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SAN DIEGO – Patients with newly diagnosed multiple myeloma who were ineligible for transplant had a 44% reduction in the risk of disease progression or death when they were treated with the anti-CD38 monoclonal antibody daratumumab (Darzalex) added to lenalidomide (Revlimid) and dexamethasone, compared with lenalidomide-dexamethasone alone, an interim analysis from the MAIA trial showed.

Among 737 patients in a phase 3 trial, median progression-free survival – the primary endpoint – had not been reached after a median follow-up of 28 months for patients randomized to daratumumab, lenalidomide, and dexamethasone (DRd), versus 31.9 months for patients randomized to lenalidomide and dexamethasone (Rd).

The 30-month PFS rate in the DRd arm was 71%, compared with 56% for the Rd arm. This difference translated into a hazard ratio (HR) for progression of 0.56 (P less than .0001), reported Thierry Facon, MD, of Hôpital Claude Huriez and the University of Lille, France.

“These results support DRd as a new standard of care for elderly patients with myeloma who are ineligible for transplant,” he said at the annual meeting of the American Society of Hematology.

Dr. Facon and his colleagues had previously shown in the FIRST trial that in newly diagnosed transplant-ineligible patients, continuous treatment with lenalidomide and low-dose dexamethasone was associated with significant overall survival and PFS benefits, compared with melphalan-prednisone-thalidomide.

In the POLLUX trial, investigators reported that in patients with multiple myeloma that was refractory or had relapsed after at least one prior line of therapy, the DRd combination was associated with a 63% reduction in the risk for disease progression or death, compared with Rd alone.
 

MAIA details

The MAIA trial is a pivotal, phase 3 study pitting DRd against Rd in transplant-ineligible patients with newly diagnosed multiple myeloma.

Patients with untreated disease who had Eastern Cooperative Oncology Group (ECOG) status of 0-2 and creatinine clearance rates of at least 30 mL/min were enrolled. Patients were randomly assigned to either DRd, with intravenous daratumumab 16 mg/kg weekly for cycles 1 and 2, every other week for cycles 3 through 6, and every 4 weeks from cycle 7 until disease progression, plus lenalidomide 25 mg orally per day on days 1-21 until disease progression, and dexamethasone 40 mg orally or intravenously weekly until disease progression; or to the same regimen without daratumumab.

The median patient age was 73 years and 99% of all patients were aged 65 years or older. Demographic and clinical characteristics were well balanced between the treatment arms.

The primary endpoint of progression-free survival was superior with DRd.

DRd also was associated with a significantly higher overall response rate (93% vs. 81%), complete response rate (48% vs. 25%), very good partial response or better rate (79% vs. 53%), and minimal residual disease (MRD) negativity rate (24% vs. 7%; P less than .0001 for all comparisons).

The DRd combination was associated with infusion-related reactions in 41% of patients, but only 3% were grade 3 or 4 in severity.

Hematologic treatment-emergent adverse events (TEAE) grade 3 or greater that were more common with DRd included neutropenia (50% vs. 35%) and lymphopenia (15% vs. 11%). Conversely, thrombocytopenia (7% vs. 9%, grade 3 or 4) and anemia (12% vs. 20%) were more frequent with Rd.

Nonhematologic TEAEs that were more frequent with DRd included diarrhea, constipation, fatigue, peripheral edema, and pneumonia. Rates of asthenia, back pain, nausea, and deep vein thrombosis/pulmonary embolism were similar between the study arms.

Janssen funded the study. Dr. Facon reported speakers bureau and advisory board participation for Celgene, Janssen, and Takeda; and advisory board participation for Sanofi, Amgen, Karyopharm, and Oncopeptides.

SOURCE: Facon T et al. ASH 2018, Abstract LBA-2.

SAN DIEGO – Patients with newly diagnosed multiple myeloma who were ineligible for transplant had a 44% reduction in the risk of disease progression or death when they were treated with the anti-CD38 monoclonal antibody daratumumab (Darzalex) added to lenalidomide (Revlimid) and dexamethasone, compared with lenalidomide-dexamethasone alone, an interim analysis from the MAIA trial showed.

Among 737 patients in a phase 3 trial, median progression-free survival – the primary endpoint – had not been reached after a median follow-up of 28 months for patients randomized to daratumumab, lenalidomide, and dexamethasone (DRd), versus 31.9 months for patients randomized to lenalidomide and dexamethasone (Rd).

The 30-month PFS rate in the DRd arm was 71%, compared with 56% for the Rd arm. This difference translated into a hazard ratio (HR) for progression of 0.56 (P less than .0001), reported Thierry Facon, MD, of Hôpital Claude Huriez and the University of Lille, France.

“These results support DRd as a new standard of care for elderly patients with myeloma who are ineligible for transplant,” he said at the annual meeting of the American Society of Hematology.

Dr. Facon and his colleagues had previously shown in the FIRST trial that in newly diagnosed transplant-ineligible patients, continuous treatment with lenalidomide and low-dose dexamethasone was associated with significant overall survival and PFS benefits, compared with melphalan-prednisone-thalidomide.

In the POLLUX trial, investigators reported that in patients with multiple myeloma that was refractory or had relapsed after at least one prior line of therapy, the DRd combination was associated with a 63% reduction in the risk for disease progression or death, compared with Rd alone.
 

MAIA details

The MAIA trial is a pivotal, phase 3 study pitting DRd against Rd in transplant-ineligible patients with newly diagnosed multiple myeloma.

Patients with untreated disease who had Eastern Cooperative Oncology Group (ECOG) status of 0-2 and creatinine clearance rates of at least 30 mL/min were enrolled. Patients were randomly assigned to either DRd, with intravenous daratumumab 16 mg/kg weekly for cycles 1 and 2, every other week for cycles 3 through 6, and every 4 weeks from cycle 7 until disease progression, plus lenalidomide 25 mg orally per day on days 1-21 until disease progression, and dexamethasone 40 mg orally or intravenously weekly until disease progression; or to the same regimen without daratumumab.

The median patient age was 73 years and 99% of all patients were aged 65 years or older. Demographic and clinical characteristics were well balanced between the treatment arms.

The primary endpoint of progression-free survival was superior with DRd.

DRd also was associated with a significantly higher overall response rate (93% vs. 81%), complete response rate (48% vs. 25%), very good partial response or better rate (79% vs. 53%), and minimal residual disease (MRD) negativity rate (24% vs. 7%; P less than .0001 for all comparisons).

The DRd combination was associated with infusion-related reactions in 41% of patients, but only 3% were grade 3 or 4 in severity.

Hematologic treatment-emergent adverse events (TEAE) grade 3 or greater that were more common with DRd included neutropenia (50% vs. 35%) and lymphopenia (15% vs. 11%). Conversely, thrombocytopenia (7% vs. 9%, grade 3 or 4) and anemia (12% vs. 20%) were more frequent with Rd.

Nonhematologic TEAEs that were more frequent with DRd included diarrhea, constipation, fatigue, peripheral edema, and pneumonia. Rates of asthenia, back pain, nausea, and deep vein thrombosis/pulmonary embolism were similar between the study arms.

Janssen funded the study. Dr. Facon reported speakers bureau and advisory board participation for Celgene, Janssen, and Takeda; and advisory board participation for Sanofi, Amgen, Karyopharm, and Oncopeptides.

SOURCE: Facon T et al. ASH 2018, Abstract LBA-2.

SAN DIEGO – Patients with newly diagnosed multiple myeloma who were ineligible for transplant had a 44% reduction in the risk of disease progression or death when they were treated with the anti-CD38 monoclonal antibody daratumumab (Darzalex) added to lenalidomide (Revlimid) and dexamethasone, compared with lenalidomide-dexamethasone alone, an interim analysis from the MAIA trial showed.

