NEW YORK - Patients with lymphedema may reduce their risk of cellulitis, as well as the number of outpatient visits, by using an advanced pneumatic compression device (APCD), according to a new study.

"Our study demonstrates, for the first time, that receipt of an advanced pneumatic compression device is associated with significant improvements in key clinical endpoints for lymphedema patients, both for those with cancer and those without," Dr. Pinar Karaca-Mandic of the University of Minnesota School of Public Health in Minneapolis said by email.

"This finding has important implications for the patients who suffer from the disease, especially for those who have high rates of cellulitis. These devices serve as a viable self-management option and can reduce the need for more intensive outpatient care in rehabilitative settings," she added.

Advanced devices have more garment chambers and greater adjustability than earlier devices, the researchers wrote.

Dr. Karaca-Mandic and colleagues used a commercial insurance claims database to compare outcomes for 12 months before and 12 months after APCD purchase (Flexitouch System, Tactile Medical) by 718 patients (374 with cancer) between 2008 and 2012.

Lymphedema-related outcomes had either primary or secondary diagnosis codes.

The patients' mean age was 54.2, 84.8% were female, and 71.6% were non-Hispanic white. Just over half (52.2%) had hypertension, and breast cancer (39.6%) was the predominant disease in the cancer group.

As reported online October 7 in JAMA Dermatology, the adjusted rate of cellulitis diagnoses fell from 21.1% before APCD use to 4.5% afterward (p<0.001), a 79% decline. The noncancer group had a 75% decline, from 28.8% to 7.3% (p<0.001).

The noncancer group also had a 54% decline in adjusted rate of hospitalizations, from 7.0% to 3.2% (p=0.02), the authors reported.

Both groups had declines in receipt of manual therapy, from an adjusted rate of 35.6% before APCD use to 24.9% afterward for cancer patients (p<0.001) and from 32.3% to 21.2% for noncancer patients (p<0.001).

The adjusted rate of outpatient visits fell from 58.6% to 41.4% in the cancer cohort and from 52.6% to 31.4% in the noncancer group (p<0.001 for both).

Total costs per patient, excluding medical equipment, declined from $2597 to $1642 for cancer patients (p=0.002) and from $2937 to $1883 (p=0.007) for noncancer patients.

"While our findings are based upon the outcomes from one specific device, it is possible other such devices may also reduce patient burden. This warrants explorations in future studies. In addition, our study was not designed to assess the long term effectiveness of the device. That should be studied in future work," Dr. Karaca-Mandic explained.

Also, she pointed out, her team didn't look at nonmonetary expenses such as productivity loss and caretaker costs. "To the extent that device use improves physical functioning and lowers such costs as well, the impact is likely much larger than we can measure," she added.

Dr. Peter J. Franks, of the Center for Research and Implementation of Clinical Practice in London, UK, said by email, "We have these devices that appear to work. The problem is that the evidence on efficacy and cost effectiveness is so poor. The article gave some retrospective observational data that implied that the incidence of infection (cellulitis) was reduced. This is important, as infections lead to further deterioration of the lymphatic system, making the situation worse for the patient and increasing the risk of further infections."

"It is hard to say how generalizable the results are to other devices, though fundamentally they all work in similar ways," said Dr. Franks, who coauthored an accompanying editorial. "I think that this is an important step in how we consider the use of medical devices."

Cynthia Shechter, an occupational therapist in New York City who is a lymphedema specialist for cancer patients, said by email, "When looking for the right device, look for a pump that contains multiple chambers, operates on a short thirty-second cycle time, and applies graduated compression."

"The body operates on a pressure gradient system, so it is imperative to obtain a gradient or graduated compression pump. Pressure at the feet or hand is greater than the thigh or shoulder," she added.

"Clinicians practicing in the treatment of lymphedema need to be open-minded regarding less traditional treatment options for this insidious condition, including the use of traditional and advanced pneumatic compression devices," Shechter said.

"This study indicates that use of an APCD reduces the necessity for therapy. However, rehabilitation therapy for primary and secondary lymphedema, at least a short course of

treatment, is important, especially in order to ensure patients are adequately educated in lymphedema care, management, and precautions," she said.

"There should be a follow-up study performed to discuss a patient's ability to sustain use of the APCD versus a traditional pneumatic pump, and the long-term success in both preventing infection and in reduction of therapy visits," Shechter said.

Tactile Medical partially supported this research and employs one coauthor as chief medical officer. Dr. Karaca-Mandic, Dr. Franks, and his coauthor reported consulting for the company.

NEW YORK - Patients with lymphedema may reduce their risk of cellulitis, as well as the number of outpatient visits, by using an advanced pneumatic compression device (APCD), according to a new study.

"Our study demonstrates, for the first time, that receipt of an advanced pneumatic compression device is associated with significant improvements in key clinical endpoints for lymphedema patients, both for those with cancer and those without," Dr. Pinar Karaca-Mandic of the University of Minnesota School of Public Health in Minneapolis said by email.

"This finding has important implications for the patients who suffer from the disease, especially for those who have high rates of cellulitis. These devices serve as a viable self-management option and can reduce the need for more intensive outpatient care in rehabilitative settings," she added.

Advanced devices have more garment chambers and greater adjustability than earlier devices, the researchers wrote.

Dr. Karaca-Mandic and colleagues used a commercial insurance claims database to compare outcomes for 12 months before and 12 months after APCD purchase (Flexitouch System, Tactile Medical) by 718 patients (374 with cancer) between 2008 and 2012.

Lymphedema-related outcomes had either primary or secondary diagnosis codes.

The patients' mean age was 54.2, 84.8% were female, and 71.6% were non-Hispanic white. Just over half (52.2%) had hypertension, and breast cancer (39.6%) was the predominant disease in the cancer group.

As reported online October 7 in JAMA Dermatology, the adjusted rate of cellulitis diagnoses fell from 21.1% before APCD use to 4.5% afterward (p<0.001), a 79% decline. The noncancer group had a 75% decline, from 28.8% to 7.3% (p<0.001).

The noncancer group also had a 54% decline in adjusted rate of hospitalizations, from 7.0% to 3.2% (p=0.02), the authors reported.

Both groups had declines in receipt of manual therapy, from an adjusted rate of 35.6% before APCD use to 24.9% afterward for cancer patients (p<0.001) and from 32.3% to 21.2% for noncancer patients (p<0.001).

The adjusted rate of outpatient visits fell from 58.6% to 41.4% in the cancer cohort and from 52.6% to 31.4% in the noncancer group (p<0.001 for both).

Total costs per patient, excluding medical equipment, declined from $2597 to $1642 for cancer patients (p=0.002) and from $2937 to $1883 (p=0.007) for noncancer patients.

"While our findings are based upon the outcomes from one specific device, it is possible other such devices may also reduce patient burden. This warrants explorations in future studies. In addition, our study was not designed to assess the long term effectiveness of the device. That should be studied in future work," Dr. Karaca-Mandic explained.

Also, she pointed out, her team didn't look at nonmonetary expenses such as productivity loss and caretaker costs. "To the extent that device use improves physical functioning and lowers such costs as well, the impact is likely much larger than we can measure," she added.

Dr. Peter J. Franks, of the Center for Research and Implementation of Clinical Practice in London, UK, said by email, "We have these devices that appear to work. The problem is that the evidence on efficacy and cost effectiveness is so poor. The article gave some retrospective observational data that implied that the incidence of infection (cellulitis) was reduced. This is important, as infections lead to further deterioration of the lymphatic system, making the situation worse for the patient and increasing the risk of further infections."

"It is hard to say how generalizable the results are to other devices, though fundamentally they all work in similar ways," said Dr. Franks, who coauthored an accompanying editorial. "I think that this is an important step in how we consider the use of medical devices."

Cynthia Shechter, an occupational therapist in New York City who is a lymphedema specialist for cancer patients, said by email, "When looking for the right device, look for a pump that contains multiple chambers, operates on a short thirty-second cycle time, and applies graduated compression."

"The body operates on a pressure gradient system, so it is imperative to obtain a gradient or graduated compression pump. Pressure at the feet or hand is greater than the thigh or shoulder," she added.

"Clinicians practicing in the treatment of lymphedema need to be open-minded regarding less traditional treatment options for this insidious condition, including the use of traditional and advanced pneumatic compression devices," Shechter said.

"This study indicates that use of an APCD reduces the necessity for therapy. However, rehabilitation therapy for primary and secondary lymphedema, at least a short course of

treatment, is important, especially in order to ensure patients are adequately educated in lymphedema care, management, and precautions," she said.

"There should be a follow-up study performed to discuss a patient's ability to sustain use of the APCD versus a traditional pneumatic pump, and the long-term success in both preventing infection and in reduction of therapy visits," Shechter said.

Tactile Medical partially supported this research and employs one coauthor as chief medical officer. Dr. Karaca-Mandic, Dr. Franks, and his coauthor reported consulting for the company.

NEW YORK - Patients with lymphedema may reduce their risk of cellulitis, as well as the number of outpatient visits, by using an advanced pneumatic compression device (APCD), according to a new study.

"Our study demonstrates, for the first time, that receipt of an advanced pneumatic compression device is associated with significant improvements in key clinical endpoints for lymphedema patients, both for those with cancer and those without," Dr. Pinar Karaca-Mandic of the University of Minnesota School of Public Health in Minneapolis said by email.

"This finding has important implications for the patients who suffer from the disease, especially for those who have high rates of cellulitis. These devices serve as a viable self-management option and can reduce the need for more intensive outpatient care in rehabilitative settings," she added.

Advanced devices have more garment chambers and greater adjustability than earlier devices, the researchers wrote.

Dr. Karaca-Mandic and colleagues used a commercial insurance claims database to compare outcomes for 12 months before and 12 months after APCD purchase (Flexitouch System, Tactile Medical) by 718 patients (374 with cancer) between 2008 and 2012.

Lymphedema-related outcomes had either primary or secondary diagnosis codes.

The patients' mean age was 54.2, 84.8% were female, and 71.6% were non-Hispanic white. Just over half (52.2%) had hypertension, and breast cancer (39.6%) was the predominant disease in the cancer group.

As reported online October 7 in JAMA Dermatology, the adjusted rate of cellulitis diagnoses fell from 21.1% before APCD use to 4.5% afterward (p<0.001), a 79% decline. The noncancer group had a 75% decline, from 28.8% to 7.3% (p<0.001).

The noncancer group also had a 54% decline in adjusted rate of hospitalizations, from 7.0% to 3.2% (p=0.02), the authors reported.

Both groups had declines in receipt of manual therapy, from an adjusted rate of 35.6% before APCD use to 24.9% afterward for cancer patients (p<0.001) and from 32.3% to 21.2% for noncancer patients (p<0.001).

The adjusted rate of outpatient visits fell from 58.6% to 41.4% in the cancer cohort and from 52.6% to 31.4% in the noncancer group (p<0.001 for both).

