SAN DIEGO—An antiretroviral drug used to treat the human immunodeficiency virus (HIV) may find a role in the treatment of multiple myeloma (MM) patients who are proteasome inhibitor (PI)-refractory.

According to investigators, nelfinavir may sensitize refractory patients so that PI-based treatments become an option for them.

In a phase 2 study of 34 patients, nelfinavir in combination with bortezomib and dexamethasone produced an objective response rate of 65%, which investigators called an “exceptional” response in this heavily pretreated, mostly dual-refractory patient population.

Christoph Driessen, MD, PhD, of Kantonsspital St Gallen in Switzerland, discussed the findings of this study, known as SAKK 39/13, at the 2016 ASH Annual Meeting as abstract 487.

Dr Driessen explained that downregulation of IRE1/XBP1 produces PI resistance, and this downregulation occurs in PI-refractory MM patients.

High expression of IRE1/XBP1 correlates with bortezomib sensitivity, and pharmacologic upregulation of IRE1/XBP1 re-sensitizes myeloma cells to PI treatment.

Nelfinavir, which overcomes PI resistance in vitro, is approved for oral HIV therapy.

“It’s an old drug, it’s a generic drug,” Dr Driessen said, and it’s approved at a dose of 2 x 1250 mg daily.

So the SAKK investigators undertook a phase 1 trial of nelfinavir in MM patients.

In an exploratory extension cohort, they found that 5 of 6 MM patients double-refractory to bortezomib and lenalidomide experienced clinical benefit from nelfinavir at the recommended phase 2 dose (2 x 2500 mg daily) in addition to standard treatment with bortezomib and dexamethasone.

Three patients achieved a partial response (PR) and 3 a minor response (MR).

The investigators’ objective in the phase 2 study was to determine whether the addition of nelfinavir to approved bortezomib-dexamethasone therapy is sufficiently active to merit further investigation in a randomized trial.

Study design

Patients in this prospective, single-arm, multicenter, open-label trial received the following treatment:

• Nelfinavir at 2 x 2500 mg orally on days 1–14
• Bortezomib at 1.3 mg/m² intravenously or subcutaneously on days 1, 4, 8, and 11
• Dexamethasone at 20 mg orally on days 1-2, 4-5, 8-9, and 11-12 of each 21-day cycle.

Trial therapy lasted for a maximum of 6 cycles (18 weeks).

Dr Driessen explained that the trial “was a truly academic trial, without any finances from industry or drug support from industry. So we actually had to get a grant to buy commercial drugs for the study on the commercial drug market, and that limited the duration of treatment in this trial.”

The primary endpoint of the trial was response rate—best response of PR or better by IMWG criteria.

Investigators considered a 30% or higher response rate promising.

Secondary endpoints included adverse events, time to next new anti-myeloma therapy or death, progressive disease under trial treatment, duration of response, progression-free survival, and time to progression.

Patients were eligible to enroll if they had been exposed to or could not tolerate an immunomodulatory drug, were refractory to their most recent PI-containing regimen, had a performance status of 3 or less, had creatinine clearance of 15 mL/minute or greater, had a platelet count of 50,000/μL or more, and had a hemoglobin level of 8.0 g/dL or higher.

Patients were excluded if they had uncontrolled, clinically significant, active concurrent disease, concomitant additional systemic cancer treatment, concomitant radiotherapy, or significant neuropathy of grades 3-4 or grade 2 with pain.

Patient population

Thirty-four patients enrolled on the trial. They were a median age of 67 (range, 42–82), 62% were male, 91% had a performance status of 0 or 1, and 76% had a prior autologous stem cell transplant.

They had a median of 5 prior systemic therapies (range, 2–10), and 38% had poor-risk cytogenetics.

The time from last dose of prior therapy to enrollment on the study was a median of 27 days.

“So [it was] a truly progressive, highly refractory myeloma population,” Dr Driessen emphasized.

All 34 patients were refractory to bortezomib. All patients were also exposed to lenalidomide, and 79% were refractory to it.

Forty-four percent were refractory to pomalidomide, and 6% were refractory to carfilzomib. One patient was refractory to all 4 agents.

“Very few patients were exposed to carfilzomib because it wasn’t available in Switzerland at that time,” Dr Driessen explained.

Efficacy

Patients received a median of 4.5 cycles of therapy (range, 1–6), and the best response of PR or greater was achieved by 22 patients (65%).

Five patients (15%) achieved a very good partial response (VGPR), 17 (50%) PR, 3 (9%) MR, and 4 (12%) stable disease.

Twenty-five patients (74%) achieved a clinical benefit (VGPR+PR+MR).

Ten of the 13 patients (77%) with poor-risk cytogenetics achieved a best response of PR or greater.

Patients had a median of 16 weeks (range, 13–24) time to a new anti-myeloma therapy or death, and 13 patients (38%) had confirmed progressive disease while on trial therapy.

In 32 patients, all but 4 had a decrease from baseline in serum M protein or serum free light chain concentration.

Efficacy by prior therapy

Twenty-two of 34 patients (65%) refractory to bortezomib had a best response of PR or greater.

For patients refractory to bortezomib and lenalidomide, 70% achieved a best response of PR or greater.

For patients refractory to bortezomib, lenalidomide, and pomalidomide, 60% achieved a best response of PR or greater.

And for patients who were refractory to bortezomib, lenalidomide, and carfilzomib, 50% achieved a best response of PR or greater.

Adverse events

“The hematologic toxicity was essentially what you would expect from this heavily pretreated population,” Dr Driessen said.

“We did, however, experience 4 deaths on the trial therapy from infectious complications of sepsis and neutropenia, and we don’t know whether this is a true signal or whether this is due to the low numbers. We did not mandate antibiotic prophylaxis on the trial.”

Grade 3 or higher adverse events (AEs) occurring in 2 or more patients were anemia (n=10), febrile neutropenia (n=4, including 1 grade 5), thrombocytopenia (n=15), lung infection (n=8), sepsis (n=3, all grade 5), fatigue (n=5), peripheral sensory neuropathy (n=3), hypertension (n=6), increased creatinine (n=4), hyperglycemia (n=6) hypokalemia (n=3), and hyponatremia (n=5).

Dr Driessen indicated that with a future generic version of bortezomib, nelfinavir plus bortezomib and dexamethasone “has the potential to become a fully generic, affordable, active therapy option for PI-refractory patients.”

The investigators believe the results of their study call for further development of nelfinavir as a sensitizing drug for PI-based treatments and as a promising new agent for MM therapy.

SAN DIEGO—An antiretroviral drug used to treat the human immunodeficiency virus (HIV) may find a role in the treatment of multiple myeloma (MM) patients who are proteasome inhibitor (PI)-refractory.

According to investigators, nelfinavir may sensitize refractory patients so that PI-based treatments become an option for them.

In a phase 2 study of 34 patients, nelfinavir in combination with bortezomib and dexamethasone produced an objective response rate of 65%, which investigators called an “exceptional” response in this heavily pretreated, mostly dual-refractory patient population.

Christoph Driessen, MD, PhD, of Kantonsspital St Gallen in Switzerland, discussed the findings of this study, known as SAKK 39/13, at the 2016 ASH Annual Meeting as abstract 487.

Dr Driessen explained that downregulation of IRE1/XBP1 produces PI resistance, and this downregulation occurs in PI-refractory MM patients.

High expression of IRE1/XBP1 correlates with bortezomib sensitivity, and pharmacologic upregulation of IRE1/XBP1 re-sensitizes myeloma cells to PI treatment.

Nelfinavir, which overcomes PI resistance in vitro, is approved for oral HIV therapy.

“It’s an old drug, it’s a generic drug,” Dr Driessen said, and it’s approved at a dose of 2 x 1250 mg daily.

So the SAKK investigators undertook a phase 1 trial of nelfinavir in MM patients.

In an exploratory extension cohort, they found that 5 of 6 MM patients double-refractory to bortezomib and lenalidomide experienced clinical benefit from nelfinavir at the recommended phase 2 dose (2 x 2500 mg daily) in addition to standard treatment with bortezomib and dexamethasone.

Three patients achieved a partial response (PR) and 3 a minor response (MR).

The investigators’ objective in the phase 2 study was to determine whether the addition of nelfinavir to approved bortezomib-dexamethasone therapy is sufficiently active to merit further investigation in a randomized trial.

Study design

Patients in this prospective, single-arm, multicenter, open-label trial received the following treatment:

• Nelfinavir at 2 x 2500 mg orally on days 1–14
• Bortezomib at 1.3 mg/m² intravenously or subcutaneously on days 1, 4, 8, and 11
• Dexamethasone at 20 mg orally on days 1-2, 4-5, 8-9, and 11-12 of each 21-day cycle.

Trial therapy lasted for a maximum of 6 cycles (18 weeks).

Dr Driessen explained that the trial “was a truly academic trial, without any finances from industry or drug support from industry. So we actually had to get a grant to buy commercial drugs for the study on the commercial drug market, and that limited the duration of treatment in this trial.”

The primary endpoint of the trial was response rate—best response of PR or better by IMWG criteria.

Investigators considered a 30% or higher response rate promising.

Secondary endpoints included adverse events, time to next new anti-myeloma therapy or death, progressive disease under trial treatment, duration of response, progression-free survival, and time to progression.

Patients were eligible to enroll if they had been exposed to or could not tolerate an immunomodulatory drug, were refractory to their most recent PI-containing regimen, had a performance status of 3 or less, had creatinine clearance of 15 mL/minute or greater, had a platelet count of 50,000/μL or more, and had a hemoglobin level of 8.0 g/dL or higher.

Patients were excluded if they had uncontrolled, clinically significant, active concurrent disease, concomitant additional systemic cancer treatment, concomitant radiotherapy, or significant neuropathy of grades 3-4 or grade 2 with pain.

Patient population

Thirty-four patients enrolled on the trial. They were a median age of 67 (range, 42–82), 62% were male, 91% had a performance status of 0 or 1, and 76% had a prior autologous stem cell transplant.

They had a median of 5 prior systemic therapies (range, 2–10), and 38% had poor-risk cytogenetics.

The time from last dose of prior therapy to enrollment on the study was a median of 27 days.

“So [it was] a truly progressive, highly refractory myeloma population,” Dr Driessen emphasized.

All 34 patients were refractory to bortezomib. All patients were also exposed to lenalidomide, and 79% were refractory to it.

Forty-four percent were refractory to pomalidomide, and 6% were refractory to carfilzomib. One patient was refractory to all 4 agents.

“Very few patients were exposed to carfilzomib because it wasn’t available in Switzerland at that time,” Dr Driessen explained.

Efficacy

Patients received a median of 4.5 cycles of therapy (range, 1–6), and the best response of PR or greater was achieved by 22 patients (65%).

Five patients (15%) achieved a very good partial response (VGPR), 17 (50%) PR, 3 (9%) MR, and 4 (12%) stable disease.

Twenty-five patients (74%) achieved a clinical benefit (VGPR+PR+MR).

Ten of the 13 patients (77%) with poor-risk cytogenetics achieved a best response of PR or greater.

Patients had a median of 16 weeks (range, 13–24) time to a new anti-myeloma therapy or death, and 13 patients (38%) had confirmed progressive disease while on trial therapy.

In 32 patients, all but 4 had a decrease from baseline in serum M protein or serum free light chain concentration.

Efficacy by prior therapy

Twenty-two of 34 patients (65%) refractory to bortezomib had a best response of PR or greater.

For patients refractory to bortezomib and lenalidomide, 70% achieved a best response of PR or greater.

For patients refractory to bortezomib, lenalidomide, and pomalidomide, 60% achieved a best response of PR or greater.

And for patients who were refractory to bortezomib, lenalidomide, and carfilzomib, 50% achieved a best response of PR or greater.

Adverse events

“The hematologic toxicity was essentially what you would expect from this heavily pretreated population,” Dr Driessen said.

“We did, however, experience 4 deaths on the trial therapy from infectious complications of sepsis and neutropenia, and we don’t know whether this is a true signal or whether this is due to the low numbers. We did not mandate antibiotic prophylaxis on the trial.”

Grade 3 or higher adverse events (AEs) occurring in 2 or more patients were anemia (n=10), febrile neutropenia (n=4, including 1 grade 5), thrombocytopenia (n=15), lung infection (n=8), sepsis (n=3, all grade 5), fatigue (n=5), peripheral sensory neuropathy (n=3), hypertension (n=6), increased creatinine (n=4), hyperglycemia (n=6) hypokalemia (n=3), and hyponatremia (n=5).

Dr Driessen indicated that with a future generic version of bortezomib, nelfinavir plus bortezomib and dexamethasone “has the potential to become a fully generic, affordable, active therapy option for PI-refractory patients.”

The investigators believe the results of their study call for further development of nelfinavir as a sensitizing drug for PI-based treatments and as a promising new agent for MM therapy.

SAN DIEGO—An antiretroviral drug used to treat the human immunodeficiency virus (HIV) may find a role in the treatment of multiple myeloma (MM) patients who are proteasome inhibitor (PI)-refractory.

According to investigators, nelfinavir may sensitize refractory patients so that PI-based treatments become an option for them.

In a phase 2 study of 34 patients, nelfinavir in combination with bortezomib and dexamethasone produced an objective response rate of 65%, which investigators called an “exceptional” response in this heavily pretreated, mostly dual-refractory patient population.

Christoph Driessen, MD, PhD, of Kantonsspital St Gallen in Switzerland, discussed the findings of this study, known as SAKK 39/13, at the 2016 ASH Annual Meeting as abstract 487.

Dr Driessen explained that downregulation of IRE1/XBP1 produces PI resistance, and this downregulation occurs in PI-refractory MM patients.

High expression of IRE1/XBP1 correlates with bortezomib sensitivity, and pharmacologic upregulation of IRE1/XBP1 re-sensitizes myeloma cells to PI treatment.

Nelfinavir, which overcomes PI resistance in vitro, is approved for oral HIV therapy.

“It’s an old drug, it’s a generic drug,” Dr Driessen said, and it’s approved at a dose of 2 x 1250 mg daily.

So the SAKK investigators undertook a phase 1 trial of nelfinavir in MM patients.

In an exploratory extension cohort, they found that 5 of 6 MM patients double-refractory to bortezomib and lenalidomide experienced clinical benefit from nelfinavir at the recommended phase 2 dose (2 x 2500 mg daily) in addition to standard treatment with bortezomib and dexamethasone.

Three patients achieved a partial response (PR) and 3 a minor response (MR).

The investigators’ objective in the phase 2 study was to determine whether the addition of nelfinavir to approved bortezomib-dexamethasone therapy is sufficiently active to merit further investigation in a randomized trial.

Study design

Patients in this prospective, single-arm, multicenter, open-label trial received the following treatment:

• Nelfinavir at 2 x 2500 mg orally on days 1–14
• Bortezomib at 1.3 mg/m² intravenously or subcutaneously on days 1, 4, 8, and 11
• Dexamethasone at 20 mg orally on days 1-2, 4-5, 8-9, and 11-12 of each 21-day cycle.

Trial therapy lasted for a maximum of 6 cycles (18 weeks).

Dr Driessen explained that the trial “was a truly academic trial, without any finances from industry or drug support from industry. So we actually had to get a grant to buy commercial drugs for the study on the commercial drug market, and that limited the duration of treatment in this trial.”

The primary endpoint of the trial was response rate—best response of PR or better by IMWG criteria.

Investigators considered a 30% or higher response rate promising.

Secondary endpoints included adverse events, time to next new anti-myeloma therapy or death, progressive disease under trial treatment, duration of response, progression-free survival, and time to progression.

