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KTE-X19 induces durable CRs, MRD negativity in ALL
SAN DIEGO—An update of the ZUMA-3 trial showed that KTE-X19—an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy—can induce high rates of undetectable minimal residual disease (MRD) and durable complete remissions (CRs) in adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).
And this was particularly the case at the middle dose level of 1 x 106 cells/kg.
William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, presented the update at the 2018 ASH Annual Meeting (abstract 897*).
Dr. Wierda explained that KTE-X19 is a new name for KTE-C19, also known as axicabtagene ciloleucel (Yescarta™), which is currently approved in the United States for the treatment of relapsed diffuse large B-cell lymphoma in adults and in Europe for diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma.
“This approval was based on the ZUMA-1 clinical trial,” he said, “which showed a 54% complete remission rate and 82% overall response rate with durable remissions.”
ZUMA-3 (NCT02614066) is a phase 1/2 study of KTE-X19—a CAR T cell with CD3ζ signaling and CD28 costimulatory domains—for relapsed or refractory adults with ALL.
Dr. Wierda presented the phase 1 data available at the cutoff of August 16.
Study design
Patients underwent leukapheresis to collect their T cells for production and received bridging therapy selected by the treating physician from several prespecified regimens to maintain disease control.
Conditioning chemotherapy included fludarabine at 25 mg/m2 on days -4, -3, and -2 and cyclophosphamide at 900 mg/m2 on day -2.
Patients received KTE-X19 on day 0. They were monitored and released from the hospital on day 7 or upon resolution of any toxicities.
The investigators assessed response, including bone marrow evaluation, on day 28, week 8, month 3, and every 3 months for the first year as well as every 6 months for the second year of follow-up.
The dose-finding portion of the trial initially enrolled three patients. They received a dose of 2 x 106 CAR T cells/kg and were monitored for dose-limiting toxicities (DLTs).
If there were no DLTs in the first three patients, phase 2 could open or investigators could further expand the 2 x 106 dose level or explore lower doses of the product (1 x 106 cells/kg and 0.5 x 106 cells/kg).
Investigators defined DLTs as:
- KTE-X19-related events in the first 28 days, including grade 4 hematologic toxicity lasting more than 30 days and not attributable to ALL
- Grade 3 nonhematologic toxicities lasting more than 7 days
- Grade 4 nonhematologic toxicities regardless of duration, excluding grade 4 cytokine release syndrome (CRS) events lasting 7 days or less
- Neurologic events that resolve to grade 1 in 2 weeks or to baseline within 4 weeks.
Dr. Wierda said no DLTs occurred among the first 3 patients treated, and all dose levels were explored in phase 1.
Patients
As of the cutoff date, 54 patients were enrolled, confirmed eligible, and underwent leukapheresis. Six patients did not receive conditioning, three patients received conditioning but not KTE-X19, and one patient withdrew from the study after the first failed production of CAR T cells.
So 44 patients received KTE-X19. Six patients received the highest dose of CAR T cells (2 x 106/kg), 22 received the middle dose (1 x 106/kg), and 16 received the lowest dose (0.5 x 106/kg).
The patients’ median age was 46 (range, 18 – 77). Almost half (48%) were male, and 68% had three or more prior treatment regimens. Forty-one percent had prior blinatumomab, and 14% had prior inotuzumab.
Patients had a median bone marrow blast percentage of 59% (n=44; range, 5% - 100%) at screening and 70% (n=40; range, 0 – 97%) prior to conditioning but after bridging therapy.
The safety analysis included all 44 treated patients, and the efficacy analysis included 36 patients.
“[T]he follow-up period was too short from dosing for the most recently treated eight patients,” Dr Wierda explained.
The median follow-up was 15.1 months for the 36 efficacy-evaluable patients.
Safety
All patients had a treatment-emergent adverse events (TEAEs), with 75% having grade 3/4 events.
Grade 5 TEAEs included three due to progressive disease, three due to infections, and one stroke 6 weeks after infusion.
Two patients died of KTE-X19-related AEs. One patient in the 2 x 106 dose group had multiorgan failure secondary to CRS on study day 6. The other patient, in the 0.5 x 106 dose group, had a stroke after infusion in the context of CRS and neurologic events (NEs) on day 7.
Investigators detected a higher incidence of grade 3 and greater CRS for the six patients treated at the highest dose. Half developed CRS of grade 3 or higher, compared with 18% in the 1 x 106 dose cohort and 19% in the 0.5 x 106 dose cohort.
Grade 3 or higher NEs were more common than CRS. The lowest incidence occurred in the lowest dose cohort, at 25%, compared with 45% in the 1 x 106 dose cohort and 50% in the 2 x 106 dose cohort.
Due to the incidence of grade 3 and greater NEs observed in the 1 x 106 dose cohort, investigators revised the management guidelines for AEs. The revisions included using tocilizumab only for CRS—and not for NEs—and initiating steroids for grade 2 NEs instead of waiting for grade 3.
Eight patients were treated under the revised recommendations, and the incidence of grade 3 NEs was 13%, with no grade 4 or 5 NEs.
“This compared favorably with the 14 patients treated at the same dose level but prior to these changes," Dr. Wierda said.
In comparison, 57% developed grade 3 NEs and 7% grade 4 with the original AE management protocol.
The incidence of grade 3 CRS remained low, with no CRS events of grade 4 or greater with the revised recommendations.
Efficacy
The best overall response in the 36 efficacy-evaluable patients was 69% CR and CR with incomplete hematologic recovery (CRi).
Seventy-five percent of these patients had undetectable MRD in the bone marrow at 10-4 sensitivity at 3 months of follow-up.
All patients in the 1 x 106 dose cohort (n=14) responded. Ninety-three percent achieved a CR/CRi, 7% had a partial response, and all had undetectable MRD in the bone marrow.
The median duration of response was 12.9 months in the 1 x 106 cohort. This was the dose selected for the phase 2 trial, which is now enrolling patients.
ZUMA-3 was sponsored by Kite, a Gilead Company.
Dr. Wierda disclosed research funding from AbbVie and Genentech.
* Data in the abstract differ from the presentation.
SAN DIEGO—An update of the ZUMA-3 trial showed that KTE-X19—an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy—can induce high rates of undetectable minimal residual disease (MRD) and durable complete remissions (CRs) in adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).
And this was particularly the case at the middle dose level of 1 x 106 cells/kg.
William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, presented the update at the 2018 ASH Annual Meeting (abstract 897*).
Dr. Wierda explained that KTE-X19 is a new name for KTE-C19, also known as axicabtagene ciloleucel (Yescarta™), which is currently approved in the United States for the treatment of relapsed diffuse large B-cell lymphoma in adults and in Europe for diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma.
“This approval was based on the ZUMA-1 clinical trial,” he said, “which showed a 54% complete remission rate and 82% overall response rate with durable remissions.”
ZUMA-3 (NCT02614066) is a phase 1/2 study of KTE-X19—a CAR T cell with CD3ζ signaling and CD28 costimulatory domains—for relapsed or refractory adults with ALL.
Dr. Wierda presented the phase 1 data available at the cutoff of August 16.
Study design
Patients underwent leukapheresis to collect their T cells for production and received bridging therapy selected by the treating physician from several prespecified regimens to maintain disease control.
Conditioning chemotherapy included fludarabine at 25 mg/m2 on days -4, -3, and -2 and cyclophosphamide at 900 mg/m2 on day -2.
Patients received KTE-X19 on day 0. They were monitored and released from the hospital on day 7 or upon resolution of any toxicities.
The investigators assessed response, including bone marrow evaluation, on day 28, week 8, month 3, and every 3 months for the first year as well as every 6 months for the second year of follow-up.
The dose-finding portion of the trial initially enrolled three patients. They received a dose of 2 x 106 CAR T cells/kg and were monitored for dose-limiting toxicities (DLTs).
If there were no DLTs in the first three patients, phase 2 could open or investigators could further expand the 2 x 106 dose level or explore lower doses of the product (1 x 106 cells/kg and 0.5 x 106 cells/kg).
Investigators defined DLTs as:
- KTE-X19-related events in the first 28 days, including grade 4 hematologic toxicity lasting more than 30 days and not attributable to ALL
- Grade 3 nonhematologic toxicities lasting more than 7 days
- Grade 4 nonhematologic toxicities regardless of duration, excluding grade 4 cytokine release syndrome (CRS) events lasting 7 days or less
- Neurologic events that resolve to grade 1 in 2 weeks or to baseline within 4 weeks.
Dr. Wierda said no DLTs occurred among the first 3 patients treated, and all dose levels were explored in phase 1.
Patients
As of the cutoff date, 54 patients were enrolled, confirmed eligible, and underwent leukapheresis. Six patients did not receive conditioning, three patients received conditioning but not KTE-X19, and one patient withdrew from the study after the first failed production of CAR T cells.
So 44 patients received KTE-X19. Six patients received the highest dose of CAR T cells (2 x 106/kg), 22 received the middle dose (1 x 106/kg), and 16 received the lowest dose (0.5 x 106/kg).
The patients’ median age was 46 (range, 18 – 77). Almost half (48%) were male, and 68% had three or more prior treatment regimens. Forty-one percent had prior blinatumomab, and 14% had prior inotuzumab.
Patients had a median bone marrow blast percentage of 59% (n=44; range, 5% - 100%) at screening and 70% (n=40; range, 0 – 97%) prior to conditioning but after bridging therapy.
The safety analysis included all 44 treated patients, and the efficacy analysis included 36 patients.
“[T]he follow-up period was too short from dosing for the most recently treated eight patients,” Dr Wierda explained.
The median follow-up was 15.1 months for the 36 efficacy-evaluable patients.
Safety
All patients had a treatment-emergent adverse events (TEAEs), with 75% having grade 3/4 events.
Grade 5 TEAEs included three due to progressive disease, three due to infections, and one stroke 6 weeks after infusion.
Two patients died of KTE-X19-related AEs. One patient in the 2 x 106 dose group had multiorgan failure secondary to CRS on study day 6. The other patient, in the 0.5 x 106 dose group, had a stroke after infusion in the context of CRS and neurologic events (NEs) on day 7.
Investigators detected a higher incidence of grade 3 and greater CRS for the six patients treated at the highest dose. Half developed CRS of grade 3 or higher, compared with 18% in the 1 x 106 dose cohort and 19% in the 0.5 x 106 dose cohort.