Total costs per patient, excluding medical equipment, declined from $2597 to $1642 for cancer patients (p=0.002) and from $2937 to $1883 (p=0.007) for noncancer patients.

"While our findings are based upon the outcomes from one specific device, it is possible other such devices may also reduce patient burden. This warrants explorations in future studies. In addition, our study was not designed to assess the long term effectiveness of the device. That should be studied in future work," Dr. Karaca-Mandic explained.

Also, she pointed out, her team didn't look at nonmonetary expenses such as productivity loss and caretaker costs. "To the extent that device use improves physical functioning and lowers such costs as well, the impact is likely much larger than we can measure," she added.

Dr. Peter J. Franks, of the Center for Research and Implementation of Clinical Practice in London, UK, said by email, "We have these devices that appear to work. The problem is that the evidence on efficacy and cost effectiveness is so poor. The article gave some retrospective observational data that implied that the incidence of infection (cellulitis) was reduced. This is important, as infections lead to further deterioration of the lymphatic system, making the situation worse for the patient and increasing the risk of further infections."

"It is hard to say how generalizable the results are to other devices, though fundamentally they all work in similar ways," said Dr. Franks, who coauthored an accompanying editorial. "I think that this is an important step in how we consider the use of medical devices."

Cynthia Shechter, an occupational therapist in New York City who is a lymphedema specialist for cancer patients, said by email, "When looking for the right device, look for a pump that contains multiple chambers, operates on a short thirty-second cycle time, and applies graduated compression."

"The body operates on a pressure gradient system, so it is imperative to obtain a gradient or graduated compression pump. Pressure at the feet or hand is greater than the thigh or shoulder," she added.

"Clinicians practicing in the treatment of lymphedema need to be open-minded regarding less traditional treatment options for this insidious condition, including the use of traditional and advanced pneumatic compression devices," Shechter said.

"This study indicates that use of an APCD reduces the necessity for therapy. However, rehabilitation therapy for primary and secondary lymphedema, at least a short course of

treatment, is important, especially in order to ensure patients are adequately educated in lymphedema care, management, and precautions," she said.

"There should be a follow-up study performed to discuss a patient's ability to sustain use of the APCD versus a traditional pneumatic pump, and the long-term success in both preventing infection and in reduction of therapy visits," Shechter said.

Tactile Medical partially supported this research and employs one coauthor as chief medical officer. Dr. Karaca-Mandic, Dr. Franks, and his coauthor reported consulting for the company.

Endovascular mechanical thrombectomy yielded better function and revascularization rates but similar mortality and intracranial hemorrhage rates as standard medical therapy using tissue plasminogen activator (tPA) in a meta-analysis of eight high-quality randomized clinical trials comparing the two approaches for acute ischemic stroke.

The results were published online Nov. 3 in JAMA.

Copyright American Stroke Association

This meta-analysis included only large multicenter trials published from 2013 to the present. Previous trials and meta-analyses “had several well-recognized limitations” including inconsistent use of vascular imaging to confirm vessel occlusion before randomization, variable use of tPA in patients who eventually were assigned to endovascular therapy, and reliance on less effective and now outdated mechanical devices, said Dr. Jetan H. Badhiwala of the division of neurosurgery, University of Toronto, and his associates.

The eight trials included 2,423 patients (mean age, 67.4 years); 46.7% were women. A total of 1,313 patients underwent endovascular therapy, defined as the intra-arterial use of a microcatheter or other device for mechanical thrombectomy, with or without the local use of a chemical thrombolytic agent. The remaining 1,110 received standard medical therapy (tPA). The interval between stroke onset and endovascular treatment varied from 5 to 12 hours across these studies, with a mean of 3.8 hours.

Patients who had endovascular thrombectomy showed significantly higher rates of functional independence at 90 days (44.6%) than did those who had tPA (31.8%), for an OR of 1.71 and a number needed to treat of 8. The rate of angiographic revascularization at 24 hours also was markedly higher for endovascular thrombectomy (75.8% vs 34.1%), for an OR of 6.49, the investigators said (JAMA 2015;314:1832-43).

However, there were no significant differences between the two study groups in rates of symptomatic intracranial hemorrhage at 90 days (5.7% vs 5.1%) or all-cause mortality at 90 days (15.8% vs 17.8%), and overall morbidity including in-hospital rates of deep venous thrombosis, MI, and pneumonia also were similar.

No sponsor or source of financial support was reported for this study. Dr. Badhiwala and his associates reported having no relevant financial disclosures.

Endovascular mechanical thrombectomy yielded better function and revascularization rates but similar mortality and intracranial hemorrhage rates as standard medical therapy using tissue plasminogen activator (tPA) in a meta-analysis of eight high-quality randomized clinical trials comparing the two approaches for acute ischemic stroke.

The results were published online Nov. 3 in JAMA.

Copyright American Stroke Association

This meta-analysis included only large multicenter trials published from 2013 to the present. Previous trials and meta-analyses “had several well-recognized limitations” including inconsistent use of vascular imaging to confirm vessel occlusion before randomization, variable use of tPA in patients who eventually were assigned to endovascular therapy, and reliance on less effective and now outdated mechanical devices, said Dr. Jetan H. Badhiwala of the division of neurosurgery, University of Toronto, and his associates.

The eight trials included 2,423 patients (mean age, 67.4 years); 46.7% were women. A total of 1,313 patients underwent endovascular therapy, defined as the intra-arterial use of a microcatheter or other device for mechanical thrombectomy, with or without the local use of a chemical thrombolytic agent. The remaining 1,110 received standard medical therapy (tPA). The interval between stroke onset and endovascular treatment varied from 5 to 12 hours across these studies, with a mean of 3.8 hours.

Patients who had endovascular thrombectomy showed significantly higher rates of functional independence at 90 days (44.6%) than did those who had tPA (31.8%), for an OR of 1.71 and a number needed to treat of 8. The rate of angiographic revascularization at 24 hours also was markedly higher for endovascular thrombectomy (75.8% vs 34.1%), for an OR of 6.49, the investigators said (JAMA 2015;314:1832-43).

However, there were no significant differences between the two study groups in rates of symptomatic intracranial hemorrhage at 90 days (5.7% vs 5.1%) or all-cause mortality at 90 days (15.8% vs 17.8%), and overall morbidity including in-hospital rates of deep venous thrombosis, MI, and pneumonia also were similar.

No sponsor or source of financial support was reported for this study. Dr. Badhiwala and his associates reported having no relevant financial disclosures.

Endovascular mechanical thrombectomy yielded better function and revascularization rates but similar mortality and intracranial hemorrhage rates as standard medical therapy using tissue plasminogen activator (tPA) in a meta-analysis of eight high-quality randomized clinical trials comparing the two approaches for acute ischemic stroke.

The results were published online Nov. 3 in JAMA.

Copyright American Stroke Association

This meta-analysis included only large multicenter trials published from 2013 to the present. Previous trials and meta-analyses “had several well-recognized limitations” including inconsistent use of vascular imaging to confirm vessel occlusion before randomization, variable use of tPA in patients who eventually were assigned to endovascular therapy, and reliance on less effective and now outdated mechanical devices, said Dr. Jetan H. Badhiwala of the division of neurosurgery, University of Toronto, and his associates.

The eight trials included 2,423 patients (mean age, 67.4 years); 46.7% were women. A total of 1,313 patients underwent endovascular therapy, defined as the intra-arterial use of a microcatheter or other device for mechanical thrombectomy, with or without the local use of a chemical thrombolytic agent. The remaining 1,110 received standard medical therapy (tPA). The interval between stroke onset and endovascular treatment varied from 5 to 12 hours across these studies, with a mean of 3.8 hours.

Patients who had endovascular thrombectomy showed significantly higher rates of functional independence at 90 days (44.6%) than did those who had tPA (31.8%), for an OR of 1.71 and a number needed to treat of 8. The rate of angiographic revascularization at 24 hours also was markedly higher for endovascular thrombectomy (75.8% vs 34.1%), for an OR of 6.49, the investigators said (JAMA 2015;314:1832-43).

However, there were no significant differences between the two study groups in rates of symptomatic intracranial hemorrhage at 90 days (5.7% vs 5.1%) or all-cause mortality at 90 days (15.8% vs 17.8%), and overall morbidity including in-hospital rates of deep venous thrombosis, MI, and pneumonia also were similar.

No sponsor or source of financial support was reported for this study. Dr. Badhiwala and his associates reported having no relevant financial disclosures.

The Susan G. Komen Foundation estimates that 84% of breast cancers are found through mammography.¹ Clearly, the value of mammography is proven. But controversy and confusion abound on how much mammography, and beginning at what age, is best for women.

Currently, the United States Preventive Services Task Force (USPSTF), the American Cancer Society (ACS), and the American College of Obstetricians and Gynecologists (ACOG) all have differing recommendations about mammography and about the importance of clinical breast examinations. These inconsistencies largely are due to different interpretations of the same data, not the data itself, and tend to center on how harm is defined and measured. Importantly, these differences can wreak havoc on our patients’ confidence in our counsel and decision making, and can complicate women’s access to screening. Under the Affordable Care Act, women are guaranteed coverage of annual mammograms, but new USPSTF recommendations, due out soon, may undermine that guarantee.

On October 20, ACOG responded to the ACS’ new recommendations on breast cancer screening by emphasizing our continued advice that women should begin annual mammography screening at age 40, along with a clinical breast exam.²

Consensus conference plansIn an effort to address widespread confusion among patients, health care professionals, and payers, ACOG is convening a consensus conference in January 2016, with the goal of arriving at a consistent set of guidelines that can be agreed to, implemented clinically across the country, and hopefully adopted by insurers, as well. Major organizations and providers of women’s health care, including ACS, will gather to evaluate and interpret the data in greater detail and to consider the available data in the broader context of patient care.

Without doubt, guidelines and recommendations will need to evolve as new evidence emerges, but our hope is that scientific and medical organizations can look at the same evidence and speak with one voice on what is best for women’s health. Our patients would benefit from that alone.

ACOG’s recommendations, summarized

• Clinical breast examination every year for women aged 19 and older.
• Screening mammography every year for women aged 40 and older.
• Breast self-awareness has the potential to detect palpable breast cancer and can be recommended.²

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The Susan G. Komen Foundation estimates that 84% of breast cancers are found through mammography.¹ Clearly, the value of mammography is proven. But controversy and confusion abound on how much mammography, and beginning at what age, is best for women.

Currently, the United States Preventive Services Task Force (USPSTF), the American Cancer Society (ACS), and the American College of Obstetricians and Gynecologists (ACOG) all have differing recommendations about mammography and about the importance of clinical breast examinations. These inconsistencies largely are due to different interpretations of the same data, not the data itself, and tend to center on how harm is defined and measured. Importantly, these differences can wreak havoc on our patients’ confidence in our counsel and decision making, and can complicate women’s access to screening. Under the Affordable Care Act, women are guaranteed coverage of annual mammograms, but new USPSTF recommendations, due out soon, may undermine that guarantee.