Patients were eligible to enroll if they had been exposed to or could not tolerate an immunomodulatory drug, were refractory to their most recent PI-containing regimen, had a performance status of 3 or less, had creatinine clearance of 15 mL/minute or greater, had a platelet count of 50,000/μL or more, and had a hemoglobin level of 8.0 g/dL or higher.

Patients were excluded if they had uncontrolled, clinically significant, active concurrent disease, concomitant additional systemic cancer treatment, concomitant radiotherapy, or significant neuropathy of grades 3-4 or grade 2 with pain.

Patient population

Thirty-four patients enrolled on the trial. They were a median age of 67 (range, 42–82), 62% were male, 91% had a performance status of 0 or 1, and 76% had a prior autologous stem cell transplant.

They had a median of 5 prior systemic therapies (range, 2–10), and 38% had poor-risk cytogenetics.

The time from last dose of prior therapy to enrollment on the study was a median of 27 days.

“So [it was] a truly progressive, highly refractory myeloma population,” Dr Driessen emphasized.

All 34 patients were refractory to bortezomib. All patients were also exposed to lenalidomide, and 79% were refractory to it.

Forty-four percent were refractory to pomalidomide, and 6% were refractory to carfilzomib. One patient was refractory to all 4 agents.

“Very few patients were exposed to carfilzomib because it wasn’t available in Switzerland at that time,” Dr Driessen explained.

Efficacy

Patients received a median of 4.5 cycles of therapy (range, 1–6), and the best response of PR or greater was achieved by 22 patients (65%).

Five patients (15%) achieved a very good partial response (VGPR), 17 (50%) PR, 3 (9%) MR, and 4 (12%) stable disease.

Twenty-five patients (74%) achieved a clinical benefit (VGPR+PR+MR).

Ten of the 13 patients (77%) with poor-risk cytogenetics achieved a best response of PR or greater.

Patients had a median of 16 weeks (range, 13–24) time to a new anti-myeloma therapy or death, and 13 patients (38%) had confirmed progressive disease while on trial therapy.

In 32 patients, all but 4 had a decrease from baseline in serum M protein or serum free light chain concentration.

Efficacy by prior therapy

Twenty-two of 34 patients (65%) refractory to bortezomib had a best response of PR or greater.

For patients refractory to bortezomib and lenalidomide, 70% achieved a best response of PR or greater.

For patients refractory to bortezomib, lenalidomide, and pomalidomide, 60% achieved a best response of PR or greater.

And for patients who were refractory to bortezomib, lenalidomide, and carfilzomib, 50% achieved a best response of PR or greater.

Adverse events

“The hematologic toxicity was essentially what you would expect from this heavily pretreated population,” Dr Driessen said.

“We did, however, experience 4 deaths on the trial therapy from infectious complications of sepsis and neutropenia, and we don’t know whether this is a true signal or whether this is due to the low numbers. We did not mandate antibiotic prophylaxis on the trial.”

Grade 3 or higher adverse events (AEs) occurring in 2 or more patients were anemia (n=10), febrile neutropenia (n=4, including 1 grade 5), thrombocytopenia (n=15), lung infection (n=8), sepsis (n=3, all grade 5), fatigue (n=5), peripheral sensory neuropathy (n=3), hypertension (n=6), increased creatinine (n=4), hyperglycemia (n=6) hypokalemia (n=3), and hyponatremia (n=5).

Dr Driessen indicated that with a future generic version of bortezomib, nelfinavir plus bortezomib and dexamethasone “has the potential to become a fully generic, affordable, active therapy option for PI-refractory patients.”

The investigators believe the results of their study call for further development of nelfinavir as a sensitizing drug for PI-based treatments and as a promising new agent for MM therapy.

The Primary Care Chronic Pain Program (PC-CPP) of the Women’s Primary Care Clinics at the VA Salt Lake City Health Care System (VASLCHCS) in Utah was the first VA primary care clinical service to incorporate patient participation in obtaining chronic opioid medications in the treatment of chronic noncancer pain. In addition, the program used a multimodality approach for chronic pain treatment and veteran education about the relationship between physical and mental health issues.

Treatment Complexity

Chronic, noncancer pain is a complex issue in the primary care setting. Diagnosis is difficult, patient education is time consuming, goals and expectations are often unclear, and the experience can be unsatisfying for the patient and the provider.¹ These issues, combined with an estimated prevalence rate of 71% for moderate pain among veterans seen in primary care, present a unique challenge for the primary care provider (PCP), given the limited time available to spend with these complex patients.² Comorbidity rates with mental health issues (eg, depression, anxiety, substance use disorders, etc), which range from 18% to 44%, add to the management challenges for PCPs.³

Veterans also pose unique challenges in pain care as they have a 2-fold greater risk of death from opioid overdose compared with that of the general population, and Utah has been shown to have the highest rate of veteran overdoses.⁴ Developing programs to help PCPs efficiently manage patients with chronic noncancer pain and mental health comorbidities was vital at VASLCHCS.

Before VASLCHCS established the PC-CPP, the treatment for chronic noncancer pain and related mental health comorbidities followed a biomedical model that separated physical and mental health with the treatment focus on pharmacologic management of symptoms by separate services. Consistent with the biomedical model, management of chronic noncancer pain commonly included long-term use of opioids.

Over the past 2 decades, the use of opioids for treating chronic noncancer pain has significantly increased, with more than 62 million opioid prescriptions dispensed in 2012.⁵ There are no longitudinal follow-up studies, however, beyond 16 weeks on the use of opioids.⁶ Further, patients who are prescribed increased opioids continue to report high levels of pain, poor quality of life, and functional disability.⁷ High-dose opioids also are associated with overdose deaths.

Likewise, PCPs in the Women’s Primary Care Clinics at the VASLCHCS struggled with decreasing opioid use, often because other interventions for managing pain and related mental health conditions in primary care were not readily available. Although the VASLCHCS has an effective specialty pain service caring for patients with complex pain issues, opioid morphine equivalent doses > 200 mg/d, and palliative care, patients with chronic noncancer pain treated in the primary care setting did not have a consistent treatment approach.

A chart review of women veterans seen in Women’s Primary Care Clinic (N = 122) revealed that the majority of patients lacked timely urine drug screening, state database queries, signed medication management agreements, and documentation consistent with state and national guidelines. Additionally, many patients lacked provider follow-through regarding alternative and adjunctive therapy consults, which were often discontinued after failed contact attempts or no-shows to scheduled appointments.

There also was a general consensus among the Women’s Primary Care Clinic PCPs that caring for patients with chronic noncancer pain was exhausting, time consuming, ineffective, and often straining on the patient-provider relationship, as evidenced in many patients’ request to change providers secondary to pain management. The PC-CPP was developed to help systematically facilitate safe opioid prescribing, manage chronic pain issues, and document evidence-based care among women veterans receiving treatment for chronic noncancer pain at the Women’s Primary Care Clinics at VASLCHCS while coordinating and following through with nonpharmacologic interventions.

Program Development

National, state, VA, and professional licensure guidelines for chronic noncancer pain treatment standards were reviewed with the goal of creating a program that was evidence based, would benefit the patient in terms of opioid prescribing and pain control, and improve function while identifying key elements of care and documentation that adequately covered the prescriber of retribution.^1,8-10

Concurrent to a review of the guidelines was a review of the literature with the goal of identifying useful patient education and alternative interventions and chronic pain programs that were already established and might meet the clinic’s needs.^10,11 These reviews provided direction for a generalized approach to caring for patients with chronic nonmalignant pain. They also clarified that although pain education programs existed nationally, a program that offered a holistic, reproducible, adherence-driven yet patient-centered approach to the patient prescribed opioids chronically in a primary care setting was lacking.

 

Guideline recommendations included but were not limited to the following^1,8-10:

• Patient education about chronic pain and opioids
• Evaluation of pain, function, opioid misuse risk at least twice yearly
• Patient-centered and driven treatment plans
• A holistic approach to chronic pain interventions
• Review of treatment plan efficacy at least twice yearly
• Enzyme multiplied immunoassay technique urine drug screening (UDS) 2 times per year
• State prescription monitoring program query annually
• Signed iMedConsent for treatment of chronic pain
• Plan for safe discontinuation of opioids
• Documentation that the above has been performed with patient understanding

The literature suggested a multimodality approach to chronic nonmalignant pain by minimizing the use of opioids over time while emphasizing nonpharmacologic therapies, such as cognitive behavioral therapy (CBT), mindfulness, meditation, yoga, and spiritual growth, to name a few.^10,11 These findings are based on several studies, which suggested that passive coping strategies (eg, use of medication for immediate relief, depending on others, restricting medications) result in an increase in subjective pain among chronic nonmalignant pain patients.¹² Helping patients reduce frequent use of passive coping strategies is believed to decrease pain.¹² Active coping strategies (eg, engaging in therapies, staying busy or active, distracting attention from pain) have been found to decrease pain.¹² The PC-CPP program shifted health care outcomes and responsibilities away from the hierarchal PCP-patient relationship toward a collaborative relationship that encourages patient-driven, patient-centered care outcomes and shared responsibilities.

Program Overview

The PC-CPP was shaped by the following hypotheses: (1) Transparent expectations and consequences would increase functional scores and decrease chronic opioid doses; (2) Treatment plans consisting of chronic opioid prescriptions linked with interactive nonpharmacologic interventions led to decreased pain and increased functional scores; (3) Transparent expectations combined with a streamlined approach to the chronic nonmalignant pain patient would improve patient and PCP satisfaction scores.

The PC-CPP was developed to provide an efficient, effective, and evidence-based approach to managing chronic nonmalignant pain and opioid therapy issues in the primary care setting. Referred patients attend 1 shared medical appointment (SMA) every 6 months with up to 19 other female veterans also referred to the PC-CPP. The group was composed of only female veterans as the pilot study for this SMA occurred in the Women’s Clinic. At each 6-month SMA, patients received education from the Taking Opioids Responsibly for Your Safety and the Safety of Others (TORYSSO) guide¹³ and signed the corresponding long-term opioid therapy for pain informed consent form (iMedConsent).

The patient and a staff member developed a treatment plan that was patient driven and included at least 1 nonpharmacologic treatment option. The 1-hour nonpharmacologic sessions were either group or individual and occurred weekly for 6 to 8 weeks. These options included CBT for chronic pain, Living Well With Chronic Conditions, trauma-sensitive yoga, smoking cessation, mindfulness for stress and anxiety, MOVE! weight management, Walk With Ease, and a self-help option (VA-issued Manage Stress Workbook, 2014). The workbook was included as an option for those who lived far away, were limited by work schedules, or were unable to afford the copays for a 6- to 8-session program.

Inclusion and Exclusion Criteria

Any female veteran patient enrolled in the VASLCHCS with a chronic nonmalignant pain diagnosis who received daily opioids for 3 or more consecutive months from a PCP was included. Excluded individuals were those with cognitive decline/dementia, serious mental illness, psychosis, active suicidality, disruptive behavior flag, or those excluded by PCP discretion if it was determined that the patient would do better in a one-on-one setting with the PCP (Table 1). Patients taking > 200 MED/d of opioids who were seen in the VASLCHCS specialty pain clinic were also excluded.

Patient and PCP Responsibilities

The patient was responsible for timely attendance and full participation in all SMA group classes as determined in the veteran’s Treatment Plan Agreement (TPA). In addition, the patient had to provide UDS when requested (a minimum of twice yearly) and communicate with the PCP if having a procedure requiring additional opioids. This was in line with the current standards set forth by the VA Opioid Safety Initiative (OSI) Taskforce.¹²

The PC-CPP provided education, evaluation, documentation, and referral and follow-up with the nonpharmacologic treatment options discussed but did not provide prescription medications. The PCP reviewed the medical documents completed in the PC-CPP, and the PCP was strongly encouraged to follow its recommendations. The expectation was that the PCP would support the PC-CPP when the care recommendation was for a pharmacist-guided opioid taper.

Lack of attendance was defined as a no-show or a reschedule. Patients were considered adherent if they missed fewer than 2 SMA appointments and 2 nonpharmacologic treatment appointments every 6 months. The patient was required to attend the SMA and nonpharmacologic treatment on the third appointment to remain adherent with PC-CPP expectations and agreements. Adherence was acknowledged after 12 and 24 months by a reduction in PC-CPP requirements.

 

Shared Medical Appointment

Patients referred to the program and who met inclusion criteria received letters explaining the importance of SMA attendance and follow-up reminder calls. At least 30 minutes before the SMA, the patient provided an UDS sample at the laboratory. Next, the patient received an individualized program packet that included the TORYSSO guide, iMedConsent, a TPA specific to the program, a brief pain inventory (BPI) and opioid risk tool, a list of medication disposal sites, and short descriptions of available nonpharmacologic therapies.

Each SMA began with a presentation delivered by a pharmacist, a psychologist, and a medical provider, discussing TORYSSO, program expectations, and holistic approaches to pain. Each SMA also included a rotating chronic pain information topic (eg, nutrition and pain, the physiology of addiction, and the value of multiple modalities in pain treatment). Together, the staff and patients reviewed and completed the blank forms enclosed in the individualized

packets. Each patient had the opportunity to develop an individualized treatment plan with a provider one-on-one, which was then signed by the patient. In addition, each patient signed the iMedConsent, which was prepared before the SMA (Figure).

Each visit was entered into a Computerized Patient Record System (CPRS) template, which included a pain diagnosis, Opioid Risk Tool score, pain and functional scores, opioid fill history, last comprehensive metabolic panel, last electrocardiogram if on methadone, dates of signed agreements, patient adherence with SMA and optional therapies, and follow-up (eFigure).

Every patient enrolled in the PC-CPP had to attend a SMA every 6 months. Patients continued this indefinitely while receiving opioids, and requirements were lessened for patients who had a history of meeting program requirements. For those fully adherent after the first year, only 1 nonpharmacologic intervention was needed (instead of 1 every 6 months) yearly. After 2 years of full adherence, nonpharmacologic interventions were no longer necessary as the expectation was that the patient would continue to use the strategies that they had learned over the previous 2 years. Patients left the PC-CPP if they chose to discontinue opioids, met any of the exclusion criteria, or were nonadherent. Tapering opioid medication was recommended for patients who missed a SMA meeting or 2 nonpharmacologic treatment meetings in a 6-month period; received opioids from more than 1 provider; test positive on a UDS for substances that should not be present; consistently testing negative on a UDS for substances that should be present (indicating diversion); or exhibiting other aberrant behavior (frequent requests for early refills, medications often lost/stolen, etc).

Program Barriers

The PC-CPP took about 2 years to set up, and several barriers were encountered. A thorough understanding of the following factors is necessary for establishing a similar program.

Initially, consults were placed by a designee (someone other than the PCP currently caring for the patient). The designee was usually a member of the PC-CPP who placed consults for all patients who had opioids listed on the CPRS profile. Further, patients who had any opioids within the past 3 months were initially included as were patients who wanted pain education but were not taking opioids. After 12 months, it became apparent that the focus of the PC-CPP should center on patients taking opioids for a minimum of 3 months consecutively. Patients who wanted only education could attend other hospital education opportunities, which helped keep the patient load manageable for PC-CPP staff. Further, to lessen patient confusion and improve adherence, the PCP placed the consult and discussed the program with the patient. Class sizes of 5 to 10 patients seemed to be ideal for patient participation and provider workload.

Patient Education

Initially, the SMA did not follow a standard curriculum, but the current format is more consistent, reproducible, streamlined, and organized. This adjustment improved SMA attendance as well as patient satisfaction, as the class started and finished on time. The SMA also started with numerous handouts, including brochures for nonpharmacologic programs offered at this facility. This led to patients feeling overwhelmed, missing the important forms, and wasted paper. Handouts were simplified to 2 color-coded forms (TPA and BPI).

