” Dr Wei noted. “BCL-2 is 1 of 5 pro-survival molecules which functions to sequester pro-apoptotic molecules and tip the balance in favor of cell survival.”
“Venetoclax is a potent and specific inhibitor of BCL-2 which releases these pro-apoptotic molecules, tipping the balance in favor of cell death. Cytotoxic drugs are well-known to increase the burden of BH3-only proteins, and so it was surmised that the combination of chemotherapy, such as cytarabine, with venetoclax could augment the clinical response.”
Patients
Dr Wei presented data on 61 AML patients treated with VEN+LDAC. He noted that this was a poor-risk population, with nearly half of patients over the age of 75 at baseline.
The patients’ median age was 74 (range, 66-87), and 64% were male. Nearly half of patients had an ECOG performance status of 1 (49%), 30% had a status of 0, and 21% had a status of 2.
Forty-four percent of patients had secondary AML, and 28% had prior treatment with a hypomethylating agent (HMA). Sixty-one percent of patients had intermediate-risk cytogenetics, and 31% had poor-risk cytogenetics.
Treatment
The patients received oral venetoclax at 600 mg daily on days 1 to 28 and subcutaneous cytarabine at 20 mg/m2 daily on days 1 to 10 of each 28-day cycle.
In the first cycle, the dose of venetoclax was ramped up gradually—no dose on day 1, 50 mg on day 2, 100 mg on day 3, 200 mg on day 4, 400 mg on day 5, and 600 mg thereafter.
Patients received prophylaxis for tumor lysis syndrome prior to starting cycle 1, and they were hospitalized to enable observation.
The median time on study treatment was 6 months (range, <1 to 19 months). Seventy-two percent of patients discontinued treatment.
Reasons for discontinuation included:
- Progressive disease without death—26%
- Progressive disease with death—10%
- Adverse event (AE) related to progression—10%
- AE not related to progression—8%
- Withdrawn consent—8%
- Other reasons—18%.
Safety
The most common AEs of any grade (occurring in at least 30% of patients) were nausea (74%), hypokalemia (46%), diarrhea (46%), fatigue (44%), decreased appetite (41%), constipation (34%), hypomagnesemia (34%), vomiting (31%), thrombocytopenia (44%), febrile neutropenia (38%), and neutropenia (33%).
Grade 3/4 hematologic AEs (occurring in at least 10% of patients) included thrombocytopenia (44%), febrile neutropenia (36%), neutropenia (33%), and anemia (28%).
Grade 3/4 non-hematologic AEs (occurring in at least 10% of patients) included hypokalemia (16%), hypophosphatemia (13%), and hypertension (12%).
Response and survival
The overall response rate was 65%, with 25% of patients achieving a complete response (CR), 38% having a CR with incomplete blood count recovery (CRi), and 2% experiencing a partial response.
Dr Wei noted that VEN+LDAC was active across subgroups.
The CR/CRi rate was 76% among patients with intermediate-risk cytogenetics and 47% among patients with poor-risk cytogenetics.
The CR/CRi rate was 70% among patients older than 75, 52% among patients with secondary AML, 66% among patients with no prior HMA exposure, and 53% in patients with prior HMA exposure.
“Although responses were slightly lower in patients with poor cytogenetic risk, prior HMA exposure, and secondary AML . . ., these responses are far in excess of what we would expect with [LDAC] alone,” Dr Wei said.
“Furthermore, the median time to response was very rapid, and this is extremely important to get patients into remission and avoid the medium-term consequences of active AML.”
The median time to response was 1 month (range, <1 to 9 months).
The 30-day death rate was 3%, the 60-day death rate was 15%, and the median overall survival was approximately 12 months.
Based on these results, AbbVie has initiated a phase 3 trial comparing VEN+LDAC to LDAC alone in elderly patients with untreated AML who are ineligible for intensive chemotherapy.
MADRID—The combination of venetoclax and low-dose cytarabine (VEN+LDAC) appears to be a feasible treatment option for elderly patients with untreated acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy.
In a phase 1/2 study of such patients, VEN+LDAC was considered well-tolerated, conferring moderate myelosuppression and largely low-grade non-hematologic toxicities.
In addition, the combination produced “rapid and durable” responses, and early death rates were low, according to Andrew H. Wei, MBBS, PhD, of Monash University in Melbourne, Victoria, Australia.
However, nearly three-quarters of patients ultimately discontinued the treatment, many due to disease progression.
Dr Wei presented these results at the 22nd Congress of the European Hematology Association (EHA) as abstract S473. AbbVie and Genentech, the companies developing and marketing venetoclax, provided financial support for this study.
“Expression of pro-survival proteins is an established mechanism of chemoresistance in diverse cancers,” Dr Wei noted. “BCL-2 is 1 of 5 pro-survival molecules which functions to sequester pro-apoptotic molecules and tip the balance in favor of cell survival.”
“Venetoclax is a potent and specific inhibitor of BCL-2 which releases these pro-apoptotic molecules, tipping the balance in favor of cell death. Cytotoxic drugs are well-known to increase the burden of BH3-only proteins, and so it was surmised that the combination of chemotherapy, such as cytarabine, with venetoclax could augment the clinical response.”
Patients
Dr Wei presented data on 61 AML patients treated with VEN+LDAC. He noted that this was a poor-risk population, with nearly half of patients over the age of 75 at baseline.
The patients’ median age was 74 (range, 66-87), and 64% were male. Nearly half of patients had an ECOG performance status of 1 (49%), 30% had a status of 0, and 21% had a status of 2.
Forty-four percent of patients had secondary AML, and 28% had prior treatment with a hypomethylating agent (HMA). Sixty-one percent of patients had intermediate-risk cytogenetics, and 31% had poor-risk cytogenetics.
Treatment
The patients received oral venetoclax at 600 mg daily on days 1 to 28 and subcutaneous cytarabine at 20 mg/m2 daily on days 1 to 10 of each 28-day cycle.
In the first cycle, the dose of venetoclax was ramped up gradually—no dose on day 1, 50 mg on day 2, 100 mg on day 3, 200 mg on day 4, 400 mg on day 5, and 600 mg thereafter.
Patients received prophylaxis for tumor lysis syndrome prior to starting cycle 1, and they were hospitalized to enable observation.
The median time on study treatment was 6 months (range, <1 to 19 months). Seventy-two percent of patients discontinued treatment.
Reasons for discontinuation included:
- Progressive disease without death—26%
- Progressive disease with death—10%
- Adverse event (AE) related to progression—10%
- AE not related to progression—8%
- Withdrawn consent—8%
- Other reasons—18%.
Safety
The most common AEs of any grade (occurring in at least 30% of patients) were nausea (74%), hypokalemia (46%), diarrhea (46%), fatigue (44%), decreased appetite (41%), constipation (34%), hypomagnesemia (34%), vomiting (31%), thrombocytopenia (44%), febrile neutropenia (38%), and neutropenia (33%).
Grade 3/4 hematologic AEs (occurring in at least 10% of patients) included thrombocytopenia (44%), febrile neutropenia (36%), neutropenia (33%), and anemia (28%).
Grade 3/4 non-hematologic AEs (occurring in at least 10% of patients) included hypokalemia (16%), hypophosphatemia (13%), and hypertension (12%).
Response and survival
The overall response rate was 65%, with 25% of patients achieving a complete response (CR), 38% having a CR with incomplete blood count recovery (CRi), and 2% experiencing a partial response.
Dr Wei noted that VEN+LDAC was active across subgroups.
The CR/CRi rate was 76% among patients with intermediate-risk cytogenetics and 47% among patients with poor-risk cytogenetics.
The CR/CRi rate was 70% among patients older than 75, 52% among patients with secondary AML, 66% among patients with no prior HMA exposure, and 53% in patients with prior HMA exposure.
“Although responses were slightly lower in patients with poor cytogenetic risk, prior HMA exposure, and secondary AML . . ., these responses are far in excess of what we would expect with [LDAC] alone,” Dr Wei said.
“Furthermore, the median time to response was very rapid, and this is extremely important to get patients into remission and avoid the medium-term consequences of active AML.”
The median time to response was 1 month (range, <1 to 9 months).
The 30-day death rate was 3%, the 60-day death rate was 15%, and the median overall survival was approximately 12 months.
Based on these results, AbbVie has initiated a phase 3 trial comparing VEN+LDAC to LDAC alone in elderly patients with untreated AML who are ineligible for intensive chemotherapy.
MADRID—The combination of venetoclax and low-dose cytarabine (VEN+LDAC) appears to be a feasible treatment option for elderly patients with untreated acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy.
In a phase 1/2 study of such patients, VEN+LDAC was considered well-tolerated, conferring moderate myelosuppression and largely low-grade non-hematologic toxicities.
In addition, the combination produced “rapid and durable” responses, and early death rates were low, according to Andrew H. Wei, MBBS, PhD, of Monash University in Melbourne, Victoria, Australia.
However, nearly three-quarters of patients ultimately discontinued the treatment, many due to disease progression.
Dr Wei presented these results at the 22nd Congress of the European Hematology Association (EHA) as abstract S473. AbbVie and Genentech, the companies developing and marketing venetoclax, provided financial support for this study.
“Expression of pro-survival proteins is an established mechanism of chemoresistance in diverse cancers,” Dr Wei noted. “BCL-2 is 1 of 5 pro-survival molecules which functions to sequester pro-apoptotic molecules and tip the balance in favor of cell survival.”