Grade 3 or higher NEs were more common than CRS. The lowest incidence occurred in the lowest dose cohort, at 25%, compared with 45% in the 1 x 106 dose cohort and 50% in the 2 x 106 dose cohort.
Due to the incidence of grade 3 and greater NEs observed in the 1 x 106 dose cohort, investigators revised the management guidelines for AEs. The revisions included using tocilizumab only for CRS—and not for NEs—and initiating steroids for grade 2 NEs instead of waiting for grade 3.
Eight patients were treated under the revised recommendations, and the incidence of grade 3 NEs was 13%, with no grade 4 or 5 NEs.
“This compared favorably with the 14 patients treated at the same dose level but prior to these changes," Dr. Wierda said.
In comparison, 57% developed grade 3 NEs and 7% grade 4 with the original AE management protocol.
The incidence of grade 3 CRS remained low, with no CRS events of grade 4 or greater with the revised recommendations.
Efficacy
The best overall response in the 36 efficacy-evaluable patients was 69% CR and CR with incomplete hematologic recovery (CRi).
Seventy-five percent of these patients had undetectable MRD in the bone marrow at 10-4 sensitivity at 3 months of follow-up.
All patients in the 1 x 106 dose cohort (n=14) responded. Ninety-three percent achieved a CR/CRi, 7% had a partial response, and all had undetectable MRD in the bone marrow.
The median duration of response was 12.9 months in the 1 x 106 cohort. This was the dose selected for the phase 2 trial, which is now enrolling patients.
ZUMA-3 was sponsored by Kite, a Gilead Company.
Dr. Wierda disclosed research funding from AbbVie and Genentech.
* Data in the abstract differ from the presentation.
SAN DIEGO—An update of the ZUMA-3 trial showed that KTE-X19—an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy—can induce high rates of undetectable minimal residual disease (MRD) and durable complete remissions (CRs) in adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).
And this was particularly the case at the middle dose level of 1 x 106 cells/kg.
William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, presented the update at the 2018 ASH Annual Meeting (abstract 897*).
Dr. Wierda explained that KTE-X19 is a new name for KTE-C19, also known as axicabtagene ciloleucel (Yescarta™), which is currently approved in the United States for the treatment of relapsed diffuse large B-cell lymphoma in adults and in Europe for diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma.
“This approval was based on the ZUMA-1 clinical trial,” he said, “which showed a 54% complete remission rate and 82% overall response rate with durable remissions.”
ZUMA-3 (NCT02614066) is a phase 1/2 study of KTE-X19—a CAR T cell with CD3ζ signaling and CD28 costimulatory domains—for relapsed or refractory adults with ALL.
Dr. Wierda presented the phase 1 data available at the cutoff of August 16.
Study design
Patients underwent leukapheresis to collect their T cells for production and received bridging therapy selected by the treating physician from several prespecified regimens to maintain disease control.
Conditioning chemotherapy included fludarabine at 25 mg/m2 on days -4, -3, and -2 and cyclophosphamide at 900 mg/m2 on day -2.
Patients received KTE-X19 on day 0. They were monitored and released from the hospital on day 7 or upon resolution of any toxicities.
The investigators assessed response, including bone marrow evaluation, on day 28, week 8, month 3, and every 3 months for the first year as well as every 6 months for the second year of follow-up.
The dose-finding portion of the trial initially enrolled three patients. They received a dose of 2 x 106 CAR T cells/kg and were monitored for dose-limiting toxicities (DLTs).
If there were no DLTs in the first three patients, phase 2 could open or investigators could further expand the 2 x 106 dose level or explore lower doses of the product (1 x 106 cells/kg and 0.5 x 106 cells/kg).
Investigators defined DLTs as:
- KTE-X19-related events in the first 28 days, including grade 4 hematologic toxicity lasting more than 30 days and not attributable to ALL
- Grade 3 nonhematologic toxicities lasting more than 7 days
- Grade 4 nonhematologic toxicities regardless of duration, excluding grade 4 cytokine release syndrome (CRS) events lasting 7 days or less
- Neurologic events that resolve to grade 1 in 2 weeks or to baseline within 4 weeks.
Dr. Wierda said no DLTs occurred among the first 3 patients treated, and all dose levels were explored in phase 1.
Patients
As of the cutoff date, 54 patients were enrolled, confirmed eligible, and underwent leukapheresis. Six patients did not receive conditioning, three patients received conditioning but not KTE-X19, and one patient withdrew from the study after the first failed production of CAR T cells.
So 44 patients received KTE-X19. Six patients received the highest dose of CAR T cells (2 x 106/kg), 22 received the middle dose (1 x 106/kg), and 16 received the lowest dose (0.5 x 106/kg).
The patients’ median age was 46 (range, 18 – 77). Almost half (48%) were male, and 68% had three or more prior treatment regimens. Forty-one percent had prior blinatumomab, and 14% had prior inotuzumab.
Patients had a median bone marrow blast percentage of 59% (n=44; range, 5% - 100%) at screening and 70% (n=40; range, 0 – 97%) prior to conditioning but after bridging therapy.
The safety analysis included all 44 treated patients, and the efficacy analysis included 36 patients.
“[T]he follow-up period was too short from dosing for the most recently treated eight patients,” Dr Wierda explained.
The median follow-up was 15.1 months for the 36 efficacy-evaluable patients.
Safety
All patients had a treatment-emergent adverse events (TEAEs), with 75% having grade 3/4 events.
Grade 5 TEAEs included three due to progressive disease, three due to infections, and one stroke 6 weeks after infusion.
Two patients died of KTE-X19-related AEs. One patient in the 2 x 106 dose group had multiorgan failure secondary to CRS on study day 6. The other patient, in the 0.5 x 106 dose group, had a stroke after infusion in the context of CRS and neurologic events (NEs) on day 7.
Investigators detected a higher incidence of grade 3 and greater CRS for the six patients treated at the highest dose. Half developed CRS of grade 3 or higher, compared with 18% in the 1 x 106 dose cohort and 19% in the 0.5 x 106 dose cohort.
Grade 3 or higher NEs were more common than CRS. The lowest incidence occurred in the lowest dose cohort, at 25%, compared with 45% in the 1 x 106 dose cohort and 50% in the 2 x 106 dose cohort.
Due to the incidence of grade 3 and greater NEs observed in the 1 x 106 dose cohort, investigators revised the management guidelines for AEs. The revisions included using tocilizumab only for CRS—and not for NEs—and initiating steroids for grade 2 NEs instead of waiting for grade 3.
Eight patients were treated under the revised recommendations, and the incidence of grade 3 NEs was 13%, with no grade 4 or 5 NEs.
“This compared favorably with the 14 patients treated at the same dose level but prior to these changes," Dr. Wierda said.
In comparison, 57% developed grade 3 NEs and 7% grade 4 with the original AE management protocol.
The incidence of grade 3 CRS remained low, with no CRS events of grade 4 or greater with the revised recommendations.
Efficacy
The best overall response in the 36 efficacy-evaluable patients was 69% CR and CR with incomplete hematologic recovery (CRi).
Seventy-five percent of these patients had undetectable MRD in the bone marrow at 10-4 sensitivity at 3 months of follow-up.
All patients in the 1 x 106 dose cohort (n=14) responded. Ninety-three percent achieved a CR/CRi, 7% had a partial response, and all had undetectable MRD in the bone marrow.
The median duration of response was 12.9 months in the 1 x 106 cohort. This was the dose selected for the phase 2 trial, which is now enrolling patients.
ZUMA-3 was sponsored by Kite, a Gilead Company.
Dr. Wierda disclosed research funding from AbbVie and Genentech.
* Data in the abstract differ from the presentation.
We Asked, You Told Us
Dear Readers,
As 2018 draws to a close, Clinician Reviews is looking ahead to its 29th year of publication. In 1991, when our publication was founded, it was a unique idea to present information to both NPs and PAs together—a recognition of common educational needs and a unified focus on delivering the best possible patient care. For the past six years, as Editor, I have been privileged to ensure the fulfillment of CR’s editorial purpose—keeping NPs and PAs up to date on all aspects of clinical practice—while navigating changes both internal and external.
When CR started, personal computers existed but were not yet in widespread use (the office had one, to be shared). Manuscripts, peer reviews, even radiographs—all were submitted on paper, via the US Postal Service. How far the world has come in the ensuing decades. Now, we can stay connected to anyone, anywhere, via devices that fit in our pockets.
And so I’m excited to share with you one of the changes we’re making: In 2019, Clinician Reviews will be published 100% digitally! Why? Yes, printing and postage costs have increased to the point of unsustainability (and all that paper is not very environmentally friendly). But most importantly, online publication allows us to provide you with more of what you need for your practice—at any time of day or night, on any device you choose. And this gives us more scope to be creative in presenting information in engaging ways.
To ensure that we are moving in the right direction in making ClinicianReviews.com a more robust and useful resource, we surveyed NPs and PAs like you about our site, our competitors’ sites, and potential new offerings. Your answers were very enlightening, providing us guidance on
Building new functionality to make the site more user friendly
✓ Automatic notification when new content is posted
✓ Video player with a list of recently posted videos
Providing new content, including
✓ Clinical crossword puzzle
✓ Malpractice Chronicle by David Lang (both of which make their debut in this print issue)
Continue to: Offering you must-have content
Offering you must-have content
✓ Enhanced disease-specific content
✓ CE/CME with transcript tracking
✓ Peer-reviewed, evidence-based articles
✓ NP/PA- and MD-specific content
✓ Real-time news and conference reports
To ensure you stay informed about new offerings—and can continue to find the content you’ve enjoyed for years—we invite you to register on our website. You can do so by scanning the QR code below, and as a thank you, you’ll be able to download a free pocket guide, “PURLs in Primary Care.” And don’t forget to bookmark ClinicianReviews.com so that you can easily access our continually updated content.
We’re excited to take this step forward—and as always, we appreciate your support. We’re here to continue to serve the NP and PA professions, so please don’t hesitate to share your feedback and suggestions with us.