The take-home assessment was streamlined to a single general assessment. This assessment consisted of 2 questions that asked patients to write a summary of what they learned and then write a summary of how they applied what they learned to their pain management. The VA Manage Stress Workbook also was added to the take-home materials. There are currently 5 different take-home options, which are necessary for those who live more than 50 miles from any VA facility or for those who have transportation issues.

 

Patient Distress

The SMA could be stressful for patients who felt they were being “punished” or who showed up more than 15 minutes late and had to reschedule the SMA. Having a mental health provider available was crucial for these situations.

Therapeutic Option Development

A cornerstone of the program was getting patients to participate in nonpharmacologic treatment options, which required a robust selection of programs. The VASLCHCS was fortunate to have many programs already available (Table 2), but this was not always the case for the VA community-based outpatient clinics (CBOCs).

Stakeholder Support

Before its start, PC-CPP was presented to the Pentad (a group of 5 individuals in the local facility who hold executive leadership positions) for approval. Tapering opioids can lead to feelings of hostility, frustration, or sadness for patients, so having the Pentad support for the program was crucial to address complaints made to patient advocates or senators. Provider support also was important to reinforce program rules. The PC-CPP inclusion criteria included only those patients whose PCP was agreeable to a taper when the patient did not comply with program expectations. This strategy helped to improve patient adherence with the PC-CPP and decrease patient arguments with clinic staff, as all patients are held to the same standards.

Staff

Finding willing staff can be a challenge. It is estimated that each site needed a program leader who can champion the program objectives and drive organization of staff, space, documentation, and consistency for the patients consulted to the PC-CPP. The goal is that the consistent, reproducible expectations for both the PCP and the patient will reduce overall workload for a clinic. Patients may test the firmness and conviction of the staff to the PC-CPP. Having staff who are able and willing to be firm on relaying information for adherence to the patient is vital.

Administrative Support

At a minimum, a medical support assistant was required to help with scheduling, reminder calls and letters, CPRS check-in/check-out, ensuring necessary forms are ready for the SMA, tracking adherence, and following-up on no-shows and rescheduling.

Documentation

The CPRS consult and note template titles required the approval of the template committee. Although the template is helpful, there is still a great deal that needs to be manually entered in the note, such as BPI scores, opioid risk scores, and chosen nonpharmacologic interventions scores of pain, function, and opioid risk as well individual comorbidities, diagnosis, and follow-up dates. Documentation is geared toward easy review for the PCP who should scan the document prior to renewing opioid medications. The PC-CPP consult became a message board. Once the patient attends the SMA, the designated staff will add a comment to the message board, identifying all dates attended, complete history of the patient’s intervention choices and rate of adherence, as well a follow-up SMA date and whether the patient should bring materials such as take-home tests.

Time Commitment

Program development carries a heavy time burden. One full-time equivalent clinician for 6 weeks for program development is needed. Time allotment is estimated to be the following:

• Medical provider—30 minutes per patient (chart review, documentation, consult resolution). With training, these duties could be completed by support staff
• Pharmacist—30 minutes per patient (chart review, UDS, Utah Division of Occupational and Professional Licensing, fill history). Additional time is needed for writing opioid tapers for qualifying patients
• Primary care mental health integration—a PhD spent 1 to 2 hours per SMA visit assisting patients who became distressed during the visit. Only once has a patient needed to be escorted to the emergency department for active suicidality. A PhD also spent 10+ hours per week running and managing the CBT for Chronic Pain Group
• Support staff—a registered nurse spent 4 hours each month preparing for the SMA (entering consults, ordering EMITs, purchasing snacks)

Conclusion

In this descriptive report, the authors presented an overview of a newly developed program to manage chronic nonmalignant pain and safe opioid prescribing in a primary care setting. A final report is pending. The intent with this interim report was to describe the PC-CPP at the VASLCHCS, its methods and protocols, and logistic considerations for other providers who are working with patients with chronic pain in a primary care model. Standard operating procedure and inclusion/exclusion criteria were included to help with clinical decision making for patients chronic pain for whom aberrant opioid-related behavior presents a problem.

The authors expect that the PC-CPP will provide more comprehensive assisted care, lending to decreased complications associated with accidental overdose, because since patients have been educated about risks for accidental overdose from chronic opioids and have the responsibility for their outcomes. The authors also anticipated that functional scores (as measured by the BPI) will increase despite lowering opioid doses because patients will use ancillary treatments for pain. The desired outcome is that patients will come to understand that pain control is best approached holistically rather than through opioid monotherapy.

There have been several recent initiatives within the VA to decrease opioid prescribing and increase patient safety. With this in mind, continued expansion of this program to CBOCs and male patients could be useful to providers. Also, this program was conducted in a small setting (Women’s Clinic), and there are many challenges with rolling out such a program in a larger clinic (eg, greater chance for provider disagreement, greater need for administrative staff support). Nonetheless, the benefits of close monitoring of prescription opioids and active encouragement to engage in nonpharmacologic therapies are substantial and deserve further advancement.

The Primary Care Chronic Pain Program (PC-CPP) of the Women’s Primary Care Clinics at the VA Salt Lake City Health Care System (VASLCHCS) in Utah was the first VA primary care clinical service to incorporate patient participation in obtaining chronic opioid medications in the treatment of chronic noncancer pain. In addition, the program used a multimodality approach for chronic pain treatment and veteran education about the relationship between physical and mental health issues.

Treatment Complexity

Chronic, noncancer pain is a complex issue in the primary care setting. Diagnosis is difficult, patient education is time consuming, goals and expectations are often unclear, and the experience can be unsatisfying for the patient and the provider.¹ These issues, combined with an estimated prevalence rate of 71% for moderate pain among veterans seen in primary care, present a unique challenge for the primary care provider (PCP), given the limited time available to spend with these complex patients.² Comorbidity rates with mental health issues (eg, depression, anxiety, substance use disorders, etc), which range from 18% to 44%, add to the management challenges for PCPs.³

Veterans also pose unique challenges in pain care as they have a 2-fold greater risk of death from opioid overdose compared with that of the general population, and Utah has been shown to have the highest rate of veteran overdoses.⁴ Developing programs to help PCPs efficiently manage patients with chronic noncancer pain and mental health comorbidities was vital at VASLCHCS.

Before VASLCHCS established the PC-CPP, the treatment for chronic noncancer pain and related mental health comorbidities followed a biomedical model that separated physical and mental health with the treatment focus on pharmacologic management of symptoms by separate services. Consistent with the biomedical model, management of chronic noncancer pain commonly included long-term use of opioids.

Over the past 2 decades, the use of opioids for treating chronic noncancer pain has significantly increased, with more than 62 million opioid prescriptions dispensed in 2012.⁵ There are no longitudinal follow-up studies, however, beyond 16 weeks on the use of opioids.⁶ Further, patients who are prescribed increased opioids continue to report high levels of pain, poor quality of life, and functional disability.⁷ High-dose opioids also are associated with overdose deaths.

Likewise, PCPs in the Women’s Primary Care Clinics at the VASLCHCS struggled with decreasing opioid use, often because other interventions for managing pain and related mental health conditions in primary care were not readily available. Although the VASLCHCS has an effective specialty pain service caring for patients with complex pain issues, opioid morphine equivalent doses > 200 mg/d, and palliative care, patients with chronic noncancer pain treated in the primary care setting did not have a consistent treatment approach.

A chart review of women veterans seen in Women’s Primary Care Clinic (N = 122) revealed that the majority of patients lacked timely urine drug screening, state database queries, signed medication management agreements, and documentation consistent with state and national guidelines. Additionally, many patients lacked provider follow-through regarding alternative and adjunctive therapy consults, which were often discontinued after failed contact attempts or no-shows to scheduled appointments.

There also was a general consensus among the Women’s Primary Care Clinic PCPs that caring for patients with chronic noncancer pain was exhausting, time consuming, ineffective, and often straining on the patient-provider relationship, as evidenced in many patients’ request to change providers secondary to pain management. The PC-CPP was developed to help systematically facilitate safe opioid prescribing, manage chronic pain issues, and document evidence-based care among women veterans receiving treatment for chronic noncancer pain at the Women’s Primary Care Clinics at VASLCHCS while coordinating and following through with nonpharmacologic interventions.

Program Development

National, state, VA, and professional licensure guidelines for chronic noncancer pain treatment standards were reviewed with the goal of creating a program that was evidence based, would benefit the patient in terms of opioid prescribing and pain control, and improve function while identifying key elements of care and documentation that adequately covered the prescriber of retribution.^1,8-10

Concurrent to a review of the guidelines was a review of the literature with the goal of identifying useful patient education and alternative interventions and chronic pain programs that were already established and might meet the clinic’s needs.^10,11 These reviews provided direction for a generalized approach to caring for patients with chronic nonmalignant pain. They also clarified that although pain education programs existed nationally, a program that offered a holistic, reproducible, adherence-driven yet patient-centered approach to the patient prescribed opioids chronically in a primary care setting was lacking.

 

Guideline recommendations included but were not limited to the following^1,8-10:

• Patient education about chronic pain and opioids
• Evaluation of pain, function, opioid misuse risk at least twice yearly
• Patient-centered and driven treatment plans
• A holistic approach to chronic pain interventions
• Review of treatment plan efficacy at least twice yearly
• Enzyme multiplied immunoassay technique urine drug screening (UDS) 2 times per year
• State prescription monitoring program query annually
• Signed iMedConsent for treatment of chronic pain
• Plan for safe discontinuation of opioids
• Documentation that the above has been performed with patient understanding

The literature suggested a multimodality approach to chronic nonmalignant pain by minimizing the use of opioids over time while emphasizing nonpharmacologic therapies, such as cognitive behavioral therapy (CBT), mindfulness, meditation, yoga, and spiritual growth, to name a few.^10,11 These findings are based on several studies, which suggested that passive coping strategies (eg, use of medication for immediate relief, depending on others, restricting medications) result in an increase in subjective pain among chronic nonmalignant pain patients.¹² Helping patients reduce frequent use of passive coping strategies is believed to decrease pain.¹² Active coping strategies (eg, engaging in therapies, staying busy or active, distracting attention from pain) have been found to decrease pain.¹² The PC-CPP program shifted health care outcomes and responsibilities away from the hierarchal PCP-patient relationship toward a collaborative relationship that encourages patient-driven, patient-centered care outcomes and shared responsibilities.

Program Overview

The PC-CPP was shaped by the following hypotheses: (1) Transparent expectations and consequences would increase functional scores and decrease chronic opioid doses; (2) Treatment plans consisting of chronic opioid prescriptions linked with interactive nonpharmacologic interventions led to decreased pain and increased functional scores; (3) Transparent expectations combined with a streamlined approach to the chronic nonmalignant pain patient would improve patient and PCP satisfaction scores.

The PC-CPP was developed to provide an efficient, effective, and evidence-based approach to managing chronic nonmalignant pain and opioid therapy issues in the primary care setting. Referred patients attend 1 shared medical appointment (SMA) every 6 months with up to 19 other female veterans also referred to the PC-CPP. The group was composed of only female veterans as the pilot study for this SMA occurred in the Women’s Clinic. At each 6-month SMA, patients received education from the Taking Opioids Responsibly for Your Safety and the Safety of Others (TORYSSO) guide¹³ and signed the corresponding long-term opioid therapy for pain informed consent form (iMedConsent).

The patient and a staff member developed a treatment plan that was patient driven and included at least 1 nonpharmacologic treatment option. The 1-hour nonpharmacologic sessions were either group or individual and occurred weekly for 6 to 8 weeks. These options included CBT for chronic pain, Living Well With Chronic Conditions, trauma-sensitive yoga, smoking cessation, mindfulness for stress and anxiety, MOVE! weight management, Walk With Ease, and a self-help option (VA-issued Manage Stress Workbook, 2014). The workbook was included as an option for those who lived far away, were limited by work schedules, or were unable to afford the copays for a 6- to 8-session program.

Inclusion and Exclusion Criteria

Any female veteran patient enrolled in the VASLCHCS with a chronic nonmalignant pain diagnosis who received daily opioids for 3 or more consecutive months from a PCP was included. Excluded individuals were those with cognitive decline/dementia, serious mental illness, psychosis, active suicidality, disruptive behavior flag, or those excluded by PCP discretion if it was determined that the patient would do better in a one-on-one setting with the PCP (Table 1). Patients taking > 200 MED/d of opioids who were seen in the VASLCHCS specialty pain clinic were also excluded.

Patient and PCP Responsibilities

The patient was responsible for timely attendance and full participation in all SMA group classes as determined in the veteran’s Treatment Plan Agreement (TPA). In addition, the patient had to provide UDS when requested (a minimum of twice yearly) and communicate with the PCP if having a procedure requiring additional opioids. This was in line with the current standards set forth by the VA Opioid Safety Initiative (OSI) Taskforce.¹²

The PC-CPP provided education, evaluation, documentation, and referral and follow-up with the nonpharmacologic treatment options discussed but did not provide prescription medications. The PCP reviewed the medical documents completed in the PC-CPP, and the PCP was strongly encouraged to follow its recommendations. The expectation was that the PCP would support the PC-CPP when the care recommendation was for a pharmacist-guided opioid taper.

Lack of attendance was defined as a no-show or a reschedule. Patients were considered adherent if they missed fewer than 2 SMA appointments and 2 nonpharmacologic treatment appointments every 6 months. The patient was required to attend the SMA and nonpharmacologic treatment on the third appointment to remain adherent with PC-CPP expectations and agreements. Adherence was acknowledged after 12 and 24 months by a reduction in PC-CPP requirements.

 

Shared Medical Appointment

Patients referred to the program and who met inclusion criteria received letters explaining the importance of SMA attendance and follow-up reminder calls. At least 30 minutes before the SMA, the patient provided an UDS sample at the laboratory. Next, the patient received an individualized program packet that included the TORYSSO guide, iMedConsent, a TPA specific to the program, a brief pain inventory (BPI) and opioid risk tool, a list of medication disposal sites, and short descriptions of available nonpharmacologic therapies.

Each SMA began with a presentation delivered by a pharmacist, a psychologist, and a medical provider, discussing TORYSSO, program expectations, and holistic approaches to pain. Each SMA also included a rotating chronic pain information topic (eg, nutrition and pain, the physiology of addiction, and the value of multiple modalities in pain treatment). Together, the staff and patients reviewed and completed the blank forms enclosed in the individualized

packets. Each patient had the opportunity to develop an individualized treatment plan with a provider one-on-one, which was then signed by the patient. In addition, each patient signed the iMedConsent, which was prepared before the SMA (Figure).

Each visit was entered into a Computerized Patient Record System (CPRS) template, which included a pain diagnosis, Opioid Risk Tool score, pain and functional scores, opioid fill history, last comprehensive metabolic panel, last electrocardiogram if on methadone, dates of signed agreements, patient adherence with SMA and optional therapies, and follow-up (eFigure).

Every patient enrolled in the PC-CPP had to attend a SMA every 6 months. Patients continued this indefinitely while receiving opioids, and requirements were lessened for patients who had a history of meeting program requirements. For those fully adherent after the first year, only 1 nonpharmacologic intervention was needed (instead of 1 every 6 months) yearly. After 2 years of full adherence, nonpharmacologic interventions were no longer necessary as the expectation was that the patient would continue to use the strategies that they had learned over the previous 2 years. Patients left the PC-CPP if they chose to discontinue opioids, met any of the exclusion criteria, or were nonadherent. Tapering opioid medication was recommended for patients who missed a SMA meeting or 2 nonpharmacologic treatment meetings in a 6-month period; received opioids from more than 1 provider; test positive on a UDS for substances that should not be present; consistently testing negative on a UDS for substances that should be present (indicating diversion); or exhibiting other aberrant behavior (frequent requests for early refills, medications often lost/stolen, etc).