“Venetoclax is a potent and specific inhibitor of BCL-2 which releases these pro-apoptotic molecules, tipping the balance in favor of cell death. Cytotoxic drugs are well-known to increase the burden of BH3-only proteins, and so it was surmised that the combination of chemotherapy, such as cytarabine, with venetoclax could augment the clinical response.”
Patients
Dr Wei presented data on 61 AML patients treated with VEN+LDAC. He noted that this was a poor-risk population, with nearly half of patients over the age of 75 at baseline.
The patients’ median age was 74 (range, 66-87), and 64% were male. Nearly half of patients had an ECOG performance status of 1 (49%), 30% had a status of 0, and 21% had a status of 2.
Forty-four percent of patients had secondary AML, and 28% had prior treatment with a hypomethylating agent (HMA). Sixty-one percent of patients had intermediate-risk cytogenetics, and 31% had poor-risk cytogenetics.
Treatment
The patients received oral venetoclax at 600 mg daily on days 1 to 28 and subcutaneous cytarabine at 20 mg/m2 daily on days 1 to 10 of each 28-day cycle.
In the first cycle, the dose of venetoclax was ramped up gradually—no dose on day 1, 50 mg on day 2, 100 mg on day 3, 200 mg on day 4, 400 mg on day 5, and 600 mg thereafter.
Patients received prophylaxis for tumor lysis syndrome prior to starting cycle 1, and they were hospitalized to enable observation.
The median time on study treatment was 6 months (range, <1 to 19 months). Seventy-two percent of patients discontinued treatment.
Reasons for discontinuation included:
- Progressive disease without death—26%
- Progressive disease with death—10%
- Adverse event (AE) related to progression—10%
- AE not related to progression—8%
- Withdrawn consent—8%
- Other reasons—18%.
Safety
The most common AEs of any grade (occurring in at least 30% of patients) were nausea (74%), hypokalemia (46%), diarrhea (46%), fatigue (44%), decreased appetite (41%), constipation (34%), hypomagnesemia (34%), vomiting (31%), thrombocytopenia (44%), febrile neutropenia (38%), and neutropenia (33%).
Grade 3/4 hematologic AEs (occurring in at least 10% of patients) included thrombocytopenia (44%), febrile neutropenia (36%), neutropenia (33%), and anemia (28%).
Grade 3/4 non-hematologic AEs (occurring in at least 10% of patients) included hypokalemia (16%), hypophosphatemia (13%), and hypertension (12%).
Response and survival
The overall response rate was 65%, with 25% of patients achieving a complete response (CR), 38% having a CR with incomplete blood count recovery (CRi), and 2% experiencing a partial response.
Dr Wei noted that VEN+LDAC was active across subgroups.
The CR/CRi rate was 76% among patients with intermediate-risk cytogenetics and 47% among patients with poor-risk cytogenetics.
The CR/CRi rate was 70% among patients older than 75, 52% among patients with secondary AML, 66% among patients with no prior HMA exposure, and 53% in patients with prior HMA exposure.
“Although responses were slightly lower in patients with poor cytogenetic risk, prior HMA exposure, and secondary AML . . ., these responses are far in excess of what we would expect with [LDAC] alone,” Dr Wei said.
“Furthermore, the median time to response was very rapid, and this is extremely important to get patients into remission and avoid the medium-term consequences of active AML.”
The median time to response was 1 month (range, <1 to 9 months).
The 30-day death rate was 3%, the 60-day death rate was 15%, and the median overall survival was approximately 12 months.
Based on these results, AbbVie has initiated a phase 3 trial comparing VEN+LDAC to LDAC alone in elderly patients with untreated AML who are ineligible for intensive chemotherapy.
Adding cefepime to vancomycin improved MRSA bacteremia outcomes
NEW ORLEANS – Compared with vancomycin monotherapy, vancomycin combined with cefepime improved some outcomes for patients with methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections, a retrospective study of 109 patients revealed.
A lower likelihood of microbiological failure and fewer bloodstream infections persisting 7 days or more were the notable differences between treatment groups.
All patients had at least 72 hours of vancomycin therapy to treat MRSA bacteremia confirmed by blood culture. During 2008-2015, 38 adults received vancomycin monotherapy and 71 received vancomycin plus 24 hours or more of cefepime.
Compared with monotherapy, the combination treatment was associated with a nonsignificant reduction in the primary composite treatment failure outcome of 30-day all-cause mortality, in bacteremia duration of 7 days or more, and in 60-day bloodstream-infection recurrence: 55% for monotherapy versus 42% for combination therapy (P = .195). The difference was primarily associated with decreased duration of sepsis and fewer MRSA bloodstream infections persisting 7 days or more in the combination cohort.
Rates of bacteremia duration of 7 days or more were 42% in monotherapy patients and 20% in combination patients (P = .013). Differences in 60-day bloodstream-infection recurrence were nonsignificant, 8% versus 4%, respectively (P = .42).
Thirty-day mortality, however, was lower among monotherapy patients than combination patients – 13% vs. 25% – although the difference was nonsignificant (P = .21).
“From what I see here … it seems like they will have a lower duration of bacteremia, which is always great,” Ms. Atwan said. “You want to decrease length of stay in the hospital,” which will cut down on costs and on patients’ risks of getting more infections.
Although the primary outcome was a composite endpoint, “when we looked at them separately, we found the patients in the combination group had more mortality,” Ms. Atwan said at the annual meeting of the American Society for Microbiology. “That surprised me initially. But those patients are sicker and more likely to get dual coverage.”
The investigators confirmed the association between the severity of MRSA bacteremia and combination therapy by looking at Acute Physiology and Chronic Health Evaluation (APACHE II) scores. The median APACHE score was 23 in the combination group, compared with 13.5 in the monotherapy group (P = 0003). Higher APACHE scores were associated with greater odds of meeting the composite failure endpoint (adjusted odds ratio, 1.08) and of developing endocarditis (aOR, 3.6) in multivariate analyses.
More patients in the combination group had pneumonia as the primary source of infection than did patients in the monotherapy group: 54% vs. 29% (P = .016). Further, more of them had skin or soft tissue infections as the primary infection source: 29% vs. 13% (P = .036).
Although the exact mechanism remains unknown, synergy between the two agents could be caused by an increase in penicillin-binding proteins, Ms. Atwan said.
The study is still ongoing; Ms. Atwan hopes additional patients and data will lead to statistically significant differences between the outcomes of combination therapy and vancomycin monotherapy.
“I want to say that combination therapy is something you will always want to go to when you have a sicker patient, but I can’t really tell you that combination therapy is going to cause better outcomes for your patient,” she cautioned. “Hopefully, I can by the end of the study.”
In the meantime, “it looks like vancomycin and beta-lactams could be beneficial for MRSA bacteremia,” she added.
The researchers noted that although vancomycin monotherapy is a mainstay of treatment for MRSA bloodstream infections, emergence of reduced susceptibility and treatment failures warrants other therapeutic strategies.
Ms. Atwan had no relevant financial disclosures.
NEW ORLEANS – Compared with vancomycin monotherapy, vancomycin combined with cefepime improved some outcomes for patients with methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections, a retrospective study of 109 patients revealed.
A lower likelihood of microbiological failure and fewer bloodstream infections persisting 7 days or more were the notable differences between treatment groups.
All patients had at least 72 hours of vancomycin therapy to treat MRSA bacteremia confirmed by blood culture. During 2008-2015, 38 adults received vancomycin monotherapy and 71 received vancomycin plus 24 hours or more of cefepime.
Compared with monotherapy, the combination treatment was associated with a nonsignificant reduction in the primary composite treatment failure outcome of 30-day all-cause mortality, in bacteremia duration of 7 days or more, and in 60-day bloodstream-infection recurrence: 55% for monotherapy versus 42% for combination therapy (P = .195). The difference was primarily associated with decreased duration of sepsis and fewer MRSA bloodstream infections persisting 7 days or more in the combination cohort.
Rates of bacteremia duration of 7 days or more were 42% in monotherapy patients and 20% in combination patients (P = .013). Differences in 60-day bloodstream-infection recurrence were nonsignificant, 8% versus 4%, respectively (P = .42).
Thirty-day mortality, however, was lower among monotherapy patients than combination patients – 13% vs. 25% – although the difference was nonsignificant (P = .21).
“From what I see here … it seems like they will have a lower duration of bacteremia, which is always great,” Ms. Atwan said. “You want to decrease length of stay in the hospital,” which will cut down on costs and on patients’ risks of getting more infections.
Although the primary outcome was a composite endpoint, “when we looked at them separately, we found the patients in the combination group had more mortality,” Ms. Atwan said at the annual meeting of the American Society for Microbiology. “That surprised me initially. But those patients are sicker and more likely to get dual coverage.”
The investigators confirmed the association between the severity of MRSA bacteremia and combination therapy by looking at Acute Physiology and Chronic Health Evaluation (APACHE II) scores. The median APACHE score was 23 in the combination group, compared with 13.5 in the monotherapy group (P = 0003). Higher APACHE scores were associated with greater odds of meeting the composite failure endpoint (adjusted odds ratio, 1.08) and of developing endocarditis (aOR, 3.6) in multivariate analyses.
More patients in the combination group had pneumonia as the primary source of infection than did patients in the monotherapy group: 54% vs. 29% (P = .016). Further, more of them had skin or soft tissue infections as the primary infection source: 29% vs. 13% (P = .036).
Although the exact mechanism remains unknown, synergy between the two agents could be caused by an increase in penicillin-binding proteins, Ms. Atwan said.