Among 737 patients in a phase 3 trial, median progression-free survival – the primary endpoint – had not been reached after a median follow-up of 28 months for patients randomized to daratumumab, lenalidomide, and dexamethasone (DRd), versus 31.9 months for patients randomized to lenalidomide and dexamethasone (Rd).

The 30-month PFS rate in the DRd arm was 71%, compared with 56% for the Rd arm. This difference translated into a hazard ratio (HR) for progression of 0.56 (P less than .0001), reported Thierry Facon, MD, of Hôpital Claude Huriez and the University of Lille, France.

“These results support DRd as a new standard of care for elderly patients with myeloma who are ineligible for transplant,” he said at the annual meeting of the American Society of Hematology.

Dr. Facon and his colleagues had previously shown in the FIRST trial that in newly diagnosed transplant-ineligible patients, continuous treatment with lenalidomide and low-dose dexamethasone was associated with significant overall survival and PFS benefits, compared with melphalan-prednisone-thalidomide.

In the POLLUX trial, investigators reported that in patients with multiple myeloma that was refractory or had relapsed after at least one prior line of therapy, the DRd combination was associated with a 63% reduction in the risk for disease progression or death, compared with Rd alone.
 

MAIA details

The MAIA trial is a pivotal, phase 3 study pitting DRd against Rd in transplant-ineligible patients with newly diagnosed multiple myeloma.

Patients with untreated disease who had Eastern Cooperative Oncology Group (ECOG) status of 0-2 and creatinine clearance rates of at least 30 mL/min were enrolled. Patients were randomly assigned to either DRd, with intravenous daratumumab 16 mg/kg weekly for cycles 1 and 2, every other week for cycles 3 through 6, and every 4 weeks from cycle 7 until disease progression, plus lenalidomide 25 mg orally per day on days 1-21 until disease progression, and dexamethasone 40 mg orally or intravenously weekly until disease progression; or to the same regimen without daratumumab.

The median patient age was 73 years and 99% of all patients were aged 65 years or older. Demographic and clinical characteristics were well balanced between the treatment arms.

The primary endpoint of progression-free survival was superior with DRd.

DRd also was associated with a significantly higher overall response rate (93% vs. 81%), complete response rate (48% vs. 25%), very good partial response or better rate (79% vs. 53%), and minimal residual disease (MRD) negativity rate (24% vs. 7%; P less than .0001 for all comparisons).

The DRd combination was associated with infusion-related reactions in 41% of patients, but only 3% were grade 3 or 4 in severity.

Hematologic treatment-emergent adverse events (TEAE) grade 3 or greater that were more common with DRd included neutropenia (50% vs. 35%) and lymphopenia (15% vs. 11%). Conversely, thrombocytopenia (7% vs. 9%, grade 3 or 4) and anemia (12% vs. 20%) were more frequent with Rd.

Nonhematologic TEAEs that were more frequent with DRd included diarrhea, constipation, fatigue, peripheral edema, and pneumonia. Rates of asthenia, back pain, nausea, and deep vein thrombosis/pulmonary embolism were similar between the study arms.

Janssen funded the study. Dr. Facon reported speakers bureau and advisory board participation for Celgene, Janssen, and Takeda; and advisory board participation for Sanofi, Amgen, Karyopharm, and Oncopeptides.

SOURCE: Facon T et al. ASH 2018, Abstract LBA-2.

SAN DIEGO – Want to have influence on social media? Dr. Amber Yates advises physicians to be authentic.

“People want to see that you’re a person and not strictly a physician,” said Dr. Yates, a pediatric hematologist at Texas Children’s Hospital in Houston, who has had an active Twitter presence for the last few years.

Dr. Yates – whose Twitter handle is @sicklecelldoc – said she dipped a toe in the social media waters because she wanted to bring accurate medical information to patients in the arena where they are seeking information.

“I want families to understand their condition as well as they can on whatever level they can, and so I just found this to be another way to do that ... outside of my clinic,” she said during an interview at the annual meeting of the American Society of Hematology.

But beyond correcting misinformation and serving as an advocate for patients, Dr. Yates said she gets professional benefits from being on Twitter. For instance, she uses the platform to find relevant articles as soon as they publish, without wading through all the journals.

“It’s allowed me to kind of streamline what I read,” she said.

Dr. Yates said Twitter is her social media platform of choice because it provides a simple, succinct way to communicate and provide links to more in-depth resources.

While social media can be fun and rewarding for physicians, Dr. Yates said think before you post. Ask yourself, “would you tell your chairperson this?”

Dr. Yates reported having no relevant financial disclosures.

[email protected]

SAN DIEGO – Want to have influence on social media? Dr. Amber Yates advises physicians to be authentic.

“People want to see that you’re a person and not strictly a physician,” said Dr. Yates, a pediatric hematologist at Texas Children’s Hospital in Houston, who has had an active Twitter presence for the last few years.

Dr. Yates – whose Twitter handle is @sicklecelldoc – said she dipped a toe in the social media waters because she wanted to bring accurate medical information to patients in the arena where they are seeking information.

“I want families to understand their condition as well as they can on whatever level they can, and so I just found this to be another way to do that ... outside of my clinic,” she said during an interview at the annual meeting of the American Society of Hematology.

But beyond correcting misinformation and serving as an advocate for patients, Dr. Yates said she gets professional benefits from being on Twitter. For instance, she uses the platform to find relevant articles as soon as they publish, without wading through all the journals.

“It’s allowed me to kind of streamline what I read,” she said.

Dr. Yates said Twitter is her social media platform of choice because it provides a simple, succinct way to communicate and provide links to more in-depth resources.

While social media can be fun and rewarding for physicians, Dr. Yates said think before you post. Ask yourself, “would you tell your chairperson this?”

Dr. Yates reported having no relevant financial disclosures.

[email protected]

SAN DIEGO – Want to have influence on social media? Dr. Amber Yates advises physicians to be authentic.

“People want to see that you’re a person and not strictly a physician,” said Dr. Yates, a pediatric hematologist at Texas Children’s Hospital in Houston, who has had an active Twitter presence for the last few years.

Dr. Yates – whose Twitter handle is @sicklecelldoc – said she dipped a toe in the social media waters because she wanted to bring accurate medical information to patients in the arena where they are seeking information.

“I want families to understand their condition as well as they can on whatever level they can, and so I just found this to be another way to do that ... outside of my clinic,” she said during an interview at the annual meeting of the American Society of Hematology.

But beyond correcting misinformation and serving as an advocate for patients, Dr. Yates said she gets professional benefits from being on Twitter. For instance, she uses the platform to find relevant articles as soon as they publish, without wading through all the journals.

“It’s allowed me to kind of streamline what I read,” she said.

Dr. Yates said Twitter is her social media platform of choice because it provides a simple, succinct way to communicate and provide links to more in-depth resources.

While social media can be fun and rewarding for physicians, Dr. Yates said think before you post. Ask yourself, “would you tell your chairperson this?”

Dr. Yates reported having no relevant financial disclosures.

[email protected]

SAN DIEGO – The combination of ibrutinib and rituximab was associated with a two-thirds reduction in chronic lymphocytic leukemia (CLL) progression, compared with standard chemoimmunotherapy in patients younger than 70 years old, interim results of a phase 3 randomized trial showed.

Among 529 patients with previously untreated, symptomatic CLL randomly assigned to ibrutinib-rituximab (IR) or to chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR), the IR regimen was associated with a 65% reduction in risk for disease progression, which was the trial’s primary endpoint.