Best regards,
Karen J. Clemments
Dear Readers,
As 2018 draws to a close, Clinician Reviews is looking ahead to its 29th year of publication. In 1991, when our publication was founded, it was a unique idea to present information to both NPs and PAs together—a recognition of common educational needs and a unified focus on delivering the best possible patient care. For the past six years, as Editor, I have been privileged to ensure the fulfillment of CR’s editorial purpose—keeping NPs and PAs up to date on all aspects of clinical practice—while navigating changes both internal and external.
When CR started, personal computers existed but were not yet in widespread use (the office had one, to be shared). Manuscripts, peer reviews, even radiographs—all were submitted on paper, via the US Postal Service. How far the world has come in the ensuing decades. Now, we can stay connected to anyone, anywhere, via devices that fit in our pockets.
And so I’m excited to share with you one of the changes we’re making: In 2019, Clinician Reviews will be published 100% digitally! Why? Yes, printing and postage costs have increased to the point of unsustainability (and all that paper is not very environmentally friendly). But most importantly, online publication allows us to provide you with more of what you need for your practice—at any time of day or night, on any device you choose. And this gives us more scope to be creative in presenting information in engaging ways.
To ensure that we are moving in the right direction in making ClinicianReviews.com a more robust and useful resource, we surveyed NPs and PAs like you about our site, our competitors’ sites, and potential new offerings. Your answers were very enlightening, providing us guidance on
Building new functionality to make the site more user friendly
✓ Automatic notification when new content is posted
✓ Video player with a list of recently posted videos
Providing new content, including
✓ Clinical crossword puzzle
✓ Malpractice Chronicle by David Lang (both of which make their debut in this print issue)
Continue to: Offering you must-have content
Offering you must-have content
✓ Enhanced disease-specific content
✓ CE/CME with transcript tracking
✓ Peer-reviewed, evidence-based articles
✓ NP/PA- and MD-specific content
✓ Real-time news and conference reports
To ensure you stay informed about new offerings—and can continue to find the content you’ve enjoyed for years—we invite you to register on our website. You can do so by scanning the QR code below, and as a thank you, you’ll be able to download a free pocket guide, “PURLs in Primary Care.” And don’t forget to bookmark ClinicianReviews.com so that you can easily access our continually updated content.
We’re excited to take this step forward—and as always, we appreciate your support. We’re here to continue to serve the NP and PA professions, so please don’t hesitate to share your feedback and suggestions with us.
Best regards,
Karen J. Clemments
Dear Readers,
As 2018 draws to a close, Clinician Reviews is looking ahead to its 29th year of publication. In 1991, when our publication was founded, it was a unique idea to present information to both NPs and PAs together—a recognition of common educational needs and a unified focus on delivering the best possible patient care. For the past six years, as Editor, I have been privileged to ensure the fulfillment of CR’s editorial purpose—keeping NPs and PAs up to date on all aspects of clinical practice—while navigating changes both internal and external.
When CR started, personal computers existed but were not yet in widespread use (the office had one, to be shared). Manuscripts, peer reviews, even radiographs—all were submitted on paper, via the US Postal Service. How far the world has come in the ensuing decades. Now, we can stay connected to anyone, anywhere, via devices that fit in our pockets.
And so I’m excited to share with you one of the changes we’re making: In 2019, Clinician Reviews will be published 100% digitally! Why? Yes, printing and postage costs have increased to the point of unsustainability (and all that paper is not very environmentally friendly). But most importantly, online publication allows us to provide you with more of what you need for your practice—at any time of day or night, on any device you choose. And this gives us more scope to be creative in presenting information in engaging ways.
To ensure that we are moving in the right direction in making ClinicianReviews.com a more robust and useful resource, we surveyed NPs and PAs like you about our site, our competitors’ sites, and potential new offerings. Your answers were very enlightening, providing us guidance on
Building new functionality to make the site more user friendly
✓ Automatic notification when new content is posted
✓ Video player with a list of recently posted videos
Providing new content, including
✓ Clinical crossword puzzle
✓ Malpractice Chronicle by David Lang (both of which make their debut in this print issue)
Continue to: Offering you must-have content
Offering you must-have content
✓ Enhanced disease-specific content
✓ CE/CME with transcript tracking
✓ Peer-reviewed, evidence-based articles
✓ NP/PA- and MD-specific content
✓ Real-time news and conference reports
To ensure you stay informed about new offerings—and can continue to find the content you’ve enjoyed for years—we invite you to register on our website. You can do so by scanning the QR code below, and as a thank you, you’ll be able to download a free pocket guide, “PURLs in Primary Care.” And don’t forget to bookmark ClinicianReviews.com so that you can easily access our continually updated content.
We’re excited to take this step forward—and as always, we appreciate your support. We’re here to continue to serve the NP and PA professions, so please don’t hesitate to share your feedback and suggestions with us.
Best regards,
Karen J. Clemments
Gala Added to 2019 VAM Lineup
This year’s Vascular Annual Meeting will have a new and elegant air about it, with the introduction of a Gala to benefit the SVS Foundation. It is replacing the traditional President’s Reception, at the request of SVS President Michel S. Makaroun. Tickets are $250 each, of which $150 is a tax-deductible contribution to the SVS Foundation’s general fund, the Greatest Need Fund. The Gala will be held Friday, June 14, at the Gaylord National Resort & Convention Center, the site for VAM. The event will include a silent auction, cocktails, dinner and entertainment. Many details are still in the planning stages and a link to purchase tickets will be available in January. Keep checking the SVS site for future details.
This year’s Vascular Annual Meeting will have a new and elegant air about it, with the introduction of a Gala to benefit the SVS Foundation. It is replacing the traditional President’s Reception, at the request of SVS President Michel S. Makaroun. Tickets are $250 each, of which $150 is a tax-deductible contribution to the SVS Foundation’s general fund, the Greatest Need Fund. The Gala will be held Friday, June 14, at the Gaylord National Resort & Convention Center, the site for VAM. The event will include a silent auction, cocktails, dinner and entertainment. Many details are still in the planning stages and a link to purchase tickets will be available in January. Keep checking the SVS site for future details.
This year’s Vascular Annual Meeting will have a new and elegant air about it, with the introduction of a Gala to benefit the SVS Foundation. It is replacing the traditional President’s Reception, at the request of SVS President Michel S. Makaroun. Tickets are $250 each, of which $150 is a tax-deductible contribution to the SVS Foundation’s general fund, the Greatest Need Fund. The Gala will be held Friday, June 14, at the Gaylord National Resort & Convention Center, the site for VAM. The event will include a silent auction, cocktails, dinner and entertainment. Many details are still in the planning stages and a link to purchase tickets will be available in January. Keep checking the SVS site for future details.
SVSConnect is Now Open – Join the Conversation
SVSConnect, your online community, is now open! This online space gives members a place for discussion, collaboration and a chance to expand their professional networks. This initial launch starts with a single forum for all members to get signed up and post discussions on everything from case complications and surgical procedures, to research projects, wellness topics and more. Users also have an opportunity to leave general questions for SVS. Login to engage and help shape this community, and your Society, for the future.
SVSConnect, your online community, is now open! This online space gives members a place for discussion, collaboration and a chance to expand their professional networks. This initial launch starts with a single forum for all members to get signed up and post discussions on everything from case complications and surgical procedures, to research projects, wellness topics and more. Users also have an opportunity to leave general questions for SVS. Login to engage and help shape this community, and your Society, for the future.
SVSConnect, your online community, is now open! This online space gives members a place for discussion, collaboration and a chance to expand their professional networks. This initial launch starts with a single forum for all members to get signed up and post discussions on everything from case complications and surgical procedures, to research projects, wellness topics and more. Users also have an opportunity to leave general questions for SVS. Login to engage and help shape this community, and your Society, for the future.
Romiplostim now approved for children with ITP
The thrombopoietin receptor agonist romiplostim (NPlate®) is now approved by the U.S. Food and Drug Administration (FDA) to treat pediatric patients 1 year and older who have had immune thrombocytopenia (ITP) for at least 6 months and have not responded sufficiently to corticosteroids, immunoglobulins, or splenectomy.
Romiplostim was originally FDA-approved in 2008 to treat adult patients with chronic ITP who had an insufficient response to the same treatments.
Romiplostim is manufactured by Amgen, Inc.
The FDA based its approval on two double-blind, placebo-controlled clinical trials.
NCT01444417
The phase 3 study (NCT01444417) enrolled 62 pediatric patients 1 year and older who had ITP for at least 6 months. They were refractory to or relapsed after at least one prior therapy.
Investigators randomized them 2:1 to receive romiplostim (n=42) or placebo (n=20).
The starting dose was 1 μg/kg weekly for all ages. The dose was titrated up over a 24-week period to a maximum of 10 μg/kg weekly.
Patients were a median age of 9.5 years (range, 3–17), and 57% were female. A little over half (58%) had baseline platelet counts of 20 x 109/L or less, which was similar in both treatment arms.
Eighty-one percent of romiplostim-treated patients had at least two prior ITP therapies, compared with 70% in the placebo group. One patient in each group had undergone splenectomy.
Twenty-two (52%) of the romiplostim-treated patients had durable platelet responses of 50 x 109/L or greater for at least six weekly assessments during weeks 18 through 25 of treatment. Two (10%) patients in the placebo arm achieved durable platelet responses.
Thirty (71%) romiplostim-treated patients achieved an overall platelet response, defined as a durable or transient platelet response. This compared with four (20%) patients in the placebo group.
Romiplostim-treated patients had platelet counts of at least 50 x 109/L for a median of 12 weeks, compared to 1 week for patients in the placebo arm.
All response endpoints were significant at P<0.05.
NCT00515203
The phase 1/2 study (NCT00515203) enrolled 22 patients who had ITP for at least 6 months prior to study enrollment and were relapsed from or refractory to prior treatment.
Investigators randomized the patients 3:1 to romiplostim (n=17) or placebo (n=5).
Patients were a median age of 10 years (range, 1–17), and 27.3% were female.
Approximately 82% of patients had baseline platelet counts of 20 x 109/L or less, which was similar between the treatment arms.
Eighty-eight percent of patients in the romiplostim arm had at least two prior ITP therapies, as did 100% in the placebo group.
Six patients in the romiplostim group and two in the placebo group had undergone splenectomy.
Of the 17 patients treated with romiplostim, 15 (88.2%) achieved a platelet count of 50 x 109/L or great for 2 consecutive weeks.