Program Barriers

The PC-CPP took about 2 years to set up, and several barriers were encountered. A thorough understanding of the following factors is necessary for establishing a similar program.

Initially, consults were placed by a designee (someone other than the PCP currently caring for the patient). The designee was usually a member of the PC-CPP who placed consults for all patients who had opioids listed on the CPRS profile. Further, patients who had any opioids within the past 3 months were initially included as were patients who wanted pain education but were not taking opioids. After 12 months, it became apparent that the focus of the PC-CPP should center on patients taking opioids for a minimum of 3 months consecutively. Patients who wanted only education could attend other hospital education opportunities, which helped keep the patient load manageable for PC-CPP staff. Further, to lessen patient confusion and improve adherence, the PCP placed the consult and discussed the program with the patient. Class sizes of 5 to 10 patients seemed to be ideal for patient participation and provider workload.

Patient Education

Initially, the SMA did not follow a standard curriculum, but the current format is more consistent, reproducible, streamlined, and organized. This adjustment improved SMA attendance as well as patient satisfaction, as the class started and finished on time. The SMA also started with numerous handouts, including brochures for nonpharmacologic programs offered at this facility. This led to patients feeling overwhelmed, missing the important forms, and wasted paper. Handouts were simplified to 2 color-coded forms (TPA and BPI).

The take-home assessment was streamlined to a single general assessment. This assessment consisted of 2 questions that asked patients to write a summary of what they learned and then write a summary of how they applied what they learned to their pain management. The VA Manage Stress Workbook also was added to the take-home materials. There are currently 5 different take-home options, which are necessary for those who live more than 50 miles from any VA facility or for those who have transportation issues.

 

Patient Distress

The SMA could be stressful for patients who felt they were being “punished” or who showed up more than 15 minutes late and had to reschedule the SMA. Having a mental health provider available was crucial for these situations.

Therapeutic Option Development

A cornerstone of the program was getting patients to participate in nonpharmacologic treatment options, which required a robust selection of programs. The VASLCHCS was fortunate to have many programs already available (Table 2), but this was not always the case for the VA community-based outpatient clinics (CBOCs).

Stakeholder Support

Before its start, PC-CPP was presented to the Pentad (a group of 5 individuals in the local facility who hold executive leadership positions) for approval. Tapering opioids can lead to feelings of hostility, frustration, or sadness for patients, so having the Pentad support for the program was crucial to address complaints made to patient advocates or senators. Provider support also was important to reinforce program rules. The PC-CPP inclusion criteria included only those patients whose PCP was agreeable to a taper when the patient did not comply with program expectations. This strategy helped to improve patient adherence with the PC-CPP and decrease patient arguments with clinic staff, as all patients are held to the same standards.

Staff

Finding willing staff can be a challenge. It is estimated that each site needed a program leader who can champion the program objectives and drive organization of staff, space, documentation, and consistency for the patients consulted to the PC-CPP. The goal is that the consistent, reproducible expectations for both the PCP and the patient will reduce overall workload for a clinic. Patients may test the firmness and conviction of the staff to the PC-CPP. Having staff who are able and willing to be firm on relaying information for adherence to the patient is vital.

Administrative Support

At a minimum, a medical support assistant was required to help with scheduling, reminder calls and letters, CPRS check-in/check-out, ensuring necessary forms are ready for the SMA, tracking adherence, and following-up on no-shows and rescheduling.

Documentation

The CPRS consult and note template titles required the approval of the template committee. Although the template is helpful, there is still a great deal that needs to be manually entered in the note, such as BPI scores, opioid risk scores, and chosen nonpharmacologic interventions scores of pain, function, and opioid risk as well individual comorbidities, diagnosis, and follow-up dates. Documentation is geared toward easy review for the PCP who should scan the document prior to renewing opioid medications. The PC-CPP consult became a message board. Once the patient attends the SMA, the designated staff will add a comment to the message board, identifying all dates attended, complete history of the patient’s intervention choices and rate of adherence, as well a follow-up SMA date and whether the patient should bring materials such as take-home tests.

Time Commitment

Program development carries a heavy time burden. One full-time equivalent clinician for 6 weeks for program development is needed. Time allotment is estimated to be the following:

• Medical provider—30 minutes per patient (chart review, documentation, consult resolution). With training, these duties could be completed by support staff
• Pharmacist—30 minutes per patient (chart review, UDS, Utah Division of Occupational and Professional Licensing, fill history). Additional time is needed for writing opioid tapers for qualifying patients
• Primary care mental health integration—a PhD spent 1 to 2 hours per SMA visit assisting patients who became distressed during the visit. Only once has a patient needed to be escorted to the emergency department for active suicidality. A PhD also spent 10+ hours per week running and managing the CBT for Chronic Pain Group
• Support staff—a registered nurse spent 4 hours each month preparing for the SMA (entering consults, ordering EMITs, purchasing snacks)

Conclusion

In this descriptive report, the authors presented an overview of a newly developed program to manage chronic nonmalignant pain and safe opioid prescribing in a primary care setting. A final report is pending. The intent with this interim report was to describe the PC-CPP at the VASLCHCS, its methods and protocols, and logistic considerations for other providers who are working with patients with chronic pain in a primary care model. Standard operating procedure and inclusion/exclusion criteria were included to help with clinical decision making for patients chronic pain for whom aberrant opioid-related behavior presents a problem.

The authors expect that the PC-CPP will provide more comprehensive assisted care, lending to decreased complications associated with accidental overdose, because since patients have been educated about risks for accidental overdose from chronic opioids and have the responsibility for their outcomes. The authors also anticipated that functional scores (as measured by the BPI) will increase despite lowering opioid doses because patients will use ancillary treatments for pain. The desired outcome is that patients will come to understand that pain control is best approached holistically rather than through opioid monotherapy.

There have been several recent initiatives within the VA to decrease opioid prescribing and increase patient safety. With this in mind, continued expansion of this program to CBOCs and male patients could be useful to providers. Also, this program was conducted in a small setting (Women’s Clinic), and there are many challenges with rolling out such a program in a larger clinic (eg, greater chance for provider disagreement, greater need for administrative staff support). Nonetheless, the benefits of close monitoring of prescription opioids and active encouragement to engage in nonpharmacologic therapies are substantial and deserve further advancement.

The Primary Care Chronic Pain Program (PC-CPP) of the Women’s Primary Care Clinics at the VA Salt Lake City Health Care System (VASLCHCS) in Utah was the first VA primary care clinical service to incorporate patient participation in obtaining chronic opioid medications in the treatment of chronic noncancer pain. In addition, the program used a multimodality approach for chronic pain treatment and veteran education about the relationship between physical and mental health issues.

Treatment Complexity

Chronic, noncancer pain is a complex issue in the primary care setting. Diagnosis is difficult, patient education is time consuming, goals and expectations are often unclear, and the experience can be unsatisfying for the patient and the provider.¹ These issues, combined with an estimated prevalence rate of 71% for moderate pain among veterans seen in primary care, present a unique challenge for the primary care provider (PCP), given the limited time available to spend with these complex patients.² Comorbidity rates with mental health issues (eg, depression, anxiety, substance use disorders, etc), which range from 18% to 44%, add to the management challenges for PCPs.³

Veterans also pose unique challenges in pain care as they have a 2-fold greater risk of death from opioid overdose compared with that of the general population, and Utah has been shown to have the highest rate of veteran overdoses.⁴ Developing programs to help PCPs efficiently manage patients with chronic noncancer pain and mental health comorbidities was vital at VASLCHCS.

Before VASLCHCS established the PC-CPP, the treatment for chronic noncancer pain and related mental health comorbidities followed a biomedical model that separated physical and mental health with the treatment focus on pharmacologic management of symptoms by separate services. Consistent with the biomedical model, management of chronic noncancer pain commonly included long-term use of opioids.

Over the past 2 decades, the use of opioids for treating chronic noncancer pain has significantly increased, with more than 62 million opioid prescriptions dispensed in 2012.⁵ There are no longitudinal follow-up studies, however, beyond 16 weeks on the use of opioids.⁶ Further, patients who are prescribed increased opioids continue to report high levels of pain, poor quality of life, and functional disability.⁷ High-dose opioids also are associated with overdose deaths.

Likewise, PCPs in the Women’s Primary Care Clinics at the VASLCHCS struggled with decreasing opioid use, often because other interventions for managing pain and related mental health conditions in primary care were not readily available. Although the VASLCHCS has an effective specialty pain service caring for patients with complex pain issues, opioid morphine equivalent doses > 200 mg/d, and palliative care, patients with chronic noncancer pain treated in the primary care setting did not have a consistent treatment approach.

A chart review of women veterans seen in Women’s Primary Care Clinic (N = 122) revealed that the majority of patients lacked timely urine drug screening, state database queries, signed medication management agreements, and documentation consistent with state and national guidelines. Additionally, many patients lacked provider follow-through regarding alternative and adjunctive therapy consults, which were often discontinued after failed contact attempts or no-shows to scheduled appointments.

There also was a general consensus among the Women’s Primary Care Clinic PCPs that caring for patients with chronic noncancer pain was exhausting, time consuming, ineffective, and often straining on the patient-provider relationship, as evidenced in many patients’ request to change providers secondary to pain management. The PC-CPP was developed to help systematically facilitate safe opioid prescribing, manage chronic pain issues, and document evidence-based care among women veterans receiving treatment for chronic noncancer pain at the Women’s Primary Care Clinics at VASLCHCS while coordinating and following through with nonpharmacologic interventions.

Program Development

National, state, VA, and professional licensure guidelines for chronic noncancer pain treatment standards were reviewed with the goal of creating a program that was evidence based, would benefit the patient in terms of opioid prescribing and pain control, and improve function while identifying key elements of care and documentation that adequately covered the prescriber of retribution.^1,8-10

Concurrent to a review of the guidelines was a review of the literature with the goal of identifying useful patient education and alternative interventions and chronic pain programs that were already established and might meet the clinic’s needs.^10,11 These reviews provided direction for a generalized approach to caring for patients with chronic nonmalignant pain. They also clarified that although pain education programs existed nationally, a program that offered a holistic, reproducible, adherence-driven yet patient-centered approach to the patient prescribed opioids chronically in a primary care setting was lacking.

 

Guideline recommendations included but were not limited to the following^1,8-10:

• Patient education about chronic pain and opioids
• Evaluation of pain, function, opioid misuse risk at least twice yearly
• Patient-centered and driven treatment plans
• A holistic approach to chronic pain interventions
• Review of treatment plan efficacy at least twice yearly
• Enzyme multiplied immunoassay technique urine drug screening (UDS) 2 times per year
• State prescription monitoring program query annually
• Signed iMedConsent for treatment of chronic pain
• Plan for safe discontinuation of opioids
• Documentation that the above has been performed with patient understanding

The literature suggested a multimodality approach to chronic nonmalignant pain by minimizing the use of opioids over time while emphasizing nonpharmacologic therapies, such as cognitive behavioral therapy (CBT), mindfulness, meditation, yoga, and spiritual growth, to name a few.^10,11 These findings are based on several studies, which suggested that passive coping strategies (eg, use of medication for immediate relief, depending on others, restricting medications) result in an increase in subjective pain among chronic nonmalignant pain patients.¹² Helping patients reduce frequent use of passive coping strategies is believed to decrease pain.¹² Active coping strategies (eg, engaging in therapies, staying busy or active, distracting attention from pain) have been found to decrease pain.¹² The PC-CPP program shifted health care outcomes and responsibilities away from the hierarchal PCP-patient relationship toward a collaborative relationship that encourages patient-driven, patient-centered care outcomes and shared responsibilities.

Program Overview

The PC-CPP was shaped by the following hypotheses: (1) Transparent expectations and consequences would increase functional scores and decrease chronic opioid doses; (2) Treatment plans consisting of chronic opioid prescriptions linked with interactive nonpharmacologic interventions led to decreased pain and increased functional scores; (3) Transparent expectations combined with a streamlined approach to the chronic nonmalignant pain patient would improve patient and PCP satisfaction scores.

The PC-CPP was developed to provide an efficient, effective, and evidence-based approach to managing chronic nonmalignant pain and opioid therapy issues in the primary care setting. Referred patients attend 1 shared medical appointment (SMA) every 6 months with up to 19 other female veterans also referred to the PC-CPP. The group was composed of only female veterans as the pilot study for this SMA occurred in the Women’s Clinic. At each 6-month SMA, patients received education from the Taking Opioids Responsibly for Your Safety and the Safety of Others (TORYSSO) guide¹³ and signed the corresponding long-term opioid therapy for pain informed consent form (iMedConsent).

The patient and a staff member developed a treatment plan that was patient driven and included at least 1 nonpharmacologic treatment option. The 1-hour nonpharmacologic sessions were either group or individual and occurred weekly for 6 to 8 weeks. These options included CBT for chronic pain, Living Well With Chronic Conditions, trauma-sensitive yoga, smoking cessation, mindfulness for stress and anxiety, MOVE! weight management, Walk With Ease, and a self-help option (VA-issued Manage Stress Workbook, 2014). The workbook was included as an option for those who lived far away, were limited by work schedules, or were unable to afford the copays for a 6- to 8-session program.

Inclusion and Exclusion Criteria

Any female veteran patient enrolled in the VASLCHCS with a chronic nonmalignant pain diagnosis who received daily opioids for 3 or more consecutive months from a PCP was included. Excluded individuals were those with cognitive decline/dementia, serious mental illness, psychosis, active suicidality, disruptive behavior flag, or those excluded by PCP discretion if it was determined that the patient would do better in a one-on-one setting with the PCP (Table 1). Patients taking > 200 MED/d of opioids who were seen in the VASLCHCS specialty pain clinic were also excluded.

Patient and PCP Responsibilities

The patient was responsible for timely attendance and full participation in all SMA group classes as determined in the veteran’s Treatment Plan Agreement (TPA). In addition, the patient had to provide UDS when requested (a minimum of twice yearly) and communicate with the PCP if having a procedure requiring additional opioids. This was in line with the current standards set forth by the VA Opioid Safety Initiative (OSI) Taskforce.¹²

The PC-CPP provided education, evaluation, documentation, and referral and follow-up with the nonpharmacologic treatment options discussed but did not provide prescription medications. The PCP reviewed the medical documents completed in the PC-CPP, and the PCP was strongly encouraged to follow its recommendations. The expectation was that the PCP would support the PC-CPP when the care recommendation was for a pharmacist-guided opioid taper.

Lack of attendance was defined as a no-show or a reschedule. Patients were considered adherent if they missed fewer than 2 SMA appointments and 2 nonpharmacologic treatment appointments every 6 months. The patient was required to attend the SMA and nonpharmacologic treatment on the third appointment to remain adherent with PC-CPP expectations and agreements. Adherence was acknowledged after 12 and 24 months by a reduction in PC-CPP requirements.

 

Shared Medical Appointment

Patients referred to the program and who met inclusion criteria received letters explaining the importance of SMA attendance and follow-up reminder calls. At least 30 minutes before the SMA, the patient provided an UDS sample at the laboratory. Next, the patient received an individualized program packet that included the TORYSSO guide, iMedConsent, a TPA specific to the program, a brief pain inventory (BPI) and opioid risk tool, a list of medication disposal sites, and short descriptions of available nonpharmacologic therapies.