The IR regimen was also associated with better overall survival out to 4 years of follow-up, reported Tait D. Shanafelt, MD, of Stanford (Calif.) University.

“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” he said at a media briefing prior at the annual meeting of the American Society of Hematology.

The study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.

In the ECOG-ACRIN Cancer Research Group E1912 trial, 529 patients aged 70 or younger with previously untreated CLL were enrolled and randomly assigned on a 2:1 basis to either standard therapy with six cycles of FCR according to standard protocols (175 patients), or IR, with ibrutinib 420 mg daily for each cycle, and rituximab delivered 50 mg/m² intravenously on day 1 of cycle 2, and 325 mg/m² on day 2 of the same cycle, and 500 mg/m² on day 1 for all remaining cycles (354 patients).

From cycle 8 until progression, patients in the IR arm received daily ibrutinib 420 mg.

Dr. Shanafelt presented results from both an intention-to-treat analysis and a per-protocol analysis excluding 22 patients in the IR arm and 9 patients in the FCR arm who were randomized but later found not to meet eligibility criteria.

After a mean follow-up of 34 months, there were 37 PFS events in the IR arm, compared with 40 events in the FCR arm in an intention-to-treat analysis. The difference translated into a hazard ratio for progression of 0.35 with IR (P less than .00001).

The results were similar in the per-protocol analysis, with an HR of 0.32 favoring IR (P less than .00001).*

There were four deaths in the IR arm, compared with 10 in the FCR arm at the time of the data lock, translating into a hazard ratio (HR) for overall survival of 0.17 (P less than .0003) in the intention-to-treat analysis, and 0.13 in the per-protocol analysis (P less than .0001).

Dr. Shanafelt noted that although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning that the rate of deaths in the FCR arm was fivefold higher than in the IR arm.

In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.

PFS was also significantly better with IR in patients with unmutated immunoglobulin heavy chain variable (IGHV) regions (HR 0.26, P less than .00001), but not in patients with mutated IGHV.*

Grade 3 or greater treatment-related adverse events occurred in 58.5% of patients in the IR arm, compared with 72.1% of patients in the FCR arm. Specific events that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P less than .001 for all comparisons).

Events that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P = .04), and hypertension (7.4% vs. 1.9%, P = .01).

Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost; the monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.

“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.

The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, Abbvie, Pharmacyclics, and Janssen.

SOURCE: Shanafelt TD et al. ASH 2018, Abstract LBA-4.

*Correction, 12/12/2018: An earlier version of this story misstated the P value in two comparisons.

SAN DIEGO – The combination of ibrutinib and rituximab was associated with a two-thirds reduction in chronic lymphocytic leukemia (CLL) progression, compared with standard chemoimmunotherapy in patients younger than 70 years old, interim results of a phase 3 randomized trial showed.

Among 529 patients with previously untreated, symptomatic CLL randomly assigned to ibrutinib-rituximab (IR) or to chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR), the IR regimen was associated with a 65% reduction in risk for disease progression, which was the trial’s primary endpoint.

The IR regimen was also associated with better overall survival out to 4 years of follow-up, reported Tait D. Shanafelt, MD, of Stanford (Calif.) University.

“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” he said at a media briefing prior at the annual meeting of the American Society of Hematology.

The study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.

In the ECOG-ACRIN Cancer Research Group E1912 trial, 529 patients aged 70 or younger with previously untreated CLL were enrolled and randomly assigned on a 2:1 basis to either standard therapy with six cycles of FCR according to standard protocols (175 patients), or IR, with ibrutinib 420 mg daily for each cycle, and rituximab delivered 50 mg/m² intravenously on day 1 of cycle 2, and 325 mg/m² on day 2 of the same cycle, and 500 mg/m² on day 1 for all remaining cycles (354 patients).

From cycle 8 until progression, patients in the IR arm received daily ibrutinib 420 mg.

Dr. Shanafelt presented results from both an intention-to-treat analysis and a per-protocol analysis excluding 22 patients in the IR arm and 9 patients in the FCR arm who were randomized but later found not to meet eligibility criteria.

After a mean follow-up of 34 months, there were 37 PFS events in the IR arm, compared with 40 events in the FCR arm in an intention-to-treat analysis. The difference translated into a hazard ratio for progression of 0.35 with IR (P less than .00001).

The results were similar in the per-protocol analysis, with an HR of 0.32 favoring IR (P less than .00001).*

There were four deaths in the IR arm, compared with 10 in the FCR arm at the time of the data lock, translating into a hazard ratio (HR) for overall survival of 0.17 (P less than .0003) in the intention-to-treat analysis, and 0.13 in the per-protocol analysis (P less than .0001).

Dr. Shanafelt noted that although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning that the rate of deaths in the FCR arm was fivefold higher than in the IR arm.

In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.

PFS was also significantly better with IR in patients with unmutated immunoglobulin heavy chain variable (IGHV) regions (HR 0.26, P less than .00001), but not in patients with mutated IGHV.*

Grade 3 or greater treatment-related adverse events occurred in 58.5% of patients in the IR arm, compared with 72.1% of patients in the FCR arm. Specific events that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P less than .001 for all comparisons).

Events that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P = .04), and hypertension (7.4% vs. 1.9%, P = .01).

Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost; the monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.

“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.

The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, Abbvie, Pharmacyclics, and Janssen.

SOURCE: Shanafelt TD et al. ASH 2018, Abstract LBA-4.

*Correction, 12/12/2018: An earlier version of this story misstated the P value in two comparisons.

SAN DIEGO – The combination of ibrutinib and rituximab was associated with a two-thirds reduction in chronic lymphocytic leukemia (CLL) progression, compared with standard chemoimmunotherapy in patients younger than 70 years old, interim results of a phase 3 randomized trial showed.

Among 529 patients with previously untreated, symptomatic CLL randomly assigned to ibrutinib-rituximab (IR) or to chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR), the IR regimen was associated with a 65% reduction in risk for disease progression, which was the trial’s primary endpoint.

The IR regimen was also associated with better overall survival out to 4 years of follow-up, reported Tait D. Shanafelt, MD, of Stanford (Calif.) University.

“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” he said at a media briefing prior at the annual meeting of the American Society of Hematology.

The study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.

In the ECOG-ACRIN Cancer Research Group E1912 trial, 529 patients aged 70 or younger with previously untreated CLL were enrolled and randomly assigned on a 2:1 basis to either standard therapy with six cycles of FCR according to standard protocols (175 patients), or IR, with ibrutinib 420 mg daily for each cycle, and rituximab delivered 50 mg/m² intravenously on day 1 of cycle 2, and 325 mg/m² on day 2 of the same cycle, and 500 mg/m² on day 1 for all remaining cycles (354 patients).

From cycle 8 until progression, patients in the IR arm received daily ibrutinib 420 mg.

Dr. Shanafelt presented results from both an intention-to-treat analysis and a per-protocol analysis excluding 22 patients in the IR arm and 9 patients in the FCR arm who were randomized but later found not to meet eligibility criteria.

After a mean follow-up of 34 months, there were 37 PFS events in the IR arm, compared with 40 events in the FCR arm in an intention-to-treat analysis. The difference translated into a hazard ratio for progression of 0.35 with IR (P less than .00001).

The results were similar in the per-protocol analysis, with an HR of 0.32 favoring IR (P less than .00001).*

There were four deaths in the IR arm, compared with 10 in the FCR arm at the time of the data lock, translating into a hazard ratio (HR) for overall survival of 0.17 (P less than .0003) in the intention-to-treat analysis, and 0.13 in the per-protocol analysis (P less than .0001).

