MADRID – Electrically stimulating the vagus nerve produced clinically meaningful responses in disease activity measures in patients with refractory RA in a small safety study.

A minimal clinically important difference in the 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) and the Clinical Disease Activity Index (CDAI) at 12 weeks was achieved or exceeded by 5 out of 10 patients; with 2 patients achieving DAS28-CRP–defined remission.

The disease activity scores also were paired with MRI scans and showed, in a handful of individuals, that there was improvement in erosions in those with a clinical response. Greater reductions in proinflammatory cytokines – interleukin (IL)-1-beta, IL-6, IL-17, IL-23, and tumor necrosis factor – were seen with neurostimulation, compared with a sham control group.

“The goal here was to use electrical stimulation to modify or modulate, and improve the treatment of active rheumatoid arthritis,” Mark C. Genovese, MD, said in an interview at the European Congress of Rheumatology.

“The reason for choosing refractory patients is, one, there’s a clear unmet need, but two, because this was a first-in-human study using a novel microregulatory device stimulating the vagus nerve, we thought the benefits-to-risk ratio was most appropriate for its first trial in patients with refractory disease,” explained Dr. Genovese, professor of medicine and director of the rheumatology clinic in the division of immunology and rheumatology at Stanford (Calif.) University.

He added: “Over time, if the device proves successful for modulating disease, one can see it potentially being used earlier in the disease. Whether it is developed as a stand-alone or used as an adjunct on additional therapy will have to be determined based on both its efficacy and its safety.”

Neurostimulation is a novel concept in rheumatology but has been used with success in other areas of medicine – including epilepsy and depression – using electrical pulses instead of drugs. The idea behind it is that it stimulates the inflammatory reflex that modulates multiple the inflammatory pathways. Essentially, it’s thought that electrically stimulating the vagus nerve sends signals to the spleen where T-lymphocytes then signal to other immune cells, such as macrophages and monocytes, to temper their production of proinflammatory cytokines and other mediators.

“Unlike traditional immunosuppressive biologics that may be specifically targeting one inflammatory process, by suppressing the inflammatory reflex we believe we can suppress a variety of inflammatory cytokines in the region of between 30% and 70%,” Dr. Genovese said at a press briefing.

Data from a 12-week, open-label study (Proc Natl Acad Sci U S A. 2016;113:8284-9) have already shown that the approach works in patients with refractory RA (n = 17). Once-daily electrical vagus nerve stimulation using an existing device made for treating epilepsy showed that clinically meaningful changes in DAS28-CRP could be achieved through TNF suppression. The effects on systemic TNF release lasted for around 24-48 hours after stimulation.

For the current study, a much smaller, leadless, investigational neurostimulation device was used. Called a MicroRegulator (SetPoint Medical), it is about 1 inch long, less than 2 cc in total volume, and is surgically implanted by a neurosurgeon at the top of the vagus nerve. When activated through an iPad app by the health care professional, it sends electrical impulses down the vagus nerve. The device’s battery is charged externally and wirelessly a few minutes each week. Dr. Genovese noted that the device needs to be turned on for only 60 seconds at a time to have an effect and that patients may feel a vibration but this was not reported in the study as an adverse event.

Results of the first in-human study with the device were presented by Dr. Genovese during the late-breaking clinical trials session at the meeting. He described how a total of 14 patients had the device implanted, the first 3 of whom received once-daily, open-label neurostimulation. The remaining 11 patients were randomized to either once-daily or four-times-daily neurostimulation via the device, or to receive sham therapy in which the device was implanted but not switched on. The patients had moderate to severe RA, defined as four or more tender joints, four or more swollen joints, and a CDAI score greater than 10, plus they had radiologically active disease and an insufficient response to at least two biologic or targeted synthetic disease-modifying antirheumatic drugs with differing mechanisms of action.

All patients went through the same schedule of device charging and they did not know if they were in the active or sham groups. At the end of the study, patients had the option to continue in a long-term safety extension phase, have the device switched off, or could have it surgically removed.

“This trial was specifically a pilot trial to assess the MicroRegulator from a safety standpoint,” Dr. Genovese noted, but it also was designed to “help understand whether or not there was going to be clinical efficacy and applicability.”

While “there were no device or treatment-related serious adverse events,” there were some “surgical complications associated with the initial procedure.” One patient experienced paralysis of the left vocal cord during implantation that later resolved, and others experienced the following: Horner’s syndrome, tenderness and swelling at the surgical site, acute postoperative pain, and rash and pruritus. That said, there were no withdrawals from the study due to adverse events.

Commenting in a press release issued by the European League Against Rheumatism, Thomas Dörner, MD, of Charité Universitätsmedizin Berlin, said, “This is a really exciting development. For many patients suffering from rheumatoid arthritis, current treatments don’t work, or aren’t tolerated. These results open the door to a novel approach to treating not only rheumatoid arthritis, but other chronic inflammatory diseases. This is certainly an area for further study.”

The study was sponsored by SetPoint Medical. Dr. Genovese disclosed receiving consulting fees from and having contracts with/grants with the company and acting as a consultant to Galvani and Vorso. He has also received research support from and served as a consultant to Sanofi/Genzyme, Genentech/Roche, and R-Pharm. Dr. Dörner was not involved in the study and commented as part of his role as the chairperson of the EULAR Scientific Program Committee.

SOURCE: Genovese M et al. Ann Rheum Dis. Jun 2019; 78(Suppl 2):264. Abstract LB0009, doi: 10.1136/annrheumdis-2019-eular.8716

MADRID – Electrically stimulating the vagus nerve produced clinically meaningful responses in disease activity measures in patients with refractory RA in a small safety study.

A minimal clinically important difference in the 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) and the Clinical Disease Activity Index (CDAI) at 12 weeks was achieved or exceeded by 5 out of 10 patients; with 2 patients achieving DAS28-CRP–defined remission.

The disease activity scores also were paired with MRI scans and showed, in a handful of individuals, that there was improvement in erosions in those with a clinical response. Greater reductions in proinflammatory cytokines – interleukin (IL)-1-beta, IL-6, IL-17, IL-23, and tumor necrosis factor – were seen with neurostimulation, compared with a sham control group.

“The goal here was to use electrical stimulation to modify or modulate, and improve the treatment of active rheumatoid arthritis,” Mark C. Genovese, MD, said in an interview at the European Congress of Rheumatology.

“The reason for choosing refractory patients is, one, there’s a clear unmet need, but two, because this was a first-in-human study using a novel microregulatory device stimulating the vagus nerve, we thought the benefits-to-risk ratio was most appropriate for its first trial in patients with refractory disease,” explained Dr. Genovese, professor of medicine and director of the rheumatology clinic in the division of immunology and rheumatology at Stanford (Calif.) University.

He added: “Over time, if the device proves successful for modulating disease, one can see it potentially being used earlier in the disease. Whether it is developed as a stand-alone or used as an adjunct on additional therapy will have to be determined based on both its efficacy and its safety.”

Neurostimulation is a novel concept in rheumatology but has been used with success in other areas of medicine – including epilepsy and depression – using electrical pulses instead of drugs. The idea behind it is that it stimulates the inflammatory reflex that modulates multiple the inflammatory pathways. Essentially, it’s thought that electrically stimulating the vagus nerve sends signals to the spleen where T-lymphocytes then signal to other immune cells, such as macrophages and monocytes, to temper their production of proinflammatory cytokines and other mediators.

“Unlike traditional immunosuppressive biologics that may be specifically targeting one inflammatory process, by suppressing the inflammatory reflex we believe we can suppress a variety of inflammatory cytokines in the region of between 30% and 70%,” Dr. Genovese said at a press briefing.

Data from a 12-week, open-label study (Proc Natl Acad Sci U S A. 2016;113:8284-9) have already shown that the approach works in patients with refractory RA (n = 17). Once-daily electrical vagus nerve stimulation using an existing device made for treating epilepsy showed that clinically meaningful changes in DAS28-CRP could be achieved through TNF suppression. The effects on systemic TNF release lasted for around 24-48 hours after stimulation.

For the current study, a much smaller, leadless, investigational neurostimulation device was used. Called a MicroRegulator (SetPoint Medical), it is about 1 inch long, less than 2 cc in total volume, and is surgically implanted by a neurosurgeon at the top of the vagus nerve. When activated through an iPad app by the health care professional, it sends electrical impulses down the vagus nerve. The device’s battery is charged externally and wirelessly a few minutes each week. Dr. Genovese noted that the device needs to be turned on for only 60 seconds at a time to have an effect and that patients may feel a vibration but this was not reported in the study as an adverse event.

Results of the first in-human study with the device were presented by Dr. Genovese during the late-breaking clinical trials session at the meeting. He described how a total of 14 patients had the device implanted, the first 3 of whom received once-daily, open-label neurostimulation. The remaining 11 patients were randomized to either once-daily or four-times-daily neurostimulation via the device, or to receive sham therapy in which the device was implanted but not switched on. The patients had moderate to severe RA, defined as four or more tender joints, four or more swollen joints, and a CDAI score greater than 10, plus they had radiologically active disease and an insufficient response to at least two biologic or targeted synthetic disease-modifying antirheumatic drugs with differing mechanisms of action.

All patients went through the same schedule of device charging and they did not know if they were in the active or sham groups. At the end of the study, patients had the option to continue in a long-term safety extension phase, have the device switched off, or could have it surgically removed.

“This trial was specifically a pilot trial to assess the MicroRegulator from a safety standpoint,” Dr. Genovese noted, but it also was designed to “help understand whether or not there was going to be clinical efficacy and applicability.”

While “there were no device or treatment-related serious adverse events,” there were some “surgical complications associated with the initial procedure.” One patient experienced paralysis of the left vocal cord during implantation that later resolved, and others experienced the following: Horner’s syndrome, tenderness and swelling at the surgical site, acute postoperative pain, and rash and pruritus. That said, there were no withdrawals from the study due to adverse events.

Commenting in a press release issued by the European League Against Rheumatism, Thomas Dörner, MD, of Charité Universitätsmedizin Berlin, said, “This is a really exciting development. For many patients suffering from rheumatoid arthritis, current treatments don’t work, or aren’t tolerated. These results open the door to a novel approach to treating not only rheumatoid arthritis, but other chronic inflammatory diseases. This is certainly an area for further study.”

The study was sponsored by SetPoint Medical. Dr. Genovese disclosed receiving consulting fees from and having contracts with/grants with the company and acting as a consultant to Galvani and Vorso. He has also received research support from and served as a consultant to Sanofi/Genzyme, Genentech/Roche, and R-Pharm. Dr. Dörner was not involved in the study and commented as part of his role as the chairperson of the EULAR Scientific Program Committee.

SOURCE: Genovese M et al. Ann Rheum Dis. Jun 2019; 78(Suppl 2):264. Abstract LB0009, doi: 10.1136/annrheumdis-2019-eular.8716

MADRID – Electrically stimulating the vagus nerve produced clinically meaningful responses in disease activity measures in patients with refractory RA in a small safety study.

A minimal clinically important difference in the 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) and the Clinical Disease Activity Index (CDAI) at 12 weeks was achieved or exceeded by 5 out of 10 patients; with 2 patients achieving DAS28-CRP–defined remission.

The disease activity scores also were paired with MRI scans and showed, in a handful of individuals, that there was improvement in erosions in those with a clinical response. Greater reductions in proinflammatory cytokines – interleukin (IL)-1-beta, IL-6, IL-17, IL-23, and tumor necrosis factor – were seen with neurostimulation, compared with a sham control group.

“The goal here was to use electrical stimulation to modify or modulate, and improve the treatment of active rheumatoid arthritis,” Mark C. Genovese, MD, said in an interview at the European Congress of Rheumatology.

“The reason for choosing refractory patients is, one, there’s a clear unmet need, but two, because this was a first-in-human study using a novel microregulatory device stimulating the vagus nerve, we thought the benefits-to-risk ratio was most appropriate for its first trial in patients with refractory disease,” explained Dr. Genovese, professor of medicine and director of the rheumatology clinic in the division of immunology and rheumatology at Stanford (Calif.) University.

He added: “Over time, if the device proves successful for modulating disease, one can see it potentially being used earlier in the disease. Whether it is developed as a stand-alone or used as an adjunct on additional therapy will have to be determined based on both its efficacy and its safety.”

Neurostimulation is a novel concept in rheumatology but has been used with success in other areas of medicine – including epilepsy and depression – using electrical pulses instead of drugs. The idea behind it is that it stimulates the inflammatory reflex that modulates multiple the inflammatory pathways. Essentially, it’s thought that electrically stimulating the vagus nerve sends signals to the spleen where T-lymphocytes then signal to other immune cells, such as macrophages and monocytes, to temper their production of proinflammatory cytokines and other mediators.

“Unlike traditional immunosuppressive biologics that may be specifically targeting one inflammatory process, by suppressing the inflammatory reflex we believe we can suppress a variety of inflammatory cytokines in the region of between 30% and 70%,” Dr. Genovese said at a press briefing.

Data from a 12-week, open-label study (Proc Natl Acad Sci U S A. 2016;113:8284-9) have already shown that the approach works in patients with refractory RA (n = 17). Once-daily electrical vagus nerve stimulation using an existing device made for treating epilepsy showed that clinically meaningful changes in DAS28-CRP could be achieved through TNF suppression. The effects on systemic TNF release lasted for around 24-48 hours after stimulation.

For the current study, a much smaller, leadless, investigational neurostimulation device was used. Called a MicroRegulator (SetPoint Medical), it is about 1 inch long, less than 2 cc in total volume, and is surgically implanted by a neurosurgeon at the top of the vagus nerve. When activated through an iPad app by the health care professional, it sends electrical impulses down the vagus nerve. The device’s battery is charged externally and wirelessly a few minutes each week. Dr. Genovese noted that the device needs to be turned on for only 60 seconds at a time to have an effect and that patients may feel a vibration but this was not reported in the study as an adverse event.

Results of the first in-human study with the device were presented by Dr. Genovese during the late-breaking clinical trials session at the meeting. He described how a total of 14 patients had the device implanted, the first 3 of whom received once-daily, open-label neurostimulation. The remaining 11 patients were randomized to either once-daily or four-times-daily neurostimulation via the device, or to receive sham therapy in which the device was implanted but not switched on. The patients had moderate to severe RA, defined as four or more tender joints, four or more swollen joints, and a CDAI score greater than 10, plus they had radiologically active disease and an insufficient response to at least two biologic or targeted synthetic disease-modifying antirheumatic drugs with differing mechanisms of action.

All patients went through the same schedule of device charging and they did not know if they were in the active or sham groups. At the end of the study, patients had the option to continue in a long-term safety extension phase, have the device switched off, or could have it surgically removed.

“This trial was specifically a pilot trial to assess the MicroRegulator from a safety standpoint,” Dr. Genovese noted, but it also was designed to “help understand whether or not there was going to be clinical efficacy and applicability.”

While “there were no device or treatment-related serious adverse events,” there were some “surgical complications associated with the initial procedure.” One patient experienced paralysis of the left vocal cord during implantation that later resolved, and others experienced the following: Horner’s syndrome, tenderness and swelling at the surgical site, acute postoperative pain, and rash and pruritus. That said, there were no withdrawals from the study due to adverse events.