Each SMA began with a presentation delivered by a pharmacist, a psychologist, and a medical provider, discussing TORYSSO, program expectations, and holistic approaches to pain. Each SMA also included a rotating chronic pain information topic (eg, nutrition and pain, the physiology of addiction, and the value of multiple modalities in pain treatment). Together, the staff and patients reviewed and completed the blank forms enclosed in the individualized

packets. Each patient had the opportunity to develop an individualized treatment plan with a provider one-on-one, which was then signed by the patient. In addition, each patient signed the iMedConsent, which was prepared before the SMA (Figure).

Each visit was entered into a Computerized Patient Record System (CPRS) template, which included a pain diagnosis, Opioid Risk Tool score, pain and functional scores, opioid fill history, last comprehensive metabolic panel, last electrocardiogram if on methadone, dates of signed agreements, patient adherence with SMA and optional therapies, and follow-up (eFigure).

Every patient enrolled in the PC-CPP had to attend a SMA every 6 months. Patients continued this indefinitely while receiving opioids, and requirements were lessened for patients who had a history of meeting program requirements. For those fully adherent after the first year, only 1 nonpharmacologic intervention was needed (instead of 1 every 6 months) yearly. After 2 years of full adherence, nonpharmacologic interventions were no longer necessary as the expectation was that the patient would continue to use the strategies that they had learned over the previous 2 years. Patients left the PC-CPP if they chose to discontinue opioids, met any of the exclusion criteria, or were nonadherent. Tapering opioid medication was recommended for patients who missed a SMA meeting or 2 nonpharmacologic treatment meetings in a 6-month period; received opioids from more than 1 provider; test positive on a UDS for substances that should not be present; consistently testing negative on a UDS for substances that should be present (indicating diversion); or exhibiting other aberrant behavior (frequent requests for early refills, medications often lost/stolen, etc).

Program Barriers

The PC-CPP took about 2 years to set up, and several barriers were encountered. A thorough understanding of the following factors is necessary for establishing a similar program.

Initially, consults were placed by a designee (someone other than the PCP currently caring for the patient). The designee was usually a member of the PC-CPP who placed consults for all patients who had opioids listed on the CPRS profile. Further, patients who had any opioids within the past 3 months were initially included as were patients who wanted pain education but were not taking opioids. After 12 months, it became apparent that the focus of the PC-CPP should center on patients taking opioids for a minimum of 3 months consecutively. Patients who wanted only education could attend other hospital education opportunities, which helped keep the patient load manageable for PC-CPP staff. Further, to lessen patient confusion and improve adherence, the PCP placed the consult and discussed the program with the patient. Class sizes of 5 to 10 patients seemed to be ideal for patient participation and provider workload.

Patient Education

Initially, the SMA did not follow a standard curriculum, but the current format is more consistent, reproducible, streamlined, and organized. This adjustment improved SMA attendance as well as patient satisfaction, as the class started and finished on time. The SMA also started with numerous handouts, including brochures for nonpharmacologic programs offered at this facility. This led to patients feeling overwhelmed, missing the important forms, and wasted paper. Handouts were simplified to 2 color-coded forms (TPA and BPI).

The take-home assessment was streamlined to a single general assessment. This assessment consisted of 2 questions that asked patients to write a summary of what they learned and then write a summary of how they applied what they learned to their pain management. The VA Manage Stress Workbook also was added to the take-home materials. There are currently 5 different take-home options, which are necessary for those who live more than 50 miles from any VA facility or for those who have transportation issues.

 

Patient Distress

The SMA could be stressful for patients who felt they were being “punished” or who showed up more than 15 minutes late and had to reschedule the SMA. Having a mental health provider available was crucial for these situations.

Therapeutic Option Development

A cornerstone of the program was getting patients to participate in nonpharmacologic treatment options, which required a robust selection of programs. The VASLCHCS was fortunate to have many programs already available (Table 2), but this was not always the case for the VA community-based outpatient clinics (CBOCs).

Stakeholder Support

Before its start, PC-CPP was presented to the Pentad (a group of 5 individuals in the local facility who hold executive leadership positions) for approval. Tapering opioids can lead to feelings of hostility, frustration, or sadness for patients, so having the Pentad support for the program was crucial to address complaints made to patient advocates or senators. Provider support also was important to reinforce program rules. The PC-CPP inclusion criteria included only those patients whose PCP was agreeable to a taper when the patient did not comply with program expectations. This strategy helped to improve patient adherence with the PC-CPP and decrease patient arguments with clinic staff, as all patients are held to the same standards.

Staff

Finding willing staff can be a challenge. It is estimated that each site needed a program leader who can champion the program objectives and drive organization of staff, space, documentation, and consistency for the patients consulted to the PC-CPP. The goal is that the consistent, reproducible expectations for both the PCP and the patient will reduce overall workload for a clinic. Patients may test the firmness and conviction of the staff to the PC-CPP. Having staff who are able and willing to be firm on relaying information for adherence to the patient is vital.

Administrative Support

At a minimum, a medical support assistant was required to help with scheduling, reminder calls and letters, CPRS check-in/check-out, ensuring necessary forms are ready for the SMA, tracking adherence, and following-up on no-shows and rescheduling.

Documentation

The CPRS consult and note template titles required the approval of the template committee. Although the template is helpful, there is still a great deal that needs to be manually entered in the note, such as BPI scores, opioid risk scores, and chosen nonpharmacologic interventions scores of pain, function, and opioid risk as well individual comorbidities, diagnosis, and follow-up dates. Documentation is geared toward easy review for the PCP who should scan the document prior to renewing opioid medications. The PC-CPP consult became a message board. Once the patient attends the SMA, the designated staff will add a comment to the message board, identifying all dates attended, complete history of the patient’s intervention choices and rate of adherence, as well a follow-up SMA date and whether the patient should bring materials such as take-home tests.

Time Commitment

Program development carries a heavy time burden. One full-time equivalent clinician for 6 weeks for program development is needed. Time allotment is estimated to be the following:

• Medical provider—30 minutes per patient (chart review, documentation, consult resolution). With training, these duties could be completed by support staff
• Pharmacist—30 minutes per patient (chart review, UDS, Utah Division of Occupational and Professional Licensing, fill history). Additional time is needed for writing opioid tapers for qualifying patients
• Primary care mental health integration—a PhD spent 1 to 2 hours per SMA visit assisting patients who became distressed during the visit. Only once has a patient needed to be escorted to the emergency department for active suicidality. A PhD also spent 10+ hours per week running and managing the CBT for Chronic Pain Group
• Support staff—a registered nurse spent 4 hours each month preparing for the SMA (entering consults, ordering EMITs, purchasing snacks)

Conclusion

In this descriptive report, the authors presented an overview of a newly developed program to manage chronic nonmalignant pain and safe opioid prescribing in a primary care setting. A final report is pending. The intent with this interim report was to describe the PC-CPP at the VASLCHCS, its methods and protocols, and logistic considerations for other providers who are working with patients with chronic pain in a primary care model. Standard operating procedure and inclusion/exclusion criteria were included to help with clinical decision making for patients chronic pain for whom aberrant opioid-related behavior presents a problem.

The authors expect that the PC-CPP will provide more comprehensive assisted care, lending to decreased complications associated with accidental overdose, because since patients have been educated about risks for accidental overdose from chronic opioids and have the responsibility for their outcomes. The authors also anticipated that functional scores (as measured by the BPI) will increase despite lowering opioid doses because patients will use ancillary treatments for pain. The desired outcome is that patients will come to understand that pain control is best approached holistically rather than through opioid monotherapy.

There have been several recent initiatives within the VA to decrease opioid prescribing and increase patient safety. With this in mind, continued expansion of this program to CBOCs and male patients could be useful to providers. Also, this program was conducted in a small setting (Women’s Clinic), and there are many challenges with rolling out such a program in a larger clinic (eg, greater chance for provider disagreement, greater need for administrative staff support). Nonetheless, the benefits of close monitoring of prescription opioids and active encouragement to engage in nonpharmacologic therapies are substantial and deserve further advancement.

The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for betrixaban, an oral factor Xa inhibitor, for extended-duration prophylaxis of venous thromboembolism (VTE) in acute medically ill patients with risk factors for VTE.

A priority review shortens the FDA review timeline to 6 months from the standard review period of 10 months.

The application for betrixaban has been given a Prescription Drug User Fee Act action date of June 24, 2017.  (Betrixaban also has fast track designation from the FDA.)

Meanwhile, the European Medicines Agency (EMA) is reviewing a marketing authorization application (MAA) for betrixaban for extended-duration prophylaxis of VTE in adults with acute medical illness and risk factors for VTE.

However, the EMA’s Committee for Medicinal Products for Human Use is reviewing the application under a standard 210-day review period.

“With the filing of the betrixaban NDA and the MAA validation, we now look forward to working with the FDA and EMA to bring this drug to market,” said Bill Lis, chief executive officer of Portola Pharmaceuticals, Inc., the company developing betrixaban.

The NDA and MAA for betrixaban are supported by data from Portola’s phase 3 APEX study, which enrolled 7513 patients at more than 450 clinical sites worldwide.

In this study, researchers compared extended-duration anticoagulation with oral betrixaban for 35-42 days to standard-duration enoxaparin for 10±4 days in preventing VTE in high-risk acute medically ill patients.

Patients who received betrixaban had a significantly lower incidence of VTE than those who received enoxaparin, and there was no significant difference in major bleeding between the treatment groups.

Full results from this study were presented at the 62nd Annual International Society on Thrombosis and Haemostasis Scientific and Standardization Committee Meeting and published in NEJM in May 2016.

The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for betrixaban, an oral factor Xa inhibitor, for extended-duration prophylaxis of venous thromboembolism (VTE) in acute medically ill patients with risk factors for VTE.

A priority review shortens the FDA review timeline to 6 months from the standard review period of 10 months.

The application for betrixaban has been given a Prescription Drug User Fee Act action date of June 24, 2017.  (Betrixaban also has fast track designation from the FDA.)

Meanwhile, the European Medicines Agency (EMA) is reviewing a marketing authorization application (MAA) for betrixaban for extended-duration prophylaxis of VTE in adults with acute medical illness and risk factors for VTE.

However, the EMA’s Committee for Medicinal Products for Human Use is reviewing the application under a standard 210-day review period.

“With the filing of the betrixaban NDA and the MAA validation, we now look forward to working with the FDA and EMA to bring this drug to market,” said Bill Lis, chief executive officer of Portola Pharmaceuticals, Inc., the company developing betrixaban.

The NDA and MAA for betrixaban are supported by data from Portola’s phase 3 APEX study, which enrolled 7513 patients at more than 450 clinical sites worldwide.

In this study, researchers compared extended-duration anticoagulation with oral betrixaban for 35-42 days to standard-duration enoxaparin for 10±4 days in preventing VTE in high-risk acute medically ill patients.

Patients who received betrixaban had a significantly lower incidence of VTE than those who received enoxaparin, and there was no significant difference in major bleeding between the treatment groups.

Full results from this study were presented at the 62nd Annual International Society on Thrombosis and Haemostasis Scientific and Standardization Committee Meeting and published in NEJM in May 2016.

The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for betrixaban, an oral factor Xa inhibitor, for extended-duration prophylaxis of venous thromboembolism (VTE) in acute medically ill patients with risk factors for VTE.

A priority review shortens the FDA review timeline to 6 months from the standard review period of 10 months.

The application for betrixaban has been given a Prescription Drug User Fee Act action date of June 24, 2017.  (Betrixaban also has fast track designation from the FDA.)

Meanwhile, the European Medicines Agency (EMA) is reviewing a marketing authorization application (MAA) for betrixaban for extended-duration prophylaxis of VTE in adults with acute medical illness and risk factors for VTE.

However, the EMA’s Committee for Medicinal Products for Human Use is reviewing the application under a standard 210-day review period.

“With the filing of the betrixaban NDA and the MAA validation, we now look forward to working with the FDA and EMA to bring this drug to market,” said Bill Lis, chief executive officer of Portola Pharmaceuticals, Inc., the company developing betrixaban.

The NDA and MAA for betrixaban are supported by data from Portola’s phase 3 APEX study, which enrolled 7513 patients at more than 450 clinical sites worldwide.

In this study, researchers compared extended-duration anticoagulation with oral betrixaban for 35-42 days to standard-duration enoxaparin for 10±4 days in preventing VTE in high-risk acute medically ill patients.

Patients who received betrixaban had a significantly lower incidence of VTE than those who received enoxaparin, and there was no significant difference in major bleeding between the treatment groups.

Full results from this study were presented at the 62nd Annual International Society on Thrombosis and Haemostasis Scientific and Standardization Committee Meeting and published in NEJM in May 2016.

 

A postlicensure safety study of a meningococcal conjugate vaccine in Southern California has shown that the vaccine may be associated with an increase in the risk of Bell’s palsy, but only if the vaccine is taken concomitantly with another vaccine.

Researchers set out to evaluate the safety of one quadrivalent meningococcal conjugate vaccine, MenACWY-CRM. Two MenACWY vaccines are currently licensed in the United States; MenACWY-D is the other. The vaccines underwent studies on the road to approval, but researchers saw an absence of data about how the vaccine was faring in routine clinical use.

copyright DesignPics/Thinkstock

Hung-Fu Tseng, PhD, of the department of research and evaluation, Kaiser Permanente Southern California, Pasadena, and his colleagues examined a cohort of 48,899 individuals aged 11-21 years who received the MenACWY-CRM vaccine between Sept. 30, 2011, and June 30, 2013 (Pediatrics. 2017 Jan. doi: 10.1542/peds.2016-2084).

Researchers looked through the electronic health records of the study population for “26 prespecified events of interest (EOIs) under investigation, including neurologic, rheumatologic, hematologic, endocrine, renal, pediatric, and pediatric infectious disease EOIs. Occurrence of incident episodes of these EOIs was identified during a 1-year observation period after the index vaccination for each individual.”

They identified 4,240 EOIs, but dismissed 3,000 of them as probable preexisting conditions. With what was left, some of the EOIs did not occur at all (such as Guillain-Barré syndrome, myasthenia gravis, or systemic lupus erythematosus). Of transverse myelitis and autoimmune hemolytic anemia, among others, there was only 1 case.

Seizure, iridocyclitis, Hashimoto’s disease, and anaphylaxis initially showed statistically significant risk incidence, but were all ruled out (of the hypothesis of possible cause by vaccination) by further review from a physician investigator.

But in the case of Bell’s palsy, the independent case review committee did not rule out the possibility that the MenACWY-CRM vaccine increased the risk incidence of the condition.

However, the increased risk was present only for subjects who received a concomitant vaccine along with the MenACWY-CRM, such as Tdap, influenza, or human papillomavirus vaccine. “Stratified analyses demonstrated an increased risk for Bell’s palsy in subjects receiving concomitant vaccines (risk incidence, 5.0; 95% confidence interval, 1.4-17.8), and no increased risk for those without concomitant vaccine (RI, 1.1; 95% CI, 0.2-5.5),” Dr. Tseng and his coauthors wrote. All eight cases of Bell’s palsy resolved completely.

They concluded, “we observed a temporal association between occurrence of Bell’s palsy and receipt of MenACWY-CRM concomitantly with other vaccines. The association needs further investigation because it could be due to chance, concomitant vaccination, or underlying medical history predisposing to Bell’s palsy.”

Dr. Tseng and numerous coauthors reported receiving research support from Novartis Vaccines, the sponsor of the study. Three coauthors were employees of Novartis at the time of the study.

[email protected]

 

A postlicensure safety study of a meningococcal conjugate vaccine in Southern California has shown that the vaccine may be associated with an increase in the risk of Bell’s palsy, but only if the vaccine is taken concomitantly with another vaccine.