Dr. Shanafelt noted that although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning that the rate of deaths in the FCR arm was fivefold higher than in the IR arm.

In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.

PFS was also significantly better with IR in patients with unmutated immunoglobulin heavy chain variable (IGHV) regions (HR 0.26, P less than .00001), but not in patients with mutated IGHV.*

Grade 3 or greater treatment-related adverse events occurred in 58.5% of patients in the IR arm, compared with 72.1% of patients in the FCR arm. Specific events that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P less than .001 for all comparisons).

Events that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P = .04), and hypertension (7.4% vs. 1.9%, P = .01).

Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost; the monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.

“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.

The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, Abbvie, Pharmacyclics, and Janssen.

SOURCE: Shanafelt TD et al. ASH 2018, Abstract LBA-4.

*Correction, 12/12/2018: An earlier version of this story misstated the P value in two comparisons.

SAN DIEGO – Prophylaxis with rivaroxaban significantly reduced the rate of venous thromboembolism and associated death in high-risk ambulatory cancer patients receiving systemic therapy, results of a randomized trial show.

The reduction in venous thromboembolism (VTE) or VTE-related death was not statistically significant in the primary analysis, in part because a large proportion of patients stopped taking the direct oral anticoagulant, according to investigator Alok A. Khorana, MD, of the Cleveland Clinic.

However, the reduction in events was significant in a prespecified secondary analysis limited to the on-treatment period, Dr. Khorana reported at the annual meeting of the American Society of Hematology, adding that rates of major and nonmajor bleeding were low.

Results are “eagerly awaited” from a different prophylaxis trial – the AVERT study – looking at another direct oral anticoagulant in high-risk cancer patients, Dr. Khorana said in a late-breaking abstracts session.

“If the findings of that trial are consistent with ours, then we certainly hope that these findings should inform future recommendations regarding thromboprophylaxis for high-risk ambulatory cancer patients, and then the landscape of anticoagulation in the cancer population should start to shift from management of events to primary prevention,” he said.

In the study by Dr. Khorana and his colleagues, known as CASSINI, 841 patients with various solid tumors and lymphomas were randomized to either rivaroxaban 10 mg or placebo once daily. The patients, enrolled at 143 study centers in 11 countries, all had a Khorana risk score of 2 or greater.

In the primary analysis period of 180 days, the composite endpoint of VTE or VTE-related death occurred in 5.95% of the rivaroxaban-treated group and 8.79% of the placebo group (hazard ratio, 0.66; 95% confidence interval, 0.40-1.09; P = .101). However, a total of 177 patients (43.7%) stopped rivaroxaban earlier than 180 days, and likewise, 203 patients (50.2%) stopped placebo early.

In a prespecified secondary analysis looking just at the period of time when patients were actually taking rivaroxaban or placebo, rivaroxaban did significantly reduce risk of VTE or VTE-related death, Dr. Khorana said. The composite endpoint occurred in 2.62% of the rivaroxaban patients and 6.41% of placebo patients in that on-treatment analysis (HR, 0.40; 95% CI, 0.20-0.80; P = .007).

Rates of major bleeding and clinically relevant nonmajor bleeding were not significantly different between groups, according to results of a safety analysis. Major bleeding occurred in eight rivaroxaban patients and four placebo patients, or 1.98% and 0.99%, respectively (P = .265).

CASSINI was sponsored by Bayer and Janssen. Dr. Khorana reported disclosures related to Janssen, Bayer, PAREXEL, Sanofi, Pfizer, TriSalus Life Sciences, Halozyme, Seattle Genetics, AngioDynamics, and others.

SAN DIEGO – Prophylaxis with rivaroxaban significantly reduced the rate of venous thromboembolism and associated death in high-risk ambulatory cancer patients receiving systemic therapy, results of a randomized trial show.

The reduction in venous thromboembolism (VTE) or VTE-related death was not statistically significant in the primary analysis, in part because a large proportion of patients stopped taking the direct oral anticoagulant, according to investigator Alok A. Khorana, MD, of the Cleveland Clinic.

However, the reduction in events was significant in a prespecified secondary analysis limited to the on-treatment period, Dr. Khorana reported at the annual meeting of the American Society of Hematology, adding that rates of major and nonmajor bleeding were low.

Results are “eagerly awaited” from a different prophylaxis trial – the AVERT study – looking at another direct oral anticoagulant in high-risk cancer patients, Dr. Khorana said in a late-breaking abstracts session.

“If the findings of that trial are consistent with ours, then we certainly hope that these findings should inform future recommendations regarding thromboprophylaxis for high-risk ambulatory cancer patients, and then the landscape of anticoagulation in the cancer population should start to shift from management of events to primary prevention,” he said.

In the study by Dr. Khorana and his colleagues, known as CASSINI, 841 patients with various solid tumors and lymphomas were randomized to either rivaroxaban 10 mg or placebo once daily. The patients, enrolled at 143 study centers in 11 countries, all had a Khorana risk score of 2 or greater.

In the primary analysis period of 180 days, the composite endpoint of VTE or VTE-related death occurred in 5.95% of the rivaroxaban-treated group and 8.79% of the placebo group (hazard ratio, 0.66; 95% confidence interval, 0.40-1.09; P = .101). However, a total of 177 patients (43.7%) stopped rivaroxaban earlier than 180 days, and likewise, 203 patients (50.2%) stopped placebo early.

In a prespecified secondary analysis looking just at the period of time when patients were actually taking rivaroxaban or placebo, rivaroxaban did significantly reduce risk of VTE or VTE-related death, Dr. Khorana said. The composite endpoint occurred in 2.62% of the rivaroxaban patients and 6.41% of placebo patients in that on-treatment analysis (HR, 0.40; 95% CI, 0.20-0.80; P = .007).

Rates of major bleeding and clinically relevant nonmajor bleeding were not significantly different between groups, according to results of a safety analysis. Major bleeding occurred in eight rivaroxaban patients and four placebo patients, or 1.98% and 0.99%, respectively (P = .265).

CASSINI was sponsored by Bayer and Janssen. Dr. Khorana reported disclosures related to Janssen, Bayer, PAREXEL, Sanofi, Pfizer, TriSalus Life Sciences, Halozyme, Seattle Genetics, AngioDynamics, and others.

SAN DIEGO – Prophylaxis with rivaroxaban significantly reduced the rate of venous thromboembolism and associated death in high-risk ambulatory cancer patients receiving systemic therapy, results of a randomized trial show.

The reduction in venous thromboembolism (VTE) or VTE-related death was not statistically significant in the primary analysis, in part because a large proportion of patients stopped taking the direct oral anticoagulant, according to investigator Alok A. Khorana, MD, of the Cleveland Clinic.

However, the reduction in events was significant in a prespecified secondary analysis limited to the on-treatment period, Dr. Khorana reported at the annual meeting of the American Society of Hematology, adding that rates of major and nonmajor bleeding were low.

Results are “eagerly awaited” from a different prophylaxis trial – the AVERT study – looking at another direct oral anticoagulant in high-risk cancer patients, Dr. Khorana said in a late-breaking abstracts session.

“If the findings of that trial are consistent with ours, then we certainly hope that these findings should inform future recommendations regarding thromboprophylaxis for high-risk ambulatory cancer patients, and then the landscape of anticoagulation in the cancer population should start to shift from management of events to primary prevention,” he said.

In the study by Dr. Khorana and his colleagues, known as CASSINI, 841 patients with various solid tumors and lymphomas were randomized to either rivaroxaban 10 mg or placebo once daily. The patients, enrolled at 143 study centers in 11 countries, all had a Khorana risk score of 2 or greater.