The study is still ongoing; Ms. Atwan hopes additional patients and data will lead to statistically significant differences between the outcomes of combination therapy and vancomycin monotherapy.
“I want to say that combination therapy is something you will always want to go to when you have a sicker patient, but I can’t really tell you that combination therapy is going to cause better outcomes for your patient,” she cautioned. “Hopefully, I can by the end of the study.”
In the meantime, “it looks like vancomycin and beta-lactams could be beneficial for MRSA bacteremia,” she added.
The researchers noted that although vancomycin monotherapy is a mainstay of treatment for MRSA bloodstream infections, emergence of reduced susceptibility and treatment failures warrants other therapeutic strategies.
Ms. Atwan had no relevant financial disclosures.
NEW ORLEANS – Compared with vancomycin monotherapy, vancomycin combined with cefepime improved some outcomes for patients with methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections, a retrospective study of 109 patients revealed.
A lower likelihood of microbiological failure and fewer bloodstream infections persisting 7 days or more were the notable differences between treatment groups.
All patients had at least 72 hours of vancomycin therapy to treat MRSA bacteremia confirmed by blood culture. During 2008-2015, 38 adults received vancomycin monotherapy and 71 received vancomycin plus 24 hours or more of cefepime.
Compared with monotherapy, the combination treatment was associated with a nonsignificant reduction in the primary composite treatment failure outcome of 30-day all-cause mortality, in bacteremia duration of 7 days or more, and in 60-day bloodstream-infection recurrence: 55% for monotherapy versus 42% for combination therapy (P = .195). The difference was primarily associated with decreased duration of sepsis and fewer MRSA bloodstream infections persisting 7 days or more in the combination cohort.
Rates of bacteremia duration of 7 days or more were 42% in monotherapy patients and 20% in combination patients (P = .013). Differences in 60-day bloodstream-infection recurrence were nonsignificant, 8% versus 4%, respectively (P = .42).
Thirty-day mortality, however, was lower among monotherapy patients than combination patients – 13% vs. 25% – although the difference was nonsignificant (P = .21).
“From what I see here … it seems like they will have a lower duration of bacteremia, which is always great,” Ms. Atwan said. “You want to decrease length of stay in the hospital,” which will cut down on costs and on patients’ risks of getting more infections.
Although the primary outcome was a composite endpoint, “when we looked at them separately, we found the patients in the combination group had more mortality,” Ms. Atwan said at the annual meeting of the American Society for Microbiology. “That surprised me initially. But those patients are sicker and more likely to get dual coverage.”
The investigators confirmed the association between the severity of MRSA bacteremia and combination therapy by looking at Acute Physiology and Chronic Health Evaluation (APACHE II) scores. The median APACHE score was 23 in the combination group, compared with 13.5 in the monotherapy group (P = 0003). Higher APACHE scores were associated with greater odds of meeting the composite failure endpoint (adjusted odds ratio, 1.08) and of developing endocarditis (aOR, 3.6) in multivariate analyses.
More patients in the combination group had pneumonia as the primary source of infection than did patients in the monotherapy group: 54% vs. 29% (P = .016). Further, more of them had skin or soft tissue infections as the primary infection source: 29% vs. 13% (P = .036).
Although the exact mechanism remains unknown, synergy between the two agents could be caused by an increase in penicillin-binding proteins, Ms. Atwan said.
The study is still ongoing; Ms. Atwan hopes additional patients and data will lead to statistically significant differences between the outcomes of combination therapy and vancomycin monotherapy.
“I want to say that combination therapy is something you will always want to go to when you have a sicker patient, but I can’t really tell you that combination therapy is going to cause better outcomes for your patient,” she cautioned. “Hopefully, I can by the end of the study.”
In the meantime, “it looks like vancomycin and beta-lactams could be beneficial for MRSA bacteremia,” she added.
The researchers noted that although vancomycin monotherapy is a mainstay of treatment for MRSA bloodstream infections, emergence of reduced susceptibility and treatment failures warrants other therapeutic strategies.
Ms. Atwan had no relevant financial disclosures.
AT ASM MICROBE 2017
Key clinical point:
Major finding: Median duration of MRSA bacteremia was 4 days with combination therapy, versus 6 days with vancomycin alone.
Data source: A retrospective, single-center comparison of 109 patients treated with either vancomycin plus cefepime or vancomycin alone.
Disclosures: Safana M. Atwan had no relevant financial disclosures.
GOP health reform dead for now
Senate Republicans are scrambling to come up with another plan now that at least four member of their caucus have said that they would vote against moving forward with debate on the Better Care Reconciliation Act.
Support for the bill, which included dramatic Medicaid cuts and stripped many coverage provisions of the Affordable Care Act, was lacking after revisions were announced on July 13. At that time, conservative Sen. Ran Paul (R-Ky.) and moderate Susan Collins (R-Maine) voiced their opposition for different ideological reasons. They were joined by Sen. Mike Lee (R-Utah) and Sen. Jerry Moran (R-Kan.), who also declined to support the bill. Senate GOP leadership, with a slim 52-48 majority, could only afford to lose two votes (Vice President Mike Pence would have been the tie-breaking vote).
No new timeline has been revealed for the next steps.
“The health reform debate is by no means over,” David Barbe, MD, president of the American Medical Association, said in a statement. “Congress must begin a collaborative process that produces a bipartisan solution. ... Near-term action is needed to stabilize the individual/nongroup health insurance marketplace. In the long term, stakeholders and policymakers need to address the unsustainable trends in health care costs while achieving meaningful, affordable coverage for all Americans.”
Senate Republicans are scrambling to come up with another plan now that at least four member of their caucus have said that they would vote against moving forward with debate on the Better Care Reconciliation Act.
Support for the bill, which included dramatic Medicaid cuts and stripped many coverage provisions of the Affordable Care Act, was lacking after revisions were announced on July 13. At that time, conservative Sen. Ran Paul (R-Ky.) and moderate Susan Collins (R-Maine) voiced their opposition for different ideological reasons. They were joined by Sen. Mike Lee (R-Utah) and Sen. Jerry Moran (R-Kan.), who also declined to support the bill. Senate GOP leadership, with a slim 52-48 majority, could only afford to lose two votes (Vice President Mike Pence would have been the tie-breaking vote).
No new timeline has been revealed for the next steps.
“The health reform debate is by no means over,” David Barbe, MD, president of the American Medical Association, said in a statement. “Congress must begin a collaborative process that produces a bipartisan solution. ... Near-term action is needed to stabilize the individual/nongroup health insurance marketplace. In the long term, stakeholders and policymakers need to address the unsustainable trends in health care costs while achieving meaningful, affordable coverage for all Americans.”
Senate Republicans are scrambling to come up with another plan now that at least four member of their caucus have said that they would vote against moving forward with debate on the Better Care Reconciliation Act.
Support for the bill, which included dramatic Medicaid cuts and stripped many coverage provisions of the Affordable Care Act, was lacking after revisions were announced on July 13. At that time, conservative Sen. Ran Paul (R-Ky.) and moderate Susan Collins (R-Maine) voiced their opposition for different ideological reasons. They were joined by Sen. Mike Lee (R-Utah) and Sen. Jerry Moran (R-Kan.), who also declined to support the bill. Senate GOP leadership, with a slim 52-48 majority, could only afford to lose two votes (Vice President Mike Pence would have been the tie-breaking vote).
No new timeline has been revealed for the next steps.
“The health reform debate is by no means over,” David Barbe, MD, president of the American Medical Association, said in a statement. “Congress must begin a collaborative process that produces a bipartisan solution. ... Near-term action is needed to stabilize the individual/nongroup health insurance marketplace. In the long term, stakeholders and policymakers need to address the unsustainable trends in health care costs while achieving meaningful, affordable coverage for all Americans.”
New trial shows thymectomy benefits myasthenia gravis
The effectiveness of thymectomy as a cure for myasthenia gravis has long been debated, but the publication of Myasthenia Gravis Thymectomy Treatment (MGTX) trial results, showing that thymectomy improved outcomes over 3 years in patients with nonthymomatous myasthenia gravis, has gone a long way toward settling the debate, Joshua R. Sonett, MD, and his coauthors noted in a feature expert opinion (J Thorac Cardiovasc Surg. 2017;154:306-9).
The MGTX trial randomized patients with nonthymomatous MG into two treatment groups: medical therapy alone or thymectomy with medical therapy (N Engl J Med. 2016;375:511-22). For uniformity, the study mandated one type of thymectomy, an extended transsternal approach. The study was 12 years in the making, with 6 years of patient accrual followed by 3 years of surveillance, Dr. Sonett and his coauthors noted.
Those markers include an average quantitative myasthenia score of 6.15 for the thymectomy group vs. 8.99 for the medical therapy group (P less than .0001); a lower dose of prednisone to attain improved neurologic status (44 mg vs. 60 mg; P less than .001); time-weighted average score on the Myasthenia Gravis Activities of Daily Living scale (2.24 vs. 3.41; P = .008); azathioprine use (17% vs. 48%; P less than .001); percentage of patients who had minimal-manifestation status at month 36 (67% vs. 47%; P = .03); and hospitalization for myasthenia-related symptoms (9% vs. 37%). “Interestingly,” the researchers wrote, “despite these quantitative results, no difference was seen in the quality of life measured surveys.”
An ancillary study, Bio-MGTX, was performed simultaneously to investigate pathologic and serum markers. “Many questions still need to be answered in regard to the role of thymectomy in MG,” Dr. Sonett and his coauthors maintained. They include an analysis of radiologic predictors of success with thymectomy, and the role of thymectomy in seronegative MG, ocular MG and elderly patients.