Commenting in a press release issued by the European League Against Rheumatism, Thomas Dörner, MD, of Charité Universitätsmedizin Berlin, said, “This is a really exciting development. For many patients suffering from rheumatoid arthritis, current treatments don’t work, or aren’t tolerated. These results open the door to a novel approach to treating not only rheumatoid arthritis, but other chronic inflammatory diseases. This is certainly an area for further study.”

The study was sponsored by SetPoint Medical. Dr. Genovese disclosed receiving consulting fees from and having contracts with/grants with the company and acting as a consultant to Galvani and Vorso. He has also received research support from and served as a consultant to Sanofi/Genzyme, Genentech/Roche, and R-Pharm. Dr. Dörner was not involved in the study and commented as part of his role as the chairperson of the EULAR Scientific Program Committee.

SOURCE: Genovese M et al. Ann Rheum Dis. Jun 2019; 78(Suppl 2):264. Abstract LB0009, doi: 10.1136/annrheumdis-2019-eular.8716

Patients benefit from multidisciplinary care that coordinates management of complex medical problems. Traditionally, multidisciplinary cancer care involves oncology specialty providers in fields that include medical oncology, radiation oncology, and surgical oncology. Multidisciplinary cancer care intends to improve patient outcomes by bringing together different health care providers (HCPs) who are involved in the treatment of patients with cancer. Because new therapies are more effective and allow patients with cancer to live longer, adverse effects (AEs) are more likely to impact patients’ well-being, both while receiving treatment and long after it has completed. Thus, this population may benefit from an expanded approach to multidisciplinary care that includes input from specialty and primary care providers (PCPs), clinical pharmacy specialists (CPS), physical and occupational therapists, and patient navigators and educators.

We present 4 hypothetical cases, based on actual patients, that illustrate opportunities where multidisciplinary care coordination may improve patient experiences. These cases draw on current quality initiatives from the National Cancer Institute Community Cancer Centers Program, which has focused on improving the quality of multidisciplinary cancer care at selected community centers, and the Veterans Health Administration (VHA) patient-aligned care team (PACT) model, which brings together different health professionals to optimize primary care coordination.^1,2 In addition, the National Committee for Quality Assurance has introduced an educational initiative to facilitate implementation of an oncologic medical home.³ This initiative stresses increased multidisciplinary communication, patient-centered care delivery, and reduced fragmentation of care for this population. Despite these guidelines and experiences from other medical specialties, models for integrated cancer care have not been implemented in a prospective fashion within the VHA.

In this article, we focus on opportunities to take collaborative care approaches for the treatment of patients with follicular lymphoma (FL): a common, incurable, and often indolent B-cell non-Hodgkin lymphoma.⁴ FL was selected because these patients may be treated numerous times and long-term sequalae can accumulate throughout their cancer continuum (a series of health events encompassing cancer screening, diagnosis, treatment, survivorship, relapse, and death).⁵ HCPs in distinct roles can assist patients with cancer in optimizing their health outcomes and overall wellbeing.⁶

Case Example 1

A 70-year-old male was diagnosed with stage IV FL. Because of his advanced disease, he began therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Prednisone was administered at 100 mg daily on the first 5 days of each 21-day cycle. On day 4 of the first treatment cycle, the patient notified his oncologist that he had been very thirsty and his random blood sugar values on 2 different days were 283 mg/dL and 312 mg/dL. A laboratory review revealed his hemoglobin A_1c (HbA_1c) 7 months prior was 5.6%.

Discussion

The high-dose prednisone component of this and other lymphoma therapy regimens can worsen diabetes mellitus (DM) control and/or worsen prediabetes. Patient characteristics that increase the risk of developing glucocorticoid-induced DM after CHOP chemotherapy include age ≥ 60 years, HbA_1c > 6.1%, and body mass index > 30.⁷ This patient did not have DM prior to the FL therapy initiation, but afterwards he met diagnostic criteria for DM. For completeness, other causes for elevated blood glucose should be ruled out (ie, infection, laboratory error, etc.). An oncologist often will triage acute hyperglycemia, treating immediately with IV fluids and/or insulin. Thereafter, ongoing chronic disease management for DM may be best managed by PCPs, certified DM educators, and registered dieticians.

Several programs involving multidisciplinary DM care, comprised of physicians, advanced practice providers, nurses, certified DM educators, and/or pharmacists have been shown to improve HbA_1c, cardiovascular outcomes, and all-cause mortality, while reducing health care costs.⁸ In addition, patient navigators can assist patients with coordinating visits to disease-state specialists and identifying further educational needs. For example, in 1 program, nonclinical peer navigators were shown to improve the number of appointments attended and reduce HbA_1c in a population of patients with DM who were primarily minority, urban, and of low socioeconomic status.⁹ Thus, integrating DM care shows potential to improve outcomes for patients with lymphoma who develop glucocorticoid-induced DM.

Case Example 2

A 75-year-old male was diagnosed with FL. He was treated initially with bendamustine and rituximab. He required reinitiation of therapy 20 months later when he developed lymphadenopathy, fatigue, and night sweats and began treatment with oral idelalisib, a second-line therapy. Later, the patient presented to his PCP for a routine visit, and on medication reconciliation review, the patient reported regular use of trimethoprim-sulfamethoxazole.

Discussion

Upon consultation with the CPS and the patient’s oncologist, the PCP confirmed trimethoprim-sulfamethoxazole should be continued during therapy and for about 6 months following completion of therapy. Trimethoprim-sulfamethoxazole is used for prophylaxis against Pneumocystis jirovecii (formerly Pneumocystis carinii). While use of prophylactic therapy is not necessary for all patients with FL, idelalisib impairs the function of circulating lymphoid B-cells and thus has been associated with an increased risk of serious infection.¹⁰ A CPS can provide insight that maximizes medication adherence and efficacy while minimizing food-drug, drug-drug interactions, and AEs. CPS have been shown to: improve adherence to oral therapies, increase prospective monitoring required for safe therapy dose selection, and document assessment of chemotherapy-related AEs.^11,12 Thus, multidisciplinary, integrated care is an important component of providing quality oncology care.

Case Example 3

A 60-year-old female presented to her PCP with a 2-week history of shortness of breath and leg swelling. She was treated for FL 4 years previously with 6 cycles of R-CHOP. She reported no chest pain and did not have a prior history of hypertension, DM, or heart disease. On physical exam, she had elevated jugular venous pressure to jaw at 45°, bilateral pulmonary rales, and 2+ pitting pretibial edema. Laboratory tests that included complete blood count, basic chemistries, and thyroid stimulating hormone were unremarkable, though brain natriuretic peptide (BNP) was elevated at 425 pg/mL.

As this patient’s laboratory results and physical examination suggested new-onset congestive heart failure, the PCP obtained an echocardiogram, which demonstrated an ejection fraction of 35% and global hypokinesis. Because the patient was symptomatic, she was admitted to the hospital to begin guideline-directed medical therapy (GDMT) including IV diuresis.

Discussion

Given the absence of significant risk factors and prior history of coronary artery disease, the most probable cause for this patient’s cardiomyopathy is doxorubicin. Doxorubicin is an anthracycline chemotherapy that can cause nonischemic, dilated cardiomyopathy, particularly when cumulative doses > 400 mg/m² are administered, or when combined with chest radiation.¹³ This patient benefited from GDMT for reduced ejection-fraction heart failure (HFrEF). Studies have demonstrated positive outcomes when HFrEF patients are cared for by a multidisciplinary team who focus of volume management as well as uptitration of therapies to target doses.¹⁴

Case Example 4

An 80-year-old female was diagnosed with stage III FL but did not require immediate therapy. After developing discomfort due to enlarging lymphadenopathy, she initiated therapy with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). She presented to her oncologist for consideration of her fifth cycle of R-CVP and reported a burning sensation on the soles of her feet and numbness in her fingertips and toes. On examination, her pulses were intact and there were no signs of infection, reduced blood flow, or edema. The patient demonstrated decreased sensation on monofilament testing. She had no history of DM and a recent HbA_1c test was 4.9% An evaluation for other causes of neuropathy, such as hypothyroidism and vitamin B₁₂ deficiency was negative. Thus, vincristine therapy was identified as the most likely etiology for her peripheral neuropathy. The oncologist decided to proceed with cycle 5 of chemotherapy but reduced the dose of vincristine by 50%.

Discussion

Vincristine is a microtubule inhibitor used in many chemotherapy regimens and may cause reversible or permanent neuropathy, including autonomic (constipation), sensory (stocking-glove distribution), or motor (foot-drop).¹⁵ A nerve conduction study may be indicated as part of the diagnostic evaluation. Treatment for painful sensory neuropathy may include pharmacologic therapy (such as gabapentin, pregabalin, capsaicin cream).¹⁶ Podiatrists can provide foot care and may provide shoes and inserts if appropriate. Physical therapists may assist with safety and mobility evaluations and can provide therapeutic exercises and assistive devices that improve function and quality of life.¹⁷

Conclusion

As cancer becomes more curable and more manageable, patients with cancer and survivors no longer rely exclusively on their oncologists for medical care. This is increasingly prevalent for patients with incurable but indolent cancers that may be present for years to decades, as acute and cumulative toxicities may complicate existing comorbidities. Thus, in this era of increasingly complex cancer therapies, multidisciplinary medical care that involves PCPs, specialists, and allied medical professionals, is essential for providing care that optimizes health and fully addresses patients’ needs.

Patients benefit from multidisciplinary care that coordinates management of complex medical problems. Traditionally, multidisciplinary cancer care involves oncology specialty providers in fields that include medical oncology, radiation oncology, and surgical oncology. Multidisciplinary cancer care intends to improve patient outcomes by bringing together different health care providers (HCPs) who are involved in the treatment of patients with cancer. Because new therapies are more effective and allow patients with cancer to live longer, adverse effects (AEs) are more likely to impact patients’ well-being, both while receiving treatment and long after it has completed. Thus, this population may benefit from an expanded approach to multidisciplinary care that includes input from specialty and primary care providers (PCPs), clinical pharmacy specialists (CPS), physical and occupational therapists, and patient navigators and educators.

We present 4 hypothetical cases, based on actual patients, that illustrate opportunities where multidisciplinary care coordination may improve patient experiences. These cases draw on current quality initiatives from the National Cancer Institute Community Cancer Centers Program, which has focused on improving the quality of multidisciplinary cancer care at selected community centers, and the Veterans Health Administration (VHA) patient-aligned care team (PACT) model, which brings together different health professionals to optimize primary care coordination.^1,2 In addition, the National Committee for Quality Assurance has introduced an educational initiative to facilitate implementation of an oncologic medical home.³ This initiative stresses increased multidisciplinary communication, patient-centered care delivery, and reduced fragmentation of care for this population. Despite these guidelines and experiences from other medical specialties, models for integrated cancer care have not been implemented in a prospective fashion within the VHA.

In this article, we focus on opportunities to take collaborative care approaches for the treatment of patients with follicular lymphoma (FL): a common, incurable, and often indolent B-cell non-Hodgkin lymphoma.⁴ FL was selected because these patients may be treated numerous times and long-term sequalae can accumulate throughout their cancer continuum (a series of health events encompassing cancer screening, diagnosis, treatment, survivorship, relapse, and death).⁵ HCPs in distinct roles can assist patients with cancer in optimizing their health outcomes and overall wellbeing.⁶

Case Example 1

A 70-year-old male was diagnosed with stage IV FL. Because of his advanced disease, he began therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Prednisone was administered at 100 mg daily on the first 5 days of each 21-day cycle. On day 4 of the first treatment cycle, the patient notified his oncologist that he had been very thirsty and his random blood sugar values on 2 different days were 283 mg/dL and 312 mg/dL. A laboratory review revealed his hemoglobin A_1c (HbA_1c) 7 months prior was 5.6%.

Discussion

The high-dose prednisone component of this and other lymphoma therapy regimens can worsen diabetes mellitus (DM) control and/or worsen prediabetes. Patient characteristics that increase the risk of developing glucocorticoid-induced DM after CHOP chemotherapy include age ≥ 60 years, HbA_1c > 6.1%, and body mass index > 30.⁷ This patient did not have DM prior to the FL therapy initiation, but afterwards he met diagnostic criteria for DM. For completeness, other causes for elevated blood glucose should be ruled out (ie, infection, laboratory error, etc.). An oncologist often will triage acute hyperglycemia, treating immediately with IV fluids and/or insulin. Thereafter, ongoing chronic disease management for DM may be best managed by PCPs, certified DM educators, and registered dieticians.

Several programs involving multidisciplinary DM care, comprised of physicians, advanced practice providers, nurses, certified DM educators, and/or pharmacists have been shown to improve HbA_1c, cardiovascular outcomes, and all-cause mortality, while reducing health care costs.⁸ In addition, patient navigators can assist patients with coordinating visits to disease-state specialists and identifying further educational needs. For example, in 1 program, nonclinical peer navigators were shown to improve the number of appointments attended and reduce HbA_1c in a population of patients with DM who were primarily minority, urban, and of low socioeconomic status.⁹ Thus, integrating DM care shows potential to improve outcomes for patients with lymphoma who develop glucocorticoid-induced DM.

Case Example 2

A 75-year-old male was diagnosed with FL. He was treated initially with bendamustine and rituximab. He required reinitiation of therapy 20 months later when he developed lymphadenopathy, fatigue, and night sweats and began treatment with oral idelalisib, a second-line therapy. Later, the patient presented to his PCP for a routine visit, and on medication reconciliation review, the patient reported regular use of trimethoprim-sulfamethoxazole.

Discussion

Upon consultation with the CPS and the patient’s oncologist, the PCP confirmed trimethoprim-sulfamethoxazole should be continued during therapy and for about 6 months following completion of therapy. Trimethoprim-sulfamethoxazole is used for prophylaxis against Pneumocystis jirovecii (formerly Pneumocystis carinii). While use of prophylactic therapy is not necessary for all patients with FL, idelalisib impairs the function of circulating lymphoid B-cells and thus has been associated with an increased risk of serious infection.¹⁰ A CPS can provide insight that maximizes medication adherence and efficacy while minimizing food-drug, drug-drug interactions, and AEs. CPS have been shown to: improve adherence to oral therapies, increase prospective monitoring required for safe therapy dose selection, and document assessment of chemotherapy-related AEs.^11,12 Thus, multidisciplinary, integrated care is an important component of providing quality oncology care.

Case Example 3

A 60-year-old female presented to her PCP with a 2-week history of shortness of breath and leg swelling. She was treated for FL 4 years previously with 6 cycles of R-CHOP. She reported no chest pain and did not have a prior history of hypertension, DM, or heart disease. On physical exam, she had elevated jugular venous pressure to jaw at 45°, bilateral pulmonary rales, and 2+ pitting pretibial edema. Laboratory tests that included complete blood count, basic chemistries, and thyroid stimulating hormone were unremarkable, though brain natriuretic peptide (BNP) was elevated at 425 pg/mL.

As this patient’s laboratory results and physical examination suggested new-onset congestive heart failure, the PCP obtained an echocardiogram, which demonstrated an ejection fraction of 35% and global hypokinesis. Because the patient was symptomatic, she was admitted to the hospital to begin guideline-directed medical therapy (GDMT) including IV diuresis.