In the primary analysis period of 180 days, the composite endpoint of VTE or VTE-related death occurred in 5.95% of the rivaroxaban-treated group and 8.79% of the placebo group (hazard ratio, 0.66; 95% confidence interval, 0.40-1.09; P = .101). However, a total of 177 patients (43.7%) stopped rivaroxaban earlier than 180 days, and likewise, 203 patients (50.2%) stopped placebo early.

In a prespecified secondary analysis looking just at the period of time when patients were actually taking rivaroxaban or placebo, rivaroxaban did significantly reduce risk of VTE or VTE-related death, Dr. Khorana said. The composite endpoint occurred in 2.62% of the rivaroxaban patients and 6.41% of placebo patients in that on-treatment analysis (HR, 0.40; 95% CI, 0.20-0.80; P = .007).

Rates of major bleeding and clinically relevant nonmajor bleeding were not significantly different between groups, according to results of a safety analysis. Major bleeding occurred in eight rivaroxaban patients and four placebo patients, or 1.98% and 0.99%, respectively (P = .265).

CASSINI was sponsored by Bayer and Janssen. Dr. Khorana reported disclosures related to Janssen, Bayer, PAREXEL, Sanofi, Pfizer, TriSalus Life Sciences, Halozyme, Seattle Genetics, AngioDynamics, and others.

SAN ANTONIO – New life for old medicine: Women aged under 75 years with breast intraepithelial neoplasms (IEN) who took tamoxifen for 3 years at a dose of 5 mg per day – one-fourth the standard dose – had a 50% reduction in risk of IEN recurrence and an even more remarkable 75% reduction in the risk of contralateral breast cancer, compared with women who took placebos in the TAMO1 study.

Despite concerns about the known side effects of tamoxifen, there were no significant differences in either the rate of endometrial cancer or of deep vein thrombosis/pulmonary embolism between groups, and there was only a borderline increase in hot flashes among patients randomized to tamoxifen, reported Dr. Andrea De Censi, MD, from Ospedali Galliera in Genoa, Italy.

In a video interview, Dr. De Censi discusses how tamoxifen, a decades-old, inexpensive drug still offers real clinical benefit in day-to-day practice for patients with IEN.

The TAM01 study was supported by the Italian Ministry of Health, Italian Association for Cancer Research, and the Italian League Against Cancer. Dr. De Censi and his coauthors reported having no direct conflicts of interest.

SAN ANTONIO – New life for old medicine: Women aged under 75 years with breast intraepithelial neoplasms (IEN) who took tamoxifen for 3 years at a dose of 5 mg per day – one-fourth the standard dose – had a 50% reduction in risk of IEN recurrence and an even more remarkable 75% reduction in the risk of contralateral breast cancer, compared with women who took placebos in the TAMO1 study.

Despite concerns about the known side effects of tamoxifen, there were no significant differences in either the rate of endometrial cancer or of deep vein thrombosis/pulmonary embolism between groups, and there was only a borderline increase in hot flashes among patients randomized to tamoxifen, reported Dr. Andrea De Censi, MD, from Ospedali Galliera in Genoa, Italy.

In a video interview, Dr. De Censi discusses how tamoxifen, a decades-old, inexpensive drug still offers real clinical benefit in day-to-day practice for patients with IEN.

The TAM01 study was supported by the Italian Ministry of Health, Italian Association for Cancer Research, and the Italian League Against Cancer. Dr. De Censi and his coauthors reported having no direct conflicts of interest.

SAN ANTONIO – New life for old medicine: Women aged under 75 years with breast intraepithelial neoplasms (IEN) who took tamoxifen for 3 years at a dose of 5 mg per day – one-fourth the standard dose – had a 50% reduction in risk of IEN recurrence and an even more remarkable 75% reduction in the risk of contralateral breast cancer, compared with women who took placebos in the TAMO1 study.

Despite concerns about the known side effects of tamoxifen, there were no significant differences in either the rate of endometrial cancer or of deep vein thrombosis/pulmonary embolism between groups, and there was only a borderline increase in hot flashes among patients randomized to tamoxifen, reported Dr. Andrea De Censi, MD, from Ospedali Galliera in Genoa, Italy.

In a video interview, Dr. De Censi discusses how tamoxifen, a decades-old, inexpensive drug still offers real clinical benefit in day-to-day practice for patients with IEN.

The TAM01 study was supported by the Italian Ministry of Health, Italian Association for Cancer Research, and the Italian League Against Cancer. Dr. De Censi and his coauthors reported having no direct conflicts of interest.

SAN DIEGO – The chimeric antigen receptor (CAR) T-cell therapy LCAR-B38M is in the race for approval in multiple myeloma following encouraging phase 1 results reported at the annual meeting of the American Society of Hematology.

In the LEGEND-2 phase 1/2 open study of 57 patients with advanced relapsed/refractory multiple myeloma treated with the investigational CAR T therapy, the overall response rate was 88% and the complete response rate was 74%. Among 42 patients who achieved complete response, 39 (68%) were negative for minimal residual disease (MRD).

With a median follow-up of 12 months, the median duration of response was 16 months and progression-free survival was 15 months. But in patients who achieved MRD-negative complete response, the median progression-free survival was extended to 24 months.

Pyrexia and cytokine release syndrome were reported in 90% or more of patients. Thrombocytopenia and leukopenia were reported in nearly half of patients.

The phase 1 study was conducted by researchers from the Second Affiliated Hospital of Xi’an Jiaotong University in Xi’an, China. The B-cell maturation antigen (BCMA)–directed CAR T-cell therapy is being jointly developed by Nanjing Legend Biotech and Janssen. A phase 2 study is currently being planned in China for LCAR-B38M. In parallel, Janssen and Legend are enrolling patients in a phase 1b/2 trial of the agent (also known as JNJ-68284528) in the United States.

The therapy joins a growing field of anti-BCMA CAR T-cell agents with promising initial trial results, including bb2121.

In a video interview at ASH, Sen Zhuang, MD, PhD, vice president of oncology clinical development at Janssen Research & Development, said this class of CAR T agents offers the potential for “very long remissions” and possibly even a “cure” for myeloma.

The LEGEND-2 study is sponsored by Nanjing Legend Biotech and two of the investigators reported employment with the company.

[email protected]

SAN DIEGO – The chimeric antigen receptor (CAR) T-cell therapy LCAR-B38M is in the race for approval in multiple myeloma following encouraging phase 1 results reported at the annual meeting of the American Society of Hematology.

In the LEGEND-2 phase 1/2 open study of 57 patients with advanced relapsed/refractory multiple myeloma treated with the investigational CAR T therapy, the overall response rate was 88% and the complete response rate was 74%. Among 42 patients who achieved complete response, 39 (68%) were negative for minimal residual disease (MRD).

With a median follow-up of 12 months, the median duration of response was 16 months and progression-free survival was 15 months. But in patients who achieved MRD-negative complete response, the median progression-free survival was extended to 24 months.

Pyrexia and cytokine release syndrome were reported in 90% or more of patients. Thrombocytopenia and leukopenia were reported in nearly half of patients.

The phase 1 study was conducted by researchers from the Second Affiliated Hospital of Xi’an Jiaotong University in Xi’an, China. The B-cell maturation antigen (BCMA)–directed CAR T-cell therapy is being jointly developed by Nanjing Legend Biotech and Janssen. A phase 2 study is currently being planned in China for LCAR-B38M. In parallel, Janssen and Legend are enrolling patients in a phase 1b/2 trial of the agent (also known as JNJ-68284528) in the United States.