Researchers set out to evaluate the safety of one quadrivalent meningococcal conjugate vaccine, MenACWY-CRM. Two MenACWY vaccines are currently licensed in the United States; MenACWY-D is the other. The vaccines underwent studies on the road to approval, but researchers saw an absence of data about how the vaccine was faring in routine clinical use.

copyright DesignPics/Thinkstock

Hung-Fu Tseng, PhD, of the department of research and evaluation, Kaiser Permanente Southern California, Pasadena, and his colleagues examined a cohort of 48,899 individuals aged 11-21 years who received the MenACWY-CRM vaccine between Sept. 30, 2011, and June 30, 2013 (Pediatrics. 2017 Jan. doi: 10.1542/peds.2016-2084).

Researchers looked through the electronic health records of the study population for “26 prespecified events of interest (EOIs) under investigation, including neurologic, rheumatologic, hematologic, endocrine, renal, pediatric, and pediatric infectious disease EOIs. Occurrence of incident episodes of these EOIs was identified during a 1-year observation period after the index vaccination for each individual.”

They identified 4,240 EOIs, but dismissed 3,000 of them as probable preexisting conditions. With what was left, some of the EOIs did not occur at all (such as Guillain-Barré syndrome, myasthenia gravis, or systemic lupus erythematosus). Of transverse myelitis and autoimmune hemolytic anemia, among others, there was only 1 case.

Seizure, iridocyclitis, Hashimoto’s disease, and anaphylaxis initially showed statistically significant risk incidence, but were all ruled out (of the hypothesis of possible cause by vaccination) by further review from a physician investigator.

But in the case of Bell’s palsy, the independent case review committee did not rule out the possibility that the MenACWY-CRM vaccine increased the risk incidence of the condition.

However, the increased risk was present only for subjects who received a concomitant vaccine along with the MenACWY-CRM, such as Tdap, influenza, or human papillomavirus vaccine. “Stratified analyses demonstrated an increased risk for Bell’s palsy in subjects receiving concomitant vaccines (risk incidence, 5.0; 95% confidence interval, 1.4-17.8), and no increased risk for those without concomitant vaccine (RI, 1.1; 95% CI, 0.2-5.5),” Dr. Tseng and his coauthors wrote. All eight cases of Bell’s palsy resolved completely.

They concluded, “we observed a temporal association between occurrence of Bell’s palsy and receipt of MenACWY-CRM concomitantly with other vaccines. The association needs further investigation because it could be due to chance, concomitant vaccination, or underlying medical history predisposing to Bell’s palsy.”

Dr. Tseng and numerous coauthors reported receiving research support from Novartis Vaccines, the sponsor of the study. Three coauthors were employees of Novartis at the time of the study.

[email protected]

 

A postlicensure safety study of a meningococcal conjugate vaccine in Southern California has shown that the vaccine may be associated with an increase in the risk of Bell’s palsy, but only if the vaccine is taken concomitantly with another vaccine.

Researchers set out to evaluate the safety of one quadrivalent meningococcal conjugate vaccine, MenACWY-CRM. Two MenACWY vaccines are currently licensed in the United States; MenACWY-D is the other. The vaccines underwent studies on the road to approval, but researchers saw an absence of data about how the vaccine was faring in routine clinical use.

copyright DesignPics/Thinkstock

Hung-Fu Tseng, PhD, of the department of research and evaluation, Kaiser Permanente Southern California, Pasadena, and his colleagues examined a cohort of 48,899 individuals aged 11-21 years who received the MenACWY-CRM vaccine between Sept. 30, 2011, and June 30, 2013 (Pediatrics. 2017 Jan. doi: 10.1542/peds.2016-2084).

Researchers looked through the electronic health records of the study population for “26 prespecified events of interest (EOIs) under investigation, including neurologic, rheumatologic, hematologic, endocrine, renal, pediatric, and pediatric infectious disease EOIs. Occurrence of incident episodes of these EOIs was identified during a 1-year observation period after the index vaccination for each individual.”

They identified 4,240 EOIs, but dismissed 3,000 of them as probable preexisting conditions. With what was left, some of the EOIs did not occur at all (such as Guillain-Barré syndrome, myasthenia gravis, or systemic lupus erythematosus). Of transverse myelitis and autoimmune hemolytic anemia, among others, there was only 1 case.

Seizure, iridocyclitis, Hashimoto’s disease, and anaphylaxis initially showed statistically significant risk incidence, but were all ruled out (of the hypothesis of possible cause by vaccination) by further review from a physician investigator.

But in the case of Bell’s palsy, the independent case review committee did not rule out the possibility that the MenACWY-CRM vaccine increased the risk incidence of the condition.

However, the increased risk was present only for subjects who received a concomitant vaccine along with the MenACWY-CRM, such as Tdap, influenza, or human papillomavirus vaccine. “Stratified analyses demonstrated an increased risk for Bell’s palsy in subjects receiving concomitant vaccines (risk incidence, 5.0; 95% confidence interval, 1.4-17.8), and no increased risk for those without concomitant vaccine (RI, 1.1; 95% CI, 0.2-5.5),” Dr. Tseng and his coauthors wrote. All eight cases of Bell’s palsy resolved completely.

They concluded, “we observed a temporal association between occurrence of Bell’s palsy and receipt of MenACWY-CRM concomitantly with other vaccines. The association needs further investigation because it could be due to chance, concomitant vaccination, or underlying medical history predisposing to Bell’s palsy.”

Dr. Tseng and numerous coauthors reported receiving research support from Novartis Vaccines, the sponsor of the study. Three coauthors were employees of Novartis at the time of the study.

[email protected]

Results of a phase 2 trial suggest a 2-drug combination may be effective in patients with chronic lymphocytic leukemia (CLL), particularly those with high-risk disease.

The combination consists of ublituximab (TG-1101), a glycoengineered anti-CD20 monoclonal antibody, and the oral BTK inhibitor ibrutinib.

Six months after starting treatment, the overall response rate was 88% among all evaluable patients and 95% among those with high-risk CLL.

Researchers said the long-term clinical benefit of the combination will be defined by an ongoing phase 3 trial.

The team reported results from the phase 2 trial in the British Journal of Haematology. The study was sponsored by TG Therapeutics, Inc., the company developing ublituximab.

The trial included 45 patients. Their median age was 71 (range, 39-86), about half were female, and the median ECOG performance score was 1.

Nearly half of patients (47%, n=21) had high-risk CLL. Twelve patients had del 17p, 12 had del 11q, 5 patients had both, and 2 had a TP53 mutation.

The patients had a median of 2 (range, 1-7) prior treatments, including purine analogues (n=22), bendamustine (n=21), idelalisib (n=2), a spleen-tyrosine kinase inhibitor (n=2), and the BTK inhibitor CC-292 (n=1).

Treatment

For this study, patients received ibrutinib at 420 mg once daily and 2 different doses of ublituximab. The study had a dose-confirmation safety run-in period that was followed by an open enrollment into phase 2.

The dose-confirmation safety assessment enrolled 6 patients in each of 2 cohorts. Patients in cohort 1 received ublituximab at 600 mg on days 1, 8, and 15 of cycle 1. If there was ≤1 dose-limiting toxicity (DLT) in this cohort, the dose escalation would proceed to cohort 2.

In cohort 2, patients’ ublituximab dose increased to 900 mg on days 1, 8, and 15 of cycle 1. If ≤ 1 DLT was reported in this cohort, the dose was considered safe for phase 2.

There were no DLTs observed in either cohort. So subsequent patients were enrolled into the open phase 2 part of the study, in which they received ublituximab at 900 mg on days 1, 8, and 15 of cycle 1, as well as on day 1 of cycles 2 to 6.

Patients had response assessments at cycles 3 and 6. After that, they continued on ibrutinib monotherapy off study.

Safety

All 45 patients were evaluable for safety. The most common adverse events (AEs) were infusion-related reactions (IRRs, 53%), diarrhea (40%), fatigue (33%), cough (27%), rash (27%), and nausea (24%).

Grade 3/4 AEs included anemia (11%), neutropenia (11%), IRRs (7%), thrombocytopenia (7%), diarrhea (4%), and arthralgia (2%).

All rash and grade 3/4 diarrhea events were attributed to ibrutinib, and all IRRs were related to ublituximab. Twenty-one patients (47%) had dose interruptions due to IRRs, and 1 patient had a dose reduction to 600 mg.

Four patients had ublituximab-related dose interruptions—2 due to neutropenia and 2 because of elevated aspartate aminotransferase.

Two patients had ibrutinib-related dose reductions (for diarrhea and dizziness). Ten patients had ibrutinib-related dose interruptions—3 due to rash, 2 due to neutropenia, and 1 each because of anemia, thrombocytopenia, nausea, hypercalcemia, and dehydration.

Efficacy

Forty-one patients were evaluable for efficacy. Two patients were lost to follow-up, and 2 discontinued due to AEs. One of the AEs, diarrhea, was considered related to ibrutinib. The other patient discontinued due to pneumonia and pleural effusion, which were not attributed to study treatment.

At 6 months, the overall response rate was 88% among evaluable patients and 95% among high-risk patients. The median time to response was 8 weeks.

 

Two patients had a complete response, 34 had a partial response, and 3 had stable disease.

Both complete responders and 1 of the partial responders achieved minimal residual disease negativity. All 3 of these patients had high-risk disease.

“[T]he addition of ublituximab to ibrutinib not only produced high response rates but also allowed patients to achieve deeper responses, with complete responses and minimal residual disease negativity seen, which is rare with ibrutinib alone,” said study author Jeff Sharman, MD, of Willamette Valley Cancer Institute in Eugene, Oregon.

“We look forward to exploring how the increased depth of response may affect the sequence of treatments given to patients.”

Results of a phase 2 trial suggest a 2-drug combination may be effective in patients with chronic lymphocytic leukemia (CLL), particularly those with high-risk disease.

The combination consists of ublituximab (TG-1101), a glycoengineered anti-CD20 monoclonal antibody, and the oral BTK inhibitor ibrutinib.

Six months after starting treatment, the overall response rate was 88% among all evaluable patients and 95% among those with high-risk CLL.

Researchers said the long-term clinical benefit of the combination will be defined by an ongoing phase 3 trial.

The team reported results from the phase 2 trial in the British Journal of Haematology. The study was sponsored by TG Therapeutics, Inc., the company developing ublituximab.

The trial included 45 patients. Their median age was 71 (range, 39-86), about half were female, and the median ECOG performance score was 1.

Nearly half of patients (47%, n=21) had high-risk CLL. Twelve patients had del 17p, 12 had del 11q, 5 patients had both, and 2 had a TP53 mutation.

The patients had a median of 2 (range, 1-7) prior treatments, including purine analogues (n=22), bendamustine (n=21), idelalisib (n=2), a spleen-tyrosine kinase inhibitor (n=2), and the BTK inhibitor CC-292 (n=1).

Treatment

For this study, patients received ibrutinib at 420 mg once daily and 2 different doses of ublituximab. The study had a dose-confirmation safety run-in period that was followed by an open enrollment into phase 2.

The dose-confirmation safety assessment enrolled 6 patients in each of 2 cohorts. Patients in cohort 1 received ublituximab at 600 mg on days 1, 8, and 15 of cycle 1. If there was ≤1 dose-limiting toxicity (DLT) in this cohort, the dose escalation would proceed to cohort 2.

In cohort 2, patients’ ublituximab dose increased to 900 mg on days 1, 8, and 15 of cycle 1. If ≤ 1 DLT was reported in this cohort, the dose was considered safe for phase 2.

There were no DLTs observed in either cohort. So subsequent patients were enrolled into the open phase 2 part of the study, in which they received ublituximab at 900 mg on days 1, 8, and 15 of cycle 1, as well as on day 1 of cycles 2 to 6.

Patients had response assessments at cycles 3 and 6. After that, they continued on ibrutinib monotherapy off study.

Safety

All 45 patients were evaluable for safety. The most common adverse events (AEs) were infusion-related reactions (IRRs, 53%), diarrhea (40%), fatigue (33%), cough (27%), rash (27%), and nausea (24%).

Grade 3/4 AEs included anemia (11%), neutropenia (11%), IRRs (7%), thrombocytopenia (7%), diarrhea (4%), and arthralgia (2%).

All rash and grade 3/4 diarrhea events were attributed to ibrutinib, and all IRRs were related to ublituximab. Twenty-one patients (47%) had dose interruptions due to IRRs, and 1 patient had a dose reduction to 600 mg.

Four patients had ublituximab-related dose interruptions—2 due to neutropenia and 2 because of elevated aspartate aminotransferase.

Two patients had ibrutinib-related dose reductions (for diarrhea and dizziness). Ten patients had ibrutinib-related dose interruptions—3 due to rash, 2 due to neutropenia, and 1 each because of anemia, thrombocytopenia, nausea, hypercalcemia, and dehydration.

Efficacy

Forty-one patients were evaluable for efficacy. Two patients were lost to follow-up, and 2 discontinued due to AEs. One of the AEs, diarrhea, was considered related to ibrutinib. The other patient discontinued due to pneumonia and pleural effusion, which were not attributed to study treatment.

At 6 months, the overall response rate was 88% among evaluable patients and 95% among high-risk patients. The median time to response was 8 weeks.

 

Two patients had a complete response, 34 had a partial response, and 3 had stable disease.

Both complete responders and 1 of the partial responders achieved minimal residual disease negativity. All 3 of these patients had high-risk disease.

“[T]he addition of ublituximab to ibrutinib not only produced high response rates but also allowed patients to achieve deeper responses, with complete responses and minimal residual disease negativity seen, which is rare with ibrutinib alone,” said study author Jeff Sharman, MD, of Willamette Valley Cancer Institute in Eugene, Oregon.

“We look forward to exploring how the increased depth of response may affect the sequence of treatments given to patients.”

Results of a phase 2 trial suggest a 2-drug combination may be effective in patients with chronic lymphocytic leukemia (CLL), particularly those with high-risk disease.

The combination consists of ublituximab (TG-1101), a glycoengineered anti-CD20 monoclonal antibody, and the oral BTK inhibitor ibrutinib.

Six months after starting treatment, the overall response rate was 88% among all evaluable patients and 95% among those with high-risk CLL.

Researchers said the long-term clinical benefit of the combination will be defined by an ongoing phase 3 trial.

The team reported results from the phase 2 trial in the British Journal of Haematology. The study was sponsored by TG Therapeutics, Inc., the company developing ublituximab.

The trial included 45 patients. Their median age was 71 (range, 39-86), about half were female, and the median ECOG performance score was 1.

Nearly half of patients (47%, n=21) had high-risk CLL. Twelve patients had del 17p, 12 had del 11q, 5 patients had both, and 2 had a TP53 mutation.

The patients had a median of 2 (range, 1-7) prior treatments, including purine analogues (n=22), bendamustine (n=21), idelalisib (n=2), a spleen-tyrosine kinase inhibitor (n=2), and the BTK inhibitor CC-292 (n=1).

Treatment

For this study, patients received ibrutinib at 420 mg once daily and 2 different doses of ublituximab. The study had a dose-confirmation safety run-in period that was followed by an open enrollment into phase 2.

The dose-confirmation safety assessment enrolled 6 patients in each of 2 cohorts. Patients in cohort 1 received ublituximab at 600 mg on days 1, 8, and 15 of cycle 1. If there was ≤1 dose-limiting toxicity (DLT) in this cohort, the dose escalation would proceed to cohort 2.