Discussion

Given the absence of significant risk factors and prior history of coronary artery disease, the most probable cause for this patient’s cardiomyopathy is doxorubicin. Doxorubicin is an anthracycline chemotherapy that can cause nonischemic, dilated cardiomyopathy, particularly when cumulative doses > 400 mg/m² are administered, or when combined with chest radiation.¹³ This patient benefited from GDMT for reduced ejection-fraction heart failure (HFrEF). Studies have demonstrated positive outcomes when HFrEF patients are cared for by a multidisciplinary team who focus of volume management as well as uptitration of therapies to target doses.¹⁴

Case Example 4

An 80-year-old female was diagnosed with stage III FL but did not require immediate therapy. After developing discomfort due to enlarging lymphadenopathy, she initiated therapy with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). She presented to her oncologist for consideration of her fifth cycle of R-CVP and reported a burning sensation on the soles of her feet and numbness in her fingertips and toes. On examination, her pulses were intact and there were no signs of infection, reduced blood flow, or edema. The patient demonstrated decreased sensation on monofilament testing. She had no history of DM and a recent HbA_1c test was 4.9% An evaluation for other causes of neuropathy, such as hypothyroidism and vitamin B₁₂ deficiency was negative. Thus, vincristine therapy was identified as the most likely etiology for her peripheral neuropathy. The oncologist decided to proceed with cycle 5 of chemotherapy but reduced the dose of vincristine by 50%.

Discussion

Vincristine is a microtubule inhibitor used in many chemotherapy regimens and may cause reversible or permanent neuropathy, including autonomic (constipation), sensory (stocking-glove distribution), or motor (foot-drop).¹⁵ A nerve conduction study may be indicated as part of the diagnostic evaluation. Treatment for painful sensory neuropathy may include pharmacologic therapy (such as gabapentin, pregabalin, capsaicin cream).¹⁶ Podiatrists can provide foot care and may provide shoes and inserts if appropriate. Physical therapists may assist with safety and mobility evaluations and can provide therapeutic exercises and assistive devices that improve function and quality of life.¹⁷

Conclusion

As cancer becomes more curable and more manageable, patients with cancer and survivors no longer rely exclusively on their oncologists for medical care. This is increasingly prevalent for patients with incurable but indolent cancers that may be present for years to decades, as acute and cumulative toxicities may complicate existing comorbidities. Thus, in this era of increasingly complex cancer therapies, multidisciplinary medical care that involves PCPs, specialists, and allied medical professionals, is essential for providing care that optimizes health and fully addresses patients’ needs.

Patients benefit from multidisciplinary care that coordinates management of complex medical problems. Traditionally, multidisciplinary cancer care involves oncology specialty providers in fields that include medical oncology, radiation oncology, and surgical oncology. Multidisciplinary cancer care intends to improve patient outcomes by bringing together different health care providers (HCPs) who are involved in the treatment of patients with cancer. Because new therapies are more effective and allow patients with cancer to live longer, adverse effects (AEs) are more likely to impact patients’ well-being, both while receiving treatment and long after it has completed. Thus, this population may benefit from an expanded approach to multidisciplinary care that includes input from specialty and primary care providers (PCPs), clinical pharmacy specialists (CPS), physical and occupational therapists, and patient navigators and educators.

We present 4 hypothetical cases, based on actual patients, that illustrate opportunities where multidisciplinary care coordination may improve patient experiences. These cases draw on current quality initiatives from the National Cancer Institute Community Cancer Centers Program, which has focused on improving the quality of multidisciplinary cancer care at selected community centers, and the Veterans Health Administration (VHA) patient-aligned care team (PACT) model, which brings together different health professionals to optimize primary care coordination.^1,2 In addition, the National Committee for Quality Assurance has introduced an educational initiative to facilitate implementation of an oncologic medical home.³ This initiative stresses increased multidisciplinary communication, patient-centered care delivery, and reduced fragmentation of care for this population. Despite these guidelines and experiences from other medical specialties, models for integrated cancer care have not been implemented in a prospective fashion within the VHA.

In this article, we focus on opportunities to take collaborative care approaches for the treatment of patients with follicular lymphoma (FL): a common, incurable, and often indolent B-cell non-Hodgkin lymphoma.⁴ FL was selected because these patients may be treated numerous times and long-term sequalae can accumulate throughout their cancer continuum (a series of health events encompassing cancer screening, diagnosis, treatment, survivorship, relapse, and death).⁵ HCPs in distinct roles can assist patients with cancer in optimizing their health outcomes and overall wellbeing.⁶

Case Example 1

A 70-year-old male was diagnosed with stage IV FL. Because of his advanced disease, he began therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Prednisone was administered at 100 mg daily on the first 5 days of each 21-day cycle. On day 4 of the first treatment cycle, the patient notified his oncologist that he had been very thirsty and his random blood sugar values on 2 different days were 283 mg/dL and 312 mg/dL. A laboratory review revealed his hemoglobin A_1c (HbA_1c) 7 months prior was 5.6%.

Discussion

The high-dose prednisone component of this and other lymphoma therapy regimens can worsen diabetes mellitus (DM) control and/or worsen prediabetes. Patient characteristics that increase the risk of developing glucocorticoid-induced DM after CHOP chemotherapy include age ≥ 60 years, HbA_1c > 6.1%, and body mass index > 30.⁷ This patient did not have DM prior to the FL therapy initiation, but afterwards he met diagnostic criteria for DM. For completeness, other causes for elevated blood glucose should be ruled out (ie, infection, laboratory error, etc.). An oncologist often will triage acute hyperglycemia, treating immediately with IV fluids and/or insulin. Thereafter, ongoing chronic disease management for DM may be best managed by PCPs, certified DM educators, and registered dieticians.

Several programs involving multidisciplinary DM care, comprised of physicians, advanced practice providers, nurses, certified DM educators, and/or pharmacists have been shown to improve HbA_1c, cardiovascular outcomes, and all-cause mortality, while reducing health care costs.⁸ In addition, patient navigators can assist patients with coordinating visits to disease-state specialists and identifying further educational needs. For example, in 1 program, nonclinical peer navigators were shown to improve the number of appointments attended and reduce HbA_1c in a population of patients with DM who were primarily minority, urban, and of low socioeconomic status.⁹ Thus, integrating DM care shows potential to improve outcomes for patients with lymphoma who develop glucocorticoid-induced DM.

Case Example 2

A 75-year-old male was diagnosed with FL. He was treated initially with bendamustine and rituximab. He required reinitiation of therapy 20 months later when he developed lymphadenopathy, fatigue, and night sweats and began treatment with oral idelalisib, a second-line therapy. Later, the patient presented to his PCP for a routine visit, and on medication reconciliation review, the patient reported regular use of trimethoprim-sulfamethoxazole.

Discussion

Upon consultation with the CPS and the patient’s oncologist, the PCP confirmed trimethoprim-sulfamethoxazole should be continued during therapy and for about 6 months following completion of therapy. Trimethoprim-sulfamethoxazole is used for prophylaxis against Pneumocystis jirovecii (formerly Pneumocystis carinii). While use of prophylactic therapy is not necessary for all patients with FL, idelalisib impairs the function of circulating lymphoid B-cells and thus has been associated with an increased risk of serious infection.¹⁰ A CPS can provide insight that maximizes medication adherence and efficacy while minimizing food-drug, drug-drug interactions, and AEs. CPS have been shown to: improve adherence to oral therapies, increase prospective monitoring required for safe therapy dose selection, and document assessment of chemotherapy-related AEs.^11,12 Thus, multidisciplinary, integrated care is an important component of providing quality oncology care.

Case Example 3

A 60-year-old female presented to her PCP with a 2-week history of shortness of breath and leg swelling. She was treated for FL 4 years previously with 6 cycles of R-CHOP. She reported no chest pain and did not have a prior history of hypertension, DM, or heart disease. On physical exam, she had elevated jugular venous pressure to jaw at 45°, bilateral pulmonary rales, and 2+ pitting pretibial edema. Laboratory tests that included complete blood count, basic chemistries, and thyroid stimulating hormone were unremarkable, though brain natriuretic peptide (BNP) was elevated at 425 pg/mL.

As this patient’s laboratory results and physical examination suggested new-onset congestive heart failure, the PCP obtained an echocardiogram, which demonstrated an ejection fraction of 35% and global hypokinesis. Because the patient was symptomatic, she was admitted to the hospital to begin guideline-directed medical therapy (GDMT) including IV diuresis.

Discussion

Given the absence of significant risk factors and prior history of coronary artery disease, the most probable cause for this patient’s cardiomyopathy is doxorubicin. Doxorubicin is an anthracycline chemotherapy that can cause nonischemic, dilated cardiomyopathy, particularly when cumulative doses > 400 mg/m² are administered, or when combined with chest radiation.¹³ This patient benefited from GDMT for reduced ejection-fraction heart failure (HFrEF). Studies have demonstrated positive outcomes when HFrEF patients are cared for by a multidisciplinary team who focus of volume management as well as uptitration of therapies to target doses.¹⁴

Case Example 4

An 80-year-old female was diagnosed with stage III FL but did not require immediate therapy. After developing discomfort due to enlarging lymphadenopathy, she initiated therapy with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). She presented to her oncologist for consideration of her fifth cycle of R-CVP and reported a burning sensation on the soles of her feet and numbness in her fingertips and toes. On examination, her pulses were intact and there were no signs of infection, reduced blood flow, or edema. The patient demonstrated decreased sensation on monofilament testing. She had no history of DM and a recent HbA_1c test was 4.9% An evaluation for other causes of neuropathy, such as hypothyroidism and vitamin B₁₂ deficiency was negative. Thus, vincristine therapy was identified as the most likely etiology for her peripheral neuropathy. The oncologist decided to proceed with cycle 5 of chemotherapy but reduced the dose of vincristine by 50%.

Discussion

Vincristine is a microtubule inhibitor used in many chemotherapy regimens and may cause reversible or permanent neuropathy, including autonomic (constipation), sensory (stocking-glove distribution), or motor (foot-drop).¹⁵ A nerve conduction study may be indicated as part of the diagnostic evaluation. Treatment for painful sensory neuropathy may include pharmacologic therapy (such as gabapentin, pregabalin, capsaicin cream).¹⁶ Podiatrists can provide foot care and may provide shoes and inserts if appropriate. Physical therapists may assist with safety and mobility evaluations and can provide therapeutic exercises and assistive devices that improve function and quality of life.¹⁷

Conclusion

As cancer becomes more curable and more manageable, patients with cancer and survivors no longer rely exclusively on their oncologists for medical care. This is increasingly prevalent for patients with incurable but indolent cancers that may be present for years to decades, as acute and cumulative toxicities may complicate existing comorbidities. Thus, in this era of increasingly complex cancer therapies, multidisciplinary medical care that involves PCPs, specialists, and allied medical professionals, is essential for providing care that optimizes health and fully addresses patients’ needs.

SAN FRANCISCO – Outside of prescription products for chemotherapy nausea/vomiting, AIDS anorexia, and rare pediatric epilepsies, medical cannabis has the strongest evidence for chronic pain, neuropathic pain, and multiple sclerosis spasticity, according to Kevin P. Hill, MD, director of the division of addiction psychiatry at Beth Israel Deaconess Medical Center, Boston.

M. Alexander Otto/MDedge News

“We are talking about multiple, positive RCTs [randomized, controlled trials]. I think you can’t ignore that. For people who are staunchly opposed to medical cannabis, [it’s becoming] harder and harder to take that tack. I do think we need to come to an understanding that there is some evidence,” Dr. Hill said at the American Psychiatric Association annual meeting.

However, “there’s incredible interest in using cannabinoids for a whole host of [other] conditions for which the level of evidence isn’t where we’d like it to be. In many ways,” legalization has “far outpaced the evidence. We need to be careful,” he said.

Perhaps that’s most true for psychiatric disorders. Although many patients swear by cannabis, what little evidence there is comes from observational studies, and those have mostly been disappointing.

Whole-plant cannabis, for instance, has been associated with an increased risk of depression in a dose-dependent fashion, and increased depression and anxiety symptoms, including panic attacks, among inexperienced users. Cutting back has been associated with symptom relief.

No placebo-controlled trials have been conducted to address cause and effect, so it’s unknown whether people use because they have worse disease or have worse disease because they use.

For now, “whole-plant cannabis to treat anxiety is probably not a good idea. We may ultimately find that cannabidiol” – CBD, the nonpsychoactive component of cannabis – “may have utility. If patients are already using, CBD is a better bet; it has no abuse potential,” Dr. Hill said.

He sometimes recommends CBD when patients fail traditional options, but over-the-counter or online products rather than the “exorbitantly expensive” Food and Drug Administration–approved version Epidiolex, indicated for the rare pediatric epilepsies Lennox-Gastaut and Dravet syndromes.

He asks patients to “tell me what you’re going to buy and we’ll go from there, and try to dose it.” Dr. Hill has confidence in only a few CBD brands to be accurately labeled, one of which is Charlotte’s Web.

There’s been a lot of excitement over cannabis for PTSD, but at this point, positive findings are mostly anecdotal, and use was associated with worse symptoms, increased violence, more alcohol and drug use, and worse therapy outcomes in a longitudinal study of 2,276 veterans. At least one ongoing RCT is underway that should address cause-and-effect (J Clin Psychiatry. 2015 Sep;76[9]:1174-80).

Like anxiety, CBD “would probably have more promise than whole-plant cannabis” for PTSD, Dr. Hill said.

That also might be the case for bipolar disorder. Whole-plant use is particularly common among patients, and it, again, seems to make symptoms worse.

The data for insomnia are much like that seen with alcohol: quicker asleep but worse sleep quality. “One of the myths about CBD is that it improves sleep; I don’t think that’s really been shown to be the case. A lot of it has to do with other chemicals included in the CBD preparation,” he said.

Dr. Hill is the author of Marijuana: The Unbiased Truth about the World’s Most Popular Weed (Center City, Minn.: Hazelden Publishing, 2015). He had no industry disclosures.

[email protected]

SAN FRANCISCO – Outside of prescription products for chemotherapy nausea/vomiting, AIDS anorexia, and rare pediatric epilepsies, medical cannabis has the strongest evidence for chronic pain, neuropathic pain, and multiple sclerosis spasticity, according to Kevin P. Hill, MD, director of the division of addiction psychiatry at Beth Israel Deaconess Medical Center, Boston.

M. Alexander Otto/MDedge News

“We are talking about multiple, positive RCTs [randomized, controlled trials]. I think you can’t ignore that. For people who are staunchly opposed to medical cannabis, [it’s becoming] harder and harder to take that tack. I do think we need to come to an understanding that there is some evidence,” Dr. Hill said at the American Psychiatric Association annual meeting.

However, “there’s incredible interest in using cannabinoids for a whole host of [other] conditions for which the level of evidence isn’t where we’d like it to be. In many ways,” legalization has “far outpaced the evidence. We need to be careful,” he said.

Perhaps that’s most true for psychiatric disorders. Although many patients swear by cannabis, what little evidence there is comes from observational studies, and those have mostly been disappointing.

Whole-plant cannabis, for instance, has been associated with an increased risk of depression in a dose-dependent fashion, and increased depression and anxiety symptoms, including panic attacks, among inexperienced users. Cutting back has been associated with symptom relief.

No placebo-controlled trials have been conducted to address cause and effect, so it’s unknown whether people use because they have worse disease or have worse disease because they use.

For now, “whole-plant cannabis to treat anxiety is probably not a good idea. We may ultimately find that cannabidiol” – CBD, the nonpsychoactive component of cannabis – “may have utility. If patients are already using, CBD is a better bet; it has no abuse potential,” Dr. Hill said.