The same 15 patients also achieved an increase in platelet count of 20 x 109/L or greater above baseline for 2 consecutive weeks during the treatment period.
None of the placebo-treated patients achieved either endpoint.
The adverse events profile in pediatric patients was compiled from the two trials and reflects a median drug exposure of 168 days for 59 patients.
The most common adverse events, occurring in 25% or more of romiplostim-treated patients, were contusion (41%), upper respiratory tract infection (31%), and oropharyngeal pain (25%). These occurred with an incidence at least 5% higher than in the placebo group.
Dosing
The recommended starting dose for pediatric patients is 1 µg/kg based on actual body weight and administered as a weekly subcutaneous injection.
The dose should be adjusted in increments of 1 µg/kg until the patient achieves a platelet count of 50 x 109/L or greater.
The prescribing information recommends reassessing patients’ body weight every 12 weeks.
The thrombopoietin receptor agonist romiplostim (NPlate®) is now approved by the U.S. Food and Drug Administration (FDA) to treat pediatric patients 1 year and older who have had immune thrombocytopenia (ITP) for at least 6 months and have not responded sufficiently to corticosteroids, immunoglobulins, or splenectomy.
Romiplostim was originally FDA-approved in 2008 to treat adult patients with chronic ITP who had an insufficient response to the same treatments.
Romiplostim is manufactured by Amgen, Inc.
The FDA based its approval on two double-blind, placebo-controlled clinical trials.
NCT01444417
The phase 3 study (NCT01444417) enrolled 62 pediatric patients 1 year and older who had ITP for at least 6 months. They were refractory to or relapsed after at least one prior therapy.
Investigators randomized them 2:1 to receive romiplostim (n=42) or placebo (n=20).
The starting dose was 1 μg/kg weekly for all ages. The dose was titrated up over a 24-week period to a maximum of 10 μg/kg weekly.
Patients were a median age of 9.5 years (range, 3–17), and 57% were female. A little over half (58%) had baseline platelet counts of 20 x 109/L or less, which was similar in both treatment arms.
Eighty-one percent of romiplostim-treated patients had at least two prior ITP therapies, compared with 70% in the placebo group. One patient in each group had undergone splenectomy.
Twenty-two (52%) of the romiplostim-treated patients had durable platelet responses of 50 x 109/L or greater for at least six weekly assessments during weeks 18 through 25 of treatment. Two (10%) patients in the placebo arm achieved durable platelet responses.
Thirty (71%) romiplostim-treated patients achieved an overall platelet response, defined as a durable or transient platelet response. This compared with four (20%) patients in the placebo group.
Romiplostim-treated patients had platelet counts of at least 50 x 109/L for a median of 12 weeks, compared to 1 week for patients in the placebo arm.
All response endpoints were significant at P<0.05.
NCT00515203
The phase 1/2 study (NCT00515203) enrolled 22 patients who had ITP for at least 6 months prior to study enrollment and were relapsed from or refractory to prior treatment.
Investigators randomized the patients 3:1 to romiplostim (n=17) or placebo (n=5).
Patients were a median age of 10 years (range, 1–17), and 27.3% were female.
Approximately 82% of patients had baseline platelet counts of 20 x 109/L or less, which was similar between the treatment arms.
Eighty-eight percent of patients in the romiplostim arm had at least two prior ITP therapies, as did 100% in the placebo group.
Six patients in the romiplostim group and two in the placebo group had undergone splenectomy.
Of the 17 patients treated with romiplostim, 15 (88.2%) achieved a platelet count of 50 x 109/L or great for 2 consecutive weeks.
The same 15 patients also achieved an increase in platelet count of 20 x 109/L or greater above baseline for 2 consecutive weeks during the treatment period.
None of the placebo-treated patients achieved either endpoint.
The adverse events profile in pediatric patients was compiled from the two trials and reflects a median drug exposure of 168 days for 59 patients.
The most common adverse events, occurring in 25% or more of romiplostim-treated patients, were contusion (41%), upper respiratory tract infection (31%), and oropharyngeal pain (25%). These occurred with an incidence at least 5% higher than in the placebo group.
Dosing
The recommended starting dose for pediatric patients is 1 µg/kg based on actual body weight and administered as a weekly subcutaneous injection.
The dose should be adjusted in increments of 1 µg/kg until the patient achieves a platelet count of 50 x 109/L or greater.
The prescribing information recommends reassessing patients’ body weight every 12 weeks.
The thrombopoietin receptor agonist romiplostim (NPlate®) is now approved by the U.S. Food and Drug Administration (FDA) to treat pediatric patients 1 year and older who have had immune thrombocytopenia (ITP) for at least 6 months and have not responded sufficiently to corticosteroids, immunoglobulins, or splenectomy.
Romiplostim was originally FDA-approved in 2008 to treat adult patients with chronic ITP who had an insufficient response to the same treatments.
Romiplostim is manufactured by Amgen, Inc.
The FDA based its approval on two double-blind, placebo-controlled clinical trials.
NCT01444417
The phase 3 study (NCT01444417) enrolled 62 pediatric patients 1 year and older who had ITP for at least 6 months. They were refractory to or relapsed after at least one prior therapy.
Investigators randomized them 2:1 to receive romiplostim (n=42) or placebo (n=20).
The starting dose was 1 μg/kg weekly for all ages. The dose was titrated up over a 24-week period to a maximum of 10 μg/kg weekly.
Patients were a median age of 9.5 years (range, 3–17), and 57% were female. A little over half (58%) had baseline platelet counts of 20 x 109/L or less, which was similar in both treatment arms.
Eighty-one percent of romiplostim-treated patients had at least two prior ITP therapies, compared with 70% in the placebo group. One patient in each group had undergone splenectomy.
Twenty-two (52%) of the romiplostim-treated patients had durable platelet responses of 50 x 109/L or greater for at least six weekly assessments during weeks 18 through 25 of treatment. Two (10%) patients in the placebo arm achieved durable platelet responses.
Thirty (71%) romiplostim-treated patients achieved an overall platelet response, defined as a durable or transient platelet response. This compared with four (20%) patients in the placebo group.
Romiplostim-treated patients had platelet counts of at least 50 x 109/L for a median of 12 weeks, compared to 1 week for patients in the placebo arm.
All response endpoints were significant at P<0.05.
NCT00515203
The phase 1/2 study (NCT00515203) enrolled 22 patients who had ITP for at least 6 months prior to study enrollment and were relapsed from or refractory to prior treatment.
Investigators randomized the patients 3:1 to romiplostim (n=17) or placebo (n=5).
Patients were a median age of 10 years (range, 1–17), and 27.3% were female.
Approximately 82% of patients had baseline platelet counts of 20 x 109/L or less, which was similar between the treatment arms.
Eighty-eight percent of patients in the romiplostim arm had at least two prior ITP therapies, as did 100% in the placebo group.
Six patients in the romiplostim group and two in the placebo group had undergone splenectomy.
Of the 17 patients treated with romiplostim, 15 (88.2%) achieved a platelet count of 50 x 109/L or great for 2 consecutive weeks.
The same 15 patients also achieved an increase in platelet count of 20 x 109/L or greater above baseline for 2 consecutive weeks during the treatment period.
None of the placebo-treated patients achieved either endpoint.
The adverse events profile in pediatric patients was compiled from the two trials and reflects a median drug exposure of 168 days for 59 patients.
The most common adverse events, occurring in 25% or more of romiplostim-treated patients, were contusion (41%), upper respiratory tract infection (31%), and oropharyngeal pain (25%). These occurred with an incidence at least 5% higher than in the placebo group.
Dosing
The recommended starting dose for pediatric patients is 1 µg/kg based on actual body weight and administered as a weekly subcutaneous injection.
The dose should be adjusted in increments of 1 µg/kg until the patient achieves a platelet count of 50 x 109/L or greater.
The prescribing information recommends reassessing patients’ body weight every 12 weeks.
December 2018 Question 2
A 26-year-old woman presents for an evaluation of an 8-month history of intermittent abdominal pain, which is associated with diarrhea. Her pain improves with bowel movements. She denies weight loss, GI bleeding, or nocturnal symptoms. There is no family history of IBD or celiac disease. Physical examination is normal. Thyroid function testing, C-reactive protein, celiac serology, stool studies for infectious pathogens, stool calprotectin, and colonoscopy with biopsies are all negative.
December 2018 Question 1
A 45-year-old woman presents with a 3-year history of a sense of incomplete evacuation, excessive straining to defecate, and rectal bleeding. Colonoscopy demonstrates an irregular, polypoid lesion on the anterior wall of the rectum. Biopsies reveal fibromuscular obliteration of the lamina propria and hypertrophied muscularis mucosa with extension of muscle fibers upward between the crypts.
10 Important VA Studies You Might Have Missed at ASH
With hundreds of sessions and thousands of abstracts, it can be difficult to wade through all the new findings to find the most significant and relevant findings. Federal Practitioner consulted with Association of VA Hematology/Oncology members who attended the meeting, VA researchers, and other sources to provide these nuggets you might have missed on lymphomas, white blood cells, leukemias, and multiple myeloma:
Lymphomas
This retrospective analysis of diffuse large B cell lymphoma (DCBL) patients who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the VA Audie Murphy Hospital in San Antonio, Texas was compared with patients with DLBCL who received R-CHOP in a community setting. According to the researchers, the response to initial treatment was inferior in the veteran population when compared with a patient population with similar demographics and having similar time from diagnosis to treatment. Veteran patients also had worse outcomes when compared with uninsured patients.
This retrospective analysis study identified 2,290 patients with follicular lymphoma treated in the Veterans Health Administration between 2006–2014 and detailed their staging, demographics, and comorbidities. The researchers found that maintenance therapy with rituximab was associated with an improvement in overall survival.
Another retrospective analysis of DBCL using VHA data examined the effectiveness of second-line chemotherapy and chemoimmunotherapy in patients aged ≥ 65 years. The researchers found 230 patients from 2001 to 2015 that met the inclusion criteria. According to the researchers, the overall survival was < 1 year and about half of the patients "did not receive or were not candidates for regimens typically used with intent for high-dose therapy and autologous transplant."