“Future studies may be directed at achieving a more rapid and consistent time to a complete symptom response,” they said.
The MGTX trial does support the use of high-dose prednisone induction combined with thymectomy to achieve higher complete early remission rates, but Bio-MGTX data may help to refine induction protocols. “The debate will likely continue in regard to widespread adoption of extended transsternal maximal thymectomy,” the researchers wrote. “What was categorically measured in this trial was the effect of maximal thymectomy, as sternotomy offers no particular independent therapeutic benefit.”
The structure of the MGTX trial despite its small cohort (126) “enabled the medical and surgical community to definitively answer an important question,” they noted. Nonetheless, further investigation of the role of thymectomy in MG is “sorely needed.”
Patients may need up to 3 years to achieve an optimal response, and complete cure in a shorter time frame should be the goal for each patient. Multimodal therapy should be the basis of MG treatment. “Continued progress in the management of MG will require diligent, multidisciplinary teams designing and completing prospective studies like the MGTX,” the researchers wrote.
Dr. Sonett and his coauthors had no financial relationships to disclose. The MGTX trial was funded by the U.S. National Institute of Neurological Disorders and Stroke. There was no commercial support for the trial.
In the MGTX trial, patients in the thymectomy group still needed a high average dose of prednisone, and the rates of remission may decrease over time, Michael K. Hsin, MD, of Queen Mary Hospital, Hong Kong, wrote in his invited commentary (J Thorac Cardiovasc Surg. 2017;154:310-1). But he added that the trial did finally answer in a positive manner whether thymectomy could serve a beneficial role.
He also noted that the MGTX trial left at least four questions unanswered:
• The long-term effect of thymectomy on MG status with regard to future relapse.
• The role of surgery in the era of advances in medical treatment, including azathioprine to reduce the prednisone dose and emergence of stem-cell transplantation.
• The extent to which MGTX findings can be applied to acetylcholine receptor-negative pediatric patients.
• Whether alternative techniques to extended transsternal thymectomy can achieve comparable results.
Dr. Hsin had no financial relationships to disclose.
In the MGTX trial, patients in the thymectomy group still needed a high average dose of prednisone, and the rates of remission may decrease over time, Michael K. Hsin, MD, of Queen Mary Hospital, Hong Kong, wrote in his invited commentary (J Thorac Cardiovasc Surg. 2017;154:310-1). But he added that the trial did finally answer in a positive manner whether thymectomy could serve a beneficial role.
He also noted that the MGTX trial left at least four questions unanswered:
• The long-term effect of thymectomy on MG status with regard to future relapse.
• The role of surgery in the era of advances in medical treatment, including azathioprine to reduce the prednisone dose and emergence of stem-cell transplantation.
• The extent to which MGTX findings can be applied to acetylcholine receptor-negative pediatric patients.
• Whether alternative techniques to extended transsternal thymectomy can achieve comparable results.
Dr. Hsin had no financial relationships to disclose.
In the MGTX trial, patients in the thymectomy group still needed a high average dose of prednisone, and the rates of remission may decrease over time, Michael K. Hsin, MD, of Queen Mary Hospital, Hong Kong, wrote in his invited commentary (J Thorac Cardiovasc Surg. 2017;154:310-1). But he added that the trial did finally answer in a positive manner whether thymectomy could serve a beneficial role.
He also noted that the MGTX trial left at least four questions unanswered:
• The long-term effect of thymectomy on MG status with regard to future relapse.
• The role of surgery in the era of advances in medical treatment, including azathioprine to reduce the prednisone dose and emergence of stem-cell transplantation.
• The extent to which MGTX findings can be applied to acetylcholine receptor-negative pediatric patients.
• Whether alternative techniques to extended transsternal thymectomy can achieve comparable results.
Dr. Hsin had no financial relationships to disclose.
The effectiveness of thymectomy as a cure for myasthenia gravis has long been debated, but the publication of Myasthenia Gravis Thymectomy Treatment (MGTX) trial results, showing that thymectomy improved outcomes over 3 years in patients with nonthymomatous myasthenia gravis, has gone a long way toward settling the debate, Joshua R. Sonett, MD, and his coauthors noted in a feature expert opinion (J Thorac Cardiovasc Surg. 2017;154:306-9).
The MGTX trial randomized patients with nonthymomatous MG into two treatment groups: medical therapy alone or thymectomy with medical therapy (N Engl J Med. 2016;375:511-22). For uniformity, the study mandated one type of thymectomy, an extended transsternal approach. The study was 12 years in the making, with 6 years of patient accrual followed by 3 years of surveillance, Dr. Sonett and his coauthors noted.
Those markers include an average quantitative myasthenia score of 6.15 for the thymectomy group vs. 8.99 for the medical therapy group (P less than .0001); a lower dose of prednisone to attain improved neurologic status (44 mg vs. 60 mg; P less than .001); time-weighted average score on the Myasthenia Gravis Activities of Daily Living scale (2.24 vs. 3.41; P = .008); azathioprine use (17% vs. 48%; P less than .001); percentage of patients who had minimal-manifestation status at month 36 (67% vs. 47%; P = .03); and hospitalization for myasthenia-related symptoms (9% vs. 37%). “Interestingly,” the researchers wrote, “despite these quantitative results, no difference was seen in the quality of life measured surveys.”
An ancillary study, Bio-MGTX, was performed simultaneously to investigate pathologic and serum markers. “Many questions still need to be answered in regard to the role of thymectomy in MG,” Dr. Sonett and his coauthors maintained. They include an analysis of radiologic predictors of success with thymectomy, and the role of thymectomy in seronegative MG, ocular MG and elderly patients.
“Future studies may be directed at achieving a more rapid and consistent time to a complete symptom response,” they said.
The MGTX trial does support the use of high-dose prednisone induction combined with thymectomy to achieve higher complete early remission rates, but Bio-MGTX data may help to refine induction protocols. “The debate will likely continue in regard to widespread adoption of extended transsternal maximal thymectomy,” the researchers wrote. “What was categorically measured in this trial was the effect of maximal thymectomy, as sternotomy offers no particular independent therapeutic benefit.”
The structure of the MGTX trial despite its small cohort (126) “enabled the medical and surgical community to definitively answer an important question,” they noted. Nonetheless, further investigation of the role of thymectomy in MG is “sorely needed.”
Patients may need up to 3 years to achieve an optimal response, and complete cure in a shorter time frame should be the goal for each patient. Multimodal therapy should be the basis of MG treatment. “Continued progress in the management of MG will require diligent, multidisciplinary teams designing and completing prospective studies like the MGTX,” the researchers wrote.
Dr. Sonett and his coauthors had no financial relationships to disclose. The MGTX trial was funded by the U.S. National Institute of Neurological Disorders and Stroke. There was no commercial support for the trial.
The effectiveness of thymectomy as a cure for myasthenia gravis has long been debated, but the publication of Myasthenia Gravis Thymectomy Treatment (MGTX) trial results, showing that thymectomy improved outcomes over 3 years in patients with nonthymomatous myasthenia gravis, has gone a long way toward settling the debate, Joshua R. Sonett, MD, and his coauthors noted in a feature expert opinion (J Thorac Cardiovasc Surg. 2017;154:306-9).
The MGTX trial randomized patients with nonthymomatous MG into two treatment groups: medical therapy alone or thymectomy with medical therapy (N Engl J Med. 2016;375:511-22). For uniformity, the study mandated one type of thymectomy, an extended transsternal approach. The study was 12 years in the making, with 6 years of patient accrual followed by 3 years of surveillance, Dr. Sonett and his coauthors noted.
Those markers include an average quantitative myasthenia score of 6.15 for the thymectomy group vs. 8.99 for the medical therapy group (P less than .0001); a lower dose of prednisone to attain improved neurologic status (44 mg vs. 60 mg; P less than .001); time-weighted average score on the Myasthenia Gravis Activities of Daily Living scale (2.24 vs. 3.41; P = .008); azathioprine use (17% vs. 48%; P less than .001); percentage of patients who had minimal-manifestation status at month 36 (67% vs. 47%; P = .03); and hospitalization for myasthenia-related symptoms (9% vs. 37%). “Interestingly,” the researchers wrote, “despite these quantitative results, no difference was seen in the quality of life measured surveys.”
An ancillary study, Bio-MGTX, was performed simultaneously to investigate pathologic and serum markers. “Many questions still need to be answered in regard to the role of thymectomy in MG,” Dr. Sonett and his coauthors maintained. They include an analysis of radiologic predictors of success with thymectomy, and the role of thymectomy in seronegative MG, ocular MG and elderly patients.
“Future studies may be directed at achieving a more rapid and consistent time to a complete symptom response,” they said.
The MGTX trial does support the use of high-dose prednisone induction combined with thymectomy to achieve higher complete early remission rates, but Bio-MGTX data may help to refine induction protocols. “The debate will likely continue in regard to widespread adoption of extended transsternal maximal thymectomy,” the researchers wrote. “What was categorically measured in this trial was the effect of maximal thymectomy, as sternotomy offers no particular independent therapeutic benefit.”
The structure of the MGTX trial despite its small cohort (126) “enabled the medical and surgical community to definitively answer an important question,” they noted. Nonetheless, further investigation of the role of thymectomy in MG is “sorely needed.”