On October 20, ACOG responded to the ACS’ new recommendations on breast cancer screening by emphasizing our continued advice that women should begin annual mammography screening at age 40, along with a clinical breast exam.²

Consensus conference plansIn an effort to address widespread confusion among patients, health care professionals, and payers, ACOG is convening a consensus conference in January 2016, with the goal of arriving at a consistent set of guidelines that can be agreed to, implemented clinically across the country, and hopefully adopted by insurers, as well. Major organizations and providers of women’s health care, including ACS, will gather to evaluate and interpret the data in greater detail and to consider the available data in the broader context of patient care.

Without doubt, guidelines and recommendations will need to evolve as new evidence emerges, but our hope is that scientific and medical organizations can look at the same evidence and speak with one voice on what is best for women’s health. Our patients would benefit from that alone.

ACOG’s recommendations, summarized

• Clinical breast examination every year for women aged 19 and older.
• Screening mammography every year for women aged 40 and older.
• Breast self-awareness has the potential to detect palpable breast cancer and can be recommended.²

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The Susan G. Komen Foundation estimates that 84% of breast cancers are found through mammography.¹ Clearly, the value of mammography is proven. But controversy and confusion abound on how much mammography, and beginning at what age, is best for women.

Currently, the United States Preventive Services Task Force (USPSTF), the American Cancer Society (ACS), and the American College of Obstetricians and Gynecologists (ACOG) all have differing recommendations about mammography and about the importance of clinical breast examinations. These inconsistencies largely are due to different interpretations of the same data, not the data itself, and tend to center on how harm is defined and measured. Importantly, these differences can wreak havoc on our patients’ confidence in our counsel and decision making, and can complicate women’s access to screening. Under the Affordable Care Act, women are guaranteed coverage of annual mammograms, but new USPSTF recommendations, due out soon, may undermine that guarantee.

On October 20, ACOG responded to the ACS’ new recommendations on breast cancer screening by emphasizing our continued advice that women should begin annual mammography screening at age 40, along with a clinical breast exam.²

Consensus conference plansIn an effort to address widespread confusion among patients, health care professionals, and payers, ACOG is convening a consensus conference in January 2016, with the goal of arriving at a consistent set of guidelines that can be agreed to, implemented clinically across the country, and hopefully adopted by insurers, as well. Major organizations and providers of women’s health care, including ACS, will gather to evaluate and interpret the data in greater detail and to consider the available data in the broader context of patient care.

Without doubt, guidelines and recommendations will need to evolve as new evidence emerges, but our hope is that scientific and medical organizations can look at the same evidence and speak with one voice on what is best for women’s health. Our patients would benefit from that alone.

ACOG’s recommendations, summarized

• Clinical breast examination every year for women aged 19 and older.
• Screening mammography every year for women aged 40 and older.
• Breast self-awareness has the potential to detect palpable breast cancer and can be recommended.²

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Mantle cell lymphoma

NEW YORK—Despite an “unprecedented” single-agent response rate and progression-free survival (PFS) in previously treated mantle cell lymphoma (MCL) patients, those with multiple risk factors have a dismal outcome following ibrutinib failure.

So after ibrutinib, what’s next in MCL? That was the question asked at Lymphoma & Myeloma 2015.

Peter Martin, MD, of Weill Cornell Medical College in New York, New York, discussed some possibilities.

Ibrutinib (Imbruvica) was approved by the US Food and Drug Administration for MCL based on the PCYC-1104 trial, which showed an overall response rate of 68%. In the MCL2001 trial, the overall response rate was 63%. 

The median PFS for MCL was 13 months in PCYC-1104 and 10.5 months in MCL2001. The median overall survival (OS) was close to 2 years in PCYC-1104 and 18 months in MCL2001.

“So this is where I think it starts to get interesting,” Dr Martin said. “People were able to live for several months after progressing on ibrutinib. [However,] our experience at Cornell was not necessarily consistent with that.”

Cornell investigators, along with colleagues from Ohio State University, compiled data on patients who had been treated in clinical trials at their institutions and reviewed their survival after progression on ibrutinib. These patients had a median OS of 4 months. 

In reviewing the patients’ Mantle Cell Lymphoma International Prognostic Index (MIPI) scores, Dr Martin said they were arguably a higher-risk population.

Dr Martin collected data on 114 relapsed/refractory MCL patients from centers around the world and found they had a lower response rate (50%) with ibrutinib overall and a lower duration of ibrutinib therapy (4.7 months).

The median OS after stopping ibrutinib was 2.9 months for the entire group. For patients who did not receive any subsequent therapy after failure, it was 0.8 months. Patients who received treatment after ibrutinib failure had a median OS of 5.8 months.

“And it didn’t seem to matter what we gave,” Dr Martin said. “Those treatments were pretty short-lived.” 

The median time to next treatment with the first subsequent therapy was 2.4 months. These therapies included bendamustine, cytarabine, and lenalidomide. 

“There was no statistical association between survival and choice of therapy,” Dr Martin said.

What was significant, by univariate Cox regression analysis, was the patients’ MIPI prior to ibrutinib therapy (P=0.0002) and the duration of ibrutinib treatment (P=0.0465).

“So at this point in time, I think it’s fair to say that there is insufficient data to recommend any specific treatment following ibrutinib failure,” Dr Martin said.

However, he did make a few suggestions for treating high-risk patients.

Treatment suggestions after ibrutinib failure

Dr Martin’s first suggestion is to focus on symptom management rather than active therapy for the older, frailer patients. Second, consider allogeneic stem cell transplant in any high-risk patient responding to ibrutinib.

Third, consider continuing ibrutinib therapy while starting the next therapy. And fourth, consider some form of continuous therapy that does not depend on TP53.

Dr Martin admitted that what to do following ibrutinib failure remains cloudy.

“Conducting a clinical trial will be tricky,” he said, “because the median time from ibrutinib failure to the next therapy was 9 days, and we’re targeting a very high-risk patient population.”

In addition, on average 80% have expression of Ki67.

Currently, a phase 2 trial of copanlisib (NCT02455297) is the only post-ibrutinib clinical trial in MCL open. Copanlisib is a potent and reversible phosphatidylinositol-3-kinase (PI3K) inhibitor with activity against both alpha and delta isoforms of PI3K. Preliminary results of the trial demonstrated response in 5 of 7 MCL patients.

So perhaps the best approach, Dr Martin suggested, would be to improve response and prevent relapse while on ibrutinib using combination therapies.

A phase 1/1b trial of ibrutinib with bendamustine and rituximab (BR) is underway. Of 17 MCL patients treated thus far, 94% have responded, and 76% have achieved a CR. But 25% developed grade 3 rash.

Ibrutinib is also being studied in combination with rituximab in MCL. The combination has produced an overall response rate of 88%, with 40% of patients achieving a CR.

“My interpretation from all these studies is you can probably add ibrutinib to any other effective anti-MCL therapy and improve that therapy,” Dr Martin said. “But there are questions, obviously, that still arise.”

Overcoming ibrutinib resistance

Dr Martin explained that, to use combinations rationally, we need to understand mechanisms of ibrutinib resistance, “and that’s not so straightforward.”

Mutations in MCL likely have multiple mechanisms of resistance. Mutations occur predominantly in 3 groups of genes involving NF-kB, PIM/mTOR, and epigenetic modifiers. 

A number of trials are underway to hit some of these pathways, Dr Martin said.

Researchers at Cornell are studying ibrutinib plus palbociclib, an inhibitor of CDK4/CDK6 approved for advanced breast cancer, in a phase 1 trial of MCL patients.

The combination “very early on, has seen a high number of complete responses, which have been exciting,” Dr Martin said.

There are many ongoing ibrutinib trials in previously treated patients, including ones with carfilzomib, palbociclib, bortezomib, venetoclax, lenalidomide, and TGR-1202. In addition, the frontline trial of BR +/- ibrutinib is expected to have results soon.  

“[A]nd once that happens, my guess is that this frontline trial, once it’s read out, essentially, makes all these other trials irrelevant because the minute ibrutinib moves into the frontline setting, it makes it very difficult to evaluate in a subsequent setting,” Dr Martin said. “So within a couple of years, it will be standard in the frontline setting.”

Dr Martin is concerned that resources are insufficient—there are too many studies, too few patients, and too little time—to find another, potentially more effective agent or combination. 

He said there won’t be a one-size-fits-all approach to MCL either before or after ibrutinib, and collaboration among institutions, companies, and cooperative groups will be needed. 

“Management in the post-ibrutinib setting remains unclear,” he said, “and these patients should be treated in a clinical trial if possible.”

Mantle cell lymphoma

NEW YORK—Despite an “unprecedented” single-agent response rate and progression-free survival (PFS) in previously treated mantle cell lymphoma (MCL) patients, those with multiple risk factors have a dismal outcome following ibrutinib failure.

So after ibrutinib, what’s next in MCL? That was the question asked at Lymphoma & Myeloma 2015.

Peter Martin, MD, of Weill Cornell Medical College in New York, New York, discussed some possibilities.

Ibrutinib (Imbruvica) was approved by the US Food and Drug Administration for MCL based on the PCYC-1104 trial, which showed an overall response rate of 68%. In the MCL2001 trial, the overall response rate was 63%. 

The median PFS for MCL was 13 months in PCYC-1104 and 10.5 months in MCL2001. The median overall survival (OS) was close to 2 years in PCYC-1104 and 18 months in MCL2001.

“So this is where I think it starts to get interesting,” Dr Martin said. “People were able to live for several months after progressing on ibrutinib. [However,] our experience at Cornell was not necessarily consistent with that.”

Cornell investigators, along with colleagues from Ohio State University, compiled data on patients who had been treated in clinical trials at their institutions and reviewed their survival after progression on ibrutinib. These patients had a median OS of 4 months. 

In reviewing the patients’ Mantle Cell Lymphoma International Prognostic Index (MIPI) scores, Dr Martin said they were arguably a higher-risk population.

Dr Martin collected data on 114 relapsed/refractory MCL patients from centers around the world and found they had a lower response rate (50%) with ibrutinib overall and a lower duration of ibrutinib therapy (4.7 months).

The median OS after stopping ibrutinib was 2.9 months for the entire group. For patients who did not receive any subsequent therapy after failure, it was 0.8 months. Patients who received treatment after ibrutinib failure had a median OS of 5.8 months.

“And it didn’t seem to matter what we gave,” Dr Martin said. “Those treatments were pretty short-lived.” 

The median time to next treatment with the first subsequent therapy was 2.4 months. These therapies included bendamustine, cytarabine, and lenalidomide. 

“There was no statistical association between survival and choice of therapy,” Dr Martin said.

What was significant, by univariate Cox regression analysis, was the patients’ MIPI prior to ibrutinib therapy (P=0.0002) and the duration of ibrutinib treatment (P=0.0465).

“So at this point in time, I think it’s fair to say that there is insufficient data to recommend any specific treatment following ibrutinib failure,” Dr Martin said.