White Blood Cells
Cost-Effective Use of White Blood Cell Growth Factors in the Veterans Administration
This study analyzed the use of granulocyte colony-stimulating (G-CSF) vs pegfilgrastim in the UD Department of Veterans Affairs (VA) health care system. The researchers looked at the relative frequency of use of filgrastim, Tbo-filgrastim, Filgrastim-sndz and pegfilgrastim at 23 VA sites and found that uptake of biosimilar G-CSF has been extremely rapid. All sites are using biosimilar GCSF for all new patients; 6 of 23 sites were comfortable shifting current patients on branded G-CSF to the biosimilar.However, switching to a Tbo-filgrastim brought a cost savings of 2.2% that was "small compared to other clinical changes."
This analysis described the association between white blood cell (EBC) levels and occurrence of thrombotic events among patients with polycythemia vera (PV) using Veterans Health Administration claims data collected between 2005 and 2012. The researchers found A significant, positive association between increased WBC counts and occurrence of thrombotic events in patients with PV was observed in this study. Patients with WBC counts ≥ 8.5 × 109/L had a significantly increased risk of thrombotic events, and those with counts ≥ 11.0 × 109/L were at greatest risk. Effective control of WBC counts is an important component of disease management and may reduce risk of thrombotic events in patients with PV.
Leukemias
Black patients with chronic lymphocytic leukemia tend to have worse overall survival and an earlier age at diagnosis with higher rates of adverse cytogenetics. This retrospective analysis of VHA patients compared black and nonblack patients. It found that black patients had worse survival compared to nonblack patients in a single health care delivery system, which limits differences in access to care. Black patients were younger and had shorter periods of observation and were more frequently given first-line fludarabine.
Induction chemotherapy (7+3) or high-dose ara-C-based (HIDAC) for acute myeloid leukemia (AML) results in prolonged neutropenia with a high risk of serious infection and attendant morbidity, and prolonged hospitalization. Researchers, including former AVAHO president Suman Kambhampati developed a randomized, open-label, controlled Phase 2 trial to study the effect of romyelocel-L in de novo patients receiving HIDAC or 7+3 induction therapy for reduction of fever and infection. The results from pooled and 7+3 cohorts, were previously presented, showing decrease in infections and days in hospital. The results from cohorts receiving HIDAC chemotherapy are presented here. The incidence of infections was decreased during the day 15-28 period and a decrease of three days in hospital stay was observed in de novo HIDAC AML subjects receiving romyelocel-L. Romyelocel-L may provide a new option to reduce infections in AML patients undergoing HIDAC induction therapy.
Multiple Myeloma
Two studies focused on racial disparities in multiple myeloma (MM), while another reported phase 2 data on a relapsed/refractory option.
This group of researchers found an absence of disparity in use of novel agents, no racial disparity was observed in overall survival between black and white patients with MM. Among patients aged < 65 years at diagnosis, the researchers observed a significantly lower age-adjusted risk of death for black patients compared with white patients. The difference in the younger population was not explained by access or utilization of resources. This analysis suggests that when healthcare access is neutralized, younger black patients may even have improved overall survival, which may indicate the possibility of genetic differences that may drive the disease biology and therapeutic outcome in AA patients.
Outcomes of Black Patients with Multiple Myeloma in the Veterans Health Administration
The second study found survival of black patients with MM was improved compared to non-blacks in the VHA, a national comprehensive care delivery system. Black patients also received similar therapies compared to non-blacks, while presenting at a younger age with more comorbidities. These results are strengthened after adjusting for treatments and patient characteristics not available in other large data studies. Despite increased incidence of MM in the black population, outcomes are improved, similar to other large studies of patients in the United States.
Multiple myeloma clinical trial CC-4047-MM-014 (NCT01946477) is a phase 2 study designed to test the safety and efficacy of pomalidomide and low-dose dexamethasone alone (arm A) or in combination with daratumumab, an anti-CD38 antibody, (arm B) subjects with relapsed or refractory MM who have received a first- or second-line treatment of lenalidomide-based therapy. In this trial, researchers (including those from VA facilities, Celgene, and multiple other locations) sought to characterize on-treatment pharmacodynamic changes of immune biomarkers associated with POM + LoDEX + DARA administration (arm B) using multicolor flow cytometry panels designed to characterize T-cell subsets and CD38+ expressing cells. The researchers reported that the triplet regimen POM + LoDEX + DARA has shown notable clinical activity with deep and durable responses in relapsed MM patients progressed and are or refractory to lenalidomide. According to the researchers the results demonstrate that patients treated with the POM + LoDEX + DARA combination do not demonstrate impairment in the innate and adaptive immune compartments and, in contrast, show significant proliferative activity in the subsets of CD4, CD8 and NK cells following treatment.
With hundreds of sessions and thousands of abstracts, it can be difficult to wade through all the new findings to find the most significant and relevant findings. Federal Practitioner consulted with Association of VA Hematology/Oncology members who attended the meeting, VA researchers, and other sources to provide these nuggets you might have missed on lymphomas, white blood cells, leukemias, and multiple myeloma:
Lymphomas
This retrospective analysis of diffuse large B cell lymphoma (DCBL) patients who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the VA Audie Murphy Hospital in San Antonio, Texas was compared with patients with DLBCL who received R-CHOP in a community setting. According to the researchers, the response to initial treatment was inferior in the veteran population when compared with a patient population with similar demographics and having similar time from diagnosis to treatment. Veteran patients also had worse outcomes when compared with uninsured patients.
This retrospective analysis study identified 2,290 patients with follicular lymphoma treated in the Veterans Health Administration between 2006–2014 and detailed their staging, demographics, and comorbidities. The researchers found that maintenance therapy with rituximab was associated with an improvement in overall survival.
Another retrospective analysis of DBCL using VHA data examined the effectiveness of second-line chemotherapy and chemoimmunotherapy in patients aged ≥ 65 years. The researchers found 230 patients from 2001 to 2015 that met the inclusion criteria. According to the researchers, the overall survival was < 1 year and about half of the patients "did not receive or were not candidates for regimens typically used with intent for high-dose therapy and autologous transplant."
White Blood Cells
Cost-Effective Use of White Blood Cell Growth Factors in the Veterans Administration
This study analyzed the use of granulocyte colony-stimulating (G-CSF) vs pegfilgrastim in the UD Department of Veterans Affairs (VA) health care system. The researchers looked at the relative frequency of use of filgrastim, Tbo-filgrastim, Filgrastim-sndz and pegfilgrastim at 23 VA sites and found that uptake of biosimilar G-CSF has been extremely rapid. All sites are using biosimilar GCSF for all new patients; 6 of 23 sites were comfortable shifting current patients on branded G-CSF to the biosimilar.However, switching to a Tbo-filgrastim brought a cost savings of 2.2% that was "small compared to other clinical changes."
This analysis described the association between white blood cell (EBC) levels and occurrence of thrombotic events among patients with polycythemia vera (PV) using Veterans Health Administration claims data collected between 2005 and 2012. The researchers found A significant, positive association between increased WBC counts and occurrence of thrombotic events in patients with PV was observed in this study. Patients with WBC counts ≥ 8.5 × 109/L had a significantly increased risk of thrombotic events, and those with counts ≥ 11.0 × 109/L were at greatest risk. Effective control of WBC counts is an important component of disease management and may reduce risk of thrombotic events in patients with PV.
Leukemias
Black patients with chronic lymphocytic leukemia tend to have worse overall survival and an earlier age at diagnosis with higher rates of adverse cytogenetics. This retrospective analysis of VHA patients compared black and nonblack patients. It found that black patients had worse survival compared to nonblack patients in a single health care delivery system, which limits differences in access to care. Black patients were younger and had shorter periods of observation and were more frequently given first-line fludarabine.
Induction chemotherapy (7+3) or high-dose ara-C-based (HIDAC) for acute myeloid leukemia (AML) results in prolonged neutropenia with a high risk of serious infection and attendant morbidity, and prolonged hospitalization. Researchers, including former AVAHO president Suman Kambhampati developed a randomized, open-label, controlled Phase 2 trial to study the effect of romyelocel-L in de novo patients receiving HIDAC or 7+3 induction therapy for reduction of fever and infection. The results from pooled and 7+3 cohorts, were previously presented, showing decrease in infections and days in hospital. The results from cohorts receiving HIDAC chemotherapy are presented here. The incidence of infections was decreased during the day 15-28 period and a decrease of three days in hospital stay was observed in de novo HIDAC AML subjects receiving romyelocel-L. Romyelocel-L may provide a new option to reduce infections in AML patients undergoing HIDAC induction therapy.
Multiple Myeloma
Two studies focused on racial disparities in multiple myeloma (MM), while another reported phase 2 data on a relapsed/refractory option.
This group of researchers found an absence of disparity in use of novel agents, no racial disparity was observed in overall survival between black and white patients with MM. Among patients aged < 65 years at diagnosis, the researchers observed a significantly lower age-adjusted risk of death for black patients compared with white patients. The difference in the younger population was not explained by access or utilization of resources. This analysis suggests that when healthcare access is neutralized, younger black patients may even have improved overall survival, which may indicate the possibility of genetic differences that may drive the disease biology and therapeutic outcome in AA patients.
Outcomes of Black Patients with Multiple Myeloma in the Veterans Health Administration
The second study found survival of black patients with MM was improved compared to non-blacks in the VHA, a national comprehensive care delivery system. Black patients also received similar therapies compared to non-blacks, while presenting at a younger age with more comorbidities. These results are strengthened after adjusting for treatments and patient characteristics not available in other large data studies. Despite increased incidence of MM in the black population, outcomes are improved, similar to other large studies of patients in the United States.
Multiple myeloma clinical trial CC-4047-MM-014 (NCT01946477) is a phase 2 study designed to test the safety and efficacy of pomalidomide and low-dose dexamethasone alone (arm A) or in combination with daratumumab, an anti-CD38 antibody, (arm B) subjects with relapsed or refractory MM who have received a first- or second-line treatment of lenalidomide-based therapy. In this trial, researchers (including those from VA facilities, Celgene, and multiple other locations) sought to characterize on-treatment pharmacodynamic changes of immune biomarkers associated with POM + LoDEX + DARA administration (arm B) using multicolor flow cytometry panels designed to characterize T-cell subsets and CD38+ expressing cells. The researchers reported that the triplet regimen POM + LoDEX + DARA has shown notable clinical activity with deep and durable responses in relapsed MM patients progressed and are or refractory to lenalidomide. According to the researchers the results demonstrate that patients treated with the POM + LoDEX + DARA combination do not demonstrate impairment in the innate and adaptive immune compartments and, in contrast, show significant proliferative activity in the subsets of CD4, CD8 and NK cells following treatment.