He sometimes recommends CBD when patients fail traditional options, but over-the-counter or online products rather than the “exorbitantly expensive” Food and Drug Administration–approved version Epidiolex, indicated for the rare pediatric epilepsies Lennox-Gastaut and Dravet syndromes.

He asks patients to “tell me what you’re going to buy and we’ll go from there, and try to dose it.” Dr. Hill has confidence in only a few CBD brands to be accurately labeled, one of which is Charlotte’s Web.

There’s been a lot of excitement over cannabis for PTSD, but at this point, positive findings are mostly anecdotal, and use was associated with worse symptoms, increased violence, more alcohol and drug use, and worse therapy outcomes in a longitudinal study of 2,276 veterans. At least one ongoing RCT is underway that should address cause-and-effect (J Clin Psychiatry. 2015 Sep;76[9]:1174-80).

Like anxiety, CBD “would probably have more promise than whole-plant cannabis” for PTSD, Dr. Hill said.

That also might be the case for bipolar disorder. Whole-plant use is particularly common among patients, and it, again, seems to make symptoms worse.

The data for insomnia are much like that seen with alcohol: quicker asleep but worse sleep quality. “One of the myths about CBD is that it improves sleep; I don’t think that’s really been shown to be the case. A lot of it has to do with other chemicals included in the CBD preparation,” he said.

Dr. Hill is the author of Marijuana: The Unbiased Truth about the World’s Most Popular Weed (Center City, Minn.: Hazelden Publishing, 2015). He had no industry disclosures.

[email protected]

SAN FRANCISCO – Outside of prescription products for chemotherapy nausea/vomiting, AIDS anorexia, and rare pediatric epilepsies, medical cannabis has the strongest evidence for chronic pain, neuropathic pain, and multiple sclerosis spasticity, according to Kevin P. Hill, MD, director of the division of addiction psychiatry at Beth Israel Deaconess Medical Center, Boston.

M. Alexander Otto/MDedge News

“We are talking about multiple, positive RCTs [randomized, controlled trials]. I think you can’t ignore that. For people who are staunchly opposed to medical cannabis, [it’s becoming] harder and harder to take that tack. I do think we need to come to an understanding that there is some evidence,” Dr. Hill said at the American Psychiatric Association annual meeting.

However, “there’s incredible interest in using cannabinoids for a whole host of [other] conditions for which the level of evidence isn’t where we’d like it to be. In many ways,” legalization has “far outpaced the evidence. We need to be careful,” he said.

Perhaps that’s most true for psychiatric disorders. Although many patients swear by cannabis, what little evidence there is comes from observational studies, and those have mostly been disappointing.

Whole-plant cannabis, for instance, has been associated with an increased risk of depression in a dose-dependent fashion, and increased depression and anxiety symptoms, including panic attacks, among inexperienced users. Cutting back has been associated with symptom relief.

No placebo-controlled trials have been conducted to address cause and effect, so it’s unknown whether people use because they have worse disease or have worse disease because they use.

For now, “whole-plant cannabis to treat anxiety is probably not a good idea. We may ultimately find that cannabidiol” – CBD, the nonpsychoactive component of cannabis – “may have utility. If patients are already using, CBD is a better bet; it has no abuse potential,” Dr. Hill said.

He sometimes recommends CBD when patients fail traditional options, but over-the-counter or online products rather than the “exorbitantly expensive” Food and Drug Administration–approved version Epidiolex, indicated for the rare pediatric epilepsies Lennox-Gastaut and Dravet syndromes.

He asks patients to “tell me what you’re going to buy and we’ll go from there, and try to dose it.” Dr. Hill has confidence in only a few CBD brands to be accurately labeled, one of which is Charlotte’s Web.

There’s been a lot of excitement over cannabis for PTSD, but at this point, positive findings are mostly anecdotal, and use was associated with worse symptoms, increased violence, more alcohol and drug use, and worse therapy outcomes in a longitudinal study of 2,276 veterans. At least one ongoing RCT is underway that should address cause-and-effect (J Clin Psychiatry. 2015 Sep;76[9]:1174-80).

Like anxiety, CBD “would probably have more promise than whole-plant cannabis” for PTSD, Dr. Hill said.

That also might be the case for bipolar disorder. Whole-plant use is particularly common among patients, and it, again, seems to make symptoms worse.

The data for insomnia are much like that seen with alcohol: quicker asleep but worse sleep quality. “One of the myths about CBD is that it improves sleep; I don’t think that’s really been shown to be the case. A lot of it has to do with other chemicals included in the CBD preparation,” he said.

Dr. Hill is the author of Marijuana: The Unbiased Truth about the World’s Most Popular Weed (Center City, Minn.: Hazelden Publishing, 2015). He had no industry disclosures.

[email protected]

AMSTERDAM – Patients with acute myeloid leukemia who were in morphological complete remission prior to allogeneic hematopoietic cell transplant but had genomic evidence of a lingering AML variant had worse posttransplant outcomes when they underwent reduced-intensity conditioning, rather than myeloablative conditioning, investigators reported.

Among adults with AML in remission after induction therapy who were randomized in a clinical trial to either reduced-intensity conditioning (RIC) or myeloablative conditioning prior to transplant, those with known AML variants detected with ultra-deep genomic sequencing who underwent RIC had significantly greater risk for relapse, decreased disease-free survival (DFS), and worse overall survival (OS), compared with similar patients who underwent myeloablative conditioning (MAC), reported Christopher S. Hourigan, DM, DPhil, of the Laboratory of Myeloid Malignancies at the National Heart, Lung, and Blood Institute in Bethesda, Md.

The findings suggest that those patients with pretransplant AML variants who can tolerate MAC should get it, and that investigators need to find new options for patients who can’t, he said in an interview at the annual congress of the European Hematology Association.

“If I wasn’t a lab investigator and was a clinical trialist, I would be very excited about doing some randomized trials now to try see about novel targeted agents. For example, we have FLT3 inhibitors, we have IDH1 and IDH2 inhibitors, and I would be looking to try to combine reduced-intensity conditioning with additional therapy to try to lower the relapse rate for that group at the highest risk,” he said.

Previous studies have shown that, regardless of the method used – flow cytometry, quantitative polymerase chain reaction, or next-generation sequencing – minimal residual disease (MRD) detected in patients with AML in complete remission prior to transplant is associated with both cumulative incidence of relapse and worse overall survival.
 

Measurable, not minimal

Dr. Hourigan contends that the word “minimal” – the “M” in “MRD” – is a misnomer and should be replaced by the word “measurable,” because MRD really reflects the limitations of disease-detection technology.

“If you tell patients ‘you have minimal residual disease, and you have a huge chance of dying over the next few years,’ there’s nothing minimal about that,” he said.

The fundamental question that Dr. Hourigan and colleagues asked is, “is MRD just useful for predicting prognosis? Is this fate, or can we as doctors do something about it?”

To get answers, they examined whole-blood samples from patients enrolled in the BMT CTN 0901 trial, which compared survival and other outcomes following allogeneic hematopoietic stem cell transplants (allo-HSCT) with either RIC or MAC for pretransplant conditioning in patients with AML or the myelodysplastic syndrome.

The trial was halted early after just 272 of a planned 356 patients were enrolled, following evidence of a significantly higher relapse rate among patients who had undergone RIC.

“Strikingly, over half the AML patients receiving RIC relapsed within 18 months after getting transplants,” Dr. Hourigan said.
 

Relapse, survival differences

For this substudy, the National Institutes of Health investigators developed a custom 13-gene panel that would detect at least one AML variant in approximately 80% of patients who were included in a previous study of genomic classification and prognosis in AML.

They used ultra-deep genomic sequencing to look for variants in blood samples from 188 patients in BMT CTN 0901. There were no variants detected in the blood of 31% of patients who had undergone MAC or in 33% of those who had undergone RIC.

Among patients who did have detectable variants, the average number of variants per patient was 2.5.

In this cohort, transplant-related mortality (TRM) was higher with MAC at 27% vs. 20% with RIC at 3 years, but there were no differences in TRM within conditioning arms for patients, with or without AML variants.

Relapse rates in the cohort studied by Dr. Hourigan and his colleagues were virtually identical to those seen in the full study set, with an 18-month relapse rate of 16% for patients treated with MAC vs. 51% for those treated with RIC.

Among patients randomized to RIC, 3-year relapse rates were 57% for patients with detectable pretransplant AML variants, compared with 32% for those without variants (P less than .001).

Although there were no significant differences in 3-year OS by variant status among patients assigned to MAC, variant-positive patients assigned to RIC had significantly worse 3-year OS than those without variants (P = .04).

Among patients with no detectable variants, there were no significant differences in OS between the MAC or RIC arms. However, among patients with variants, survival was significantly worse with RIC (P = .02).

In multivariate analysis controlling for disease risk and donor group among patients who tested positive for an AML variant pretransplant, RIC was significantly associated with an increased risk for relapse (hazard ratio, 5.98; P less than .001); decreased DFS (HR, 2.80; P less than .001), and worse OS (HR, 2.16; P = .003).

“This study provides evidence that intervention for AML patients with evidence of MRD can result in improved survival,” Dr. Hourigan said.

Questions that still need to be addressed include whether variants in different genes confer different degrees of relapse risk, whether next-generation sequencing positivity is equivalent to MRD positivity, and whether the 13-gene panel could be improved upon to lower the chance for false negatives, he said.

The study was supported by the NIH. Dr. Hourigan reported research funding from Merck and Sellas Life Sciences AG, research collaboration with Qiagen and Archer, advisory board participation as an NIH official duty for Janssen and Novartis, and part-time employment with the Johns Hopkins School of Medicine.

SOURCE: Hourigan CS et al. EHA Congress, Abstract LB2600.

AMSTERDAM – Patients with acute myeloid leukemia who were in morphological complete remission prior to allogeneic hematopoietic cell transplant but had genomic evidence of a lingering AML variant had worse posttransplant outcomes when they underwent reduced-intensity conditioning, rather than myeloablative conditioning, investigators reported.

Among adults with AML in remission after induction therapy who were randomized in a clinical trial to either reduced-intensity conditioning (RIC) or myeloablative conditioning prior to transplant, those with known AML variants detected with ultra-deep genomic sequencing who underwent RIC had significantly greater risk for relapse, decreased disease-free survival (DFS), and worse overall survival (OS), compared with similar patients who underwent myeloablative conditioning (MAC), reported Christopher S. Hourigan, DM, DPhil, of the Laboratory of Myeloid Malignancies at the National Heart, Lung, and Blood Institute in Bethesda, Md.

The findings suggest that those patients with pretransplant AML variants who can tolerate MAC should get it, and that investigators need to find new options for patients who can’t, he said in an interview at the annual congress of the European Hematology Association.

“If I wasn’t a lab investigator and was a clinical trialist, I would be very excited about doing some randomized trials now to try see about novel targeted agents. For example, we have FLT3 inhibitors, we have IDH1 and IDH2 inhibitors, and I would be looking to try to combine reduced-intensity conditioning with additional therapy to try to lower the relapse rate for that group at the highest risk,” he said.

Previous studies have shown that, regardless of the method used – flow cytometry, quantitative polymerase chain reaction, or next-generation sequencing – minimal residual disease (MRD) detected in patients with AML in complete remission prior to transplant is associated with both cumulative incidence of relapse and worse overall survival.
 

Measurable, not minimal

Dr. Hourigan contends that the word “minimal” – the “M” in “MRD” – is a misnomer and should be replaced by the word “measurable,” because MRD really reflects the limitations of disease-detection technology.

“If you tell patients ‘you have minimal residual disease, and you have a huge chance of dying over the next few years,’ there’s nothing minimal about that,” he said.

The fundamental question that Dr. Hourigan and colleagues asked is, “is MRD just useful for predicting prognosis? Is this fate, or can we as doctors do something about it?”

To get answers, they examined whole-blood samples from patients enrolled in the BMT CTN 0901 trial, which compared survival and other outcomes following allogeneic hematopoietic stem cell transplants (allo-HSCT) with either RIC or MAC for pretransplant conditioning in patients with AML or the myelodysplastic syndrome.

The trial was halted early after just 272 of a planned 356 patients were enrolled, following evidence of a significantly higher relapse rate among patients who had undergone RIC.

“Strikingly, over half the AML patients receiving RIC relapsed within 18 months after getting transplants,” Dr. Hourigan said.
 

Relapse, survival differences

For this substudy, the National Institutes of Health investigators developed a custom 13-gene panel that would detect at least one AML variant in approximately 80% of patients who were included in a previous study of genomic classification and prognosis in AML.

They used ultra-deep genomic sequencing to look for variants in blood samples from 188 patients in BMT CTN 0901. There were no variants detected in the blood of 31% of patients who had undergone MAC or in 33% of those who had undergone RIC.

Among patients who did have detectable variants, the average number of variants per patient was 2.5.

In this cohort, transplant-related mortality (TRM) was higher with MAC at 27% vs. 20% with RIC at 3 years, but there were no differences in TRM within conditioning arms for patients, with or without AML variants.

Relapse rates in the cohort studied by Dr. Hourigan and his colleagues were virtually identical to those seen in the full study set, with an 18-month relapse rate of 16% for patients treated with MAC vs. 51% for those treated with RIC.

Among patients randomized to RIC, 3-year relapse rates were 57% for patients with detectable pretransplant AML variants, compared with 32% for those without variants (P less than .001).

Although there were no significant differences in 3-year OS by variant status among patients assigned to MAC, variant-positive patients assigned to RIC had significantly worse 3-year OS than those without variants (P = .04).

Among patients with no detectable variants, there were no significant differences in OS between the MAC or RIC arms. However, among patients with variants, survival was significantly worse with RIC (P = .02).

In multivariate analysis controlling for disease risk and donor group among patients who tested positive for an AML variant pretransplant, RIC was significantly associated with an increased risk for relapse (hazard ratio, 5.98; P less than .001); decreased DFS (HR, 2.80; P less than .001), and worse OS (HR, 2.16; P = .003).

“This study provides evidence that intervention for AML patients with evidence of MRD can result in improved survival,” Dr. Hourigan said.

Questions that still need to be addressed include whether variants in different genes confer different degrees of relapse risk, whether next-generation sequencing positivity is equivalent to MRD positivity, and whether the 13-gene panel could be improved upon to lower the chance for false negatives, he said.

The study was supported by the NIH. Dr. Hourigan reported research funding from Merck and Sellas Life Sciences AG, research collaboration with Qiagen and Archer, advisory board participation as an NIH official duty for Janssen and Novartis, and part-time employment with the Johns Hopkins School of Medicine.

SOURCE: Hourigan CS et al. EHA Congress, Abstract LB2600.

AMSTERDAM – Patients with acute myeloid leukemia who were in morphological complete remission prior to allogeneic hematopoietic cell transplant but had genomic evidence of a lingering AML variant had worse posttransplant outcomes when they underwent reduced-intensity conditioning, rather than myeloablative conditioning, investigators reported.

Among adults with AML in remission after induction therapy who were randomized in a clinical trial to either reduced-intensity conditioning (RIC) or myeloablative conditioning prior to transplant, those with known AML variants detected with ultra-deep genomic sequencing who underwent RIC had significantly greater risk for relapse, decreased disease-free survival (DFS), and worse overall survival (OS), compared with similar patients who underwent myeloablative conditioning (MAC), reported Christopher S. Hourigan, DM, DPhil, of the Laboratory of Myeloid Malignancies at the National Heart, Lung, and Blood Institute in Bethesda, Md.