However, he did make a few suggestions for treating high-risk patients.

Treatment suggestions after ibrutinib failure

Dr Martin’s first suggestion is to focus on symptom management rather than active therapy for the older, frailer patients. Second, consider allogeneic stem cell transplant in any high-risk patient responding to ibrutinib.

Third, consider continuing ibrutinib therapy while starting the next therapy. And fourth, consider some form of continuous therapy that does not depend on TP53.

Dr Martin admitted that what to do following ibrutinib failure remains cloudy.

“Conducting a clinical trial will be tricky,” he said, “because the median time from ibrutinib failure to the next therapy was 9 days, and we’re targeting a very high-risk patient population.”

In addition, on average 80% have expression of Ki67.

Currently, a phase 2 trial of copanlisib (NCT02455297) is the only post-ibrutinib clinical trial in MCL open. Copanlisib is a potent and reversible phosphatidylinositol-3-kinase (PI3K) inhibitor with activity against both alpha and delta isoforms of PI3K. Preliminary results of the trial demonstrated response in 5 of 7 MCL patients.

So perhaps the best approach, Dr Martin suggested, would be to improve response and prevent relapse while on ibrutinib using combination therapies.

A phase 1/1b trial of ibrutinib with bendamustine and rituximab (BR) is underway. Of 17 MCL patients treated thus far, 94% have responded, and 76% have achieved a CR. But 25% developed grade 3 rash.

Ibrutinib is also being studied in combination with rituximab in MCL. The combination has produced an overall response rate of 88%, with 40% of patients achieving a CR.

“My interpretation from all these studies is you can probably add ibrutinib to any other effective anti-MCL therapy and improve that therapy,” Dr Martin said. “But there are questions, obviously, that still arise.”

Overcoming ibrutinib resistance

Dr Martin explained that, to use combinations rationally, we need to understand mechanisms of ibrutinib resistance, “and that’s not so straightforward.”

Mutations in MCL likely have multiple mechanisms of resistance. Mutations occur predominantly in 3 groups of genes involving NF-kB, PIM/mTOR, and epigenetic modifiers. 

A number of trials are underway to hit some of these pathways, Dr Martin said.

Researchers at Cornell are studying ibrutinib plus palbociclib, an inhibitor of CDK4/CDK6 approved for advanced breast cancer, in a phase 1 trial of MCL patients.

The combination “very early on, has seen a high number of complete responses, which have been exciting,” Dr Martin said.

There are many ongoing ibrutinib trials in previously treated patients, including ones with carfilzomib, palbociclib, bortezomib, venetoclax, lenalidomide, and TGR-1202. In addition, the frontline trial of BR +/- ibrutinib is expected to have results soon.  

“[A]nd once that happens, my guess is that this frontline trial, once it’s read out, essentially, makes all these other trials irrelevant because the minute ibrutinib moves into the frontline setting, it makes it very difficult to evaluate in a subsequent setting,” Dr Martin said. “So within a couple of years, it will be standard in the frontline setting.”

Dr Martin is concerned that resources are insufficient—there are too many studies, too few patients, and too little time—to find another, potentially more effective agent or combination. 

He said there won’t be a one-size-fits-all approach to MCL either before or after ibrutinib, and collaboration among institutions, companies, and cooperative groups will be needed. 

“Management in the post-ibrutinib setting remains unclear,” he said, “and these patients should be treated in a clinical trial if possible.”

Mantle cell lymphoma

NEW YORK—Despite an “unprecedented” single-agent response rate and progression-free survival (PFS) in previously treated mantle cell lymphoma (MCL) patients, those with multiple risk factors have a dismal outcome following ibrutinib failure.

So after ibrutinib, what’s next in MCL? That was the question asked at Lymphoma & Myeloma 2015.

Peter Martin, MD, of Weill Cornell Medical College in New York, New York, discussed some possibilities.

Ibrutinib (Imbruvica) was approved by the US Food and Drug Administration for MCL based on the PCYC-1104 trial, which showed an overall response rate of 68%. In the MCL2001 trial, the overall response rate was 63%. 

The median PFS for MCL was 13 months in PCYC-1104 and 10.5 months in MCL2001. The median overall survival (OS) was close to 2 years in PCYC-1104 and 18 months in MCL2001.

“So this is where I think it starts to get interesting,” Dr Martin said. “People were able to live for several months after progressing on ibrutinib. [However,] our experience at Cornell was not necessarily consistent with that.”

Cornell investigators, along with colleagues from Ohio State University, compiled data on patients who had been treated in clinical trials at their institutions and reviewed their survival after progression on ibrutinib. These patients had a median OS of 4 months. 

In reviewing the patients’ Mantle Cell Lymphoma International Prognostic Index (MIPI) scores, Dr Martin said they were arguably a higher-risk population.

Dr Martin collected data on 114 relapsed/refractory MCL patients from centers around the world and found they had a lower response rate (50%) with ibrutinib overall and a lower duration of ibrutinib therapy (4.7 months).

The median OS after stopping ibrutinib was 2.9 months for the entire group. For patients who did not receive any subsequent therapy after failure, it was 0.8 months. Patients who received treatment after ibrutinib failure had a median OS of 5.8 months.

“And it didn’t seem to matter what we gave,” Dr Martin said. “Those treatments were pretty short-lived.” 

The median time to next treatment with the first subsequent therapy was 2.4 months. These therapies included bendamustine, cytarabine, and lenalidomide. 

“There was no statistical association between survival and choice of therapy,” Dr Martin said.

What was significant, by univariate Cox regression analysis, was the patients’ MIPI prior to ibrutinib therapy (P=0.0002) and the duration of ibrutinib treatment (P=0.0465).

“So at this point in time, I think it’s fair to say that there is insufficient data to recommend any specific treatment following ibrutinib failure,” Dr Martin said.

However, he did make a few suggestions for treating high-risk patients.

Treatment suggestions after ibrutinib failure

Dr Martin’s first suggestion is to focus on symptom management rather than active therapy for the older, frailer patients. Second, consider allogeneic stem cell transplant in any high-risk patient responding to ibrutinib.

Third, consider continuing ibrutinib therapy while starting the next therapy. And fourth, consider some form of continuous therapy that does not depend on TP53.

Dr Martin admitted that what to do following ibrutinib failure remains cloudy.

“Conducting a clinical trial will be tricky,” he said, “because the median time from ibrutinib failure to the next therapy was 9 days, and we’re targeting a very high-risk patient population.”

In addition, on average 80% have expression of Ki67.

Currently, a phase 2 trial of copanlisib (NCT02455297) is the only post-ibrutinib clinical trial in MCL open. Copanlisib is a potent and reversible phosphatidylinositol-3-kinase (PI3K) inhibitor with activity against both alpha and delta isoforms of PI3K. Preliminary results of the trial demonstrated response in 5 of 7 MCL patients.

So perhaps the best approach, Dr Martin suggested, would be to improve response and prevent relapse while on ibrutinib using combination therapies.

A phase 1/1b trial of ibrutinib with bendamustine and rituximab (BR) is underway. Of 17 MCL patients treated thus far, 94% have responded, and 76% have achieved a CR. But 25% developed grade 3 rash.

Ibrutinib is also being studied in combination with rituximab in MCL. The combination has produced an overall response rate of 88%, with 40% of patients achieving a CR.

“My interpretation from all these studies is you can probably add ibrutinib to any other effective anti-MCL therapy and improve that therapy,” Dr Martin said. “But there are questions, obviously, that still arise.”

Overcoming ibrutinib resistance

Dr Martin explained that, to use combinations rationally, we need to understand mechanisms of ibrutinib resistance, “and that’s not so straightforward.”

Mutations in MCL likely have multiple mechanisms of resistance. Mutations occur predominantly in 3 groups of genes involving NF-kB, PIM/mTOR, and epigenetic modifiers. 

A number of trials are underway to hit some of these pathways, Dr Martin said.

Researchers at Cornell are studying ibrutinib plus palbociclib, an inhibitor of CDK4/CDK6 approved for advanced breast cancer, in a phase 1 trial of MCL patients.

The combination “very early on, has seen a high number of complete responses, which have been exciting,” Dr Martin said.

There are many ongoing ibrutinib trials in previously treated patients, including ones with carfilzomib, palbociclib, bortezomib, venetoclax, lenalidomide, and TGR-1202. In addition, the frontline trial of BR +/- ibrutinib is expected to have results soon.  

“[A]nd once that happens, my guess is that this frontline trial, once it’s read out, essentially, makes all these other trials irrelevant because the minute ibrutinib moves into the frontline setting, it makes it very difficult to evaluate in a subsequent setting,” Dr Martin said. “So within a couple of years, it will be standard in the frontline setting.”

Dr Martin is concerned that resources are insufficient—there are too many studies, too few patients, and too little time—to find another, potentially more effective agent or combination. 

He said there won’t be a one-size-fits-all approach to MCL either before or after ibrutinib, and collaboration among institutions, companies, and cooperative groups will be needed. 

“Management in the post-ibrutinib setting remains unclear,” he said, “and these patients should be treated in a clinical trial if possible.”

Blood donation in progress

ANAHEIM, CA—Data from the STRIDE study have revealed interventions that can mitigate iron deficiency in repeat blood donors.

The study showed that providing repeat blood donors with iron supplements significantly improved their iron status.

But informing donors about their ferritin levels and recommending they take iron pills also significantly improved their iron status.

Meanwhile, patients in control groups became more iron-deficient over the study period.

The study also revealed no difference in ferritin or hemoglobin levels between patients who took 19 mg of iron and those who took 38 mg.

Alan E. Mast, MD, PhD, of the Blood Center of Wisconsin in Milwaukee, presented these results at the 2015 AABB Annual Meeting (abstract S34-030E).

Dr Mast said blood donation removes a lot of iron, and iron is used to make hemoglobin in new red blood cells. But the measurement of hemoglobin does not accurately reflect iron stores.

“That’s really important,” he said. “The only test we do to qualify a blood donor doesn’t tell us if they have iron deficiency or not. And because of that, many regular blood donors become iron-deficient and continue to donate blood.”

Dr Mast said the strategies that appear to mitigate iron deficiency in regular blood donors are oral iron supplements and delaying the donation interval for more than 6 months.

“[However,] the effectiveness of providing iron pills versus providing the donor with information about their iron status has not been previously examined,” he noted.

This was the goal of the STRIDE (Strategies to Reduce Iron Deficiency) study.

Study design

This blinded, randomized, placebo-controlled study enrolled 692 frequent blood donors from 3 blood centers. They were assigned to 1 of 5 arms for 2 years of follow-up.

In 3 arms, donors received pills for 60 days after each donation. They received 38 mg or 19 mg of elemental iron, or they received a placebo.

Donors in the remaining 2 arms received letters after each donation—either a letter informing them of their iron status or a “control” letter thanking them for donating blood and urging them to donate again.