With hundreds of sessions and thousands of abstracts, it can be difficult to wade through all the new findings to find the most significant and relevant findings. Federal Practitioner consulted with Association of VA Hematology/Oncology members who attended the meeting, VA researchers, and other sources to provide these nuggets you might have missed on lymphomas, white blood cells, leukemias, and multiple myeloma:
Lymphomas
This retrospective analysis of diffuse large B cell lymphoma (DCBL) patients who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the VA Audie Murphy Hospital in San Antonio, Texas was compared with patients with DLBCL who received R-CHOP in a community setting. According to the researchers, the response to initial treatment was inferior in the veteran population when compared with a patient population with similar demographics and having similar time from diagnosis to treatment. Veteran patients also had worse outcomes when compared with uninsured patients.
This retrospective analysis study identified 2,290 patients with follicular lymphoma treated in the Veterans Health Administration between 2006–2014 and detailed their staging, demographics, and comorbidities. The researchers found that maintenance therapy with rituximab was associated with an improvement in overall survival.
Another retrospective analysis of DBCL using VHA data examined the effectiveness of second-line chemotherapy and chemoimmunotherapy in patients aged ≥ 65 years. The researchers found 230 patients from 2001 to 2015 that met the inclusion criteria. According to the researchers, the overall survival was < 1 year and about half of the patients "did not receive or were not candidates for regimens typically used with intent for high-dose therapy and autologous transplant."
White Blood Cells
Cost-Effective Use of White Blood Cell Growth Factors in the Veterans Administration
This study analyzed the use of granulocyte colony-stimulating (G-CSF) vs pegfilgrastim in the UD Department of Veterans Affairs (VA) health care system. The researchers looked at the relative frequency of use of filgrastim, Tbo-filgrastim, Filgrastim-sndz and pegfilgrastim at 23 VA sites and found that uptake of biosimilar G-CSF has been extremely rapid. All sites are using biosimilar GCSF for all new patients; 6 of 23 sites were comfortable shifting current patients on branded G-CSF to the biosimilar.However, switching to a Tbo-filgrastim brought a cost savings of 2.2% that was "small compared to other clinical changes."
This analysis described the association between white blood cell (EBC) levels and occurrence of thrombotic events among patients with polycythemia vera (PV) using Veterans Health Administration claims data collected between 2005 and 2012. The researchers found A significant, positive association between increased WBC counts and occurrence of thrombotic events in patients with PV was observed in this study. Patients with WBC counts ≥ 8.5 × 109/L had a significantly increased risk of thrombotic events, and those with counts ≥ 11.0 × 109/L were at greatest risk. Effective control of WBC counts is an important component of disease management and may reduce risk of thrombotic events in patients with PV.
Leukemias
Black patients with chronic lymphocytic leukemia tend to have worse overall survival and an earlier age at diagnosis with higher rates of adverse cytogenetics. This retrospective analysis of VHA patients compared black and nonblack patients. It found that black patients had worse survival compared to nonblack patients in a single health care delivery system, which limits differences in access to care. Black patients were younger and had shorter periods of observation and were more frequently given first-line fludarabine.
Induction chemotherapy (7+3) or high-dose ara-C-based (HIDAC) for acute myeloid leukemia (AML) results in prolonged neutropenia with a high risk of serious infection and attendant morbidity, and prolonged hospitalization. Researchers, including former AVAHO president Suman Kambhampati developed a randomized, open-label, controlled Phase 2 trial to study the effect of romyelocel-L in de novo patients receiving HIDAC or 7+3 induction therapy for reduction of fever and infection. The results from pooled and 7+3 cohorts, were previously presented, showing decrease in infections and days in hospital. The results from cohorts receiving HIDAC chemotherapy are presented here. The incidence of infections was decreased during the day 15-28 period and a decrease of three days in hospital stay was observed in de novo HIDAC AML subjects receiving romyelocel-L. Romyelocel-L may provide a new option to reduce infections in AML patients undergoing HIDAC induction therapy.
Multiple Myeloma
Two studies focused on racial disparities in multiple myeloma (MM), while another reported phase 2 data on a relapsed/refractory option.
This group of researchers found an absence of disparity in use of novel agents, no racial disparity was observed in overall survival between black and white patients with MM. Among patients aged < 65 years at diagnosis, the researchers observed a significantly lower age-adjusted risk of death for black patients compared with white patients. The difference in the younger population was not explained by access or utilization of resources. This analysis suggests that when healthcare access is neutralized, younger black patients may even have improved overall survival, which may indicate the possibility of genetic differences that may drive the disease biology and therapeutic outcome in AA patients.
Outcomes of Black Patients with Multiple Myeloma in the Veterans Health Administration
The second study found survival of black patients with MM was improved compared to non-blacks in the VHA, a national comprehensive care delivery system. Black patients also received similar therapies compared to non-blacks, while presenting at a younger age with more comorbidities. These results are strengthened after adjusting for treatments and patient characteristics not available in other large data studies. Despite increased incidence of MM in the black population, outcomes are improved, similar to other large studies of patients in the United States.
Multiple myeloma clinical trial CC-4047-MM-014 (NCT01946477) is a phase 2 study designed to test the safety and efficacy of pomalidomide and low-dose dexamethasone alone (arm A) or in combination with daratumumab, an anti-CD38 antibody, (arm B) subjects with relapsed or refractory MM who have received a first- or second-line treatment of lenalidomide-based therapy. In this trial, researchers (including those from VA facilities, Celgene, and multiple other locations) sought to characterize on-treatment pharmacodynamic changes of immune biomarkers associated with POM + LoDEX + DARA administration (arm B) using multicolor flow cytometry panels designed to characterize T-cell subsets and CD38+ expressing cells. The researchers reported that the triplet regimen POM + LoDEX + DARA has shown notable clinical activity with deep and durable responses in relapsed MM patients progressed and are or refractory to lenalidomide. According to the researchers the results demonstrate that patients treated with the POM + LoDEX + DARA combination do not demonstrate impairment in the innate and adaptive immune compartments and, in contrast, show significant proliferative activity in the subsets of CD4, CD8 and NK cells following treatment.
How often is AED treatment delayed for patients with epilepsy?
NEW ORLEANS – , according to an Australian study presented at the annual meeting of the American Epilepsy Society. Most untreated patients begin an AED after experiencing subsequent seizures, however.
“The decision to start or withhold treatment reflects the complex interplay between factors perceived to influence the predicted risk of seizure recurrence, which remain imprecise, and personal factors,” said lead study author Zhibin Chen, PhD, a biostatistician at the University of Melbourne and colleagues.
Many patients with epilepsy in resource-poor countries may not receive AED therapy for socioeconomic reasons, but little is known about untreated epilepsy in high-income countries. To assess the extent of and reasons for patients not receiving AEDs when treatment is accessible and affordable, Dr. Chen and colleagues prospectively recruited adult patients who attended the first-seizure clinics of publicly funded hospitals in Western Australia between May 1, 1999, and May 31, 2016. The patients had new-onset seizures and were referred by primary care or emergency department physicians. The health care system provided universal coverage for patients’ hospital admissions, outpatient visits, investigations, and treatment.
The researchers identified patients with newly diagnosed epilepsy and reviewed medical records to determine the proportion of untreated patients and the reasons for not starting treatment at each follow-up visit. The investigators compared the sociodemographic factors, neuroimaging, and EEG findings of treated and untreated patients.
In all, 1,317 people attended the clinics during the study period, and 610 patients (61% male; median age, 40) received a diagnosis of epilepsy and met 2014 International League Against Epilepsy (ILAE) diagnostic criteria for epilepsy. Patients were followed for a median of 5.7 years.
Of the 610 patients with epilepsy, 31% did not start AED treatment at the time of diagnosis – 16.4% because the neurologist did not recommend treatment and 14.6% because the patient declined treatment despite a neurologist’s recommendation to start therapy.
Patients’ reasons for not starting treatment included doubts about the need for treatment or about the epilepsy diagnosis, as well as concerns about medication side effects. Neurologists’ reasons for not beginning treatment included a patient having only one seizure and awaiting further results. The presence of seizure-precipitating factors (e.g., flashing lights, sleep deprivation, stress, or alcohol use) was another reason that patients and neurologists commonly cited for not initiating treatment.
Among the 189 initially untreated patients, 62.4% started treatment after a median delay of 95 days, “mainly after further seizures,” the investigators said. Patients with epilepsy who were older, from lower socioeconomic areas, had experienced more seizures, or had epileptogenic lesions on neuroimaging were more likely to initiate AED treatment at diagnosis.
“The percentage of people who were not initially prescribed AEDs was much higher than expected and suggests that untreated epilepsy exists not just in resource-poor, but also in wealthy countries,” said Dr. Chen.
More research is needed to assess the long-term outcomes of patient with seizure-precipitating factors who initiate AEDs immediately, compared with those who try avoidance of precipitating factors alone, said Dr. Chen.
This study was supported by a grant from UCB Pharma.
SOURCE: Chen Z et al. AES 2018, Abstract 3.421.
NEW ORLEANS – , according to an Australian study presented at the annual meeting of the American Epilepsy Society. Most untreated patients begin an AED after experiencing subsequent seizures, however.
“The decision to start or withhold treatment reflects the complex interplay between factors perceived to influence the predicted risk of seizure recurrence, which remain imprecise, and personal factors,” said lead study author Zhibin Chen, PhD, a biostatistician at the University of Melbourne and colleagues.
Many patients with epilepsy in resource-poor countries may not receive AED therapy for socioeconomic reasons, but little is known about untreated epilepsy in high-income countries. To assess the extent of and reasons for patients not receiving AEDs when treatment is accessible and affordable, Dr. Chen and colleagues prospectively recruited adult patients who attended the first-seizure clinics of publicly funded hospitals in Western Australia between May 1, 1999, and May 31, 2016. The patients had new-onset seizures and were referred by primary care or emergency department physicians. The health care system provided universal coverage for patients’ hospital admissions, outpatient visits, investigations, and treatment.