Patients may need up to 3 years to achieve an optimal response, and complete cure in a shorter time frame should be the goal for each patient. Multimodal therapy should be the basis of MG treatment. “Continued progress in the management of MG will require diligent, multidisciplinary teams designing and completing prospective studies like the MGTX,” the researchers wrote.
Dr. Sonett and his coauthors had no financial relationships to disclose. The MGTX trial was funded by the U.S. National Institute of Neurological Disorders and Stroke. There was no commercial support for the trial.
FROM THE JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY
Key clinical point: A recently published prospective randomized trial provides definitive evidence that thymectomy significantly improves outcomes of patients with myasthenia gravis.
Major finding: Patients who underwent thymectomy had an average quantitative myasthenia score of 6.15 vs. 8.99 for the medical therapy group, a significant difference.
Data source: Myasthenia Gravis Thymectomy Trial, a prospective trial of 126 patients randomized to thymectomy with medical therapy or medical therapy alone.
Disclosures: Dr. Sonett and his coauthors had no financial relationships to disclose. The MGTX trial was funded by the U.S. National Institute of Neurological Disorders and Stroke. There was no commercial support for the trial.
Understanding the Link Between Epilepsy and Psychiatric Disorders
A better understanding of the relationship between psychiatric disorders and epilepsy is needed to help clinicians and researchers find the best treatment options, and to avoid the many misconceptions that currently exist. In a recent critical review, Berg et al address the biases in the literature and the diagnostic errors that may occur because of the difficulty in distinguishing psychogenic nonepileptic seizures from epilepsy.
Berg AT, Altalib HH, Devinsky O. Psychiatric and behavioral comorbidities in epilepsy: A critical reappraisal. Epilepsia. 2017;58:1123-1130.
A better understanding of the relationship between psychiatric disorders and epilepsy is needed to help clinicians and researchers find the best treatment options, and to avoid the many misconceptions that currently exist. In a recent critical review, Berg et al address the biases in the literature and the diagnostic errors that may occur because of the difficulty in distinguishing psychogenic nonepileptic seizures from epilepsy.
Berg AT, Altalib HH, Devinsky O. Psychiatric and behavioral comorbidities in epilepsy: A critical reappraisal. Epilepsia. 2017;58:1123-1130.
A better understanding of the relationship between psychiatric disorders and epilepsy is needed to help clinicians and researchers find the best treatment options, and to avoid the many misconceptions that currently exist. In a recent critical review, Berg et al address the biases in the literature and the diagnostic errors that may occur because of the difficulty in distinguishing psychogenic nonepileptic seizures from epilepsy.
Berg AT, Altalib HH, Devinsky O. Psychiatric and behavioral comorbidities in epilepsy: A critical reappraisal. Epilepsia. 2017;58:1123-1130.
Maternal protection against measles steadily declines prior to vaccination
, and for coxsackievirus (CoxA16), for which there currently is no vaccine.
EV71 and CoxA16 are enteroviruses that are common agents of hand-foot-and-mouth disease. Some patients infected with EV71 or CoxA16 develop neurological and systemic complications that can kill them. An EV71 vaccine, which is initially administered at 6 months, has been licensed in China since December 2015.
In a longitudinally designed study conducted by Chuanxi Fu and Jichuan Shen of Guangzhou (China) Center for Disease Control and Prevention, and their associates, sera was collected from 717 infants ages 0, 3, and 6 months, and examined for levels of measles IgG antibodies, and neutralizing antibodies for EV71 and CoxA16. Measles IgG antibody concentration from 717, 233, and 75 sera were assessed in infants of 0 month, 3 months, and 6 months, and 225, 217, and 72 sera were assessed for EV71 and CoxA16 at these time periods.
This study provides evidence of the rapid declining of measles antibodies in infants prior to vaccination under the Expanded Program on Immunization schedule in China, and confirms the rapid decrease of measles antibody levels suggested by prior cross-sectional studies in China. “Further modifications of vaccination strategies for measles, earlier vaccination for EV71 infection, and development and provision of a CoxA16 vaccine should be investigated and considered in the future,” concluded the researchers.
, and for coxsackievirus (CoxA16), for which there currently is no vaccine.
EV71 and CoxA16 are enteroviruses that are common agents of hand-foot-and-mouth disease. Some patients infected with EV71 or CoxA16 develop neurological and systemic complications that can kill them. An EV71 vaccine, which is initially administered at 6 months, has been licensed in China since December 2015.
In a longitudinally designed study conducted by Chuanxi Fu and Jichuan Shen of Guangzhou (China) Center for Disease Control and Prevention, and their associates, sera was collected from 717 infants ages 0, 3, and 6 months, and examined for levels of measles IgG antibodies, and neutralizing antibodies for EV71 and CoxA16. Measles IgG antibody concentration from 717, 233, and 75 sera were assessed in infants of 0 month, 3 months, and 6 months, and 225, 217, and 72 sera were assessed for EV71 and CoxA16 at these time periods.
This study provides evidence of the rapid declining of measles antibodies in infants prior to vaccination under the Expanded Program on Immunization schedule in China, and confirms the rapid decrease of measles antibody levels suggested by prior cross-sectional studies in China. “Further modifications of vaccination strategies for measles, earlier vaccination for EV71 infection, and development and provision of a CoxA16 vaccine should be investigated and considered in the future,” concluded the researchers.
, and for coxsackievirus (CoxA16), for which there currently is no vaccine.
EV71 and CoxA16 are enteroviruses that are common agents of hand-foot-and-mouth disease. Some patients infected with EV71 or CoxA16 develop neurological and systemic complications that can kill them. An EV71 vaccine, which is initially administered at 6 months, has been licensed in China since December 2015.
In a longitudinally designed study conducted by Chuanxi Fu and Jichuan Shen of Guangzhou (China) Center for Disease Control and Prevention, and their associates, sera was collected from 717 infants ages 0, 3, and 6 months, and examined for levels of measles IgG antibodies, and neutralizing antibodies for EV71 and CoxA16. Measles IgG antibody concentration from 717, 233, and 75 sera were assessed in infants of 0 month, 3 months, and 6 months, and 225, 217, and 72 sera were assessed for EV71 and CoxA16 at these time periods.
This study provides evidence of the rapid declining of measles antibodies in infants prior to vaccination under the Expanded Program on Immunization schedule in China, and confirms the rapid decrease of measles antibody levels suggested by prior cross-sectional studies in China. “Further modifications of vaccination strategies for measles, earlier vaccination for EV71 infection, and development and provision of a CoxA16 vaccine should be investigated and considered in the future,” concluded the researchers.
FROM VACCINE
Liver cancer risk lower after sustained response to DAAs
Individuals with hepatitis C infection who achieved a sustained virologic response (SVR) to treatment with direct-acting antivirals had a significantly lower risk of hepatocellular carcinoma (HCC), a new study suggests.
A retrospective cohort study of 22,500 U.S. veterans with hepatitis C who had been treated with direct-acting antivirals (DAAs) found those with an SVR had a 72% lower risk of HCC, compared with those who did not achieve that response (hazard ratio, 0.28; 95% confidence interval, 0.22-0.36; P less than .0001), even after adjusting for demographics as well as clinical and health utilization factors.
“These data show that successful eradication of HCV [hepatitis C virus] confers a benefit in DAA-treated patients,” wrote Fasiha Kanwal, MD, from the Michael E. DeBakey Veterans Affairs Medical Center in Houston and her coauthors. “Although a few recent studies have raised concerns that DAA might accelerate the risk of HCC in some patients early in the course of treatment, we did not find any factors that differentiated patients with HCC that developed during DAA treatment.”
The results highlighted the importance of early treatment with antivirals, beginning well before the patients showed signs of progressing to advanced fibrosis or cirrhosis, the investigators noted.
“Delaying treatment until patients progress to cirrhosis might be associated with substantial downstream costs incurred as part of lifelong HCC surveillance and/or management of HCC,” they wrote.
Sustained virologic response to DAAs also was associated with a longer time to diagnosis, and patients who didn’t achieve it showed higher rates of cancer much earlier. The most common antivirals used were sofosbuvir (75.2%; 51.1% in combination with ledipasvir), the combination of paritaprevir/ritonavir (23.3%), daclatasvir-based treatments (0.8%), and simeprevir (0.7%).
While the patients achieved SVR that showed similarly beneficial effects on HCC risk in patients with or without cirrhosis, the authors also noted that patients with cirrhosis had a nearly fivefold greater risk of developing cancer than did those without (HR, 4.73; 95% CI, 3.34-6.68). Similarly, patients with a fibrosis score (FIB-4) greater than 3.25 had a sixfold higher risk of HCC, compared with those with a value of 1.45 or lower.
Researchers commented that, at this level of risk, surveillance for HCC in these patients may be cost effective.
“Based on these data, HCC surveillance or risk modification may be needed for all patients who have progressed to cirrhosis or advanced fibrosis (as indicated by high FIB-4) at the time of SVR,” they wrote.
Alcohol use was also associated with a significantly higher annual incidence of HCC (HR, 1.56; 95% CI, 1.11-2.18).
Among the study cohort, 39% had cirrhosis, 29.7% had advanced fibrosis, and nearly one-quarter had previously been treated for hepatitis C infection. More than 40% also had diabetes, 61.4% reported alcohol use, and 54.2% had a history of drug use.
“DAAs offer a chance of cure for all patients with HCV, including patients with advanced cirrhosis, older patients, and those with alcohol use – all characteristics independently associated with risk of HCC in HCV,” the authors explained. “These data show the treated population has changed significantly in the DAA era to include many patients with other HCC risk factors; these differences likely explain why the newer cohorts of DAA-treated patients face higher absolute HCC risk than expected, based on historic data.”