The findings suggest that those patients with pretransplant AML variants who can tolerate MAC should get it, and that investigators need to find new options for patients who can’t, he said in an interview at the annual congress of the European Hematology Association.

“If I wasn’t a lab investigator and was a clinical trialist, I would be very excited about doing some randomized trials now to try see about novel targeted agents. For example, we have FLT3 inhibitors, we have IDH1 and IDH2 inhibitors, and I would be looking to try to combine reduced-intensity conditioning with additional therapy to try to lower the relapse rate for that group at the highest risk,” he said.

Previous studies have shown that, regardless of the method used – flow cytometry, quantitative polymerase chain reaction, or next-generation sequencing – minimal residual disease (MRD) detected in patients with AML in complete remission prior to transplant is associated with both cumulative incidence of relapse and worse overall survival.
 

Measurable, not minimal

Dr. Hourigan contends that the word “minimal” – the “M” in “MRD” – is a misnomer and should be replaced by the word “measurable,” because MRD really reflects the limitations of disease-detection technology.

“If you tell patients ‘you have minimal residual disease, and you have a huge chance of dying over the next few years,’ there’s nothing minimal about that,” he said.

The fundamental question that Dr. Hourigan and colleagues asked is, “is MRD just useful for predicting prognosis? Is this fate, or can we as doctors do something about it?”

To get answers, they examined whole-blood samples from patients enrolled in the BMT CTN 0901 trial, which compared survival and other outcomes following allogeneic hematopoietic stem cell transplants (allo-HSCT) with either RIC or MAC for pretransplant conditioning in patients with AML or the myelodysplastic syndrome.

The trial was halted early after just 272 of a planned 356 patients were enrolled, following evidence of a significantly higher relapse rate among patients who had undergone RIC.

“Strikingly, over half the AML patients receiving RIC relapsed within 18 months after getting transplants,” Dr. Hourigan said.
 

Relapse, survival differences

For this substudy, the National Institutes of Health investigators developed a custom 13-gene panel that would detect at least one AML variant in approximately 80% of patients who were included in a previous study of genomic classification and prognosis in AML.

They used ultra-deep genomic sequencing to look for variants in blood samples from 188 patients in BMT CTN 0901. There were no variants detected in the blood of 31% of patients who had undergone MAC or in 33% of those who had undergone RIC.

Among patients who did have detectable variants, the average number of variants per patient was 2.5.

In this cohort, transplant-related mortality (TRM) was higher with MAC at 27% vs. 20% with RIC at 3 years, but there were no differences in TRM within conditioning arms for patients, with or without AML variants.

Relapse rates in the cohort studied by Dr. Hourigan and his colleagues were virtually identical to those seen in the full study set, with an 18-month relapse rate of 16% for patients treated with MAC vs. 51% for those treated with RIC.

Among patients randomized to RIC, 3-year relapse rates were 57% for patients with detectable pretransplant AML variants, compared with 32% for those without variants (P less than .001).

Although there were no significant differences in 3-year OS by variant status among patients assigned to MAC, variant-positive patients assigned to RIC had significantly worse 3-year OS than those without variants (P = .04).

Among patients with no detectable variants, there were no significant differences in OS between the MAC or RIC arms. However, among patients with variants, survival was significantly worse with RIC (P = .02).

In multivariate analysis controlling for disease risk and donor group among patients who tested positive for an AML variant pretransplant, RIC was significantly associated with an increased risk for relapse (hazard ratio, 5.98; P less than .001); decreased DFS (HR, 2.80; P less than .001), and worse OS (HR, 2.16; P = .003).

“This study provides evidence that intervention for AML patients with evidence of MRD can result in improved survival,” Dr. Hourigan said.

Questions that still need to be addressed include whether variants in different genes confer different degrees of relapse risk, whether next-generation sequencing positivity is equivalent to MRD positivity, and whether the 13-gene panel could be improved upon to lower the chance for false negatives, he said.

The study was supported by the NIH. Dr. Hourigan reported research funding from Merck and Sellas Life Sciences AG, research collaboration with Qiagen and Archer, advisory board participation as an NIH official duty for Janssen and Novartis, and part-time employment with the Johns Hopkins School of Medicine.

SOURCE: Hourigan CS et al. EHA Congress, Abstract LB2600.

AMSTERDAM – Patients with relapsed or refractory acute myeloid leukemia (AML) may be more likely to respond when selinexor is added to standard chemotherapy, according to investigators.

Will Pass/MDedge News

In a recent phase 2 trial, selinexor given with cytarabine and idarubicin led to a 50% overall response rate, reported lead author Walter Fiedler, MD, of University Medical Center Hamburg-Eppendorf (Germany). This response rate is at the upper end of what has been seen in published studies, Dr. Fiedler said at the annual congress of the European Hematology Association.

He also noted that giving a flat dose of selinexor improved tolerability in the trial, a significant finding in light of common adverse events and recent concerns from the Food and Drug Administration about the safety of selinexor for patients with multiple myeloma.

“The rationale to employ selinexor in this study is that there is a synergy between anthracyclines and selinexor,” Dr. Fiedler said, which may restore anthracycline sensitivity in relapsed or refractory patients. “Secondly, there is a c-myc reduction pathway that leads to a reduction of DNA damage repair genes such as Rad51 and Chk1, and this might result in inhibition of homologous recombination.”

The study involved 44 patients with relapsed or refractory AML, of whom 17 (39%) had previously received stem cell transplantation and 11 (25%) exhibited therapy-induced or secondary disease. The median patient age was 59.5 years.

Patients were given idarubicin 10 mg/m² on days 1, 3, and 5, and cytarabine 100 mg/m² on days 1-7. Initially, selinexor was given at a dose of 40 mg/m² twice per week for 4 weeks, but this led to high rates of febrile neutropenia and grade 3 or higher diarrhea, along with prolonged aplasia. In response to this issue, after the first 27 patients, the dose was reduced to a flat amount of 60 mg, given twice weekly for 3 weeks.

For patients not undergoing transplantation after the first or second induction cycle, selinexor maintenance monotherapy was offered for up to 1 year.

The primary endpoint was overall remission rate, reported as complete remission, complete remission with incomplete blood count recovery, and morphological leukemia-free status. Secondary endpoints included the rate of partial remissions, percentage of patients being transplanted after induction, early death rate, overall survival, event-free survival, and relapse-free survival.

The efficacy analysis revealed an overall response rate of 50%. A total of 9 patients had complete remission (21.4%), 11 achieved complete remission with incomplete blood count recovery (26.2%), and 1 exhibited morphological leukemia-free status (2.4%). Of note, almost half of the patients (47%) who had relapsed after previous stem cell transplantation responded, as did three-quarters who tested positive for an NPM1 mutation. After a median follow-up of 8.2 months, the median overall survival was 8.2 months, relapse-free survival was 17.7 months, and event-free survival was 4.9 months.

Adverse events occurred frequently, with a majority of patients experiencing nausea (86%), diarrhea (83%), vomiting (74%), decreased appetite (71%), febrile neutropenia (67%), fatigue (64%), leukopenia (62%), thrombocytopenia (62%), or anemia (60%).

Grade 3 or higher adverse events were almost as common, and included febrile neutropenia (67%), leukopenia (62%), thrombocytopenia (62%), anemia (57%), and diarrhea (50%). Reducing the dose did improve tolerability, with notable drops in the rate of severe diarrhea (56% vs. 40%) and febrile neutropenia (85% vs. 33%). In total, 19% of patients discontinued treatment because of adverse events.

A total of 25 patients (60%) died during the study, with about half dying from disease progression (n = 12), and fewer succumbing to infectious complications, graft-versus-host disease, multiorgan failure, multiple brain infarct, or asystole. Two deaths, one from suspected hemophagocytosis and another from systemic inflammatory response syndrome, were considered possibly related to selinexor.

“The results should be further evaluated in a phase 3 study,” Dr. Fiedler said. However, plans for this are not yet underway, he said, adding that Karyopharm Therapeutics will be focusing its efforts on selinexor for myeloma first.

The study was funded by Karyopharm. Dr. Fielder reported financial relationships with Amgen, Pfizer, Jazz Pharmaceuticals, and other companies.

SOURCE: Fiedler W et al. EHA Congress, Abstract S880.

AMSTERDAM – Patients with relapsed or refractory acute myeloid leukemia (AML) may be more likely to respond when selinexor is added to standard chemotherapy, according to investigators.

Will Pass/MDedge News

In a recent phase 2 trial, selinexor given with cytarabine and idarubicin led to a 50% overall response rate, reported lead author Walter Fiedler, MD, of University Medical Center Hamburg-Eppendorf (Germany). This response rate is at the upper end of what has been seen in published studies, Dr. Fiedler said at the annual congress of the European Hematology Association.

He also noted that giving a flat dose of selinexor improved tolerability in the trial, a significant finding in light of common adverse events and recent concerns from the Food and Drug Administration about the safety of selinexor for patients with multiple myeloma.

“The rationale to employ selinexor in this study is that there is a synergy between anthracyclines and selinexor,” Dr. Fiedler said, which may restore anthracycline sensitivity in relapsed or refractory patients. “Secondly, there is a c-myc reduction pathway that leads to a reduction of DNA damage repair genes such as Rad51 and Chk1, and this might result in inhibition of homologous recombination.”

The study involved 44 patients with relapsed or refractory AML, of whom 17 (39%) had previously received stem cell transplantation and 11 (25%) exhibited therapy-induced or secondary disease. The median patient age was 59.5 years.

Patients were given idarubicin 10 mg/m² on days 1, 3, and 5, and cytarabine 100 mg/m² on days 1-7. Initially, selinexor was given at a dose of 40 mg/m² twice per week for 4 weeks, but this led to high rates of febrile neutropenia and grade 3 or higher diarrhea, along with prolonged aplasia. In response to this issue, after the first 27 patients, the dose was reduced to a flat amount of 60 mg, given twice weekly for 3 weeks.

For patients not undergoing transplantation after the first or second induction cycle, selinexor maintenance monotherapy was offered for up to 1 year.

The primary endpoint was overall remission rate, reported as complete remission, complete remission with incomplete blood count recovery, and morphological leukemia-free status. Secondary endpoints included the rate of partial remissions, percentage of patients being transplanted after induction, early death rate, overall survival, event-free survival, and relapse-free survival.

The efficacy analysis revealed an overall response rate of 50%. A total of 9 patients had complete remission (21.4%), 11 achieved complete remission with incomplete blood count recovery (26.2%), and 1 exhibited morphological leukemia-free status (2.4%). Of note, almost half of the patients (47%) who had relapsed after previous stem cell transplantation responded, as did three-quarters who tested positive for an NPM1 mutation. After a median follow-up of 8.2 months, the median overall survival was 8.2 months, relapse-free survival was 17.7 months, and event-free survival was 4.9 months.

Adverse events occurred frequently, with a majority of patients experiencing nausea (86%), diarrhea (83%), vomiting (74%), decreased appetite (71%), febrile neutropenia (67%), fatigue (64%), leukopenia (62%), thrombocytopenia (62%), or anemia (60%).

Grade 3 or higher adverse events were almost as common, and included febrile neutropenia (67%), leukopenia (62%), thrombocytopenia (62%), anemia (57%), and diarrhea (50%). Reducing the dose did improve tolerability, with notable drops in the rate of severe diarrhea (56% vs. 40%) and febrile neutropenia (85% vs. 33%). In total, 19% of patients discontinued treatment because of adverse events.

A total of 25 patients (60%) died during the study, with about half dying from disease progression (n = 12), and fewer succumbing to infectious complications, graft-versus-host disease, multiorgan failure, multiple brain infarct, or asystole. Two deaths, one from suspected hemophagocytosis and another from systemic inflammatory response syndrome, were considered possibly related to selinexor.

“The results should be further evaluated in a phase 3 study,” Dr. Fiedler said. However, plans for this are not yet underway, he said, adding that Karyopharm Therapeutics will be focusing its efforts on selinexor for myeloma first.

The study was funded by Karyopharm. Dr. Fielder reported financial relationships with Amgen, Pfizer, Jazz Pharmaceuticals, and other companies.

SOURCE: Fiedler W et al. EHA Congress, Abstract S880.

AMSTERDAM – Patients with relapsed or refractory acute myeloid leukemia (AML) may be more likely to respond when selinexor is added to standard chemotherapy, according to investigators.

Will Pass/MDedge News

In a recent phase 2 trial, selinexor given with cytarabine and idarubicin led to a 50% overall response rate, reported lead author Walter Fiedler, MD, of University Medical Center Hamburg-Eppendorf (Germany). This response rate is at the upper end of what has been seen in published studies, Dr. Fiedler said at the annual congress of the European Hematology Association.

He also noted that giving a flat dose of selinexor improved tolerability in the trial, a significant finding in light of common adverse events and recent concerns from the Food and Drug Administration about the safety of selinexor for patients with multiple myeloma.

“The rationale to employ selinexor in this study is that there is a synergy between anthracyclines and selinexor,” Dr. Fiedler said, which may restore anthracycline sensitivity in relapsed or refractory patients. “Secondly, there is a c-myc reduction pathway that leads to a reduction of DNA damage repair genes such as Rad51 and Chk1, and this might result in inhibition of homologous recombination.”

The study involved 44 patients with relapsed or refractory AML, of whom 17 (39%) had previously received stem cell transplantation and 11 (25%) exhibited therapy-induced or secondary disease. The median patient age was 59.5 years.

Patients were given idarubicin 10 mg/m² on days 1, 3, and 5, and cytarabine 100 mg/m² on days 1-7. Initially, selinexor was given at a dose of 40 mg/m² twice per week for 4 weeks, but this led to high rates of febrile neutropenia and grade 3 or higher diarrhea, along with prolonged aplasia. In response to this issue, after the first 27 patients, the dose was reduced to a flat amount of 60 mg, given twice weekly for 3 weeks.

For patients not undergoing transplantation after the first or second induction cycle, selinexor maintenance monotherapy was offered for up to 1 year.

The primary endpoint was overall remission rate, reported as complete remission, complete remission with incomplete blood count recovery, and morphological leukemia-free status. Secondary endpoints included the rate of partial remissions, percentage of patients being transplanted after induction, early death rate, overall survival, event-free survival, and relapse-free survival.

The efficacy analysis revealed an overall response rate of 50%. A total of 9 patients had complete remission (21.4%), 11 achieved complete remission with incomplete blood count recovery (26.2%), and 1 exhibited morphological leukemia-free status (2.4%). Of note, almost half of the patients (47%) who had relapsed after previous stem cell transplantation responded, as did three-quarters who tested positive for an NPM1 mutation. After a median follow-up of 8.2 months, the median overall survival was 8.2 months, relapse-free survival was 17.7 months, and event-free survival was 4.9 months.

Adverse events occurred frequently, with a majority of patients experiencing nausea (86%), diarrhea (83%), vomiting (74%), decreased appetite (71%), febrile neutropenia (67%), fatigue (64%), leukopenia (62%), thrombocytopenia (62%), or anemia (60%).

Grade 3 or higher adverse events were almost as common, and included febrile neutropenia (67%), leukopenia (62%), thrombocytopenia (62%), anemia (57%), and diarrhea (50%). Reducing the dose did improve tolerability, with notable drops in the rate of severe diarrhea (56% vs. 40%) and febrile neutropenia (85% vs. 33%). In total, 19% of patients discontinued treatment because of adverse events.