Every iron status letter reported the donor’s ferritin level. If the level was >26 mg/L, the letter simply urged donors to donate again. If the ferritin level was ≤26 mg/L, the letter recommended taking a self-purchased iron supplement (17 mg to 38 mg) and/or delaying donation for 6 months. Donors were allowed to choose either option, both, or neither.

The researchers measured ferritin, soluble transferrin receptor, and complete blood count at each donation.

Study completion

Of the 692 subjects randomized, 393 completed a final visit. The researchers noted that a donor’s ferritin level at enrollment, race, or gender did not impact study completion. However, older subjects were more likely to complete the study.

In all, 116 subjects were lost to follow-up, and the numbers were similar between the study arms. Thirty-nine subjects discontinued due to adverse events—16 in the 38 mg iron group, 12 in the 19 mg iron group, and 11 in the placebo group.

And 144 subjects discontinued for “other reasons”—9 in the iron status letter arm, 10 in the control letter arm, 30 in the 38 mg iron arm, 42 in the 19 mg iron arm, and 53 in the placebo arm.

Subjects’ reasons for discontinuation included not wanting to take a pill every day, believing they are in the placebo group and wanting to take iron, and subjects’ physicians recommending they start taking iron.

“Donors in pill arms de-enrolled more frequently than those in the letter arms, and the important thing to remember is that this is a controlled, randomized study where the donors did not know what they were taking,” Dr Mast said. “And I think that, a lot of the time, if donors had known what they were taking, they might have continued to participate in the study or continued to take the pills.”

Results

Dr Mast noted that, at the study’s end, all measures of iron deficiency were statistically indistinguishable in the 3 intervention arms, which were statistically different from the 2 control arms.

Between study enrollment and the donors’ final visit, the prevalence of ferritin <26 mg/L was unchanged in the control groups. But it had declined by more than 50% in the 3 intervention groups—19 mg iron, 38 mg iron, and iron status letter (P<0.0001 for all 3).

The prevalence of ferritin <12 mg/L was unchanged in the 2 control arms, but it had declined by more than 70% in the 3 intervention arms—19 mg iron (P<0.0001), 38 mg iron (P<0.01), and iron status letter (P<0.0001).

The researchers also calculated the odds ratios for iron deficiency over all donor visits. The odds for ferritin <26 or <12 mg/L decreased more than 80% in the 19 mg iron group (P<0.01 for both ferritin measurements) and the 38 mg iron group (P<0.01 for both).

The odds for ferritin <26 or <12 mg/L decreased about 50% in the iron status letter arm (P<0.01 for both).

And the odds for ferritin <12 mg/L increased about 50% in the control groups (P<0.01 for both the placebo and control letter groups). However, there was no significant difference for ferritin <26 mg/L in either control group.

Lastly, the researchers performed longitudinal modeling of hemoglobin. They found that hemoglobin increased >0.03 g/dL in the 19 mg and 38 mg iron arms (P<0.01 for both), decreasing the odds for low hemoglobin deferral about 50%.

Hemoglobin decreased >0.3 g/dL in the control groups (P<0.0001 for both the placebo and control letter groups), increasing the odds for low hemoglobin deferral about 70%.

“Interestingly, [being] in the iron status letter group did not affect hemoglobin that much in the longitudinal modeling of the donors,” Dr Mast noted.

In closing, he pointed out that the 19 mg and 38 mg iron pills were equally effective for mitigating iron deficiency and improving hemoglobin in these blood donors.

“From a physiology point of view, I think this is one of the most important results of this study,” Dr Mast said. “There’s absolutely no difference. There was no trend for 38 mg to be better than 19 in any analysis that we did.”

“There’s lots of reasons that could be happening, but I think it’s scientifically interesting and operationally interesting. And it’s important because we can tell donors—ask them to take a multivitamin with 19 mg of iron, and that will be sufficient to treat iron deficiency.”

Blood donation in progress

ANAHEIM, CA—Data from the STRIDE study have revealed interventions that can mitigate iron deficiency in repeat blood donors.

The study showed that providing repeat blood donors with iron supplements significantly improved their iron status.

But informing donors about their ferritin levels and recommending they take iron pills also significantly improved their iron status.

Meanwhile, patients in control groups became more iron-deficient over the study period.

The study also revealed no difference in ferritin or hemoglobin levels between patients who took 19 mg of iron and those who took 38 mg.

Alan E. Mast, MD, PhD, of the Blood Center of Wisconsin in Milwaukee, presented these results at the 2015 AABB Annual Meeting (abstract S34-030E).

Dr Mast said blood donation removes a lot of iron, and iron is used to make hemoglobin in new red blood cells. But the measurement of hemoglobin does not accurately reflect iron stores.

“That’s really important,” he said. “The only test we do to qualify a blood donor doesn’t tell us if they have iron deficiency or not. And because of that, many regular blood donors become iron-deficient and continue to donate blood.”

Dr Mast said the strategies that appear to mitigate iron deficiency in regular blood donors are oral iron supplements and delaying the donation interval for more than 6 months.

“[However,] the effectiveness of providing iron pills versus providing the donor with information about their iron status has not been previously examined,” he noted.

This was the goal of the STRIDE (Strategies to Reduce Iron Deficiency) study.

Study design

This blinded, randomized, placebo-controlled study enrolled 692 frequent blood donors from 3 blood centers. They were assigned to 1 of 5 arms for 2 years of follow-up.

In 3 arms, donors received pills for 60 days after each donation. They received 38 mg or 19 mg of elemental iron, or they received a placebo.

Donors in the remaining 2 arms received letters after each donation—either a letter informing them of their iron status or a “control” letter thanking them for donating blood and urging them to donate again.

Every iron status letter reported the donor’s ferritin level. If the level was >26 mg/L, the letter simply urged donors to donate again. If the ferritin level was ≤26 mg/L, the letter recommended taking a self-purchased iron supplement (17 mg to 38 mg) and/or delaying donation for 6 months. Donors were allowed to choose either option, both, or neither.

The researchers measured ferritin, soluble transferrin receptor, and complete blood count at each donation.

Study completion

Of the 692 subjects randomized, 393 completed a final visit. The researchers noted that a donor’s ferritin level at enrollment, race, or gender did not impact study completion. However, older subjects were more likely to complete the study.

In all, 116 subjects were lost to follow-up, and the numbers were similar between the study arms. Thirty-nine subjects discontinued due to adverse events—16 in the 38 mg iron group, 12 in the 19 mg iron group, and 11 in the placebo group.

And 144 subjects discontinued for “other reasons”—9 in the iron status letter arm, 10 in the control letter arm, 30 in the 38 mg iron arm, 42 in the 19 mg iron arm, and 53 in the placebo arm.

Subjects’ reasons for discontinuation included not wanting to take a pill every day, believing they are in the placebo group and wanting to take iron, and subjects’ physicians recommending they start taking iron.

“Donors in pill arms de-enrolled more frequently than those in the letter arms, and the important thing to remember is that this is a controlled, randomized study where the donors did not know what they were taking,” Dr Mast said. “And I think that, a lot of the time, if donors had known what they were taking, they might have continued to participate in the study or continued to take the pills.”

Results

Dr Mast noted that, at the study’s end, all measures of iron deficiency were statistically indistinguishable in the 3 intervention arms, which were statistically different from the 2 control arms.

Between study enrollment and the donors’ final visit, the prevalence of ferritin <26 mg/L was unchanged in the control groups. But it had declined by more than 50% in the 3 intervention groups—19 mg iron, 38 mg iron, and iron status letter (P<0.0001 for all 3).

The prevalence of ferritin <12 mg/L was unchanged in the 2 control arms, but it had declined by more than 70% in the 3 intervention arms—19 mg iron (P<0.0001), 38 mg iron (P<0.01), and iron status letter (P<0.0001).

The researchers also calculated the odds ratios for iron deficiency over all donor visits. The odds for ferritin <26 or <12 mg/L decreased more than 80% in the 19 mg iron group (P<0.01 for both ferritin measurements) and the 38 mg iron group (P<0.01 for both).

The odds for ferritin <26 or <12 mg/L decreased about 50% in the iron status letter arm (P<0.01 for both).

And the odds for ferritin <12 mg/L increased about 50% in the control groups (P<0.01 for both the placebo and control letter groups). However, there was no significant difference for ferritin <26 mg/L in either control group.

Lastly, the researchers performed longitudinal modeling of hemoglobin. They found that hemoglobin increased >0.03 g/dL in the 19 mg and 38 mg iron arms (P<0.01 for both), decreasing the odds for low hemoglobin deferral about 50%.

Hemoglobin decreased >0.3 g/dL in the control groups (P<0.0001 for both the placebo and control letter groups), increasing the odds for low hemoglobin deferral about 70%.

“Interestingly, [being] in the iron status letter group did not affect hemoglobin that much in the longitudinal modeling of the donors,” Dr Mast noted.

In closing, he pointed out that the 19 mg and 38 mg iron pills were equally effective for mitigating iron deficiency and improving hemoglobin in these blood donors.

“From a physiology point of view, I think this is one of the most important results of this study,” Dr Mast said. “There’s absolutely no difference. There was no trend for 38 mg to be better than 19 in any analysis that we did.”

“There’s lots of reasons that could be happening, but I think it’s scientifically interesting and operationally interesting. And it’s important because we can tell donors—ask them to take a multivitamin with 19 mg of iron, and that will be sufficient to treat iron deficiency.”

Blood donation in progress

ANAHEIM, CA—Data from the STRIDE study have revealed interventions that can mitigate iron deficiency in repeat blood donors.

The study showed that providing repeat blood donors with iron supplements significantly improved their iron status.

But informing donors about their ferritin levels and recommending they take iron pills also significantly improved their iron status.

Meanwhile, patients in control groups became more iron-deficient over the study period.

The study also revealed no difference in ferritin or hemoglobin levels between patients who took 19 mg of iron and those who took 38 mg.

Alan E. Mast, MD, PhD, of the Blood Center of Wisconsin in Milwaukee, presented these results at the 2015 AABB Annual Meeting (abstract S34-030E).

Dr Mast said blood donation removes a lot of iron, and iron is used to make hemoglobin in new red blood cells. But the measurement of hemoglobin does not accurately reflect iron stores.

“That’s really important,” he said. “The only test we do to qualify a blood donor doesn’t tell us if they have iron deficiency or not. And because of that, many regular blood donors become iron-deficient and continue to donate blood.”

Dr Mast said the strategies that appear to mitigate iron deficiency in regular blood donors are oral iron supplements and delaying the donation interval for more than 6 months.

“[However,] the effectiveness of providing iron pills versus providing the donor with information about their iron status has not been previously examined,” he noted.

This was the goal of the STRIDE (Strategies to Reduce Iron Deficiency) study.

Study design

This blinded, randomized, placebo-controlled study enrolled 692 frequent blood donors from 3 blood centers. They were assigned to 1 of 5 arms for 2 years of follow-up.

In 3 arms, donors received pills for 60 days after each donation. They received 38 mg or 19 mg of elemental iron, or they received a placebo.