The researchers identified patients with newly diagnosed epilepsy and reviewed medical records to determine the proportion of untreated patients and the reasons for not starting treatment at each follow-up visit. The investigators compared the sociodemographic factors, neuroimaging, and EEG findings of treated and untreated patients.
In all, 1,317 people attended the clinics during the study period, and 610 patients (61% male; median age, 40) received a diagnosis of epilepsy and met 2014 International League Against Epilepsy (ILAE) diagnostic criteria for epilepsy. Patients were followed for a median of 5.7 years.
Of the 610 patients with epilepsy, 31% did not start AED treatment at the time of diagnosis – 16.4% because the neurologist did not recommend treatment and 14.6% because the patient declined treatment despite a neurologist’s recommendation to start therapy.
Patients’ reasons for not starting treatment included doubts about the need for treatment or about the epilepsy diagnosis, as well as concerns about medication side effects. Neurologists’ reasons for not beginning treatment included a patient having only one seizure and awaiting further results. The presence of seizure-precipitating factors (e.g., flashing lights, sleep deprivation, stress, or alcohol use) was another reason that patients and neurologists commonly cited for not initiating treatment.
Among the 189 initially untreated patients, 62.4% started treatment after a median delay of 95 days, “mainly after further seizures,” the investigators said. Patients with epilepsy who were older, from lower socioeconomic areas, had experienced more seizures, or had epileptogenic lesions on neuroimaging were more likely to initiate AED treatment at diagnosis.
“The percentage of people who were not initially prescribed AEDs was much higher than expected and suggests that untreated epilepsy exists not just in resource-poor, but also in wealthy countries,” said Dr. Chen.
More research is needed to assess the long-term outcomes of patient with seizure-precipitating factors who initiate AEDs immediately, compared with those who try avoidance of precipitating factors alone, said Dr. Chen.
This study was supported by a grant from UCB Pharma.
SOURCE: Chen Z et al. AES 2018, Abstract 3.421.
NEW ORLEANS – , according to an Australian study presented at the annual meeting of the American Epilepsy Society. Most untreated patients begin an AED after experiencing subsequent seizures, however.
“The decision to start or withhold treatment reflects the complex interplay between factors perceived to influence the predicted risk of seizure recurrence, which remain imprecise, and personal factors,” said lead study author Zhibin Chen, PhD, a biostatistician at the University of Melbourne and colleagues.
Many patients with epilepsy in resource-poor countries may not receive AED therapy for socioeconomic reasons, but little is known about untreated epilepsy in high-income countries. To assess the extent of and reasons for patients not receiving AEDs when treatment is accessible and affordable, Dr. Chen and colleagues prospectively recruited adult patients who attended the first-seizure clinics of publicly funded hospitals in Western Australia between May 1, 1999, and May 31, 2016. The patients had new-onset seizures and were referred by primary care or emergency department physicians. The health care system provided universal coverage for patients’ hospital admissions, outpatient visits, investigations, and treatment.
The researchers identified patients with newly diagnosed epilepsy and reviewed medical records to determine the proportion of untreated patients and the reasons for not starting treatment at each follow-up visit. The investigators compared the sociodemographic factors, neuroimaging, and EEG findings of treated and untreated patients.
In all, 1,317 people attended the clinics during the study period, and 610 patients (61% male; median age, 40) received a diagnosis of epilepsy and met 2014 International League Against Epilepsy (ILAE) diagnostic criteria for epilepsy. Patients were followed for a median of 5.7 years.
Of the 610 patients with epilepsy, 31% did not start AED treatment at the time of diagnosis – 16.4% because the neurologist did not recommend treatment and 14.6% because the patient declined treatment despite a neurologist’s recommendation to start therapy.
Patients’ reasons for not starting treatment included doubts about the need for treatment or about the epilepsy diagnosis, as well as concerns about medication side effects. Neurologists’ reasons for not beginning treatment included a patient having only one seizure and awaiting further results. The presence of seizure-precipitating factors (e.g., flashing lights, sleep deprivation, stress, or alcohol use) was another reason that patients and neurologists commonly cited for not initiating treatment.
Among the 189 initially untreated patients, 62.4% started treatment after a median delay of 95 days, “mainly after further seizures,” the investigators said. Patients with epilepsy who were older, from lower socioeconomic areas, had experienced more seizures, or had epileptogenic lesions on neuroimaging were more likely to initiate AED treatment at diagnosis.
“The percentage of people who were not initially prescribed AEDs was much higher than expected and suggests that untreated epilepsy exists not just in resource-poor, but also in wealthy countries,” said Dr. Chen.
More research is needed to assess the long-term outcomes of patient with seizure-precipitating factors who initiate AEDs immediately, compared with those who try avoidance of precipitating factors alone, said Dr. Chen.
This study was supported by a grant from UCB Pharma.
SOURCE: Chen Z et al. AES 2018, Abstract 3.421.
REPORTING FROM AES 2018
Key clinical point: Delayed initiation of antiepileptic drug treatment may be more common than thought.
Major finding: More than 30% of patients with epilepsy do not initiate treatment at diagnosis.
Study details: Review of 610 patients with newly diagnosed epilepsy who were seen at clinics in Western Australia.
Disclosures: The study was supported by a grant from UCB Pharma.
Source: Chen Z et al. AES 2018, Abstract 3.421.
Motor neuron disease spasticity improved with cannabis-based oral spray, antispasticity drugs
Nabiximols, a cannabis-based oral spray containing delta-9 tetrahydrocannabinol and cannabidiol, significantly improved spasticity symptoms in combination with antispasticity drugs in patients with motor neuron disease in a randomized, double-blind, placebo-controlled, parallel-group, phase 2 clinical trial.
Nabiximols proved superior to a placebo spray when both were given to patients with either amyotrophic lateral sclerosis or primary lateral sclerosis as part of an antispasticity regimen in the 6-week, CANALS (Cannabis Sativa Extract in Amyotrophic Lateral Sclerosis and other Motor Neuron Disease) study at four Italian centers, Nilo Riva, MD, PhD, of the San Raffaele Scientific Institute in Milan and his colleagues reported in The Lancet Neurology. Nabiximols is approved for the treatment of spasticity due to multiple sclerosis in multiple countries, but not in the United States.
“There is no cure for motor neuron disease, so improved symptom control and quality of life are important for patients,” Dr. Riva stated in a press release. “Our proof-of-concept trial showed a beneficial effect of THC-CBD [delta-9 tetrahydrocannabinol and cannabidiol] spray in people on treatment-resistant spasticity and pain.
“Despite these encouraging findings, we must first confirm that THC-CBD spray is effective and safe in larger, longer-term phase 3 trials,” Dr. Riva added.
The patients enrolled in the phase 2 trial between January 2013 and December 2014 and were between 18 and 80 years old with a probable diagnosis of amyotrophic lateral sclerosis or primary lateral sclerosis, were on an antispasticity regimen for at least 30 days, and had a spasticity score of at least 1 in two muscle groups on the 5-point Modified Ashworth Scale. Participants titrated for the first 2 weeks before maintaining their treatment for 4 weeks.
Of 59 participants at final follow-up, Modified Ashworth Scale scores improved in the nabiximols group (29 participants) by a mean of –0.11 points, compared with worsening by a mean of 0.16 points in the placebo group (30 participants). The researchers noted that there were no participants who withdrew from the study, nabiximols was well-tolerated, and there were no serious adverse events in the nabiximols group; however, there were 22 participants in the nabiximols group and 8 participants in the placebo group who experienced an adverse event from any cause.
“This study is, to our knowledge, the first randomized controlled trial of safety and efficacy of a pharmacological treatment for spasticity and the first trial of nabiximols in motor neuron disease,” Dr. Riva and his colleagues wrote. “Our results suggest that the study drug is well tolerated and provides first evidence of efficacy in terms of controlling spasticity in patients with motor neuron disease.”
The study was funded by the Italian Research Foundation for Amyotrophic Lateral Sclerosis. GW Pharma, which developed nabiximols, provided the study drug and placebo. Many of the authors reported financial disclosures with pharmaceutical companies.
SOURCE: Riva N et al. Lancet Neurol. 2018 Dec 13. doi: 10.1016/S1474-4422(18)30406-X.
Although the results of Riva et al. are encouraging, the study had several major limitations and future research in the form of larger, multicenter, randomized controlled trials is needed, Marianne de Visser, MD, PhD, wrote in a related editorial.
Dr. de Visser noted a bias in the study as it randomized 16 patients with predominantly upper motor neuron involvement to the nabiximols group. The treatment could potentially have benefited those patients, for whom spasticity is the prevailing symptom, more than the 13 patients randomized to the nabiximols group who had classic amyotrophic lateral sclerosis involving both upper and lower neurons. In addition, Riva et al. did not differentiate between patients with upper and lower limb spasticity or patients with bulbar spasticity and those without, she said.
The use of the Modified Ashworth Scale was also a potential issue, because while it has been used in previous studies examining antispastic treatment efficacy, “it lacked sensitivity in studies of the efficacy of cannabinoids in patients with multiple sclerosis–related spasticity, and new spasticity numeric rating or visual analogue scales are being adopted,” Dr. de Visser wrote.
The number of adverse effects in the treatment group could have also unblinded researchers, which may have affected the significant findings, she said.
“Before asking for approval of cannabinoids for symptomatic treatment of spasticity in patients with amyotrophic lateral sclerosis, further studies are needed to establish the frequency of spasticity in the various presentations of motor neuron disease, and also whether reductions in spasticity improve quality of life,” Dr. de Visser said in a press release. “Natural history studies including all subtypes of motor neuron disease and better outcome measures aimed at assessment of spasticity are required. Dr. Riva and colleagues’ data are encouraging, and larger multicenter, randomized controlled trials should be done to identify which subgroups of patients derive clinically significant benefits from nabiximols.”
Marianne de Visser, MD, PhD, is with the department of neurology at Amsterdam University Medical Center. She reported no relevant conflicts of interest. Her remarks are taken from an editorial accompanying the study by Dr. Riva and associates (Lancet Neurol. 2018 Dec 13. doi: 10.1016/S1474-4422[18]30493-9 ).
Although the results of Riva et al. are encouraging, the study had several major limitations and future research in the form of larger, multicenter, randomized controlled trials is needed, Marianne de Visser, MD, PhD, wrote in a related editorial.