A total of 25 patients (60%) died during the study, with about half dying from disease progression (n = 12), and fewer succumbing to infectious complications, graft-versus-host disease, multiorgan failure, multiple brain infarct, or asystole. Two deaths, one from suspected hemophagocytosis and another from systemic inflammatory response syndrome, were considered possibly related to selinexor.

“The results should be further evaluated in a phase 3 study,” Dr. Fiedler said. However, plans for this are not yet underway, he said, adding that Karyopharm Therapeutics will be focusing its efforts on selinexor for myeloma first.

The study was funded by Karyopharm. Dr. Fielder reported financial relationships with Amgen, Pfizer, Jazz Pharmaceuticals, and other companies.

SOURCE: Fiedler W et al. EHA Congress, Abstract S880.

For previously untreated patients with severe hemophilia A, the risk of developing factor VIII (FVIII) inhibitors becomes marginal after 75 exposure days, according to an observational study of more than 1,000 infants on prophylaxis.

“Most inhibitors develop during the first 50 exposure days to FVIII, with 50% of inhibitors already present after 14-15 exposure days,” wrote H. Marijke van den Berg, MD, PhD, of the PedNet Haemophilia Research Foundation, Baarn, the Netherlands. The findings were published in Blood.

Dr. van den Berg and her colleagues aimed to characterize the risk of inhibitor development beyond 50 exposure days and to calculate the age when patients reach near-zero risk. The researchers followed 1,038 previously untreated patients with severe hemophilia A from first exposure to FVIII until inhibitor development, up to a maximum of 1,000 exposure days. Data was obtained from the PedNet Haemophilia Registry.

From the initial cohort, 943 patients (91%) were followed until 50 exposure days, and 899 (87%) were followed until 75 exposure days. Inhibitor development was defined by a minimum of two positive inhibitor titers in conjunction with reduced in-vivo FVIII recovery. The team also conducted a survival analysis to measure inhibitor incidence and reported median ages at initial exposure and at exposure day 75.

After analysis, the researchers found that 298 of 300 (99.3%) occurrences of inhibitor development ensued within 75 exposure days. No inhibitor development occurred between exposure day 75 and 150. The final two occurrences developed at exposure day 249 and 262, each with a low titer. The median age at first exposure was 1.1 years versus 2.3 years at exposure day 75.

“Our study shows that children on prophylaxis reach a near-zero risk plateau of inhibitor development at 75 [exposure days] only 1.2 years after the first [exposure day],” they wrote.

The researchers explained that these findings could impact the design of future clinical studies for previously untreated patients with severe hemophilia A. And they noted that these data are applicable to patients administered early prophylaxis, since the majority of study participants began prophylaxis early in life. “Frequent testing for inhibitors until 75 instead of 50 exposure days, therefore, is feasible and should be recommended for all [previously untreated patients],” they concluded.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: van den Berg HM et al. Blood. 2019 Jun 11. doi: 10.1182/blood.2019000658.

For previously untreated patients with severe hemophilia A, the risk of developing factor VIII (FVIII) inhibitors becomes marginal after 75 exposure days, according to an observational study of more than 1,000 infants on prophylaxis.

“Most inhibitors develop during the first 50 exposure days to FVIII, with 50% of inhibitors already present after 14-15 exposure days,” wrote H. Marijke van den Berg, MD, PhD, of the PedNet Haemophilia Research Foundation, Baarn, the Netherlands. The findings were published in Blood.

Dr. van den Berg and her colleagues aimed to characterize the risk of inhibitor development beyond 50 exposure days and to calculate the age when patients reach near-zero risk. The researchers followed 1,038 previously untreated patients with severe hemophilia A from first exposure to FVIII until inhibitor development, up to a maximum of 1,000 exposure days. Data was obtained from the PedNet Haemophilia Registry.

From the initial cohort, 943 patients (91%) were followed until 50 exposure days, and 899 (87%) were followed until 75 exposure days. Inhibitor development was defined by a minimum of two positive inhibitor titers in conjunction with reduced in-vivo FVIII recovery. The team also conducted a survival analysis to measure inhibitor incidence and reported median ages at initial exposure and at exposure day 75.

After analysis, the researchers found that 298 of 300 (99.3%) occurrences of inhibitor development ensued within 75 exposure days. No inhibitor development occurred between exposure day 75 and 150. The final two occurrences developed at exposure day 249 and 262, each with a low titer. The median age at first exposure was 1.1 years versus 2.3 years at exposure day 75.

“Our study shows that children on prophylaxis reach a near-zero risk plateau of inhibitor development at 75 [exposure days] only 1.2 years after the first [exposure day],” they wrote.

The researchers explained that these findings could impact the design of future clinical studies for previously untreated patients with severe hemophilia A. And they noted that these data are applicable to patients administered early prophylaxis, since the majority of study participants began prophylaxis early in life. “Frequent testing for inhibitors until 75 instead of 50 exposure days, therefore, is feasible and should be recommended for all [previously untreated patients],” they concluded.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: van den Berg HM et al. Blood. 2019 Jun 11. doi: 10.1182/blood.2019000658.

For previously untreated patients with severe hemophilia A, the risk of developing factor VIII (FVIII) inhibitors becomes marginal after 75 exposure days, according to an observational study of more than 1,000 infants on prophylaxis.

“Most inhibitors develop during the first 50 exposure days to FVIII, with 50% of inhibitors already present after 14-15 exposure days,” wrote H. Marijke van den Berg, MD, PhD, of the PedNet Haemophilia Research Foundation, Baarn, the Netherlands. The findings were published in Blood.

Dr. van den Berg and her colleagues aimed to characterize the risk of inhibitor development beyond 50 exposure days and to calculate the age when patients reach near-zero risk. The researchers followed 1,038 previously untreated patients with severe hemophilia A from first exposure to FVIII until inhibitor development, up to a maximum of 1,000 exposure days. Data was obtained from the PedNet Haemophilia Registry.

From the initial cohort, 943 patients (91%) were followed until 50 exposure days, and 899 (87%) were followed until 75 exposure days. Inhibitor development was defined by a minimum of two positive inhibitor titers in conjunction with reduced in-vivo FVIII recovery. The team also conducted a survival analysis to measure inhibitor incidence and reported median ages at initial exposure and at exposure day 75.

After analysis, the researchers found that 298 of 300 (99.3%) occurrences of inhibitor development ensued within 75 exposure days. No inhibitor development occurred between exposure day 75 and 150. The final two occurrences developed at exposure day 249 and 262, each with a low titer. The median age at first exposure was 1.1 years versus 2.3 years at exposure day 75.

“Our study shows that children on prophylaxis reach a near-zero risk plateau of inhibitor development at 75 [exposure days] only 1.2 years after the first [exposure day],” they wrote.

The researchers explained that these findings could impact the design of future clinical studies for previously untreated patients with severe hemophilia A. And they noted that these data are applicable to patients administered early prophylaxis, since the majority of study participants began prophylaxis early in life. “Frequent testing for inhibitors until 75 instead of 50 exposure days, therefore, is feasible and should be recommended for all [previously untreated patients],” they concluded.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: van den Berg HM et al. Blood. 2019 Jun 11. doi: 10.1182/blood.2019000658.

SAN DIEGO – Inadequate bowel preparation was significantly more likely for colonoscopies performed after holidays, according to a single-center retrospective study presented at the annual Digestive Disease Week.

Of patients whose colonoscopies were performed the day after a holiday, 55.4% had inadequate bowel preparation, compared with 45.7% of those receiving colonoscopies on other days, for an odds ratio of 1.5 for inadequate preparation on the day after a holiday (95% confidence interval, 1.1-1.9; P = .006).

In addition to the lead finding, inadequate bowel prep was also more likely in the afternoon, and earlier in the week (OR, 1.6 and 1.3, respectively), said Ammar Nassri, MD, a gastroenterology fellow at the University of Florida, Jacksonville.

Patients who were male and white were more likely to have inadequate bowel preparation (OR, 1.3 and 2.7, respectively). Having Medicaid as opposed to other forms of insurance also upped the likelihood of inadequate bowel preparation (OR, 1.9).

It’s important to identify modifiable factors associated with inadequate bowel preparation for a number of reasons. Among them, said Dr. Nassri, is cost-effectiveness: Screening colonoscopy has been found to be cost effective, compared with fecal immunochemical testing only when the inadequate bowel prep rate is 13% or less.

Adenomas are more likely to be missed with inadequate bowel preparation as well, he noted, with one study finding missed adenomas on 33% of subsequent colonoscopies performed after an initial colonoscopy with inadequate preparation.

Also, inadequate preparation can mean longer procedures and increased likelihood of failed procedures – and higher costs, he said.

“Several studies have created prediction models to predict the likelihood of having an inadequate bowel preparation, but these models have not gained widespread acceptance,” said Dr. Nassri.

He and his collaborators aimed to identify the rate of inadequate bowel preparation in their patient population, and to examine the association of modifiable variables with adequacy of preparation. These included the day of the week, the time of day, and whether a colonoscopy followed a holiday.

Additionally, the investigators looked at various patient demographic variables to see whether they were associated with adequacy of bowel preparation. Adult patients who received outpatient colonoscopy over a 3-year period were included. Preparation was considered adequate if it was assigned a score of at least 6 on the Boston Bowel Preparation Scale, or at least “fair” on the Aronchik scale.

A total of 6,510 patients were included. The mean age was 56.3 years, and about 60% were female. Just over half (51.3%) were African American; 46.6% were white. Over half of patients (56.4%) had health insurance provided by city contract or Florida Medicaid; the remainder had either Medicare or commercial insurance.

Overall, nearly half of patients (46%) had inadequate bowel preparation. Half of males overall had adequate bowel preparation, compared with 57% of females (P less than .001). As the hour of the colonoscopy grew later, the likelihood of adequacy of bowel preparation dropped. The inverse relationship was statistically significant (P less than .001), with over 60% of 7 a.m. colonoscopies having adequate preparation. By 3 p.m., over 60% of bowel preparations were inadequate in the University of Florida cohort.

Colonoscopies performed later in the week were most likely to have adequate bowel preparation, with rates nearing 60% by Friday, compared with rates just over or at 50% for the first 3 days of the week (P less than .001).

“This study showed that a colonoscopy on the day after a holiday has a higher rate of inadequate bowel preparation,” said Dr. Nassri. Conversely, he said, “Colonoscopy toward the end of the week has a higher likelihood of adequate bowel preparation.”

The present work, he said, “re-demonstrated that procedures done later in the day have a poorer bowel preparation.”

Dr. Nassri reported no conflicts of interest.

[email protected]

SAN DIEGO – Inadequate bowel preparation was significantly more likely for colonoscopies performed after holidays, according to a single-center retrospective study presented at the annual Digestive Disease Week.

Of patients whose colonoscopies were performed the day after a holiday, 55.4% had inadequate bowel preparation, compared with 45.7% of those receiving colonoscopies on other days, for an odds ratio of 1.5 for inadequate preparation on the day after a holiday (95% confidence interval, 1.1-1.9; P = .006).

In addition to the lead finding, inadequate bowel prep was also more likely in the afternoon, and earlier in the week (OR, 1.6 and 1.3, respectively), said Ammar Nassri, MD, a gastroenterology fellow at the University of Florida, Jacksonville.

Patients who were male and white were more likely to have inadequate bowel preparation (OR, 1.3 and 2.7, respectively). Having Medicaid as opposed to other forms of insurance also upped the likelihood of inadequate bowel preparation (OR, 1.9).

It’s important to identify modifiable factors associated with inadequate bowel preparation for a number of reasons. Among them, said Dr. Nassri, is cost-effectiveness: Screening colonoscopy has been found to be cost effective, compared with fecal immunochemical testing only when the inadequate bowel prep rate is 13% or less.

Adenomas are more likely to be missed with inadequate bowel preparation as well, he noted, with one study finding missed adenomas on 33% of subsequent colonoscopies performed after an initial colonoscopy with inadequate preparation.

Also, inadequate preparation can mean longer procedures and increased likelihood of failed procedures – and higher costs, he said.

“Several studies have created prediction models to predict the likelihood of having an inadequate bowel preparation, but these models have not gained widespread acceptance,” said Dr. Nassri.

He and his collaborators aimed to identify the rate of inadequate bowel preparation in their patient population, and to examine the association of modifiable variables with adequacy of preparation. These included the day of the week, the time of day, and whether a colonoscopy followed a holiday.

Additionally, the investigators looked at various patient demographic variables to see whether they were associated with adequacy of bowel preparation. Adult patients who received outpatient colonoscopy over a 3-year period were included. Preparation was considered adequate if it was assigned a score of at least 6 on the Boston Bowel Preparation Scale, or at least “fair” on the Aronchik scale.

A total of 6,510 patients were included. The mean age was 56.3 years, and about 60% were female. Just over half (51.3%) were African American; 46.6% were white. Over half of patients (56.4%) had health insurance provided by city contract or Florida Medicaid; the remainder had either Medicare or commercial insurance.

Overall, nearly half of patients (46%) had inadequate bowel preparation. Half of males overall had adequate bowel preparation, compared with 57% of females (P less than .001). As the hour of the colonoscopy grew later, the likelihood of adequacy of bowel preparation dropped. The inverse relationship was statistically significant (P less than .001), with over 60% of 7 a.m. colonoscopies having adequate preparation. By 3 p.m., over 60% of bowel preparations were inadequate in the University of Florida cohort.

Colonoscopies performed later in the week were most likely to have adequate bowel preparation, with rates nearing 60% by Friday, compared with rates just over or at 50% for the first 3 days of the week (P less than .001).

“This study showed that a colonoscopy on the day after a holiday has a higher rate of inadequate bowel preparation,” said Dr. Nassri. Conversely, he said, “Colonoscopy toward the end of the week has a higher likelihood of adequate bowel preparation.”

The present work, he said, “re-demonstrated that procedures done later in the day have a poorer bowel preparation.”

Dr. Nassri reported no conflicts of interest.

[email protected]

SAN DIEGO – Inadequate bowel preparation was significantly more likely for colonoscopies performed after holidays, according to a single-center retrospective study presented at the annual Digestive Disease Week.

Of patients whose colonoscopies were performed the day after a holiday, 55.4% had inadequate bowel preparation, compared with 45.7% of those receiving colonoscopies on other days, for an odds ratio of 1.5 for inadequate preparation on the day after a holiday (95% confidence interval, 1.1-1.9; P = .006).

In addition to the lead finding, inadequate bowel prep was also more likely in the afternoon, and earlier in the week (OR, 1.6 and 1.3, respectively), said Ammar Nassri, MD, a gastroenterology fellow at the University of Florida, Jacksonville.

Patients who were male and white were more likely to have inadequate bowel preparation (OR, 1.3 and 2.7, respectively). Having Medicaid as opposed to other forms of insurance also upped the likelihood of inadequate bowel preparation (OR, 1.9).

It’s important to identify modifiable factors associated with inadequate bowel preparation for a number of reasons. Among them, said Dr. Nassri, is cost-effectiveness: Screening colonoscopy has been found to be cost effective, compared with fecal immunochemical testing only when the inadequate bowel prep rate is 13% or less.

Adenomas are more likely to be missed with inadequate bowel preparation as well, he noted, with one study finding missed adenomas on 33% of subsequent colonoscopies performed after an initial colonoscopy with inadequate preparation.

Also, inadequate preparation can mean longer procedures and increased likelihood of failed procedures – and higher costs, he said.