In cohort 2, patients’ ublituximab dose increased to 900 mg on days 1, 8, and 15 of cycle 1. If ≤ 1 DLT was reported in this cohort, the dose was considered safe for phase 2.

There were no DLTs observed in either cohort. So subsequent patients were enrolled into the open phase 2 part of the study, in which they received ublituximab at 900 mg on days 1, 8, and 15 of cycle 1, as well as on day 1 of cycles 2 to 6.

Patients had response assessments at cycles 3 and 6. After that, they continued on ibrutinib monotherapy off study.

Safety

All 45 patients were evaluable for safety. The most common adverse events (AEs) were infusion-related reactions (IRRs, 53%), diarrhea (40%), fatigue (33%), cough (27%), rash (27%), and nausea (24%).

Grade 3/4 AEs included anemia (11%), neutropenia (11%), IRRs (7%), thrombocytopenia (7%), diarrhea (4%), and arthralgia (2%).

All rash and grade 3/4 diarrhea events were attributed to ibrutinib, and all IRRs were related to ublituximab. Twenty-one patients (47%) had dose interruptions due to IRRs, and 1 patient had a dose reduction to 600 mg.

Four patients had ublituximab-related dose interruptions—2 due to neutropenia and 2 because of elevated aspartate aminotransferase.

Two patients had ibrutinib-related dose reductions (for diarrhea and dizziness). Ten patients had ibrutinib-related dose interruptions—3 due to rash, 2 due to neutropenia, and 1 each because of anemia, thrombocytopenia, nausea, hypercalcemia, and dehydration.

Efficacy

Forty-one patients were evaluable for efficacy. Two patients were lost to follow-up, and 2 discontinued due to AEs. One of the AEs, diarrhea, was considered related to ibrutinib. The other patient discontinued due to pneumonia and pleural effusion, which were not attributed to study treatment.

At 6 months, the overall response rate was 88% among evaluable patients and 95% among high-risk patients. The median time to response was 8 weeks.

 

Two patients had a complete response, 34 had a partial response, and 3 had stable disease.

Both complete responders and 1 of the partial responders achieved minimal residual disease negativity. All 3 of these patients had high-risk disease.

“[T]he addition of ublituximab to ibrutinib not only produced high response rates but also allowed patients to achieve deeper responses, with complete responses and minimal residual disease negativity seen, which is rare with ibrutinib alone,” said study author Jeff Sharman, MD, of Willamette Valley Cancer Institute in Eugene, Oregon.

“We look forward to exploring how the increased depth of response may affect the sequence of treatments given to patients.”

The Geriatric Research Education and Clinical Center (GRECC) Memory Disorders Clinic at the VA Puget Sound Health Care System (VAPSHCS) in Seattle, Washington, receives referrals from primary and specialty care. About a decade ago, this clinic began to see an influx of Vietnam-era veterans who presented with a variety of symptoms: not remembering where they were going when driving, forgetting why they went into another room, not remembering what their spouse told them, and feeling “out of it.” These symptoms were not associated with the loss of independence, but they were cause for concern. Family members and care providers typically corroborated the symptom description and perception of decline. Yet during workups, these veterans showed no primary medical causes for cognitive impairments and on neuropsychological evaluation demonstrated essentially normal cognition.

Memory Disorders Clinic staff largely were at a loss to know how to care for these patients. The simple reassurance, “You do not have dementia now,” seemed unsatisfactory given the patients’ ongoing concerns and the established risk factors for neurodegenerative disease.^1,2 One theme emerged when talking with these veterans and their families: They all had a diagnosis of or history of treatment for posttraumatic stress disorder (PTSD).

To help these veterans, the VAPSHCS GRECC sought to address their key areas of concern related to memory. With input from veterans and their families, a quality improvement project was developed with the following goals: (1) to educate veterans and their families about PTSD and cognitive changes; (2) to build and field test a psychoeducational class to teach memory skills in this population; and (3) to inform VA staff about PTSD and cognitive change. In this article, the authors focus on how the first 2 goals were addressed and present preliminary results related to quality improvement.

Memory Skills Classes

The VAPSHCS GRECC Memory Disorders Clinic sought to use an approach that would be readily accepted, efficient, and effective. To that end, the authors developed a clinical model for enhancing memory skills and self-management for veterans with a history of PTSD by adapting existing clinical and educational tools.

Several strategies might promote memory skills, including printed materials for self-directed learning, individual sessions, interactive technologies, or groups. Given the patients’ reports about concentration problems, asking them to work through structured materials independently seemed unproductive. Individual clinical evaluations and cognitive interventions likely would not meet the demand or be cost-effective. Groups have long been used to treat PTSD, and Norrie and colleagues reported that at-risk adults benefited from a group psychoeducation program targeting healthy brain aging.³ At the same time, the Memory Disorders Clinic sought to distinguish itself from PTSD groups, because these groups tend to focus on treating active PTSD.

A better fit for this offering was the description of the sessions as classes. Although the focus was on promoting memory skills among those capable of learning them, the authors were mindful that some veterans might truly have prodromal dementia or acute PTSD symptoms that would require clinical management. The classes were not intended to address all these issues, and there was a plan to refer participants either before or during the class if warranted.

There was no formal evaluation of memory prior to starting the class. These classes were not developed as a research intervention and were exempt from institutional review board (IRB) approval requirements, according to prescreening by the VAPSHCS IRB and a memo from the GRECC director.

Core Components of Memory Skills

It may not be evident at first glance that PTSD or a history of PTSD influences memory. The symptom criteria for PTSD (involving reexperiencing, hyperarousal, and avoidance) might be described as “too much remembering” rather than forgetting. Yet problems with attention and concentration often occur in the setting of intrusive memories and alterations in reactivity. Research has found that older adults with PTSD have deficits of memory, especially new learning.⁴ In other words, while older memories may be “stuck,” PTSD seems to impair the processing of information in the here and now.

 

To appreciate these effects, it was important for participants in the memory skills classes to have some understanding of how memory works. The authors developed the Memory Model (Figure) as a visual aid and reference point to discuss the stages of new learning and how different aspects of brain activity are required for new learning and for memory to occur. This straightforward model is based on cognitive science and presented in layman’s terms. An important part of this model is the “filter” stage, which controls the information and stimuli that are available to the brain. Posttraumatic stress disorder involves involuntary emotional responses and efforts to avoid them and selects and colors the information that is processed in some situations (eg, avoidance of situations associated with trauma or dissociation of extreme memories). At other times, such as when a powerful stimulus is presented (eg, a helicopter flying close overhead), the filter may try to block out all inputs in order to preserve safety. The Memory Model also served as a visual aid during class discussions of normal cognitive aging.

The importance of being kind to oneself when lapses occur is emphasized in the class, and patients are urged to seek additional evaluation should lapses increase in severity or frequency.

Class sessions incorporated specific, measurable, attainable, realistic, and timely (SMART) goals, regular exercises based on mindfulness-based stress reduction approaches, and principles of behavioral activation.⁵ The SMART goals structure the sessions and permit customization of learning for participants. Class leaders record a goal for each participant and use these throughout the sessions to build rapport, develop communication, and teach memory skills.

Mindfulness-based stress reduction is an evidence-based treatment used in PTSD.⁶ It provides a counterpoint to the more didactic memory skills and is a method that even those with objective memory impairments can practice and apply successfully. Being in the current moment and emotional regulation are important skills to teach veterans as they learn to exert

some control over their filter and thus, how PTSD affects them. Behavioral activation brings together the literatures on nonpharmacotherapies for mood support as well as dementia prevention strategies (eg, increasing physical activity, social interaction, and cognitive stimulation).

Organization

Class sessions occurred weekly for 1 hour for a total of 8 sessions. The weekly class topics included introduction to memory; mood disorders, cognition, and cognitive disorders; barriers to effective memory: assessing readiness for change; developing a routine and becoming organized; attention and concentration; memory improvement (strategies internal and external aids); and reassessing goals.

Over the 3 years of classes reported in this article, the class sizes varied from 4 to 12 participants based on veteran interest, retention, and room size. The classes were structured so that important content areas were covered but with enough elasticity so leaders and veterans would develop a rapport and explore in greater depth the topics that resonated most for the attendees. Group participation was strongly encouraged. Veterans were expressly informed that the class was not for treatment of PTSD and that evidence-based therapies were encouraged to address PTSD especially if their symptoms flared up when compared with previous levels. The attendees also understood that they did not receive formal cognitive or memory testing but were encouraged to pursue testing if they showed significant deficits.

Preliminary Findings

From spring 2012 until spring 2015, 69 veterans agreed to participate and attended at least 1 memory skills class. Eighty-seven percent of participants (n = 60) attended 4 or more classes. The mean age (SD) was 67.3 years (4.2). All the participants were men, and the race/ethnic distribution was similar to that of the aging veteran population and very close to racial demographics for Washington state: 80% white, 14% African American, 2% Asian/Pacific Islander, 2% Native American, and 2% unknown.

Attendees were asked, but not required, to complete questionnaires before the classes began and again at completion. These questionnaires included self-assessments of cognitive strategies and compensatory methods used; an assessment of concern regarding cognition, life satisfaction, and community integration; the PTSD CheckList-Civilian Version (PCL-C); and the Geriatric Depression Scale (GDS).^7,8 The questionnaire also included open response questions to providefeedback on what attendees liked about the classes and recommendations for improvements. The majority of comments for improvement focused on attendees’ desire for longer sessions and repeat offerings. Five veterans did not complete the full set of questionnaires at the beginning of the classes, and 7 did not complete the questionnaires at completion (the 2 subsets did not perfectly overlap).

At the start of the class, on average, veteran participants were experiencing mild depression and moderate symptoms of PTSD as measured by the GDS (n = 54) and the PCL-C (n = 56), respectively. Preliminary comparisons of ratings pre- and post-classes, using simple paired t tests, indicated a reduction in symptoms of depression on the GDS, improved sense of mastery over their memory symptoms, as well as improved quality of life ratings (all P < .01, no corrections). There was no evidence for a significant reduction in PTSD symptoms or report of elimination of cognitive difficulties. With the small sample and modest effects, the clinical significance of these scores cannot be determined. The authors are planning more detailed analyses on a larger set of participants, including measures of health care utilization before and after the class.

 

Future Directions

The cohort of Vietnam-era veterans likely will manifest more geriatric mental health issues over time, and the number of veterans with a history of PTSD and memory concerns will increase. There ismounting evidence that PTSD alone can be associated with cognitive difficulties across the lifespan, and aspects of aging can both exacerbate and highlight these changes.^9-12 In addition, there is roughly a doubled dementia risk in older veterans with chronic PTSD.¹³ A variety of clinical interventions will be needed to address these issues. For those who have cognitive concerns, teaching older veterans self-management skills while also monitoring their cognition and keeping them engaged in proactive health care are worthy endeavors. The authors hope that by making the program and materials broadly available, more veterans can address their cognitive concerns in a productive, engaging manner. To learn more about the project or to receive class materials, please contact the authors ([email protected]).

The Geriatric Research Education and Clinical Center (GRECC) Memory Disorders Clinic at the VA Puget Sound Health Care System (VAPSHCS) in Seattle, Washington, receives referrals from primary and specialty care. About a decade ago, this clinic began to see an influx of Vietnam-era veterans who presented with a variety of symptoms: not remembering where they were going when driving, forgetting why they went into another room, not remembering what their spouse told them, and feeling “out of it.” These symptoms were not associated with the loss of independence, but they were cause for concern. Family members and care providers typically corroborated the symptom description and perception of decline. Yet during workups, these veterans showed no primary medical causes for cognitive impairments and on neuropsychological evaluation demonstrated essentially normal cognition.

Memory Disorders Clinic staff largely were at a loss to know how to care for these patients. The simple reassurance, “You do not have dementia now,” seemed unsatisfactory given the patients’ ongoing concerns and the established risk factors for neurodegenerative disease.^1,2 One theme emerged when talking with these veterans and their families: They all had a diagnosis of or history of treatment for posttraumatic stress disorder (PTSD).

To help these veterans, the VAPSHCS GRECC sought to address their key areas of concern related to memory. With input from veterans and their families, a quality improvement project was developed with the following goals: (1) to educate veterans and their families about PTSD and cognitive changes; (2) to build and field test a psychoeducational class to teach memory skills in this population; and (3) to inform VA staff about PTSD and cognitive change. In this article, the authors focus on how the first 2 goals were addressed and present preliminary results related to quality improvement.

Memory Skills Classes

The VAPSHCS GRECC Memory Disorders Clinic sought to use an approach that would be readily accepted, efficient, and effective. To that end, the authors developed a clinical model for enhancing memory skills and self-management for veterans with a history of PTSD by adapting existing clinical and educational tools.

Several strategies might promote memory skills, including printed materials for self-directed learning, individual sessions, interactive technologies, or groups. Given the patients’ reports about concentration problems, asking them to work through structured materials independently seemed unproductive. Individual clinical evaluations and cognitive interventions likely would not meet the demand or be cost-effective. Groups have long been used to treat PTSD, and Norrie and colleagues reported that at-risk adults benefited from a group psychoeducation program targeting healthy brain aging.³ At the same time, the Memory Disorders Clinic sought to distinguish itself from PTSD groups, because these groups tend to focus on treating active PTSD.

A better fit for this offering was the description of the sessions as classes. Although the focus was on promoting memory skills among those capable of learning them, the authors were mindful that some veterans might truly have prodromal dementia or acute PTSD symptoms that would require clinical management. The classes were not intended to address all these issues, and there was a plan to refer participants either before or during the class if warranted.

There was no formal evaluation of memory prior to starting the class. These classes were not developed as a research intervention and were exempt from institutional review board (IRB) approval requirements, according to prescreening by the VAPSHCS IRB and a memo from the GRECC director.

Core Components of Memory Skills

It may not be evident at first glance that PTSD or a history of PTSD influences memory. The symptom criteria for PTSD (involving reexperiencing, hyperarousal, and avoidance) might be described as “too much remembering” rather than forgetting. Yet problems with attention and concentration often occur in the setting of intrusive memories and alterations in reactivity. Research has found that older adults with PTSD have deficits of memory, especially new learning.⁴ In other words, while older memories may be “stuck,” PTSD seems to impair the processing of information in the here and now.

 

To appreciate these effects, it was important for participants in the memory skills classes to have some understanding of how memory works. The authors developed the Memory Model (Figure) as a visual aid and reference point to discuss the stages of new learning and how different aspects of brain activity are required for new learning and for memory to occur. This straightforward model is based on cognitive science and presented in layman’s terms. An important part of this model is the “filter” stage, which controls the information and stimuli that are available to the brain. Posttraumatic stress disorder involves involuntary emotional responses and efforts to avoid them and selects and colors the information that is processed in some situations (eg, avoidance of situations associated with trauma or dissociation of extreme memories). At other times, such as when a powerful stimulus is presented (eg, a helicopter flying close overhead), the filter may try to block out all inputs in order to preserve safety. The Memory Model also served as a visual aid during class discussions of normal cognitive aging.

The importance of being kind to oneself when lapses occur is emphasized in the class, and patients are urged to seek additional evaluation should lapses increase in severity or frequency.

Class sessions incorporated specific, measurable, attainable, realistic, and timely (SMART) goals, regular exercises based on mindfulness-based stress reduction approaches, and principles of behavioral activation.⁵ The SMART goals structure the sessions and permit customization of learning for participants. Class leaders record a goal for each participant and use these throughout the sessions to build rapport, develop communication, and teach memory skills.