Dr. de Visser noted a bias in the study as it randomized 16 patients with predominantly upper motor neuron involvement to the nabiximols group. The treatment could potentially have benefited those patients, for whom spasticity is the prevailing symptom, more than the 13 patients randomized to the nabiximols group who had classic amyotrophic lateral sclerosis involving both upper and lower neurons. In addition, Riva et al. did not differentiate between patients with upper and lower limb spasticity or patients with bulbar spasticity and those without, she said.
The use of the Modified Ashworth Scale was also a potential issue, because while it has been used in previous studies examining antispastic treatment efficacy, “it lacked sensitivity in studies of the efficacy of cannabinoids in patients with multiple sclerosis–related spasticity, and new spasticity numeric rating or visual analogue scales are being adopted,” Dr. de Visser wrote.
The number of adverse effects in the treatment group could have also unblinded researchers, which may have affected the significant findings, she said.
“Before asking for approval of cannabinoids for symptomatic treatment of spasticity in patients with amyotrophic lateral sclerosis, further studies are needed to establish the frequency of spasticity in the various presentations of motor neuron disease, and also whether reductions in spasticity improve quality of life,” Dr. de Visser said in a press release. “Natural history studies including all subtypes of motor neuron disease and better outcome measures aimed at assessment of spasticity are required. Dr. Riva and colleagues’ data are encouraging, and larger multicenter, randomized controlled trials should be done to identify which subgroups of patients derive clinically significant benefits from nabiximols.”
Marianne de Visser, MD, PhD, is with the department of neurology at Amsterdam University Medical Center. She reported no relevant conflicts of interest. Her remarks are taken from an editorial accompanying the study by Dr. Riva and associates (Lancet Neurol. 2018 Dec 13. doi: 10.1016/S1474-4422[18]30493-9 ).
Although the results of Riva et al. are encouraging, the study had several major limitations and future research in the form of larger, multicenter, randomized controlled trials is needed, Marianne de Visser, MD, PhD, wrote in a related editorial.
Dr. de Visser noted a bias in the study as it randomized 16 patients with predominantly upper motor neuron involvement to the nabiximols group. The treatment could potentially have benefited those patients, for whom spasticity is the prevailing symptom, more than the 13 patients randomized to the nabiximols group who had classic amyotrophic lateral sclerosis involving both upper and lower neurons. In addition, Riva et al. did not differentiate between patients with upper and lower limb spasticity or patients with bulbar spasticity and those without, she said.
The use of the Modified Ashworth Scale was also a potential issue, because while it has been used in previous studies examining antispastic treatment efficacy, “it lacked sensitivity in studies of the efficacy of cannabinoids in patients with multiple sclerosis–related spasticity, and new spasticity numeric rating or visual analogue scales are being adopted,” Dr. de Visser wrote.
The number of adverse effects in the treatment group could have also unblinded researchers, which may have affected the significant findings, she said.
“Before asking for approval of cannabinoids for symptomatic treatment of spasticity in patients with amyotrophic lateral sclerosis, further studies are needed to establish the frequency of spasticity in the various presentations of motor neuron disease, and also whether reductions in spasticity improve quality of life,” Dr. de Visser said in a press release. “Natural history studies including all subtypes of motor neuron disease and better outcome measures aimed at assessment of spasticity are required. Dr. Riva and colleagues’ data are encouraging, and larger multicenter, randomized controlled trials should be done to identify which subgroups of patients derive clinically significant benefits from nabiximols.”
Marianne de Visser, MD, PhD, is with the department of neurology at Amsterdam University Medical Center. She reported no relevant conflicts of interest. Her remarks are taken from an editorial accompanying the study by Dr. Riva and associates (Lancet Neurol. 2018 Dec 13. doi: 10.1016/S1474-4422[18]30493-9 ).
Nabiximols, a cannabis-based oral spray containing delta-9 tetrahydrocannabinol and cannabidiol, significantly improved spasticity symptoms in combination with antispasticity drugs in patients with motor neuron disease in a randomized, double-blind, placebo-controlled, parallel-group, phase 2 clinical trial.
Nabiximols proved superior to a placebo spray when both were given to patients with either amyotrophic lateral sclerosis or primary lateral sclerosis as part of an antispasticity regimen in the 6-week, CANALS (Cannabis Sativa Extract in Amyotrophic Lateral Sclerosis and other Motor Neuron Disease) study at four Italian centers, Nilo Riva, MD, PhD, of the San Raffaele Scientific Institute in Milan and his colleagues reported in The Lancet Neurology. Nabiximols is approved for the treatment of spasticity due to multiple sclerosis in multiple countries, but not in the United States.
“There is no cure for motor neuron disease, so improved symptom control and quality of life are important for patients,” Dr. Riva stated in a press release. “Our proof-of-concept trial showed a beneficial effect of THC-CBD [delta-9 tetrahydrocannabinol and cannabidiol] spray in people on treatment-resistant spasticity and pain.
“Despite these encouraging findings, we must first confirm that THC-CBD spray is effective and safe in larger, longer-term phase 3 trials,” Dr. Riva added.
The patients enrolled in the phase 2 trial between January 2013 and December 2014 and were between 18 and 80 years old with a probable diagnosis of amyotrophic lateral sclerosis or primary lateral sclerosis, were on an antispasticity regimen for at least 30 days, and had a spasticity score of at least 1 in two muscle groups on the 5-point Modified Ashworth Scale. Participants titrated for the first 2 weeks before maintaining their treatment for 4 weeks.
Of 59 participants at final follow-up, Modified Ashworth Scale scores improved in the nabiximols group (29 participants) by a mean of –0.11 points, compared with worsening by a mean of 0.16 points in the placebo group (30 participants). The researchers noted that there were no participants who withdrew from the study, nabiximols was well-tolerated, and there were no serious adverse events in the nabiximols group; however, there were 22 participants in the nabiximols group and 8 participants in the placebo group who experienced an adverse event from any cause.
“This study is, to our knowledge, the first randomized controlled trial of safety and efficacy of a pharmacological treatment for spasticity and the first trial of nabiximols in motor neuron disease,” Dr. Riva and his colleagues wrote. “Our results suggest that the study drug is well tolerated and provides first evidence of efficacy in terms of controlling spasticity in patients with motor neuron disease.”
The study was funded by the Italian Research Foundation for Amyotrophic Lateral Sclerosis. GW Pharma, which developed nabiximols, provided the study drug and placebo. Many of the authors reported financial disclosures with pharmaceutical companies.
SOURCE: Riva N et al. Lancet Neurol. 2018 Dec 13. doi: 10.1016/S1474-4422(18)30406-X.
Nabiximols, a cannabis-based oral spray containing delta-9 tetrahydrocannabinol and cannabidiol, significantly improved spasticity symptoms in combination with antispasticity drugs in patients with motor neuron disease in a randomized, double-blind, placebo-controlled, parallel-group, phase 2 clinical trial.
Nabiximols proved superior to a placebo spray when both were given to patients with either amyotrophic lateral sclerosis or primary lateral sclerosis as part of an antispasticity regimen in the 6-week, CANALS (Cannabis Sativa Extract in Amyotrophic Lateral Sclerosis and other Motor Neuron Disease) study at four Italian centers, Nilo Riva, MD, PhD, of the San Raffaele Scientific Institute in Milan and his colleagues reported in The Lancet Neurology. Nabiximols is approved for the treatment of spasticity due to multiple sclerosis in multiple countries, but not in the United States.
“There is no cure for motor neuron disease, so improved symptom control and quality of life are important for patients,” Dr. Riva stated in a press release. “Our proof-of-concept trial showed a beneficial effect of THC-CBD [delta-9 tetrahydrocannabinol and cannabidiol] spray in people on treatment-resistant spasticity and pain.
“Despite these encouraging findings, we must first confirm that THC-CBD spray is effective and safe in larger, longer-term phase 3 trials,” Dr. Riva added.
The patients enrolled in the phase 2 trial between January 2013 and December 2014 and were between 18 and 80 years old with a probable diagnosis of amyotrophic lateral sclerosis or primary lateral sclerosis, were on an antispasticity regimen for at least 30 days, and had a spasticity score of at least 1 in two muscle groups on the 5-point Modified Ashworth Scale. Participants titrated for the first 2 weeks before maintaining their treatment for 4 weeks.
Of 59 participants at final follow-up, Modified Ashworth Scale scores improved in the nabiximols group (29 participants) by a mean of –0.11 points, compared with worsening by a mean of 0.16 points in the placebo group (30 participants). The researchers noted that there were no participants who withdrew from the study, nabiximols was well-tolerated, and there were no serious adverse events in the nabiximols group; however, there were 22 participants in the nabiximols group and 8 participants in the placebo group who experienced an adverse event from any cause.
“This study is, to our knowledge, the first randomized controlled trial of safety and efficacy of a pharmacological treatment for spasticity and the first trial of nabiximols in motor neuron disease,” Dr. Riva and his colleagues wrote. “Our results suggest that the study drug is well tolerated and provides first evidence of efficacy in terms of controlling spasticity in patients with motor neuron disease.”
The study was funded by the Italian Research Foundation for Amyotrophic Lateral Sclerosis. GW Pharma, which developed nabiximols, provided the study drug and placebo. Many of the authors reported financial disclosures with pharmaceutical companies.
SOURCE: Riva N et al. Lancet Neurol. 2018 Dec 13. doi: 10.1016/S1474-4422(18)30406-X.
FROM THE LANCET NEUROLOGY
Key clinical point:
Major finding: In the nabiximols group, Modified Ashworth Scale scores improved by mean of –0.11 points, compared with worsening by a mean of 0.16 points in the placebo group.
Study details: A multicenter, double-blinded, randomized, placebo-controlled, phase 2 trial of 59 participants with spasticity symptoms from motor neuron disease from four tertiary motor neuron centers in Italy.
Disclosures: The study was funded by the Italian Research Foundation for Amyotrophic Lateral Sclerosis. GW Pharma, which developed nabiximols, provided the study drug and placebo. Many of the authors reported financial disclosures with pharmaceutical companies.
Source: Riva N et al. Lancet Neurol. 2018 Dec 13. doi: 10.1016/S1474-4422(18)30406-X