The study was partly supported by the Department of Veteran Affairs’ Center for Innovations in Quality, Effectiveness, and Safety at the Michael E. DeBakey VA Medical Center. No conflicts of interest were declared.
The availability of direct-acting antivirals (DAAs) has revolutionized treatment of hepatitis C. Sustained virologic response (SVR) can be routinely achieved in more than 95% of patients – except in those with decompensated cirrhosis – with a 12-week course of these oral drugs, which have minimal adverse effects. Thus, guidelines recommend that all patients with hepatitis C should be treated with DAAs.1 It was a shock to the medical community when the recent Cochrane review concluded there was insufficient evidence to confirm or reject an effect of DAA therapy on HCV-related morbidity or all-cause mortality.2 The authors cautioned that the lack of valid evidence for DAAs’ effectiveness and the possibility of potential harm should be considered before treating people with hepatitis C with DAAs. Their conclusion was in part based on their rejection of SVR as a valid surrogate for clinical outcome. Previous studies of interferon-based therapies showed that SVR was associated with improvement in liver histology, decreased risk of hepatocellular carcinoma (HCC), and mortality.
Treatment of hepatitis C with DAAs represents one out of a handful of cases in which we can claim that a cure for a chronic disease is possible; however, treatment must be initiated early before advanced fibrosis or cirrhosis to prevent a persistent, though greatly reduced, risk of HCC. Physicians managing patients with hepatitis C should make treatment decisions based on evidence from the entire literature – which supports claims of the DAA treatment’s benefits and refutes allegations of its harmfulness – and should not be swayed by the misguided conclusions of the Cochrane review.
References
1. AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. www.hcvguidelines.org. Accessed on July 2, 2017.
2. Jakobsen J.C., Nielsen E.E., Feinberg J., et al. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev. 2017 Jun 6;6:CD012143.
3. Curry M.P., O’Leary J.G., Bzowej N., et al. Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med. 2015;373(27):2618-28.
4. Kanwal F., Kramer J., Asch S.M., et al. Risk of hepatocellular cancer in HCV patients treated with direct acting antiviral agents. Gastroenterology. 2017 Jun 19. pii: S0016-5085(17)35797.
Anna S. Lok, MD, AGAF, FAASLD, is the Alice Lohrman Andrews Research Professor in Hepatology in the department of internal medicine at the University of Michigan Health System in Ann Arbor. She has received research grants from Bristol-Myers Squibb and Gilead through the University of Michigan.
The availability of direct-acting antivirals (DAAs) has revolutionized treatment of hepatitis C. Sustained virologic response (SVR) can be routinely achieved in more than 95% of patients – except in those with decompensated cirrhosis – with a 12-week course of these oral drugs, which have minimal adverse effects. Thus, guidelines recommend that all patients with hepatitis C should be treated with DAAs.1 It was a shock to the medical community when the recent Cochrane review concluded there was insufficient evidence to confirm or reject an effect of DAA therapy on HCV-related morbidity or all-cause mortality.2 The authors cautioned that the lack of valid evidence for DAAs’ effectiveness and the possibility of potential harm should be considered before treating people with hepatitis C with DAAs. Their conclusion was in part based on their rejection of SVR as a valid surrogate for clinical outcome. Previous studies of interferon-based therapies showed that SVR was associated with improvement in liver histology, decreased risk of hepatocellular carcinoma (HCC), and mortality.
Treatment of hepatitis C with DAAs represents one out of a handful of cases in which we can claim that a cure for a chronic disease is possible; however, treatment must be initiated early before advanced fibrosis or cirrhosis to prevent a persistent, though greatly reduced, risk of HCC. Physicians managing patients with hepatitis C should make treatment decisions based on evidence from the entire literature – which supports claims of the DAA treatment’s benefits and refutes allegations of its harmfulness – and should not be swayed by the misguided conclusions of the Cochrane review.
References
1. AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. www.hcvguidelines.org. Accessed on July 2, 2017.
2. Jakobsen J.C., Nielsen E.E., Feinberg J., et al. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev. 2017 Jun 6;6:CD012143.
3. Curry M.P., O’Leary J.G., Bzowej N., et al. Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med. 2015;373(27):2618-28.
4. Kanwal F., Kramer J., Asch S.M., et al. Risk of hepatocellular cancer in HCV patients treated with direct acting antiviral agents. Gastroenterology. 2017 Jun 19. pii: S0016-5085(17)35797.
Anna S. Lok, MD, AGAF, FAASLD, is the Alice Lohrman Andrews Research Professor in Hepatology in the department of internal medicine at the University of Michigan Health System in Ann Arbor. She has received research grants from Bristol-Myers Squibb and Gilead through the University of Michigan.
The availability of direct-acting antivirals (DAAs) has revolutionized treatment of hepatitis C. Sustained virologic response (SVR) can be routinely achieved in more than 95% of patients – except in those with decompensated cirrhosis – with a 12-week course of these oral drugs, which have minimal adverse effects. Thus, guidelines recommend that all patients with hepatitis C should be treated with DAAs.1 It was a shock to the medical community when the recent Cochrane review concluded there was insufficient evidence to confirm or reject an effect of DAA therapy on HCV-related morbidity or all-cause mortality.2 The authors cautioned that the lack of valid evidence for DAAs’ effectiveness and the possibility of potential harm should be considered before treating people with hepatitis C with DAAs. Their conclusion was in part based on their rejection of SVR as a valid surrogate for clinical outcome. Previous studies of interferon-based therapies showed that SVR was associated with improvement in liver histology, decreased risk of hepatocellular carcinoma (HCC), and mortality.
Treatment of hepatitis C with DAAs represents one out of a handful of cases in which we can claim that a cure for a chronic disease is possible; however, treatment must be initiated early before advanced fibrosis or cirrhosis to prevent a persistent, though greatly reduced, risk of HCC. Physicians managing patients with hepatitis C should make treatment decisions based on evidence from the entire literature – which supports claims of the DAA treatment’s benefits and refutes allegations of its harmfulness – and should not be swayed by the misguided conclusions of the Cochrane review.
References
1. AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. www.hcvguidelines.org. Accessed on July 2, 2017.
2. Jakobsen J.C., Nielsen E.E., Feinberg J., et al. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev. 2017 Jun 6;6:CD012143.
3. Curry M.P., O’Leary J.G., Bzowej N., et al. Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med. 2015;373(27):2618-28.
4. Kanwal F., Kramer J., Asch S.M., et al. Risk of hepatocellular cancer in HCV patients treated with direct acting antiviral agents. Gastroenterology. 2017 Jun 19. pii: S0016-5085(17)35797.
Anna S. Lok, MD, AGAF, FAASLD, is the Alice Lohrman Andrews Research Professor in Hepatology in the department of internal medicine at the University of Michigan Health System in Ann Arbor. She has received research grants from Bristol-Myers Squibb and Gilead through the University of Michigan.
Individuals with hepatitis C infection who achieved a sustained virologic response (SVR) to treatment with direct-acting antivirals had a significantly lower risk of hepatocellular carcinoma (HCC), a new study suggests.
A retrospective cohort study of 22,500 U.S. veterans with hepatitis C who had been treated with direct-acting antivirals (DAAs) found those with an SVR had a 72% lower risk of HCC, compared with those who did not achieve that response (hazard ratio, 0.28; 95% confidence interval, 0.22-0.36; P less than .0001), even after adjusting for demographics as well as clinical and health utilization factors.
“These data show that successful eradication of HCV [hepatitis C virus] confers a benefit in DAA-treated patients,” wrote Fasiha Kanwal, MD, from the Michael E. DeBakey Veterans Affairs Medical Center in Houston and her coauthors. “Although a few recent studies have raised concerns that DAA might accelerate the risk of HCC in some patients early in the course of treatment, we did not find any factors that differentiated patients with HCC that developed during DAA treatment.”
The results highlighted the importance of early treatment with antivirals, beginning well before the patients showed signs of progressing to advanced fibrosis or cirrhosis, the investigators noted.
“Delaying treatment until patients progress to cirrhosis might be associated with substantial downstream costs incurred as part of lifelong HCC surveillance and/or management of HCC,” they wrote.
Sustained virologic response to DAAs also was associated with a longer time to diagnosis, and patients who didn’t achieve it showed higher rates of cancer much earlier. The most common antivirals used were sofosbuvir (75.2%; 51.1% in combination with ledipasvir), the combination of paritaprevir/ritonavir (23.3%), daclatasvir-based treatments (0.8%), and simeprevir (0.7%).
While the patients achieved SVR that showed similarly beneficial effects on HCC risk in patients with or without cirrhosis, the authors also noted that patients with cirrhosis had a nearly fivefold greater risk of developing cancer than did those without (HR, 4.73; 95% CI, 3.34-6.68). Similarly, patients with a fibrosis score (FIB-4) greater than 3.25 had a sixfold higher risk of HCC, compared with those with a value of 1.45 or lower.
Researchers commented that, at this level of risk, surveillance for HCC in these patients may be cost effective.
“Based on these data, HCC surveillance or risk modification may be needed for all patients who have progressed to cirrhosis or advanced fibrosis (as indicated by high FIB-4) at the time of SVR,” they wrote.
Alcohol use was also associated with a significantly higher annual incidence of HCC (HR, 1.56; 95% CI, 1.11-2.18).