Donors in the remaining 2 arms received letters after each donation—either a letter informing them of their iron status or a “control” letter thanking them for donating blood and urging them to donate again.

Every iron status letter reported the donor’s ferritin level. If the level was >26 mg/L, the letter simply urged donors to donate again. If the ferritin level was ≤26 mg/L, the letter recommended taking a self-purchased iron supplement (17 mg to 38 mg) and/or delaying donation for 6 months. Donors were allowed to choose either option, both, or neither.

The researchers measured ferritin, soluble transferrin receptor, and complete blood count at each donation.

Study completion

Of the 692 subjects randomized, 393 completed a final visit. The researchers noted that a donor’s ferritin level at enrollment, race, or gender did not impact study completion. However, older subjects were more likely to complete the study.

In all, 116 subjects were lost to follow-up, and the numbers were similar between the study arms. Thirty-nine subjects discontinued due to adverse events—16 in the 38 mg iron group, 12 in the 19 mg iron group, and 11 in the placebo group.

And 144 subjects discontinued for “other reasons”—9 in the iron status letter arm, 10 in the control letter arm, 30 in the 38 mg iron arm, 42 in the 19 mg iron arm, and 53 in the placebo arm.

Subjects’ reasons for discontinuation included not wanting to take a pill every day, believing they are in the placebo group and wanting to take iron, and subjects’ physicians recommending they start taking iron.

“Donors in pill arms de-enrolled more frequently than those in the letter arms, and the important thing to remember is that this is a controlled, randomized study where the donors did not know what they were taking,” Dr Mast said. “And I think that, a lot of the time, if donors had known what they were taking, they might have continued to participate in the study or continued to take the pills.”

Results

Dr Mast noted that, at the study’s end, all measures of iron deficiency were statistically indistinguishable in the 3 intervention arms, which were statistically different from the 2 control arms.

Between study enrollment and the donors’ final visit, the prevalence of ferritin <26 mg/L was unchanged in the control groups. But it had declined by more than 50% in the 3 intervention groups—19 mg iron, 38 mg iron, and iron status letter (P<0.0001 for all 3).

The prevalence of ferritin <12 mg/L was unchanged in the 2 control arms, but it had declined by more than 70% in the 3 intervention arms—19 mg iron (P<0.0001), 38 mg iron (P<0.01), and iron status letter (P<0.0001).

The researchers also calculated the odds ratios for iron deficiency over all donor visits. The odds for ferritin <26 or <12 mg/L decreased more than 80% in the 19 mg iron group (P<0.01 for both ferritin measurements) and the 38 mg iron group (P<0.01 for both).

The odds for ferritin <26 or <12 mg/L decreased about 50% in the iron status letter arm (P<0.01 for both).

And the odds for ferritin <12 mg/L increased about 50% in the control groups (P<0.01 for both the placebo and control letter groups). However, there was no significant difference for ferritin <26 mg/L in either control group.

Lastly, the researchers performed longitudinal modeling of hemoglobin. They found that hemoglobin increased >0.03 g/dL in the 19 mg and 38 mg iron arms (P<0.01 for both), decreasing the odds for low hemoglobin deferral about 50%.

Hemoglobin decreased >0.3 g/dL in the control groups (P<0.0001 for both the placebo and control letter groups), increasing the odds for low hemoglobin deferral about 70%.

“Interestingly, [being] in the iron status letter group did not affect hemoglobin that much in the longitudinal modeling of the donors,” Dr Mast noted.

In closing, he pointed out that the 19 mg and 38 mg iron pills were equally effective for mitigating iron deficiency and improving hemoglobin in these blood donors.

“From a physiology point of view, I think this is one of the most important results of this study,” Dr Mast said. “There’s absolutely no difference. There was no trend for 38 mg to be better than 19 in any analysis that we did.”

“There’s lots of reasons that could be happening, but I think it’s scientifically interesting and operationally interesting. And it’s important because we can tell donors—ask them to take a multivitamin with 19 mg of iron, and that will be sufficient to treat iron deficiency.”

Fresh frozen plasma

An “early and aggressive” approach to massive blood transfusion can save lives in military combat zones and may provide the same benefit in civilian trauma care as well, according to an article published in the AANA Journal.

The article describes 2 patients who required massive transfusions due to multiple gunshot wounds sustained while in combat zones.

One patient received an inadequate amount of blood products and ultimately died.

But the other patient benefitted from a protocol change to ensure an adequate amount of blood products was delivered quickly.

David Gaskin, CRNA, of Huntsville Memorial Hospital in Texas, and his colleagues described these cases in the journal.

The authors noted that, while providing care in a combat zone, the transfusion of packed red blood cells (PRBC) and fresh frozen plasma (FFP) is performed in a 1:1 ratio. However, the packaging and thawing techniques of the plasma can delay the delivery of blood products and prevent a patient from receiving enough blood.

Another issue in a military environment is the challenge of effectively communicating with live donors on site, which can cause delays in obtaining fresh blood supplies. Both of these issues can have life-threatening consequences for patients.

This is what happened with the first patient described in the article. The 38-year-old man sustained multiple gunshot wounds to the left side of the chest, left side of the back, and flank.

The surgical team was unable to maintain a high ratio of PRBCs to plasma and to infuse an adequate quantity of fresh whole blood (FWB) into this patient. He received 26 units of PRBCs, 5 units of FFP, 3 units of FWB, and 1 unit of cryoprecipitate.

The patient experienced trauma-induced coagulopathy, acidosis, and hypothermia. He died within 2 hours of presentation.

Because of this death, the team identified and implemented a protocol to keep 4 FFP units thawed and ready for immediate use at all times. They also identified and prescreened additional blood donors and implemented a phone roster and base-wide overhead system to enable rapid notification of these donors.

The second patient described in the article benefitted from these changes. This 23-year-old male sustained a gunshot wound to the left lower aspect of the abdomen and multiple gunshot wounds to bilateral lower extremities.

The “early and aggressive” use of FWB and plasma provided the necessary endogenous clotting factors and platelets to promote hemostasis in this patient. He received 18 units of PRBCs, 18 units of FFP, 2 units of cryoprecipitate, and 24 units of FWB.

Gaskin and his colleagues said these results suggest that efforts to incorporate a similar resuscitation strategy into civilian practice may improve outcomes, but it warrants continued study.

Fresh frozen plasma

An “early and aggressive” approach to massive blood transfusion can save lives in military combat zones and may provide the same benefit in civilian trauma care as well, according to an article published in the AANA Journal.

The article describes 2 patients who required massive transfusions due to multiple gunshot wounds sustained while in combat zones.

One patient received an inadequate amount of blood products and ultimately died.

But the other patient benefitted from a protocol change to ensure an adequate amount of blood products was delivered quickly.

David Gaskin, CRNA, of Huntsville Memorial Hospital in Texas, and his colleagues described these cases in the journal.

The authors noted that, while providing care in a combat zone, the transfusion of packed red blood cells (PRBC) and fresh frozen plasma (FFP) is performed in a 1:1 ratio. However, the packaging and thawing techniques of the plasma can delay the delivery of blood products and prevent a patient from receiving enough blood.

Another issue in a military environment is the challenge of effectively communicating with live donors on site, which can cause delays in obtaining fresh blood supplies. Both of these issues can have life-threatening consequences for patients.

This is what happened with the first patient described in the article. The 38-year-old man sustained multiple gunshot wounds to the left side of the chest, left side of the back, and flank.

The surgical team was unable to maintain a high ratio of PRBCs to plasma and to infuse an adequate quantity of fresh whole blood (FWB) into this patient. He received 26 units of PRBCs, 5 units of FFP, 3 units of FWB, and 1 unit of cryoprecipitate.

The patient experienced trauma-induced coagulopathy, acidosis, and hypothermia. He died within 2 hours of presentation.

Because of this death, the team identified and implemented a protocol to keep 4 FFP units thawed and ready for immediate use at all times. They also identified and prescreened additional blood donors and implemented a phone roster and base-wide overhead system to enable rapid notification of these donors.

The second patient described in the article benefitted from these changes. This 23-year-old male sustained a gunshot wound to the left lower aspect of the abdomen and multiple gunshot wounds to bilateral lower extremities.

The “early and aggressive” use of FWB and plasma provided the necessary endogenous clotting factors and platelets to promote hemostasis in this patient. He received 18 units of PRBCs, 18 units of FFP, 2 units of cryoprecipitate, and 24 units of FWB.

Gaskin and his colleagues said these results suggest that efforts to incorporate a similar resuscitation strategy into civilian practice may improve outcomes, but it warrants continued study.

Fresh frozen plasma

An “early and aggressive” approach to massive blood transfusion can save lives in military combat zones and may provide the same benefit in civilian trauma care as well, according to an article published in the AANA Journal.

The article describes 2 patients who required massive transfusions due to multiple gunshot wounds sustained while in combat zones.

One patient received an inadequate amount of blood products and ultimately died.

But the other patient benefitted from a protocol change to ensure an adequate amount of blood products was delivered quickly.

David Gaskin, CRNA, of Huntsville Memorial Hospital in Texas, and his colleagues described these cases in the journal.

The authors noted that, while providing care in a combat zone, the transfusion of packed red blood cells (PRBC) and fresh frozen plasma (FFP) is performed in a 1:1 ratio. However, the packaging and thawing techniques of the plasma can delay the delivery of blood products and prevent a patient from receiving enough blood.

Another issue in a military environment is the challenge of effectively communicating with live donors on site, which can cause delays in obtaining fresh blood supplies. Both of these issues can have life-threatening consequences for patients.

This is what happened with the first patient described in the article. The 38-year-old man sustained multiple gunshot wounds to the left side of the chest, left side of the back, and flank.

The surgical team was unable to maintain a high ratio of PRBCs to plasma and to infuse an adequate quantity of fresh whole blood (FWB) into this patient. He received 26 units of PRBCs, 5 units of FFP, 3 units of FWB, and 1 unit of cryoprecipitate.

The patient experienced trauma-induced coagulopathy, acidosis, and hypothermia. He died within 2 hours of presentation.

Because of this death, the team identified and implemented a protocol to keep 4 FFP units thawed and ready for immediate use at all times. They also identified and prescreened additional blood donors and implemented a phone roster and base-wide overhead system to enable rapid notification of these donors.

The second patient described in the article benefitted from these changes. This 23-year-old male sustained a gunshot wound to the left lower aspect of the abdomen and multiple gunshot wounds to bilateral lower extremities.

The “early and aggressive” use of FWB and plasma provided the necessary endogenous clotting factors and platelets to promote hemostasis in this patient. He received 18 units of PRBCs, 18 units of FFP, 2 units of cryoprecipitate, and 24 units of FWB.

Gaskin and his colleagues said these results suggest that efforts to incorporate a similar resuscitation strategy into civilian practice may improve outcomes, but it warrants continued study.

Micrograph of dendritic cells

The European Medicines Agency (EMA) has granted orphan drug designation to SL-401 for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN).