“Several studies have created prediction models to predict the likelihood of having an inadequate bowel preparation, but these models have not gained widespread acceptance,” said Dr. Nassri.

He and his collaborators aimed to identify the rate of inadequate bowel preparation in their patient population, and to examine the association of modifiable variables with adequacy of preparation. These included the day of the week, the time of day, and whether a colonoscopy followed a holiday.

Additionally, the investigators looked at various patient demographic variables to see whether they were associated with adequacy of bowel preparation. Adult patients who received outpatient colonoscopy over a 3-year period were included. Preparation was considered adequate if it was assigned a score of at least 6 on the Boston Bowel Preparation Scale, or at least “fair” on the Aronchik scale.

A total of 6,510 patients were included. The mean age was 56.3 years, and about 60% were female. Just over half (51.3%) were African American; 46.6% were white. Over half of patients (56.4%) had health insurance provided by city contract or Florida Medicaid; the remainder had either Medicare or commercial insurance.

Overall, nearly half of patients (46%) had inadequate bowel preparation. Half of males overall had adequate bowel preparation, compared with 57% of females (P less than .001). As the hour of the colonoscopy grew later, the likelihood of adequacy of bowel preparation dropped. The inverse relationship was statistically significant (P less than .001), with over 60% of 7 a.m. colonoscopies having adequate preparation. By 3 p.m., over 60% of bowel preparations were inadequate in the University of Florida cohort.

Colonoscopies performed later in the week were most likely to have adequate bowel preparation, with rates nearing 60% by Friday, compared with rates just over or at 50% for the first 3 days of the week (P less than .001).

“This study showed that a colonoscopy on the day after a holiday has a higher rate of inadequate bowel preparation,” said Dr. Nassri. Conversely, he said, “Colonoscopy toward the end of the week has a higher likelihood of adequate bowel preparation.”

The present work, he said, “re-demonstrated that procedures done later in the day have a poorer bowel preparation.”

Dr. Nassri reported no conflicts of interest.

[email protected]

Although earlier research may suggest otherwise, traditional Medicare may actually do a better job of lowering the risk of hospital readmissions than Medicare Advantage, new research suggests.

Copyright Kimberly Pack/Thinkstock

Researchers used what they described as “a novel data linkage” comparing 30-day readmission rates after hospitalization for three major conditions in the Hospital Readmissions Reduction Program for patients using traditional Medicare versus Medicare Advantage. Those conditions included acute MI, heart failure, and pneumonia.

“Our results contrast with those of previous studies that have reported lower or statistically similar readmission rates for Medicare Advantage beneficiaries,” Orestis A. Panagiotou, MD, of Brown University, Providence, R.I., and colleagues wrote in a research report published in Annals of Internal Medicine.

In this retrospective cohort study, the researchers linked data from 2011 to 2014 from the Medicare Provider Analysis and Review (MedPAR) file to the Healthcare Effectiveness Data and Information Set (HEDIS).

The novel linkage found that HEDIS data underreported hospital admissions for acute MI, heart failure, and pneumonia, the researchers stated. “Plans incorrectly excluded hospitalizations that should have qualified for the readmission measure, and readmission rates were substantially higher among incorrectly excluded hospitalizations.”

Despite this, in analyses using the linkage of HEDIS and MedPAR, “Medicare Advantage beneficiaries had higher 30-day risk-adjusted readmission rates after [acute MI, heart failure, and pneumonia] than did traditional Medicare beneficiaries,” the investigators noted.

Patients in Medicare Advantage had lower unadjusted readmission rates compared with those in traditional Medicare (16.6% vs. 17.1% for acute MI; 21.4% vs. 21.7% for heart failure; and 16.3% vs. 16.4% for pneumonia). After standardization, Medicare Advantage patients had higher readmission rates, compared with those in traditional Medicare (17.2% vs. 16.9% for acute MI; 21.7% vs. 21.4% for heart failure; and 16.5% vs. 16.0% for pneumonia).

The study authors added that, while unadjusted readmission rates were higher for traditional Medicare beneficiaries, “the direction of the difference reversed after standardization. This occurred because Medicare Advantage beneficiaries have, on average, a lower expected readmission risk [that is, they are ‘healthier’].” Prior studies have documented that Medicare Advantage plans enroll beneficiaries with fewer comorbid conditions and that high-cost beneficiaries switch out of Medicare Advantage and into traditional Medicare.

The researchers suggested four reasons for the differences between the results in this study versus others that compared patients using Medicare with those using Medicare Advantage. These were that the new study included a more comprehensive data set, analyses with comorbid conditions “from a well-validated model applied by CMS [Centers for Medicare & Medicaid Services],” national data focused on three conditions included in the Hospital Readmissions Reduction Program, and patients discharged to places other than skilled nursing facilities and inpatient rehabilitation facilities.

Authors of an accompanying editorial called for caution to be used in interpreting Medicare Advantage enrollment as causing an increased readmission risk.

“[The] results are sensitive to adjustment for case mix,” wrote Peter Huckfeldt, PhD, of the University of Minnesota, Minneapolis, and Neeraj Sood, PhD, of the University of Southern California, Los Angeles, in the editorial published in Annals of Internal Medicine (2019 June 25. doi:10.7326/M19-1599) “Using diagnosis codes on hospital claims for case-mix adjustments may be increasingly perilous. ... To our knowledge, there is no recent evidence comparing the intensity of diagnostic coding between clinically similar [traditional Medicare] and [Medicare Advantage] hospital admissions, but if [traditional Medicare] enrollees were coded more intensively than [Medicare Advantage] enrollees, this could lead to [traditional Medicare] enrollees having lower risk-adjusted readmission rares due to coding practices.”

The editorialists added that using a cross-sectional comparison of Medicare Advantage and traditional Medicare patients is concerning because a “key challenge in estimating the effect of [Medicare Advantage] is that enrollment is voluntary,” which can lead to a number of analytical concerns.

The researchers concluded that their findings “are concerning because CMS uses HEDIS performance to construct composite quality ratings and assign payment bonuses to Medicare Advantage plans.

“Our study suggests a need for improved monitoring of the accuracy of HEDIS data,” they noted.

The National Institute on Aging provided the primary funding for this study. A number of the authors received grants from the National Institutes of Health during the conduct of the study. No other relevant disclosures were reported.

[email protected]

SOURCE: Panagiotou OA et al. Ann Intern Med. 2019 Jun 25. doi: 10.7326/M18-1795.

Although earlier research may suggest otherwise, traditional Medicare may actually do a better job of lowering the risk of hospital readmissions than Medicare Advantage, new research suggests.

Copyright Kimberly Pack/Thinkstock

Researchers used what they described as “a novel data linkage” comparing 30-day readmission rates after hospitalization for three major conditions in the Hospital Readmissions Reduction Program for patients using traditional Medicare versus Medicare Advantage. Those conditions included acute MI, heart failure, and pneumonia.

“Our results contrast with those of previous studies that have reported lower or statistically similar readmission rates for Medicare Advantage beneficiaries,” Orestis A. Panagiotou, MD, of Brown University, Providence, R.I., and colleagues wrote in a research report published in Annals of Internal Medicine.

In this retrospective cohort study, the researchers linked data from 2011 to 2014 from the Medicare Provider Analysis and Review (MedPAR) file to the Healthcare Effectiveness Data and Information Set (HEDIS).

The novel linkage found that HEDIS data underreported hospital admissions for acute MI, heart failure, and pneumonia, the researchers stated. “Plans incorrectly excluded hospitalizations that should have qualified for the readmission measure, and readmission rates were substantially higher among incorrectly excluded hospitalizations.”

Despite this, in analyses using the linkage of HEDIS and MedPAR, “Medicare Advantage beneficiaries had higher 30-day risk-adjusted readmission rates after [acute MI, heart failure, and pneumonia] than did traditional Medicare beneficiaries,” the investigators noted.

Patients in Medicare Advantage had lower unadjusted readmission rates compared with those in traditional Medicare (16.6% vs. 17.1% for acute MI; 21.4% vs. 21.7% for heart failure; and 16.3% vs. 16.4% for pneumonia). After standardization, Medicare Advantage patients had higher readmission rates, compared with those in traditional Medicare (17.2% vs. 16.9% for acute MI; 21.7% vs. 21.4% for heart failure; and 16.5% vs. 16.0% for pneumonia).

The study authors added that, while unadjusted readmission rates were higher for traditional Medicare beneficiaries, “the direction of the difference reversed after standardization. This occurred because Medicare Advantage beneficiaries have, on average, a lower expected readmission risk [that is, they are ‘healthier’].” Prior studies have documented that Medicare Advantage plans enroll beneficiaries with fewer comorbid conditions and that high-cost beneficiaries switch out of Medicare Advantage and into traditional Medicare.

The researchers suggested four reasons for the differences between the results in this study versus others that compared patients using Medicare with those using Medicare Advantage. These were that the new study included a more comprehensive data set, analyses with comorbid conditions “from a well-validated model applied by CMS [Centers for Medicare & Medicaid Services],” national data focused on three conditions included in the Hospital Readmissions Reduction Program, and patients discharged to places other than skilled nursing facilities and inpatient rehabilitation facilities.

Authors of an accompanying editorial called for caution to be used in interpreting Medicare Advantage enrollment as causing an increased readmission risk.

“[The] results are sensitive to adjustment for case mix,” wrote Peter Huckfeldt, PhD, of the University of Minnesota, Minneapolis, and Neeraj Sood, PhD, of the University of Southern California, Los Angeles, in the editorial published in Annals of Internal Medicine (2019 June 25. doi:10.7326/M19-1599) “Using diagnosis codes on hospital claims for case-mix adjustments may be increasingly perilous. ... To our knowledge, there is no recent evidence comparing the intensity of diagnostic coding between clinically similar [traditional Medicare] and [Medicare Advantage] hospital admissions, but if [traditional Medicare] enrollees were coded more intensively than [Medicare Advantage] enrollees, this could lead to [traditional Medicare] enrollees having lower risk-adjusted readmission rares due to coding practices.”

The editorialists added that using a cross-sectional comparison of Medicare Advantage and traditional Medicare patients is concerning because a “key challenge in estimating the effect of [Medicare Advantage] is that enrollment is voluntary,” which can lead to a number of analytical concerns.

The researchers concluded that their findings “are concerning because CMS uses HEDIS performance to construct composite quality ratings and assign payment bonuses to Medicare Advantage plans.

“Our study suggests a need for improved monitoring of the accuracy of HEDIS data,” they noted.

The National Institute on Aging provided the primary funding for this study. A number of the authors received grants from the National Institutes of Health during the conduct of the study. No other relevant disclosures were reported.

[email protected]

SOURCE: Panagiotou OA et al. Ann Intern Med. 2019 Jun 25. doi: 10.7326/M18-1795.

Although earlier research may suggest otherwise, traditional Medicare may actually do a better job of lowering the risk of hospital readmissions than Medicare Advantage, new research suggests.

Copyright Kimberly Pack/Thinkstock

Researchers used what they described as “a novel data linkage” comparing 30-day readmission rates after hospitalization for three major conditions in the Hospital Readmissions Reduction Program for patients using traditional Medicare versus Medicare Advantage. Those conditions included acute MI, heart failure, and pneumonia.

“Our results contrast with those of previous studies that have reported lower or statistically similar readmission rates for Medicare Advantage beneficiaries,” Orestis A. Panagiotou, MD, of Brown University, Providence, R.I., and colleagues wrote in a research report published in Annals of Internal Medicine.

In this retrospective cohort study, the researchers linked data from 2011 to 2014 from the Medicare Provider Analysis and Review (MedPAR) file to the Healthcare Effectiveness Data and Information Set (HEDIS).

The novel linkage found that HEDIS data underreported hospital admissions for acute MI, heart failure, and pneumonia, the researchers stated. “Plans incorrectly excluded hospitalizations that should have qualified for the readmission measure, and readmission rates were substantially higher among incorrectly excluded hospitalizations.”

Despite this, in analyses using the linkage of HEDIS and MedPAR, “Medicare Advantage beneficiaries had higher 30-day risk-adjusted readmission rates after [acute MI, heart failure, and pneumonia] than did traditional Medicare beneficiaries,” the investigators noted.

Patients in Medicare Advantage had lower unadjusted readmission rates compared with those in traditional Medicare (16.6% vs. 17.1% for acute MI; 21.4% vs. 21.7% for heart failure; and 16.3% vs. 16.4% for pneumonia). After standardization, Medicare Advantage patients had higher readmission rates, compared with those in traditional Medicare (17.2% vs. 16.9% for acute MI; 21.7% vs. 21.4% for heart failure; and 16.5% vs. 16.0% for pneumonia).

The study authors added that, while unadjusted readmission rates were higher for traditional Medicare beneficiaries, “the direction of the difference reversed after standardization. This occurred because Medicare Advantage beneficiaries have, on average, a lower expected readmission risk [that is, they are ‘healthier’].” Prior studies have documented that Medicare Advantage plans enroll beneficiaries with fewer comorbid conditions and that high-cost beneficiaries switch out of Medicare Advantage and into traditional Medicare.

The researchers suggested four reasons for the differences between the results in this study versus others that compared patients using Medicare with those using Medicare Advantage. These were that the new study included a more comprehensive data set, analyses with comorbid conditions “from a well-validated model applied by CMS [Centers for Medicare & Medicaid Services],” national data focused on three conditions included in the Hospital Readmissions Reduction Program, and patients discharged to places other than skilled nursing facilities and inpatient rehabilitation facilities.

Authors of an accompanying editorial called for caution to be used in interpreting Medicare Advantage enrollment as causing an increased readmission risk.

“[The] results are sensitive to adjustment for case mix,” wrote Peter Huckfeldt, PhD, of the University of Minnesota, Minneapolis, and Neeraj Sood, PhD, of the University of Southern California, Los Angeles, in the editorial published in Annals of Internal Medicine (2019 June 25. doi:10.7326/M19-1599) “Using diagnosis codes on hospital claims for case-mix adjustments may be increasingly perilous. ... To our knowledge, there is no recent evidence comparing the intensity of diagnostic coding between clinically similar [traditional Medicare] and [Medicare Advantage] hospital admissions, but if [traditional Medicare] enrollees were coded more intensively than [Medicare Advantage] enrollees, this could lead to [traditional Medicare] enrollees having lower risk-adjusted readmission rares due to coding practices.”

The editorialists added that using a cross-sectional comparison of Medicare Advantage and traditional Medicare patients is concerning because a “key challenge in estimating the effect of [Medicare Advantage] is that enrollment is voluntary,” which can lead to a number of analytical concerns.

The researchers concluded that their findings “are concerning because CMS uses HEDIS performance to construct composite quality ratings and assign payment bonuses to Medicare Advantage plans.

“Our study suggests a need for improved monitoring of the accuracy of HEDIS data,” they noted.

The National Institute on Aging provided the primary funding for this study. A number of the authors received grants from the National Institutes of Health during the conduct of the study. No other relevant disclosures were reported.

[email protected]

SOURCE: Panagiotou OA et al. Ann Intern Med. 2019 Jun 25. doi: 10.7326/M18-1795.

SAN ANTONIO – Of 196 U.S. youth who reported use of at least one prescribed stimulant in their lifetimes, 25% also said they used the drugs nonmedically, based on a survey of children and adolescents aged 10-17 years.

Another 5% of the youth surveyed reported exclusively nonmedical use of stimulants. The survey participants lived in six U.S. cities and their outlying areas.