Among the study cohort, 39% had cirrhosis, 29.7% had advanced fibrosis, and nearly one-quarter had previously been treated for hepatitis C infection. More than 40% also had diabetes, 61.4% reported alcohol use, and 54.2% had a history of drug use.
“DAAs offer a chance of cure for all patients with HCV, including patients with advanced cirrhosis, older patients, and those with alcohol use – all characteristics independently associated with risk of HCC in HCV,” the authors explained. “These data show the treated population has changed significantly in the DAA era to include many patients with other HCC risk factors; these differences likely explain why the newer cohorts of DAA-treated patients face higher absolute HCC risk than expected, based on historic data.”
The study was partly supported by the Department of Veteran Affairs’ Center for Innovations in Quality, Effectiveness, and Safety at the Michael E. DeBakey VA Medical Center. No conflicts of interest were declared.
Individuals with hepatitis C infection who achieved a sustained virologic response (SVR) to treatment with direct-acting antivirals had a significantly lower risk of hepatocellular carcinoma (HCC), a new study suggests.
A retrospective cohort study of 22,500 U.S. veterans with hepatitis C who had been treated with direct-acting antivirals (DAAs) found those with an SVR had a 72% lower risk of HCC, compared with those who did not achieve that response (hazard ratio, 0.28; 95% confidence interval, 0.22-0.36; P less than .0001), even after adjusting for demographics as well as clinical and health utilization factors.
“These data show that successful eradication of HCV [hepatitis C virus] confers a benefit in DAA-treated patients,” wrote Fasiha Kanwal, MD, from the Michael E. DeBakey Veterans Affairs Medical Center in Houston and her coauthors. “Although a few recent studies have raised concerns that DAA might accelerate the risk of HCC in some patients early in the course of treatment, we did not find any factors that differentiated patients with HCC that developed during DAA treatment.”
The results highlighted the importance of early treatment with antivirals, beginning well before the patients showed signs of progressing to advanced fibrosis or cirrhosis, the investigators noted.
“Delaying treatment until patients progress to cirrhosis might be associated with substantial downstream costs incurred as part of lifelong HCC surveillance and/or management of HCC,” they wrote.
Sustained virologic response to DAAs also was associated with a longer time to diagnosis, and patients who didn’t achieve it showed higher rates of cancer much earlier. The most common antivirals used were sofosbuvir (75.2%; 51.1% in combination with ledipasvir), the combination of paritaprevir/ritonavir (23.3%), daclatasvir-based treatments (0.8%), and simeprevir (0.7%).
While the patients achieved SVR that showed similarly beneficial effects on HCC risk in patients with or without cirrhosis, the authors also noted that patients with cirrhosis had a nearly fivefold greater risk of developing cancer than did those without (HR, 4.73; 95% CI, 3.34-6.68). Similarly, patients with a fibrosis score (FIB-4) greater than 3.25 had a sixfold higher risk of HCC, compared with those with a value of 1.45 or lower.
Researchers commented that, at this level of risk, surveillance for HCC in these patients may be cost effective.
“Based on these data, HCC surveillance or risk modification may be needed for all patients who have progressed to cirrhosis or advanced fibrosis (as indicated by high FIB-4) at the time of SVR,” they wrote.
Alcohol use was also associated with a significantly higher annual incidence of HCC (HR, 1.56; 95% CI, 1.11-2.18).
Among the study cohort, 39% had cirrhosis, 29.7% had advanced fibrosis, and nearly one-quarter had previously been treated for hepatitis C infection. More than 40% also had diabetes, 61.4% reported alcohol use, and 54.2% had a history of drug use.
“DAAs offer a chance of cure for all patients with HCV, including patients with advanced cirrhosis, older patients, and those with alcohol use – all characteristics independently associated with risk of HCC in HCV,” the authors explained. “These data show the treated population has changed significantly in the DAA era to include many patients with other HCC risk factors; these differences likely explain why the newer cohorts of DAA-treated patients face higher absolute HCC risk than expected, based on historic data.”
The study was partly supported by the Department of Veteran Affairs’ Center for Innovations in Quality, Effectiveness, and Safety at the Michael E. DeBakey VA Medical Center. No conflicts of interest were declared.
FROM GASTROENTEROLOGY
Key clinical point:
Major finding: Individuals who achieved an SVR to antiviral treatment for hepatitis C infection had a 72% lower risk of hepatocellular carcinoma than those who do not show a sustained response.
Data source: Retrospective cohort study in 22,500 U.S. veterans with hepatitis C.
Disclosures: The study was partly supported by the Department of Veterans Affairs’ Center for Innovations in Quality, Effectiveness, and Safety at the Michael E. DeBakey VA Medical Center. No conflicts of interest were declared.
Pulmonary metastasectomy may be useful for soft-tissue sarcoma spread
The rate of soft-tissue sarcoma has nearly doubled over the past two decades, and up to 50% of patients with tissue sarcoma develop lung metastasis. A single-center study of 539 patients who had treatment for soft-tissue sarcoma has revealed disease and treatment characteristics that may aid patient selection and help predict overall and disease-free survival after diagnosis and treatment.
“Histologic subtype and size of the primary tumor were significantly associated with overall survival,” said lead author Neel P. Chudgar, MD, and his coauthors in the July issue of the Journal of Thoracic and Cardiovascular Surgery (2017;154:319-30).
“Patients who underwent pulmonary metastasectomy [PM] for pleomorphic sarcoma/malignant fibrous histocytoma had the shortest median overall survival (23.6 months), whereas those who underwent PM for leiomyosarcoma had a median overall survival of 42 months,” he said.
The study subjects had pulmonary metastasectomies at Memorial Sloan Kettering Cancer Center, New York, during September 1991–June 2014. The median overall survival was 33.2 months, and median disease-free survival was 6.8 months for the entire cohort.
Among the disease characteristics associated with a lower hazard ratio of death shown by multivariable analyses were leiomyosarcoma histologic subtype (HR, 0.57), primary tumor size of 10 cm or less (HR, 1.00 vs. HR, 1.37 for those greater than 10 cm), increasing time from primary tumor resection to development of metastases (HR, 0.4 at less than 24 months vs. 1.0 at less than 6 months), solitary lung metastasis (HR, 1.0 vs. 1.8 for one year or more), and minimally invasive resection (HR, 0.71), all of which were statistically significant differences. Disease-free interval of more than one year and one pulmonary metastasis were significantly associated with lower hazard of disease recurrence.
Of patients, 70% had pulmonary metastasectomy as their primary treatment. The remainder had induction chemotherapy. In addition, 71% had open procedures over the 23-year study period, but minimally invasive operations became more common with time, increasing more than fourfold from the first half of the study period, vs. the last. They accounted for more than half of all procedures in the last five years of the study.
With regard to tumor type, fibrosarcoma was associated with longest median overall survival (65.2 months). Dr. Chudgar and his colleagues noted that 43% of these patients had low-grade primary tumors. Patients with low-grade tumors of all types had a median overall survival of 71.8 months, vs. 30.8 months for those with high-grade tumors.
“Our results indicate that therapeutic-intent pulmonary metastasectomy for soft-tissue sarcoma can be associated with prolonged survival,” Dr. Chudgar and his coauthors said. “The median survivals in our study are comparable with those in previous studies.” However, their analysis went beyond previous studies because they identified positive prognostic factors.
Dr. Chudgar and his coauthors acknowledge that various studies have drawn conflicting conclusions about the validity of histologic subtype as a prognostic factor, but their study differs from previous studies because it is a single-center cohort, “which increases the power to potentially identify significant differences, and we focused on soft-tissue sarcoma exclusively to enhance the homogeneity of the study population.”
Nonetheless, the researchers noted some limitations of their study, namely their collective analysis of the various soft-tissue sarcoma subtypes and the lack of a control group. Soft tissue sarcoma, because of its heterogeneous nature, challenges the adoption of precision medicine for this cancer type, but, until clinicians better understand the underlying mechanism of metastasis in these tumor types, Dr. Chudgar and his coauthors said, pulmonary metastasectomy “remains the best available treatment for soft tissue sarcoma pulmonary metastases.”
Dr. Chudgar and his coauthors had no financial relationships to disclose.
The findings that surgery for pulmonary metastases achieves “relatively good median survival” that Dr. Chudgar and coauthors reported are “especially impressive when considering that more than 25% of these patients with metastatic cancer had five or more pulmonary lesions,” said Mark F. Berry, MD, MHS, of Stanford University in his invited commentary (J Thorac Cardiovasc Surg. 2017;154:117-8).
Dr. Berry also said, however, that surgeons still must consider these results cautiously for several reasons. One, the study is retrospective and uncontrolled. Two, the study does not address whether the researchers selected healthy patients “with favorable disease characteristics” for pulmonary metastasectomy. “The sobering reality is that most patients still had recurrence relatively soon after complete pulmonary resection,” Dr. Berry said.
The study does support the current practice of pulmonary metastasectomy, which many patients may prefer for its invasive nature, compared with systemic chemotherapy treatment, he said. “Overall, surgeons can use this study to aid patient selection [and] to support the clinical decision to pursue resection of soft-tissue sarcoma pulmonary metastases for patients judged to be appropriate surgical candidates,” Dr. Berry concluded.
Dr. Berry had reported no financial disclosures.
The findings that surgery for pulmonary metastases achieves “relatively good median survival” that Dr. Chudgar and coauthors reported are “especially impressive when considering that more than 25% of these patients with metastatic cancer had five or more pulmonary lesions,” said Mark F. Berry, MD, MHS, of Stanford University in his invited commentary (J Thorac Cardiovasc Surg. 2017;154:117-8).