SL-401 is a targeted therapy directed to the interleukin-3 receptor (IL-3R), which is present on cancer stem cells and tumor bulk in a range of hematologic malignancies.

The drug is composed of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis.

SL-401 already has orphan designation from the EMA to treat acute myeloid leukemia (AML) and from the US Food and Drug Administration (FDA) for the treatment of AML and BPDCN. The drug is under development by Stemline Therapeutics, Inc.

SL-401 research

At ASH 2012 (abstract 3625), researchers reported results with SL-401 in a study of patients with AML, BPDCN, and myelodysplastic syndromes (MDS).

At that time, the study had enrolled 80 patients, including 59 with relapsed or refractory AML, 11 with de novo AML unfit for chemotherapy, 7 with high-risk MDS, and 3 with relapsed/refractory BPDCN.

Patients received a single cycle of SL-401 as a 15-minute intravenous infusion in 1 of 2 dosing regimens to determine the maximum tolerated dose (MTD) and assess antitumor activity.

With regimen A, 45 patients received doses ranging from 4 μg/kg to 12.5 μg/kg every other day for up to 6 doses. With regimen B, 35 patients received doses ranging from 7.1 μg/kg to 22.1 μg/kg daily for up to 5 doses.

Of the 59 patients with relapsed/refractory AML, 2 achieved complete responses (CRs), 5 had partial responses (PRs), and 8 had minor responses (MRs). One CR lasted more than 8 months, and the other lasted more than 25 months.

Of the 11 patients with AML who were not candidates for chemotherapy, 2 had PRs and 1 had an MR. Among the 7 patients with high-risk MDS, there was 1 PR and 1 MR.

And among the 3 patients with BPDCN, there were 2 CRs. One CR lasted more than 2 months, and the other lasted more than 4 months.

The MTD was not achieved with regimen A, but the MTD for regimen B was 16.6 μg/kg/day. The dose-limiting toxicities were a gastrointestinal bleed (n=1), transaminase and creatinine kinase elevations (n=1), and capillary leak syndrome (n=3). There was no evidence of treatment-related bone marrow suppression.

Last year, researchers reported additional results in BPDCN patients (Frankel et al, Blood 2014).

Eleven BPDCN patients received a single course of SL-401 (at 12.5 μg/kg intravenously over 15 minutes) daily for up to 5 doses. Three patients who had initial responses to SL-401 received a second course while in relapse.

Seven of 9 evaluable (78%) patients responded to a single course of SL-401. There were 5 CRs and 2 PRs. The median duration of responses was 5 months (range, 1-20+ months).

The most common adverse events were transient and included fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia.

Three multicenter clinical trials of SL-401 are currently open in the following indications:

• BPDCN and relapsed/refractory AML
• AML patients in first complete remission with minimal residual disease
• Four types of advanced, high-risk myeloproliferative neoplasms, including systemic mastocytosis, advanced symptomatic hypereosinophilic disorder, myelofibrosis, and chronic myelomonocytic leukemia.

Additional SL-401 studies are planned for patients with myeloma, lymphomas, and other leukemias.

About orphan designation

In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug in the European Union benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is on the market. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

In the US, orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

Micrograph of dendritic cells

The European Medicines Agency (EMA) has granted orphan drug designation to SL-401 for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN).

SL-401 is a targeted therapy directed to the interleukin-3 receptor (IL-3R), which is present on cancer stem cells and tumor bulk in a range of hematologic malignancies.

The drug is composed of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis.

SL-401 already has orphan designation from the EMA to treat acute myeloid leukemia (AML) and from the US Food and Drug Administration (FDA) for the treatment of AML and BPDCN. The drug is under development by Stemline Therapeutics, Inc.

SL-401 research

At ASH 2012 (abstract 3625), researchers reported results with SL-401 in a study of patients with AML, BPDCN, and myelodysplastic syndromes (MDS).

At that time, the study had enrolled 80 patients, including 59 with relapsed or refractory AML, 11 with de novo AML unfit for chemotherapy, 7 with high-risk MDS, and 3 with relapsed/refractory BPDCN.

Patients received a single cycle of SL-401 as a 15-minute intravenous infusion in 1 of 2 dosing regimens to determine the maximum tolerated dose (MTD) and assess antitumor activity.

With regimen A, 45 patients received doses ranging from 4 μg/kg to 12.5 μg/kg every other day for up to 6 doses. With regimen B, 35 patients received doses ranging from 7.1 μg/kg to 22.1 μg/kg daily for up to 5 doses.

Of the 59 patients with relapsed/refractory AML, 2 achieved complete responses (CRs), 5 had partial responses (PRs), and 8 had minor responses (MRs). One CR lasted more than 8 months, and the other lasted more than 25 months.

Of the 11 patients with AML who were not candidates for chemotherapy, 2 had PRs and 1 had an MR. Among the 7 patients with high-risk MDS, there was 1 PR and 1 MR.

And among the 3 patients with BPDCN, there were 2 CRs. One CR lasted more than 2 months, and the other lasted more than 4 months.

The MTD was not achieved with regimen A, but the MTD for regimen B was 16.6 μg/kg/day. The dose-limiting toxicities were a gastrointestinal bleed (n=1), transaminase and creatinine kinase elevations (n=1), and capillary leak syndrome (n=3). There was no evidence of treatment-related bone marrow suppression.

Last year, researchers reported additional results in BPDCN patients (Frankel et al, Blood 2014).

Eleven BPDCN patients received a single course of SL-401 (at 12.5 μg/kg intravenously over 15 minutes) daily for up to 5 doses. Three patients who had initial responses to SL-401 received a second course while in relapse.

Seven of 9 evaluable (78%) patients responded to a single course of SL-401. There were 5 CRs and 2 PRs. The median duration of responses was 5 months (range, 1-20+ months).

The most common adverse events were transient and included fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia.

Three multicenter clinical trials of SL-401 are currently open in the following indications:

• BPDCN and relapsed/refractory AML
• AML patients in first complete remission with minimal residual disease
• Four types of advanced, high-risk myeloproliferative neoplasms, including systemic mastocytosis, advanced symptomatic hypereosinophilic disorder, myelofibrosis, and chronic myelomonocytic leukemia.

Additional SL-401 studies are planned for patients with myeloma, lymphomas, and other leukemias.

About orphan designation

In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug in the European Union benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is on the market. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

In the US, orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

Micrograph of dendritic cells

The European Medicines Agency (EMA) has granted orphan drug designation to SL-401 for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN).

SL-401 is a targeted therapy directed to the interleukin-3 receptor (IL-3R), which is present on cancer stem cells and tumor bulk in a range of hematologic malignancies.

The drug is composed of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis.

SL-401 already has orphan designation from the EMA to treat acute myeloid leukemia (AML) and from the US Food and Drug Administration (FDA) for the treatment of AML and BPDCN. The drug is under development by Stemline Therapeutics, Inc.

SL-401 research

At ASH 2012 (abstract 3625), researchers reported results with SL-401 in a study of patients with AML, BPDCN, and myelodysplastic syndromes (MDS).

At that time, the study had enrolled 80 patients, including 59 with relapsed or refractory AML, 11 with de novo AML unfit for chemotherapy, 7 with high-risk MDS, and 3 with relapsed/refractory BPDCN.

Patients received a single cycle of SL-401 as a 15-minute intravenous infusion in 1 of 2 dosing regimens to determine the maximum tolerated dose (MTD) and assess antitumor activity.

With regimen A, 45 patients received doses ranging from 4 μg/kg to 12.5 μg/kg every other day for up to 6 doses. With regimen B, 35 patients received doses ranging from 7.1 μg/kg to 22.1 μg/kg daily for up to 5 doses.

Of the 59 patients with relapsed/refractory AML, 2 achieved complete responses (CRs), 5 had partial responses (PRs), and 8 had minor responses (MRs). One CR lasted more than 8 months, and the other lasted more than 25 months.

Of the 11 patients with AML who were not candidates for chemotherapy, 2 had PRs and 1 had an MR. Among the 7 patients with high-risk MDS, there was 1 PR and 1 MR.

And among the 3 patients with BPDCN, there were 2 CRs. One CR lasted more than 2 months, and the other lasted more than 4 months.

The MTD was not achieved with regimen A, but the MTD for regimen B was 16.6 μg/kg/day. The dose-limiting toxicities were a gastrointestinal bleed (n=1), transaminase and creatinine kinase elevations (n=1), and capillary leak syndrome (n=3). There was no evidence of treatment-related bone marrow suppression.

Last year, researchers reported additional results in BPDCN patients (Frankel et al, Blood 2014).

Eleven BPDCN patients received a single course of SL-401 (at 12.5 μg/kg intravenously over 15 minutes) daily for up to 5 doses. Three patients who had initial responses to SL-401 received a second course while in relapse.

Seven of 9 evaluable (78%) patients responded to a single course of SL-401. There were 5 CRs and 2 PRs. The median duration of responses was 5 months (range, 1-20+ months).

The most common adverse events were transient and included fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia.

Three multicenter clinical trials of SL-401 are currently open in the following indications:

• BPDCN and relapsed/refractory AML
• AML patients in first complete remission with minimal residual disease
• Four types of advanced, high-risk myeloproliferative neoplasms, including systemic mastocytosis, advanced symptomatic hypereosinophilic disorder, myelofibrosis, and chronic myelomonocytic leukemia.

Additional SL-401 studies are planned for patients with myeloma, lymphomas, and other leukemias.

About orphan designation

In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug in the European Union benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is on the market. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

In the US, orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

Clinical question: Does palliative chemotherapy improve quality of life (QOL) in patients with end-stage cancer, regardless of performance status?

Background: There is continued debate about the benefit of palliative chemotherapy at the end of life. Guidelines recommend a good performance score as an indicator of appropriate use of therapy; however, little is known about the benefits and harms of chemotherapy in metastatic cancer patients stratified by performance status.

Study design: Longitudinal, prospective cohort study.

Setting: Multi-institutional in the United States.

Synopsis: Five U.S. institutions enrolled 661 patients with metastatic cancer and estimated life expectancy less than six months; 312 patients who died during the study period were included in the final analysis of postmortem questionnaires of caretakers regarding QOL in the patients’ last week of life. Contrary to current thought, the study demonstrated that patients undergoing end-of-life palliative chemotherapy with good ECOG performance status (0-1) had significantly worse QOL than those avoiding palliative chemotherapy. There was no difference in QOL in patients with worse performance status (ECOG 2-3).

This study is one of the first prospective investigations of this topic and makes a compelling case for withholding palliative chemotherapy at the end of life regardless of performance status. The study is somewhat limited in that the QOL measurement is only for the last week of life and the patients were not randomized into the chemotherapy arm, which could bias results.

Bottom line: Palliative chemotherapy does not improve QOL near death, and may actually worsen QOL in patients with good performance status.

Citation: Prigerson HG, Bao Y, Shah MA, et al. Chemotherapy use, performance status, and quality of life at the end of life. JAMA Oncol. 2015;1(6):778-784.