“Parents of both users and nonusers should warn their children of the dangers of using others’ stimulants and giving their own stimulants to others,” concluded Linda B. Cottler, PhD, MPH of the University of Florida, and colleagues.

“Physicians and pharmacists should make users and their families aware of the need to take medications as prescribed and not to share medications with others,” they wrote in their research poster at the annual meeting of the College on Problems of Drug Dependence. “Continuous monitoring of these medications in the community should be a priority.”

Though prevalence research has shown increasing stimulant misuse among youth, little data exist for younger children, the researchers noted. They therefore conducted a survey of 1,777 youth aged 10-17 years from September to October 2018 in six cities in California, Texas, and Florida, the most populous U.S. states.

The participants included youth from urban, rural, and suburban areas of Los Angeles, Dallas, Houston, Tampa, Orlando, and Miami. Trained graduate students and professional raters approached the respondents in entertainment venues and obtained assent but did not require parental consent. The respondents received $30 for completing the survey.

A total of 11.1% of respondents reporting having used prescription stimulants in their lifetime, and 7.6% had done so in the past 30 days. Just under a third of those who used stimulants (30.1%) did so for nonmedical purposes, defined as taking the stimulant nonorally (except for the patch Daytrana), getting the stimulant from someone else, or taking more of the drug than prescribed.

A quarter of the respondents who used stimulants reported both medical use and nonmedical use. And 5.1% of these youths reported only using stimulants nonmedically.

Among those with any lifetime stimulant use, 13.8% reported nonoral administration, including 9.7% who snorted or sniffed the drugs, 4.1% who smoked them, and 1.0% who injected them. Just over half (51.8%) of those reporting nonoral use had also used prescription stimulants orally.

The likelihood of using stimulants nonmedically increased with age (P less than .0001). The researchers found no significant associations between nonmedical use and geography or race/ethnicity. Among 10- to 12-year-olds, 3.1% reported only medical use of stimulants, and 0.7% (2 of 286 respondents in this age group) reported any nonmedical use of stimulants.

Of those aged 13-15 years, 2.1% reported any nonmedical stimulant use.

Nonmedical stimulant use was reported by twice as many boys (67.8%) as girls (32.2%), though this finding may not be surprising as the majority of nonmedical users were also medical users and stimulants are prescribed more frequently to boys than to girls (P less than .0006).

The research was funded by Arbor Pharmaceuticals. The authors noted no conflicts of interest.

SAN ANTONIO – Of 196 U.S. youth who reported use of at least one prescribed stimulant in their lifetimes, 25% also said they used the drugs nonmedically, based on a survey of children and adolescents aged 10-17 years.

Another 5% of the youth surveyed reported exclusively nonmedical use of stimulants. The survey participants lived in six U.S. cities and their outlying areas.

“Parents of both users and nonusers should warn their children of the dangers of using others’ stimulants and giving their own stimulants to others,” concluded Linda B. Cottler, PhD, MPH of the University of Florida, and colleagues.

“Physicians and pharmacists should make users and their families aware of the need to take medications as prescribed and not to share medications with others,” they wrote in their research poster at the annual meeting of the College on Problems of Drug Dependence. “Continuous monitoring of these medications in the community should be a priority.”

Though prevalence research has shown increasing stimulant misuse among youth, little data exist for younger children, the researchers noted. They therefore conducted a survey of 1,777 youth aged 10-17 years from September to October 2018 in six cities in California, Texas, and Florida, the most populous U.S. states.

The participants included youth from urban, rural, and suburban areas of Los Angeles, Dallas, Houston, Tampa, Orlando, and Miami. Trained graduate students and professional raters approached the respondents in entertainment venues and obtained assent but did not require parental consent. The respondents received $30 for completing the survey.

A total of 11.1% of respondents reporting having used prescription stimulants in their lifetime, and 7.6% had done so in the past 30 days. Just under a third of those who used stimulants (30.1%) did so for nonmedical purposes, defined as taking the stimulant nonorally (except for the patch Daytrana), getting the stimulant from someone else, or taking more of the drug than prescribed.

A quarter of the respondents who used stimulants reported both medical use and nonmedical use. And 5.1% of these youths reported only using stimulants nonmedically.

Among those with any lifetime stimulant use, 13.8% reported nonoral administration, including 9.7% who snorted or sniffed the drugs, 4.1% who smoked them, and 1.0% who injected them. Just over half (51.8%) of those reporting nonoral use had also used prescription stimulants orally.

The likelihood of using stimulants nonmedically increased with age (P less than .0001). The researchers found no significant associations between nonmedical use and geography or race/ethnicity. Among 10- to 12-year-olds, 3.1% reported only medical use of stimulants, and 0.7% (2 of 286 respondents in this age group) reported any nonmedical use of stimulants.

Of those aged 13-15 years, 2.1% reported any nonmedical stimulant use.

Nonmedical stimulant use was reported by twice as many boys (67.8%) as girls (32.2%), though this finding may not be surprising as the majority of nonmedical users were also medical users and stimulants are prescribed more frequently to boys than to girls (P less than .0006).

The research was funded by Arbor Pharmaceuticals. The authors noted no conflicts of interest.

SAN ANTONIO – Of 196 U.S. youth who reported use of at least one prescribed stimulant in their lifetimes, 25% also said they used the drugs nonmedically, based on a survey of children and adolescents aged 10-17 years.

Another 5% of the youth surveyed reported exclusively nonmedical use of stimulants. The survey participants lived in six U.S. cities and their outlying areas.

“Parents of both users and nonusers should warn their children of the dangers of using others’ stimulants and giving their own stimulants to others,” concluded Linda B. Cottler, PhD, MPH of the University of Florida, and colleagues.

“Physicians and pharmacists should make users and their families aware of the need to take medications as prescribed and not to share medications with others,” they wrote in their research poster at the annual meeting of the College on Problems of Drug Dependence. “Continuous monitoring of these medications in the community should be a priority.”

Though prevalence research has shown increasing stimulant misuse among youth, little data exist for younger children, the researchers noted. They therefore conducted a survey of 1,777 youth aged 10-17 years from September to October 2018 in six cities in California, Texas, and Florida, the most populous U.S. states.

The participants included youth from urban, rural, and suburban areas of Los Angeles, Dallas, Houston, Tampa, Orlando, and Miami. Trained graduate students and professional raters approached the respondents in entertainment venues and obtained assent but did not require parental consent. The respondents received $30 for completing the survey.

A total of 11.1% of respondents reporting having used prescription stimulants in their lifetime, and 7.6% had done so in the past 30 days. Just under a third of those who used stimulants (30.1%) did so for nonmedical purposes, defined as taking the stimulant nonorally (except for the patch Daytrana), getting the stimulant from someone else, or taking more of the drug than prescribed.

A quarter of the respondents who used stimulants reported both medical use and nonmedical use. And 5.1% of these youths reported only using stimulants nonmedically.

Among those with any lifetime stimulant use, 13.8% reported nonoral administration, including 9.7% who snorted or sniffed the drugs, 4.1% who smoked them, and 1.0% who injected them. Just over half (51.8%) of those reporting nonoral use had also used prescription stimulants orally.

The likelihood of using stimulants nonmedically increased with age (P less than .0001). The researchers found no significant associations between nonmedical use and geography or race/ethnicity. Among 10- to 12-year-olds, 3.1% reported only medical use of stimulants, and 0.7% (2 of 286 respondents in this age group) reported any nonmedical use of stimulants.

Of those aged 13-15 years, 2.1% reported any nonmedical stimulant use.

Nonmedical stimulant use was reported by twice as many boys (67.8%) as girls (32.2%), though this finding may not be surprising as the majority of nonmedical users were also medical users and stimulants are prescribed more frequently to boys than to girls (P less than .0006).

The research was funded by Arbor Pharmaceuticals. The authors noted no conflicts of interest.

PHILADELPHIA – Diffusion-weighted MRI and the presence of at least five of seven clinical features may prove useful for determining which newly diagnosed patients with Parkinson’s disease are likely to have rapidly progressive disease, Frank M. Skidmore, MD, reported at the annual meeting of the American Academy of Neurology.

Patients with gray matter and axonal disease on initial imaging were found to have more aggressive disease associated with early gait dysfunction than were patients with primarily white matter and axonal disease, said Dr. Skidmore, associate professor of neurology at the University of Alabama, Birmingham.

Diffusion-weighted imaging provides a way to assess cellular fluid partitioning and directional information in gray and white matter. Thus, it has the potential to identify brainstem pathology that is associated with disease progression, he said. “Our approach provides a pathway towards using MR to detect early, prognostic, neurodegenerative changes in diseases of the brain.”

Dr. Skidmore and colleagues performed diffusion-weighted imaging on 101 patients with newly diagnosed Parkinson’s disease and 56 healthy controls. They found that Parkinson’s disease was associated with altered radial diffusion in white matter. Changes were observed mainly in the striatonigral tract and the substantia nigra. The investigators also noted atrophy in the cerebellar peduncle among patients with Parkinson’s disease.

At baseline, the patients who went on to have subsequent development of early postural instability and gait dysfunction had decreased intracellular fluid partitioning in the substantia nigra and the mesencephalic locomotor region, which are predominantly gray matter regions. These participants had a lower orientation diffusion index (ODI) and a lower estimate of cellularity, Dr. Skidmore said.

The researchers defined early gait dysfunction as the achievement of a Hoehn and Yahr score of 3 at least once while on medication during the first 5 years after Parkinson’s disease diagnosis. Follow-up was at least 5 years in 79 of the patients.

To identify clinical features associated with early postural instability and gait difficulty, the investigators examined data for 301 patients. In this population, Dr. Skidmore and colleagues identified 218 patients whose Hoehn and Yahr scores never exceeded 2 and 83 patients with at least one Hoehn and Yahr score of 3 or more. Using Bonferroni correction, they examined Unified Parkinson’s Disease Rating Scale (UPDRS) data for all patients to identify significant differences between these two groups. Seven items distinguished patients who developed early postural instability and gait difficulty. They included lightheadedness, fatigue, difficulty walking, ability to rise from a chair, and postural problems. The seven-item scale was superior to the Unified Parkinson’s Disease Rating Scale (UPDRS) at predicting which newly diagnosed patients would develop early postural and gait difficulties

[email protected]

SOURCE: Skidmore F et al. AANN 2019, Abstract S41.004.

PHILADELPHIA – Diffusion-weighted MRI and the presence of at least five of seven clinical features may prove useful for determining which newly diagnosed patients with Parkinson’s disease are likely to have rapidly progressive disease, Frank M. Skidmore, MD, reported at the annual meeting of the American Academy of Neurology.

Patients with gray matter and axonal disease on initial imaging were found to have more aggressive disease associated with early gait dysfunction than were patients with primarily white matter and axonal disease, said Dr. Skidmore, associate professor of neurology at the University of Alabama, Birmingham.

Diffusion-weighted imaging provides a way to assess cellular fluid partitioning and directional information in gray and white matter. Thus, it has the potential to identify brainstem pathology that is associated with disease progression, he said. “Our approach provides a pathway towards using MR to detect early, prognostic, neurodegenerative changes in diseases of the brain.”

Dr. Skidmore and colleagues performed diffusion-weighted imaging on 101 patients with newly diagnosed Parkinson’s disease and 56 healthy controls. They found that Parkinson’s disease was associated with altered radial diffusion in white matter. Changes were observed mainly in the striatonigral tract and the substantia nigra. The investigators also noted atrophy in the cerebellar peduncle among patients with Parkinson’s disease.

At baseline, the patients who went on to have subsequent development of early postural instability and gait dysfunction had decreased intracellular fluid partitioning in the substantia nigra and the mesencephalic locomotor region, which are predominantly gray matter regions. These participants had a lower orientation diffusion index (ODI) and a lower estimate of cellularity, Dr. Skidmore said.

The researchers defined early gait dysfunction as the achievement of a Hoehn and Yahr score of 3 at least once while on medication during the first 5 years after Parkinson’s disease diagnosis. Follow-up was at least 5 years in 79 of the patients.

To identify clinical features associated with early postural instability and gait difficulty, the investigators examined data for 301 patients. In this population, Dr. Skidmore and colleagues identified 218 patients whose Hoehn and Yahr scores never exceeded 2 and 83 patients with at least one Hoehn and Yahr score of 3 or more. Using Bonferroni correction, they examined Unified Parkinson’s Disease Rating Scale (UPDRS) data for all patients to identify significant differences between these two groups. Seven items distinguished patients who developed early postural instability and gait difficulty. They included lightheadedness, fatigue, difficulty walking, ability to rise from a chair, and postural problems. The seven-item scale was superior to the Unified Parkinson’s Disease Rating Scale (UPDRS) at predicting which newly diagnosed patients would develop early postural and gait difficulties

[email protected]

SOURCE: Skidmore F et al. AANN 2019, Abstract S41.004.

PHILADELPHIA – Diffusion-weighted MRI and the presence of at least five of seven clinical features may prove useful for determining which newly diagnosed patients with Parkinson’s disease are likely to have rapidly progressive disease, Frank M. Skidmore, MD, reported at the annual meeting of the American Academy of Neurology.

Patients with gray matter and axonal disease on initial imaging were found to have more aggressive disease associated with early gait dysfunction than were patients with primarily white matter and axonal disease, said Dr. Skidmore, associate professor of neurology at the University of Alabama, Birmingham.

Diffusion-weighted imaging provides a way to assess cellular fluid partitioning and directional information in gray and white matter. Thus, it has the potential to identify brainstem pathology that is associated with disease progression, he said. “Our approach provides a pathway towards using MR to detect early, prognostic, neurodegenerative changes in diseases of the brain.”

Dr. Skidmore and colleagues performed diffusion-weighted imaging on 101 patients with newly diagnosed Parkinson’s disease and 56 healthy controls. They found that Parkinson’s disease was associated with altered radial diffusion in white matter. Changes were observed mainly in the striatonigral tract and the substantia nigra. The investigators also noted atrophy in the cerebellar peduncle among patients with Parkinson’s disease.

At baseline, the patients who went on to have subsequent development of early postural instability and gait dysfunction had decreased intracellular fluid partitioning in the substantia nigra and the mesencephalic locomotor region, which are predominantly gray matter regions. These participants had a lower orientation diffusion index (ODI) and a lower estimate of cellularity, Dr. Skidmore said.

The researchers defined early gait dysfunction as the achievement of a Hoehn and Yahr score of 3 at least once while on medication during the first 5 years after Parkinson’s disease diagnosis. Follow-up was at least 5 years in 79 of the patients.

To identify clinical features associated with early postural instability and gait difficulty, the investigators examined data for 301 patients. In this population, Dr. Skidmore and colleagues identified 218 patients whose Hoehn and Yahr scores never exceeded 2 and 83 patients with at least one Hoehn and Yahr score of 3 or more. Using Bonferroni correction, they examined Unified Parkinson’s Disease Rating Scale (UPDRS) data for all patients to identify significant differences between these two groups. Seven items distinguished patients who developed early postural instability and gait difficulty. They included lightheadedness, fatigue, difficulty walking, ability to rise from a chair, and postural problems. The seven-item scale was superior to the Unified Parkinson’s Disease Rating Scale (UPDRS) at predicting which newly diagnosed patients would develop early postural and gait difficulties

[email protected]

SOURCE: Skidmore F et al. AANN 2019, Abstract S41.004.