Dr. Berry also said, however, that surgeons still must consider these results cautiously for several reasons. One, the study is retrospective and uncontrolled. Two, the study does not address whether the researchers selected healthy patients “with favorable disease characteristics” for pulmonary metastasectomy. “The sobering reality is that most patients still had recurrence relatively soon after complete pulmonary resection,” Dr. Berry said.
The study does support the current practice of pulmonary metastasectomy, which many patients may prefer for its invasive nature, compared with systemic chemotherapy treatment, he said. “Overall, surgeons can use this study to aid patient selection [and] to support the clinical decision to pursue resection of soft-tissue sarcoma pulmonary metastases for patients judged to be appropriate surgical candidates,” Dr. Berry concluded.
Dr. Berry had reported no financial disclosures.
The findings that surgery for pulmonary metastases achieves “relatively good median survival” that Dr. Chudgar and coauthors reported are “especially impressive when considering that more than 25% of these patients with metastatic cancer had five or more pulmonary lesions,” said Mark F. Berry, MD, MHS, of Stanford University in his invited commentary (J Thorac Cardiovasc Surg. 2017;154:117-8).
Dr. Berry also said, however, that surgeons still must consider these results cautiously for several reasons. One, the study is retrospective and uncontrolled. Two, the study does not address whether the researchers selected healthy patients “with favorable disease characteristics” for pulmonary metastasectomy. “The sobering reality is that most patients still had recurrence relatively soon after complete pulmonary resection,” Dr. Berry said.
The study does support the current practice of pulmonary metastasectomy, which many patients may prefer for its invasive nature, compared with systemic chemotherapy treatment, he said. “Overall, surgeons can use this study to aid patient selection [and] to support the clinical decision to pursue resection of soft-tissue sarcoma pulmonary metastases for patients judged to be appropriate surgical candidates,” Dr. Berry concluded.
Dr. Berry had reported no financial disclosures.
The rate of soft-tissue sarcoma has nearly doubled over the past two decades, and up to 50% of patients with tissue sarcoma develop lung metastasis. A single-center study of 539 patients who had treatment for soft-tissue sarcoma has revealed disease and treatment characteristics that may aid patient selection and help predict overall and disease-free survival after diagnosis and treatment.
“Histologic subtype and size of the primary tumor were significantly associated with overall survival,” said lead author Neel P. Chudgar, MD, and his coauthors in the July issue of the Journal of Thoracic and Cardiovascular Surgery (2017;154:319-30).
“Patients who underwent pulmonary metastasectomy [PM] for pleomorphic sarcoma/malignant fibrous histocytoma had the shortest median overall survival (23.6 months), whereas those who underwent PM for leiomyosarcoma had a median overall survival of 42 months,” he said.
The study subjects had pulmonary metastasectomies at Memorial Sloan Kettering Cancer Center, New York, during September 1991–June 2014. The median overall survival was 33.2 months, and median disease-free survival was 6.8 months for the entire cohort.
Among the disease characteristics associated with a lower hazard ratio of death shown by multivariable analyses were leiomyosarcoma histologic subtype (HR, 0.57), primary tumor size of 10 cm or less (HR, 1.00 vs. HR, 1.37 for those greater than 10 cm), increasing time from primary tumor resection to development of metastases (HR, 0.4 at less than 24 months vs. 1.0 at less than 6 months), solitary lung metastasis (HR, 1.0 vs. 1.8 for one year or more), and minimally invasive resection (HR, 0.71), all of which were statistically significant differences. Disease-free interval of more than one year and one pulmonary metastasis were significantly associated with lower hazard of disease recurrence.
Of patients, 70% had pulmonary metastasectomy as their primary treatment. The remainder had induction chemotherapy. In addition, 71% had open procedures over the 23-year study period, but minimally invasive operations became more common with time, increasing more than fourfold from the first half of the study period, vs. the last. They accounted for more than half of all procedures in the last five years of the study.
With regard to tumor type, fibrosarcoma was associated with longest median overall survival (65.2 months). Dr. Chudgar and his colleagues noted that 43% of these patients had low-grade primary tumors. Patients with low-grade tumors of all types had a median overall survival of 71.8 months, vs. 30.8 months for those with high-grade tumors.
“Our results indicate that therapeutic-intent pulmonary metastasectomy for soft-tissue sarcoma can be associated with prolonged survival,” Dr. Chudgar and his coauthors said. “The median survivals in our study are comparable with those in previous studies.” However, their analysis went beyond previous studies because they identified positive prognostic factors.
Dr. Chudgar and his coauthors acknowledge that various studies have drawn conflicting conclusions about the validity of histologic subtype as a prognostic factor, but their study differs from previous studies because it is a single-center cohort, “which increases the power to potentially identify significant differences, and we focused on soft-tissue sarcoma exclusively to enhance the homogeneity of the study population.”
Nonetheless, the researchers noted some limitations of their study, namely their collective analysis of the various soft-tissue sarcoma subtypes and the lack of a control group. Soft tissue sarcoma, because of its heterogeneous nature, challenges the adoption of precision medicine for this cancer type, but, until clinicians better understand the underlying mechanism of metastasis in these tumor types, Dr. Chudgar and his coauthors said, pulmonary metastasectomy “remains the best available treatment for soft tissue sarcoma pulmonary metastases.”
Dr. Chudgar and his coauthors had no financial relationships to disclose.
The rate of soft-tissue sarcoma has nearly doubled over the past two decades, and up to 50% of patients with tissue sarcoma develop lung metastasis. A single-center study of 539 patients who had treatment for soft-tissue sarcoma has revealed disease and treatment characteristics that may aid patient selection and help predict overall and disease-free survival after diagnosis and treatment.
“Histologic subtype and size of the primary tumor were significantly associated with overall survival,” said lead author Neel P. Chudgar, MD, and his coauthors in the July issue of the Journal of Thoracic and Cardiovascular Surgery (2017;154:319-30).
“Patients who underwent pulmonary metastasectomy [PM] for pleomorphic sarcoma/malignant fibrous histocytoma had the shortest median overall survival (23.6 months), whereas those who underwent PM for leiomyosarcoma had a median overall survival of 42 months,” he said.
The study subjects had pulmonary metastasectomies at Memorial Sloan Kettering Cancer Center, New York, during September 1991–June 2014. The median overall survival was 33.2 months, and median disease-free survival was 6.8 months for the entire cohort.
Among the disease characteristics associated with a lower hazard ratio of death shown by multivariable analyses were leiomyosarcoma histologic subtype (HR, 0.57), primary tumor size of 10 cm or less (HR, 1.00 vs. HR, 1.37 for those greater than 10 cm), increasing time from primary tumor resection to development of metastases (HR, 0.4 at less than 24 months vs. 1.0 at less than 6 months), solitary lung metastasis (HR, 1.0 vs. 1.8 for one year or more), and minimally invasive resection (HR, 0.71), all of which were statistically significant differences. Disease-free interval of more than one year and one pulmonary metastasis were significantly associated with lower hazard of disease recurrence.
Of patients, 70% had pulmonary metastasectomy as their primary treatment. The remainder had induction chemotherapy. In addition, 71% had open procedures over the 23-year study period, but minimally invasive operations became more common with time, increasing more than fourfold from the first half of the study period, vs. the last. They accounted for more than half of all procedures in the last five years of the study.
With regard to tumor type, fibrosarcoma was associated with longest median overall survival (65.2 months). Dr. Chudgar and his colleagues noted that 43% of these patients had low-grade primary tumors. Patients with low-grade tumors of all types had a median overall survival of 71.8 months, vs. 30.8 months for those with high-grade tumors.
“Our results indicate that therapeutic-intent pulmonary metastasectomy for soft-tissue sarcoma can be associated with prolonged survival,” Dr. Chudgar and his coauthors said. “The median survivals in our study are comparable with those in previous studies.” However, their analysis went beyond previous studies because they identified positive prognostic factors.
Dr. Chudgar and his coauthors acknowledge that various studies have drawn conflicting conclusions about the validity of histologic subtype as a prognostic factor, but their study differs from previous studies because it is a single-center cohort, “which increases the power to potentially identify significant differences, and we focused on soft-tissue sarcoma exclusively to enhance the homogeneity of the study population.”
Nonetheless, the researchers noted some limitations of their study, namely their collective analysis of the various soft-tissue sarcoma subtypes and the lack of a control group. Soft tissue sarcoma, because of its heterogeneous nature, challenges the adoption of precision medicine for this cancer type, but, until clinicians better understand the underlying mechanism of metastasis in these tumor types, Dr. Chudgar and his coauthors said, pulmonary metastasectomy “remains the best available treatment for soft tissue sarcoma pulmonary metastases.”
Dr. Chudgar and his coauthors had no financial relationships to disclose.
FROM THE JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY
Key clinical point: Characteristics that determine survival in patients with sarcomatous pulmonary metastases are tumor subtype and size, number of and time to metastases, and minimally invasive surgery.
Major finding: Patients with leiomyosarcoma histologic subtype tumor had a hazard ratio of 0.57 (P = .001), and those with a primary tumor size of 10 cm or less had an HR of 1, vs. an HR of 1.37 for those greater than 10 cm (P = .006)
Data source: A single-institution study of 539 patients who had pulmonary mastectomy for metastatic soft tissue sarcoma from September 1991 to June 2014.
Disclosures: Dr. Chudgar and his coauthors had no financial relationships to disclose.