Clinical question: Does palliative chemotherapy improve quality of life (QOL) in patients with end-stage cancer, regardless of performance status?

Background: There is continued debate about the benefit of palliative chemotherapy at the end of life. Guidelines recommend a good performance score as an indicator of appropriate use of therapy; however, little is known about the benefits and harms of chemotherapy in metastatic cancer patients stratified by performance status.

Study design: Longitudinal, prospective cohort study.

Setting: Multi-institutional in the United States.

Synopsis: Five U.S. institutions enrolled 661 patients with metastatic cancer and estimated life expectancy less than six months; 312 patients who died during the study period were included in the final analysis of postmortem questionnaires of caretakers regarding QOL in the patients’ last week of life. Contrary to current thought, the study demonstrated that patients undergoing end-of-life palliative chemotherapy with good ECOG performance status (0-1) had significantly worse QOL than those avoiding palliative chemotherapy. There was no difference in QOL in patients with worse performance status (ECOG 2-3).

This study is one of the first prospective investigations of this topic and makes a compelling case for withholding palliative chemotherapy at the end of life regardless of performance status. The study is somewhat limited in that the QOL measurement is only for the last week of life and the patients were not randomized into the chemotherapy arm, which could bias results.

Bottom line: Palliative chemotherapy does not improve QOL near death, and may actually worsen QOL in patients with good performance status.

Citation: Prigerson HG, Bao Y, Shah MA, et al. Chemotherapy use, performance status, and quality of life at the end of life. JAMA Oncol. 2015;1(6):778-784.

Clinical question: Does palliative chemotherapy improve quality of life (QOL) in patients with end-stage cancer, regardless of performance status?

Background: There is continued debate about the benefit of palliative chemotherapy at the end of life. Guidelines recommend a good performance score as an indicator of appropriate use of therapy; however, little is known about the benefits and harms of chemotherapy in metastatic cancer patients stratified by performance status.

Study design: Longitudinal, prospective cohort study.

Setting: Multi-institutional in the United States.

Synopsis: Five U.S. institutions enrolled 661 patients with metastatic cancer and estimated life expectancy less than six months; 312 patients who died during the study period were included in the final analysis of postmortem questionnaires of caretakers regarding QOL in the patients’ last week of life. Contrary to current thought, the study demonstrated that patients undergoing end-of-life palliative chemotherapy with good ECOG performance status (0-1) had significantly worse QOL than those avoiding palliative chemotherapy. There was no difference in QOL in patients with worse performance status (ECOG 2-3).

This study is one of the first prospective investigations of this topic and makes a compelling case for withholding palliative chemotherapy at the end of life regardless of performance status. The study is somewhat limited in that the QOL measurement is only for the last week of life and the patients were not randomized into the chemotherapy arm, which could bias results.

Bottom line: Palliative chemotherapy does not improve QOL near death, and may actually worsen QOL in patients with good performance status.

Citation: Prigerson HG, Bao Y, Shah MA, et al. Chemotherapy use, performance status, and quality of life at the end of life. JAMA Oncol. 2015;1(6):778-784.

Clinical question: Does the use of sliding-scale insulin improve blood glucose control in hospitalized patients?

Bottom line: Sliding-scale insulin is commonly used to manage hyperglycemia in hospitalized patients. The evidence suggests that this regimen does not result in better blood glucose control. (LOE = 1a-)

Reference: Lee Y, Lin Y, Leu W et al. Sliding-scale insulin used for blood glucose control: a meta-analysis of randomized controlled trials. Metabolism 2015;64:1183-1192.

Study design: Meta-analysis (randomized controlled trials)

Funding source: Government

Allocation: Uncertain

Setting: Inpatient (any location)

Synopsis: These investigators searched multiple databases including PubMed, EMBASE, and the Cochrane Library to find randomized controlled trials that evaluated the efficacy of sliding-scale insulin to manage hyperglycemia in hospitalized patients. Two authors independently evaluated the studies for inclusion, extracted the data, and performed quality assessments.

Eight of the 11 included studies compared regular insulin sliding scale (RISS) regimens with non–sliding-scale regimens. All RISS regimens consisted of subcutaneous regular insulin injections according to patients' blood glucose levels. Non–sliding-scale regimens consisted of basal-bolus or basal insulin regimens, continuous intravenous insulin infusions, and closed-loop artificial pancreas systems. Target blood glucose levels for individual studies varied greatly and included a range of 100 mg/dL to 150 mg/dL, a goal of less than 140 mg/dL, and a goal of less than 180 mg/dL. Hypoglycemia was generally defined as a glucose level of less than 70 mg/dL, though three of the studies had an even lower cut-off.

In the two studies that evaluated hyperglycemia, one defined it as a glucose level greater than 180 mg/dL while the other defined it as greater than 240 mg/dL. A meta-analysis of relevant data showed no significant difference in the percentage of patients who achieved an average blood glucose level in the target range when comparing RISS with non–sliding-scale regimens. The trend, however, favored the non–sliding-scale group and the difference became significant (relative risk 1.48, 95% CI 1.09-2.02) after one study with a very wide confidence interval was removed. Furthermore, the incidence of hyperglycemia and the mean blood glucose levels were significantly higher in the RISS group.

Although overall hypoglycemic episodes occurred more frequently in the non–sliding-scale group, there was no significant difference detected in the incidence of severe or symptomatic hypoglycemia. Length of hospital stay was also similar in both groups. Finally, one study compared the use of routine diabetes medications plus RISS with routine diabetes medications alone and found no difference in the number of hypoglycemic or hyperglycemic events.

Significant heterogeneity was detected in the results of this meta-analysis and can be attributed to the differing patient populations, insulin regimens, and working definitions in the individual studies as noted above.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question: Does the use of sliding-scale insulin improve blood glucose control in hospitalized patients?

Bottom line: Sliding-scale insulin is commonly used to manage hyperglycemia in hospitalized patients. The evidence suggests that this regimen does not result in better blood glucose control. (LOE = 1a-)

Reference: Lee Y, Lin Y, Leu W et al. Sliding-scale insulin used for blood glucose control: a meta-analysis of randomized controlled trials. Metabolism 2015;64:1183-1192.

Study design: Meta-analysis (randomized controlled trials)

Funding source: Government

Allocation: Uncertain

Setting: Inpatient (any location)

Synopsis: These investigators searched multiple databases including PubMed, EMBASE, and the Cochrane Library to find randomized controlled trials that evaluated the efficacy of sliding-scale insulin to manage hyperglycemia in hospitalized patients. Two authors independently evaluated the studies for inclusion, extracted the data, and performed quality assessments.

Eight of the 11 included studies compared regular insulin sliding scale (RISS) regimens with non–sliding-scale regimens. All RISS regimens consisted of subcutaneous regular insulin injections according to patients' blood glucose levels. Non–sliding-scale regimens consisted of basal-bolus or basal insulin regimens, continuous intravenous insulin infusions, and closed-loop artificial pancreas systems. Target blood glucose levels for individual studies varied greatly and included a range of 100 mg/dL to 150 mg/dL, a goal of less than 140 mg/dL, and a goal of less than 180 mg/dL. Hypoglycemia was generally defined as a glucose level of less than 70 mg/dL, though three of the studies had an even lower cut-off.

In the two studies that evaluated hyperglycemia, one defined it as a glucose level greater than 180 mg/dL while the other defined it as greater than 240 mg/dL. A meta-analysis of relevant data showed no significant difference in the percentage of patients who achieved an average blood glucose level in the target range when comparing RISS with non–sliding-scale regimens. The trend, however, favored the non–sliding-scale group and the difference became significant (relative risk 1.48, 95% CI 1.09-2.02) after one study with a very wide confidence interval was removed. Furthermore, the incidence of hyperglycemia and the mean blood glucose levels were significantly higher in the RISS group.

Although overall hypoglycemic episodes occurred more frequently in the non–sliding-scale group, there was no significant difference detected in the incidence of severe or symptomatic hypoglycemia. Length of hospital stay was also similar in both groups. Finally, one study compared the use of routine diabetes medications plus RISS with routine diabetes medications alone and found no difference in the number of hypoglycemic or hyperglycemic events.

Significant heterogeneity was detected in the results of this meta-analysis and can be attributed to the differing patient populations, insulin regimens, and working definitions in the individual studies as noted above.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question: Does the use of sliding-scale insulin improve blood glucose control in hospitalized patients?

Bottom line: Sliding-scale insulin is commonly used to manage hyperglycemia in hospitalized patients. The evidence suggests that this regimen does not result in better blood glucose control. (LOE = 1a-)

Reference: Lee Y, Lin Y, Leu W et al. Sliding-scale insulin used for blood glucose control: a meta-analysis of randomized controlled trials. Metabolism 2015;64:1183-1192.

Study design: Meta-analysis (randomized controlled trials)

Funding source: Government

Allocation: Uncertain

Setting: Inpatient (any location)

Synopsis: These investigators searched multiple databases including PubMed, EMBASE, and the Cochrane Library to find randomized controlled trials that evaluated the efficacy of sliding-scale insulin to manage hyperglycemia in hospitalized patients. Two authors independently evaluated the studies for inclusion, extracted the data, and performed quality assessments.

Eight of the 11 included studies compared regular insulin sliding scale (RISS) regimens with non–sliding-scale regimens. All RISS regimens consisted of subcutaneous regular insulin injections according to patients' blood glucose levels. Non–sliding-scale regimens consisted of basal-bolus or basal insulin regimens, continuous intravenous insulin infusions, and closed-loop artificial pancreas systems. Target blood glucose levels for individual studies varied greatly and included a range of 100 mg/dL to 150 mg/dL, a goal of less than 140 mg/dL, and a goal of less than 180 mg/dL. Hypoglycemia was generally defined as a glucose level of less than 70 mg/dL, though three of the studies had an even lower cut-off.

In the two studies that evaluated hyperglycemia, one defined it as a glucose level greater than 180 mg/dL while the other defined it as greater than 240 mg/dL. A meta-analysis of relevant data showed no significant difference in the percentage of patients who achieved an average blood glucose level in the target range when comparing RISS with non–sliding-scale regimens. The trend, however, favored the non–sliding-scale group and the difference became significant (relative risk 1.48, 95% CI 1.09-2.02) after one study with a very wide confidence interval was removed. Furthermore, the incidence of hyperglycemia and the mean blood glucose levels were significantly higher in the RISS group.

Although overall hypoglycemic episodes occurred more frequently in the non–sliding-scale group, there was no significant difference detected in the incidence of severe or symptomatic hypoglycemia. Length of hospital stay was also similar in both groups. Finally, one study compared the use of routine diabetes medications plus RISS with routine diabetes medications alone and found no difference in the number of hypoglycemic or hyperglycemic events.

Significant heterogeneity was detected in the results of this meta-analysis and can be attributed to the differing patient populations, insulin regimens, and working definitions in the individual studies as noted above.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.