The therapy joins a growing field of anti-BCMA CAR T-cell agents with promising initial trial results, including bb2121.

In a video interview at ASH, Sen Zhuang, MD, PhD, vice president of oncology clinical development at Janssen Research & Development, said this class of CAR T agents offers the potential for “very long remissions” and possibly even a “cure” for myeloma.

The LEGEND-2 study is sponsored by Nanjing Legend Biotech and two of the investigators reported employment with the company.

[email protected]

SAN DIEGO – The chimeric antigen receptor (CAR) T-cell therapy LCAR-B38M is in the race for approval in multiple myeloma following encouraging phase 1 results reported at the annual meeting of the American Society of Hematology.

In the LEGEND-2 phase 1/2 open study of 57 patients with advanced relapsed/refractory multiple myeloma treated with the investigational CAR T therapy, the overall response rate was 88% and the complete response rate was 74%. Among 42 patients who achieved complete response, 39 (68%) were negative for minimal residual disease (MRD).

With a median follow-up of 12 months, the median duration of response was 16 months and progression-free survival was 15 months. But in patients who achieved MRD-negative complete response, the median progression-free survival was extended to 24 months.

Pyrexia and cytokine release syndrome were reported in 90% or more of patients. Thrombocytopenia and leukopenia were reported in nearly half of patients.

The phase 1 study was conducted by researchers from the Second Affiliated Hospital of Xi’an Jiaotong University in Xi’an, China. The B-cell maturation antigen (BCMA)–directed CAR T-cell therapy is being jointly developed by Nanjing Legend Biotech and Janssen. A phase 2 study is currently being planned in China for LCAR-B38M. In parallel, Janssen and Legend are enrolling patients in a phase 1b/2 trial of the agent (also known as JNJ-68284528) in the United States.

The therapy joins a growing field of anti-BCMA CAR T-cell agents with promising initial trial results, including bb2121.

In a video interview at ASH, Sen Zhuang, MD, PhD, vice president of oncology clinical development at Janssen Research & Development, said this class of CAR T agents offers the potential for “very long remissions” and possibly even a “cure” for myeloma.

The LEGEND-2 study is sponsored by Nanjing Legend Biotech and two of the investigators reported employment with the company.

[email protected]

SAN DIEGO – It was banner year for new hematology drug approvals, according to R. Angelo de Claro, MD, of the Food and Drug Administration.

So far in 2018 there have been 32 new malignant hematology and nonmalignant hematology drug approvals by the FDA, including 12 first-time approvals, 5 new biosimilars, and 15 new indications for previously approved drugs, Dr. de Claro, clinical team leader in the FDA’s division of hematology products in Silver Spring, Md., said during an overview of the approvals at the annual meeting of the American Society of Hematology.

These include six new approvals for first-line treatment, and eight for pediatric indications, he said.

Highlights were discussed at two ASH-FDA joint symposia at the meeting, including one focused on the malignant hematology approvals, and another on the nonmalignant hematology approvals. In a video interview, Dr. de Claro provides some additional insight into their importance and about what might lie ahead.

“I think what’s exciting is that you have drug development occurring in more common conditions such as chronic lymphocytic leukemia, as well as in rare conditions, including hairy cell leukemia – and the first-ever approval in hemophagocytic lymphohistiocytosis,” he said. “It’s been very busy at the FDA; stay tuned ... the year’s not done yet. There could be more coming and we certainly anticipate more applications in the future.”

Dr. de Claro is an FDA employee. He reported having no other relevant disclosures.

[email protected]

SAN DIEGO – It was banner year for new hematology drug approvals, according to R. Angelo de Claro, MD, of the Food and Drug Administration.

So far in 2018 there have been 32 new malignant hematology and nonmalignant hematology drug approvals by the FDA, including 12 first-time approvals, 5 new biosimilars, and 15 new indications for previously approved drugs, Dr. de Claro, clinical team leader in the FDA’s division of hematology products in Silver Spring, Md., said during an overview of the approvals at the annual meeting of the American Society of Hematology.

These include six new approvals for first-line treatment, and eight for pediatric indications, he said.

Highlights were discussed at two ASH-FDA joint symposia at the meeting, including one focused on the malignant hematology approvals, and another on the nonmalignant hematology approvals. In a video interview, Dr. de Claro provides some additional insight into their importance and about what might lie ahead.

“I think what’s exciting is that you have drug development occurring in more common conditions such as chronic lymphocytic leukemia, as well as in rare conditions, including hairy cell leukemia – and the first-ever approval in hemophagocytic lymphohistiocytosis,” he said. “It’s been very busy at the FDA; stay tuned ... the year’s not done yet. There could be more coming and we certainly anticipate more applications in the future.”

Dr. de Claro is an FDA employee. He reported having no other relevant disclosures.

[email protected]

SAN DIEGO – It was banner year for new hematology drug approvals, according to R. Angelo de Claro, MD, of the Food and Drug Administration.

So far in 2018 there have been 32 new malignant hematology and nonmalignant hematology drug approvals by the FDA, including 12 first-time approvals, 5 new biosimilars, and 15 new indications for previously approved drugs, Dr. de Claro, clinical team leader in the FDA’s division of hematology products in Silver Spring, Md., said during an overview of the approvals at the annual meeting of the American Society of Hematology.

These include six new approvals for first-line treatment, and eight for pediatric indications, he said.

Highlights were discussed at two ASH-FDA joint symposia at the meeting, including one focused on the malignant hematology approvals, and another on the nonmalignant hematology approvals. In a video interview, Dr. de Claro provides some additional insight into their importance and about what might lie ahead.

“I think what’s exciting is that you have drug development occurring in more common conditions such as chronic lymphocytic leukemia, as well as in rare conditions, including hairy cell leukemia – and the first-ever approval in hemophagocytic lymphohistiocytosis,” he said. “It’s been very busy at the FDA; stay tuned ... the year’s not done yet. There could be more coming and we certainly anticipate more applications in the future.”

Dr. de Claro is an FDA employee. He reported having no other relevant disclosures.

[email protected]

SAN DIEGO – A recurrent mutation in BCL2, the therapeutic target of venetoclax (Venclexta), appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.

The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, said lead author Piers Blombery, MBBS, from the Peter MacCallum Cancer Center in Melbourne.

“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said in a late-breaking oral abstract session at the annual meeting of the American Society of Hematology.

The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” he added.

The paper was published online in Cancer Discovery (2018 Dec 4. doi: 10.1158/2159-8290.CD-18-1119) to coincide with the presentation at ASH.

Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.

To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.

In seven of the patients, they identified a novel mutation that showed up at the time of progression, but was absent from the pre-venetoclax samples. The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.

They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found that the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies. Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.

In other experiments, they determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and that in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage, compared with wild type cells.

Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.

“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.

In an interview, Dr. Blombery said that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.

The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.

SOURCE: Blombery P et al. ASH 2018, Abstract LBA-7.

SAN DIEGO – A recurrent mutation in BCL2, the therapeutic target of venetoclax (Venclexta), appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.

The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, said lead author Piers Blombery, MBBS, from the Peter MacCallum Cancer Center in Melbourne.

“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said in a late-breaking oral abstract session at the annual meeting of the American Society of Hematology.

The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” he added.

The paper was published online in Cancer Discovery (2018 Dec 4. doi: 10.1158/2159-8290.CD-18-1119) to coincide with the presentation at ASH.

Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.

To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.

In seven of the patients, they identified a novel mutation that showed up at the time of progression, but was absent from the pre-venetoclax samples. The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.

They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found that the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies. Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.

In other experiments, they determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and that in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage, compared with wild type cells.

Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.

“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.

In an interview, Dr. Blombery said that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.

The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.

SOURCE: Blombery P et al. ASH 2018, Abstract LBA-7.

SAN DIEGO – A recurrent mutation in BCL2, the therapeutic target of venetoclax (Venclexta), appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.

The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, said lead author Piers Blombery, MBBS, from the Peter MacCallum Cancer Center in Melbourne.

“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said in a late-breaking oral abstract session at the annual meeting of the American Society of Hematology.

The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” he added.

The paper was published online in Cancer Discovery (2018 Dec 4. doi: 10.1158/2159-8290.CD-18-1119) to coincide with the presentation at ASH.

Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.

To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.

In seven of the patients, they identified a novel mutation that showed up at the time of progression, but was absent from the pre-venetoclax samples. The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.

They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found that the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies. Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.

In other experiments, they determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and that in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage, compared with wild type cells.

Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.

“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.

In an interview, Dr. Blombery said that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.

The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.

SOURCE: Blombery P et al. ASH 2018, Abstract LBA-7.

SAN DIEGO – In an ongoing phase 1 study, the oral FMS-like tyrosine kinase 3 (FLT3)/AXL inhibitor gilteritinib produced a response rate of more than 90% in newly diagnosed patients with acute myeloid leukemia (AML) with a FLT3 mutation.

The dose escalation/expansion study coupled the oral agent with induction and consolidation chemotherapy and was aimed at establishing the dosing and safety of gilteritinib.

The findings – reported at the annual meeting of the American Society of Hematology – mean that the FLT3 inhibitor will next be compared with the current standard of care, which has a 60%-65% remission rate, according to Keith W. Pratz, MD, of Johns Hopkins University in Baltimore.

“The later-phase clinical studies that we will be doing with gilteritinib will look to compare midostaurin-based chemotherapy with gilteritinib and looking for outcomes, with hopes of improving upon this 60%-65% remission rate,” Dr. Pratz said in a video interview.

Gilteritinib was recently approved by the Food and Drug Administration for relapsed/refractory AML patients with FLT3 mutations.

Dr. Pratz said the approval will provide a needed new treatment option in that patient population, which has had a low response rate to conventional therapy, in the range of 10%-15%.

“There really wasn’t a standard approved therapy prior to this and this will be what is given to most patients who have a FLT3 mutation and relapse,” he said.

Dr. Pratz reported consultancy and research funding from Astellas, which markets gilteritinib, as well as other companies.

[email protected]

SAN DIEGO – In an ongoing phase 1 study, the oral FMS-like tyrosine kinase 3 (FLT3)/AXL inhibitor gilteritinib produced a response rate of more than 90% in newly diagnosed patients with acute myeloid leukemia (AML) with a FLT3 mutation.

The dose escalation/expansion study coupled the oral agent with induction and consolidation chemotherapy and was aimed at establishing the dosing and safety of gilteritinib.

The findings – reported at the annual meeting of the American Society of Hematology – mean that the FLT3 inhibitor will next be compared with the current standard of care, which has a 60%-65% remission rate, according to Keith W. Pratz, MD, of Johns Hopkins University in Baltimore.

“The later-phase clinical studies that we will be doing with gilteritinib will look to compare midostaurin-based chemotherapy with gilteritinib and looking for outcomes, with hopes of improving upon this 60%-65% remission rate,” Dr. Pratz said in a video interview.

Gilteritinib was recently approved by the Food and Drug Administration for relapsed/refractory AML patients with FLT3 mutations.

Dr. Pratz said the approval will provide a needed new treatment option in that patient population, which has had a low response rate to conventional therapy, in the range of 10%-15%.

“There really wasn’t a standard approved therapy prior to this and this will be what is given to most patients who have a FLT3 mutation and relapse,” he said.

Dr. Pratz reported consultancy and research funding from Astellas, which markets gilteritinib, as well as other companies.

[email protected]

SAN DIEGO – In an ongoing phase 1 study, the oral FMS-like tyrosine kinase 3 (FLT3)/AXL inhibitor gilteritinib produced a response rate of more than 90% in newly diagnosed patients with acute myeloid leukemia (AML) with a FLT3 mutation.

The dose escalation/expansion study coupled the oral agent with induction and consolidation chemotherapy and was aimed at establishing the dosing and safety of gilteritinib.

The findings – reported at the annual meeting of the American Society of Hematology – mean that the FLT3 inhibitor will next be compared with the current standard of care, which has a 60%-65% remission rate, according to Keith W. Pratz, MD, of Johns Hopkins University in Baltimore.

“The later-phase clinical studies that we will be doing with gilteritinib will look to compare midostaurin-based chemotherapy with gilteritinib and looking for outcomes, with hopes of improving upon this 60%-65% remission rate,” Dr. Pratz said in a video interview.

Gilteritinib was recently approved by the Food and Drug Administration for relapsed/refractory AML patients with FLT3 mutations.

Dr. Pratz said the approval will provide a needed new treatment option in that patient population, which has had a low response rate to conventional therapy, in the range of 10%-15%.

“There really wasn’t a standard approved therapy prior to this and this will be what is given to most patients who have a FLT3 mutation and relapse,” he said.

Dr. Pratz reported consultancy and research funding from Astellas, which markets gilteritinib, as well as other companies.

[email protected]

San Diego – In patients with atrial fibrillation who had direct oral anticoagulant (DOAC) interruption for an elective surgery, a simple and standardized management strategy yielded low rates of bleeding and thromboembolism, according to results of a prospective study of more than 3,000 patients.

Rates of major bleeding were less than 2% and rates of arterial thromboembolism were less than 1% in patients managed in accordance with the strategy, which foregoes heparin bridging and preoperative coagulation testing, according to investigator James D. Douketis, MD, of St. Joseph’s Healthcare and McMaster University, Hamilton, Ont.

“This is the first study to demonstrate the safety of a standardized perioperative management approach in a patients with atrial fibrillation who are taking a DOAC, and we hope will establish a standard and will have an effect on our clinical practice guidelines,” Dr. Douketis said during a press briefing at the annual meeting of the American Society of Hematology.

This trial offers the “most definitive evidence to date” that atrial fibrillation patients can – in an organized fashion based on bleeding risk – safely stop taking DOACs, said Mark Crowther, MD, chair and professor of medicine at McMaster University.

“This study will almost instantaneously establish a treatment practice and a treatment standard for the vast number of patients in North America and around the world who take these drugs,” added Dr. Crowther, who moderated the press briefing.

The PAUSE study included three parallel cohorts of atrial fibrillation patients taking DOACs (apixaban, dabigatran, or rivaroxaban) who required anticoagulant interruption for an elective surgery or procedure.

The DOAC interruptions were done using standardized protocols based on the pharmacokinetic properties of each DOAC, procedure-associated bleeding risk, and creatinine clearance, the investigators reported.

The interruptions occurred 1 day before and after low bleeding risk surgeries, and 2 days before and after high bleeding risk surgeries, while longer interruptions were used in patients receiving dabigatran who had a creatinine clearance below 50 mL/min.

A total of 3,007 patients at 23 sites in Canada, the United States, and Europe were managed by this approach in the PAUSE study – 1,257 patients receiving apixaban, 668 receiving dabigatran, and 1,082 receiving rivaroxaban – and were evaluated weekly for 30 days post-procedure.

PAUSE is the largest study to date that addresses how to manage the common problem of perioperative DOAC management. It is likely to have a practice-changing impact and will inform future practice guidelines in perioperative care.

The 30-day postoperative rate of major bleeding was low, according to investigators, at 1.35% (95% confidence interval, 0-2.00%) for apixaban, 0.90% (95% CI, 0-1.73%) for dabigatran, and 1.85% (95% CI, 0-2.65%) for rivaroxaban, Dr. Douketis reported.

Likewise, the rate of arterial thromboembolism was low at 0.16% (95% CI, 0-0.48%) for apixaban, 0.6% (95% CI, 0-1.33%) for dabigatran, and 0.37% (95% CI, 0-0.82%) for rivaroxaban, he said.

Most patients (greater than 90%) had minimal to no residual DOAC levels at the time of surgery, the investigator added.

The study was funded by the Canadian Institutes of Health Research and the H&S Foundation of Canada. Dr. Douketis reported disclosures related to Janssen, which makes rivaroxaban; Boehringer-Ingelheim, which makes dabigatran; and other companies. Dr. Crowther reported financial relationships with Bristol-Myers Squibb and other companies.

SOURCE: Douketis J et al. ASH 2018, Abstract LBA-5.

San Diego – In patients with atrial fibrillation who had direct oral anticoagulant (DOAC) interruption for an elective surgery, a simple and standardized management strategy yielded low rates of bleeding and thromboembolism, according to results of a prospective study of more than 3,000 patients.

Rates of major bleeding were less than 2% and rates of arterial thromboembolism were less than 1% in patients managed in accordance with the strategy, which foregoes heparin bridging and preoperative coagulation testing, according to investigator James D. Douketis, MD, of St. Joseph’s Healthcare and McMaster University, Hamilton, Ont.

“This is the first study to demonstrate the safety of a standardized perioperative management approach in a patients with atrial fibrillation who are taking a DOAC, and we hope will establish a standard and will have an effect on our clinical practice guidelines,” Dr. Douketis said during a press briefing at the annual meeting of the American Society of Hematology.

This trial offers the “most definitive evidence to date” that atrial fibrillation patients can – in an organized fashion based on bleeding risk – safely stop taking DOACs, said Mark Crowther, MD, chair and professor of medicine at McMaster University.

“This study will almost instantaneously establish a treatment practice and a treatment standard for the vast number of patients in North America and around the world who take these drugs,” added Dr. Crowther, who moderated the press briefing.

The PAUSE study included three parallel cohorts of atrial fibrillation patients taking DOACs (apixaban, dabigatran, or rivaroxaban) who required anticoagulant interruption for an elective surgery or procedure.

The DOAC interruptions were done using standardized protocols based on the pharmacokinetic properties of each DOAC, procedure-associated bleeding risk, and creatinine clearance, the investigators reported.

The interruptions occurred 1 day before and after low bleeding risk surgeries, and 2 days before and after high bleeding risk surgeries, while longer interruptions were used in patients receiving dabigatran who had a creatinine clearance below 50 mL/min.

A total of 3,007 patients at 23 sites in Canada, the United States, and Europe were managed by this approach in the PAUSE study – 1,257 patients receiving apixaban, 668 receiving dabigatran, and 1,082 receiving rivaroxaban – and were evaluated weekly for 30 days post-procedure.

PAUSE is the largest study to date that addresses how to manage the common problem of perioperative DOAC management. It is likely to have a practice-changing impact and will inform future practice guidelines in perioperative care.

The 30-day postoperative rate of major bleeding was low, according to investigators, at 1.35% (95% confidence interval, 0-2.00%) for apixaban, 0.90% (95% CI, 0-1.73%) for dabigatran, and 1.85% (95% CI, 0-2.65%) for rivaroxaban, Dr. Douketis reported.

Likewise, the rate of arterial thromboembolism was low at 0.16% (95% CI, 0-0.48%) for apixaban, 0.6% (95% CI, 0-1.33%) for dabigatran, and 0.37% (95% CI, 0-0.82%) for rivaroxaban, he said.

Most patients (greater than 90%) had minimal to no residual DOAC levels at the time of surgery, the investigator added.

The study was funded by the Canadian Institutes of Health Research and the H&S Foundation of Canada. Dr. Douketis reported disclosures related to Janssen, which makes rivaroxaban; Boehringer-Ingelheim, which makes dabigatran; and other companies. Dr. Crowther reported financial relationships with Bristol-Myers Squibb and other companies.

SOURCE: Douketis J et al. ASH 2018, Abstract LBA-5.

San Diego – In patients with atrial fibrillation who had direct oral anticoagulant (DOAC) interruption for an elective surgery, a simple and standardized management strategy yielded low rates of bleeding and thromboembolism, according to results of a prospective study of more than 3,000 patients.

Rates of major bleeding were less than 2% and rates of arterial thromboembolism were less than 1% in patients managed in accordance with the strategy, which foregoes heparin bridging and preoperative coagulation testing, according to investigator James D. Douketis, MD, of St. Joseph’s Healthcare and McMaster University, Hamilton, Ont.

“This is the first study to demonstrate the safety of a standardized perioperative management approach in a patients with atrial fibrillation who are taking a DOAC, and we hope will establish a standard and will have an effect on our clinical practice guidelines,” Dr. Douketis said during a press briefing at the annual meeting of the American Society of Hematology.

This trial offers the “most definitive evidence to date” that atrial fibrillation patients can – in an organized fashion based on bleeding risk – safely stop taking DOACs, said Mark Crowther, MD, chair and professor of medicine at McMaster University.

“This study will almost instantaneously establish a treatment practice and a treatment standard for the vast number of patients in North America and around the world who take these drugs,” added Dr. Crowther, who moderated the press briefing.

The PAUSE study included three parallel cohorts of atrial fibrillation patients taking DOACs (apixaban, dabigatran, or rivaroxaban) who required anticoagulant interruption for an elective surgery or procedure.

The DOAC interruptions were done using standardized protocols based on the pharmacokinetic properties of each DOAC, procedure-associated bleeding risk, and creatinine clearance, the investigators reported.

The interruptions occurred 1 day before and after low bleeding risk surgeries, and 2 days before and after high bleeding risk surgeries, while longer interruptions were used in patients receiving dabigatran who had a creatinine clearance below 50 mL/min.

A total of 3,007 patients at 23 sites in Canada, the United States, and Europe were managed by this approach in the PAUSE study – 1,257 patients receiving apixaban, 668 receiving dabigatran, and 1,082 receiving rivaroxaban – and were evaluated weekly for 30 days post-procedure.

PAUSE is the largest study to date that addresses how to manage the common problem of perioperative DOAC management. It is likely to have a practice-changing impact and will inform future practice guidelines in perioperative care.

The 30-day postoperative rate of major bleeding was low, according to investigators, at 1.35% (95% confidence interval, 0-2.00%) for apixaban, 0.90% (95% CI, 0-1.73%) for dabigatran, and 1.85% (95% CI, 0-2.65%) for rivaroxaban, Dr. Douketis reported.

Likewise, the rate of arterial thromboembolism was low at 0.16% (95% CI, 0-0.48%) for apixaban, 0.6% (95% CI, 0-1.33%) for dabigatran, and 0.37% (95% CI, 0-0.82%) for rivaroxaban, he said.

Most patients (greater than 90%) had minimal to no residual DOAC levels at the time of surgery, the investigator added.

The study was funded by the Canadian Institutes of Health Research and the H&S Foundation of Canada. Dr. Douketis reported disclosures related to Janssen, which makes rivaroxaban; Boehringer-Ingelheim, which makes dabigatran; and other companies. Dr. Crowther reported financial relationships with Bristol-Myers Squibb and other companies.

SOURCE: Douketis J et al. ASH 2018, Abstract LBA-5.