Mindfulness-based stress reduction is an evidence-based treatment used in PTSD.⁶ It provides a counterpoint to the more didactic memory skills and is a method that even those with objective memory impairments can practice and apply successfully. Being in the current moment and emotional regulation are important skills to teach veterans as they learn to exert

some control over their filter and thus, how PTSD affects them. Behavioral activation brings together the literatures on nonpharmacotherapies for mood support as well as dementia prevention strategies (eg, increasing physical activity, social interaction, and cognitive stimulation).

Organization

Class sessions occurred weekly for 1 hour for a total of 8 sessions. The weekly class topics included introduction to memory; mood disorders, cognition, and cognitive disorders; barriers to effective memory: assessing readiness for change; developing a routine and becoming organized; attention and concentration; memory improvement (strategies internal and external aids); and reassessing goals.

Over the 3 years of classes reported in this article, the class sizes varied from 4 to 12 participants based on veteran interest, retention, and room size. The classes were structured so that important content areas were covered but with enough elasticity so leaders and veterans would develop a rapport and explore in greater depth the topics that resonated most for the attendees. Group participation was strongly encouraged. Veterans were expressly informed that the class was not for treatment of PTSD and that evidence-based therapies were encouraged to address PTSD especially if their symptoms flared up when compared with previous levels. The attendees also understood that they did not receive formal cognitive or memory testing but were encouraged to pursue testing if they showed significant deficits.

Preliminary Findings

From spring 2012 until spring 2015, 69 veterans agreed to participate and attended at least 1 memory skills class. Eighty-seven percent of participants (n = 60) attended 4 or more classes. The mean age (SD) was 67.3 years (4.2). All the participants were men, and the race/ethnic distribution was similar to that of the aging veteran population and very close to racial demographics for Washington state: 80% white, 14% African American, 2% Asian/Pacific Islander, 2% Native American, and 2% unknown.

Attendees were asked, but not required, to complete questionnaires before the classes began and again at completion. These questionnaires included self-assessments of cognitive strategies and compensatory methods used; an assessment of concern regarding cognition, life satisfaction, and community integration; the PTSD CheckList-Civilian Version (PCL-C); and the Geriatric Depression Scale (GDS).^7,8 The questionnaire also included open response questions to providefeedback on what attendees liked about the classes and recommendations for improvements. The majority of comments for improvement focused on attendees’ desire for longer sessions and repeat offerings. Five veterans did not complete the full set of questionnaires at the beginning of the classes, and 7 did not complete the questionnaires at completion (the 2 subsets did not perfectly overlap).

At the start of the class, on average, veteran participants were experiencing mild depression and moderate symptoms of PTSD as measured by the GDS (n = 54) and the PCL-C (n = 56), respectively. Preliminary comparisons of ratings pre- and post-classes, using simple paired t tests, indicated a reduction in symptoms of depression on the GDS, improved sense of mastery over their memory symptoms, as well as improved quality of life ratings (all P < .01, no corrections). There was no evidence for a significant reduction in PTSD symptoms or report of elimination of cognitive difficulties. With the small sample and modest effects, the clinical significance of these scores cannot be determined. The authors are planning more detailed analyses on a larger set of participants, including measures of health care utilization before and after the class.

 

Future Directions

The cohort of Vietnam-era veterans likely will manifest more geriatric mental health issues over time, and the number of veterans with a history of PTSD and memory concerns will increase. There ismounting evidence that PTSD alone can be associated with cognitive difficulties across the lifespan, and aspects of aging can both exacerbate and highlight these changes.^9-12 In addition, there is roughly a doubled dementia risk in older veterans with chronic PTSD.¹³ A variety of clinical interventions will be needed to address these issues. For those who have cognitive concerns, teaching older veterans self-management skills while also monitoring their cognition and keeping them engaged in proactive health care are worthy endeavors. The authors hope that by making the program and materials broadly available, more veterans can address their cognitive concerns in a productive, engaging manner. To learn more about the project or to receive class materials, please contact the authors ([email protected]).

The Geriatric Research Education and Clinical Center (GRECC) Memory Disorders Clinic at the VA Puget Sound Health Care System (VAPSHCS) in Seattle, Washington, receives referrals from primary and specialty care. About a decade ago, this clinic began to see an influx of Vietnam-era veterans who presented with a variety of symptoms: not remembering where they were going when driving, forgetting why they went into another room, not remembering what their spouse told them, and feeling “out of it.” These symptoms were not associated with the loss of independence, but they were cause for concern. Family members and care providers typically corroborated the symptom description and perception of decline. Yet during workups, these veterans showed no primary medical causes for cognitive impairments and on neuropsychological evaluation demonstrated essentially normal cognition.

Memory Disorders Clinic staff largely were at a loss to know how to care for these patients. The simple reassurance, “You do not have dementia now,” seemed unsatisfactory given the patients’ ongoing concerns and the established risk factors for neurodegenerative disease.^1,2 One theme emerged when talking with these veterans and their families: They all had a diagnosis of or history of treatment for posttraumatic stress disorder (PTSD).

To help these veterans, the VAPSHCS GRECC sought to address their key areas of concern related to memory. With input from veterans and their families, a quality improvement project was developed with the following goals: (1) to educate veterans and their families about PTSD and cognitive changes; (2) to build and field test a psychoeducational class to teach memory skills in this population; and (3) to inform VA staff about PTSD and cognitive change. In this article, the authors focus on how the first 2 goals were addressed and present preliminary results related to quality improvement.

Memory Skills Classes

The VAPSHCS GRECC Memory Disorders Clinic sought to use an approach that would be readily accepted, efficient, and effective. To that end, the authors developed a clinical model for enhancing memory skills and self-management for veterans with a history of PTSD by adapting existing clinical and educational tools.

Several strategies might promote memory skills, including printed materials for self-directed learning, individual sessions, interactive technologies, or groups. Given the patients’ reports about concentration problems, asking them to work through structured materials independently seemed unproductive. Individual clinical evaluations and cognitive interventions likely would not meet the demand or be cost-effective. Groups have long been used to treat PTSD, and Norrie and colleagues reported that at-risk adults benefited from a group psychoeducation program targeting healthy brain aging.³ At the same time, the Memory Disorders Clinic sought to distinguish itself from PTSD groups, because these groups tend to focus on treating active PTSD.

A better fit for this offering was the description of the sessions as classes. Although the focus was on promoting memory skills among those capable of learning them, the authors were mindful that some veterans might truly have prodromal dementia or acute PTSD symptoms that would require clinical management. The classes were not intended to address all these issues, and there was a plan to refer participants either before or during the class if warranted.

There was no formal evaluation of memory prior to starting the class. These classes were not developed as a research intervention and were exempt from institutional review board (IRB) approval requirements, according to prescreening by the VAPSHCS IRB and a memo from the GRECC director.

Core Components of Memory Skills

It may not be evident at first glance that PTSD or a history of PTSD influences memory. The symptom criteria for PTSD (involving reexperiencing, hyperarousal, and avoidance) might be described as “too much remembering” rather than forgetting. Yet problems with attention and concentration often occur in the setting of intrusive memories and alterations in reactivity. Research has found that older adults with PTSD have deficits of memory, especially new learning.⁴ In other words, while older memories may be “stuck,” PTSD seems to impair the processing of information in the here and now.

 

To appreciate these effects, it was important for participants in the memory skills classes to have some understanding of how memory works. The authors developed the Memory Model (Figure) as a visual aid and reference point to discuss the stages of new learning and how different aspects of brain activity are required for new learning and for memory to occur. This straightforward model is based on cognitive science and presented in layman’s terms. An important part of this model is the “filter” stage, which controls the information and stimuli that are available to the brain. Posttraumatic stress disorder involves involuntary emotional responses and efforts to avoid them and selects and colors the information that is processed in some situations (eg, avoidance of situations associated with trauma or dissociation of extreme memories). At other times, such as when a powerful stimulus is presented (eg, a helicopter flying close overhead), the filter may try to block out all inputs in order to preserve safety. The Memory Model also served as a visual aid during class discussions of normal cognitive aging.

The importance of being kind to oneself when lapses occur is emphasized in the class, and patients are urged to seek additional evaluation should lapses increase in severity or frequency.

Class sessions incorporated specific, measurable, attainable, realistic, and timely (SMART) goals, regular exercises based on mindfulness-based stress reduction approaches, and principles of behavioral activation.⁵ The SMART goals structure the sessions and permit customization of learning for participants. Class leaders record a goal for each participant and use these throughout the sessions to build rapport, develop communication, and teach memory skills.

Mindfulness-based stress reduction is an evidence-based treatment used in PTSD.⁶ It provides a counterpoint to the more didactic memory skills and is a method that even those with objective memory impairments can practice and apply successfully. Being in the current moment and emotional regulation are important skills to teach veterans as they learn to exert

some control over their filter and thus, how PTSD affects them. Behavioral activation brings together the literatures on nonpharmacotherapies for mood support as well as dementia prevention strategies (eg, increasing physical activity, social interaction, and cognitive stimulation).

Organization

Class sessions occurred weekly for 1 hour for a total of 8 sessions. The weekly class topics included introduction to memory; mood disorders, cognition, and cognitive disorders; barriers to effective memory: assessing readiness for change; developing a routine and becoming organized; attention and concentration; memory improvement (strategies internal and external aids); and reassessing goals.

Over the 3 years of classes reported in this article, the class sizes varied from 4 to 12 participants based on veteran interest, retention, and room size. The classes were structured so that important content areas were covered but with enough elasticity so leaders and veterans would develop a rapport and explore in greater depth the topics that resonated most for the attendees. Group participation was strongly encouraged. Veterans were expressly informed that the class was not for treatment of PTSD and that evidence-based therapies were encouraged to address PTSD especially if their symptoms flared up when compared with previous levels. The attendees also understood that they did not receive formal cognitive or memory testing but were encouraged to pursue testing if they showed significant deficits.

Preliminary Findings

From spring 2012 until spring 2015, 69 veterans agreed to participate and attended at least 1 memory skills class. Eighty-seven percent of participants (n = 60) attended 4 or more classes. The mean age (SD) was 67.3 years (4.2). All the participants were men, and the race/ethnic distribution was similar to that of the aging veteran population and very close to racial demographics for Washington state: 80% white, 14% African American, 2% Asian/Pacific Islander, 2% Native American, and 2% unknown.

Attendees were asked, but not required, to complete questionnaires before the classes began and again at completion. These questionnaires included self-assessments of cognitive strategies and compensatory methods used; an assessment of concern regarding cognition, life satisfaction, and community integration; the PTSD CheckList-Civilian Version (PCL-C); and the Geriatric Depression Scale (GDS).^7,8 The questionnaire also included open response questions to providefeedback on what attendees liked about the classes and recommendations for improvements. The majority of comments for improvement focused on attendees’ desire for longer sessions and repeat offerings. Five veterans did not complete the full set of questionnaires at the beginning of the classes, and 7 did not complete the questionnaires at completion (the 2 subsets did not perfectly overlap).

At the start of the class, on average, veteran participants were experiencing mild depression and moderate symptoms of PTSD as measured by the GDS (n = 54) and the PCL-C (n = 56), respectively. Preliminary comparisons of ratings pre- and post-classes, using simple paired t tests, indicated a reduction in symptoms of depression on the GDS, improved sense of mastery over their memory symptoms, as well as improved quality of life ratings (all P < .01, no corrections). There was no evidence for a significant reduction in PTSD symptoms or report of elimination of cognitive difficulties. With the small sample and modest effects, the clinical significance of these scores cannot be determined. The authors are planning more detailed analyses on a larger set of participants, including measures of health care utilization before and after the class.

 

Future Directions

The cohort of Vietnam-era veterans likely will manifest more geriatric mental health issues over time, and the number of veterans with a history of PTSD and memory concerns will increase. There ismounting evidence that PTSD alone can be associated with cognitive difficulties across the lifespan, and aspects of aging can both exacerbate and highlight these changes.^9-12 In addition, there is roughly a doubled dementia risk in older veterans with chronic PTSD.¹³ A variety of clinical interventions will be needed to address these issues. For those who have cognitive concerns, teaching older veterans self-management skills while also monitoring their cognition and keeping them engaged in proactive health care are worthy endeavors. The authors hope that by making the program and materials broadly available, more veterans can address their cognitive concerns in a productive, engaging manner. To learn more about the project or to receive class materials, please contact the authors ([email protected]).

SAN DIEGO—Venetoclax, the oral BCL-2 inhibitor approved by the US Food and Drug Administration to treat chronic lymphocytic leukemia (CLL) patients with 17p deletion, is also showing activity in multiple myeloma (MM) patients, particularly those with t(11;14).

Final results of a phase 1 study showed venetoclax to be safe as monotherapy in relapsed or refractory MM, producing a response rate of 40% in patients with the translocation and 21% overall.

Preliminary results of the study were presented at the 2015 ASH Annual Meeting, and final results were presented at the 2016 ASH Annual Meeting.

“So I think we have a drug that potentially can change the outcome of a lot of patients with myeloma,” Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota, said during the presentation of the findings at ASH (abstract 488*).

“[It] also opens the possibility of being combined with a variety of other therapeutics that we have in this disease today.”

Venetoclax induces cell death in MM cell lines, particularly those positive for t(11;14). The translocation correlates with higher ratios of BCL-2 to MCL-1 and BCL-2 to MCL-2L1 (BCL-X_L) mRNA. BCL-2 and MCL-1 promote survival of MM cells.

Study design and enrollment

The phase 1, open-label, multicenter study was designed to determine the best tolerated dose of venetoclax.

Secondary and exploratory objectives included overall response rate (ORR), time to progression, duration of response, and predictive biomarkers.

Patients had to have previously treated MM with measurable disease, ECOG status of 0 or 1, and adequate organ function.

They were excluded if they had an active infection, a history of significant renal, neurologic, psychiatric, endocrine, immunologic, cardiovascular, or hepatic disease within 6 months of study entry, or a history of other active malignancies within 3 years of study entry.

The study called for a 2-week lead-in period of venetoclax with weekly dose escalation. Four different dose cohorts were evaluated—300 mg, 600 mg, 900 mg, and 1200 mg.

Thirty patients were enrolled during the lead-in period, and 36 additional patients enrolled at the maximum evaluated dose of 1200 mg in the safety expansion cohort, for a total of 66 patients.

Patients were treated on a 21-day cycle with daily venetoclax. They could also receive dexamethasone to continue on the study if they progressed while receiving the monotherapy.

Patient characteristics

Patient characteristics were “similar to what you would see in relapsed/refractory multiple myloma,” Dr Kumar said.

Median age was 63 (range, 31–79), and most (62%) were ISS stage II/III.

“I want to draw your attention to two features here,” Dr Kumar said.

“Thirty patients, or 46% of the patients, had 11;14 translocation, and that reflects the interest in this drug for this particular class of patients.”

Twelve patients (18%) had 17p deletion, 32 (48%) had 13q deletion, and 27 (41%) were hyperdiploid.

“What is most striking in this cohort of patients,” Dr Kumar added, “is the fact that the median number of prior lines of therapy was 5, with some as high as 15 prior lines of therapy.”

Seventy percent were refractory to bortezomib, 77% refractory to lenalidomide, and 61% refractory to both. Fifty-two patients (79%) were refractory to their last prior therapy.

Patient disposition

At the time of data cutoff on August 19, 2016, 11 patients (17%) were still active on the study.

The median time on study was 3.3 months (range, 0.2–27), median time on venetoclax monotherapy was 2.5 months (range, 0.2–25), and median time on venetoclax plus dexamethasone was 1.4 months (range, 1–13). Seventeen patients received the combination after disease progression.

Fifty-five patients (83%) discontinued treatment, 41 (62%) because of disease progression, 5 (8%) because of adverse events, 2 (3%) withdrew consent, 1 (2%) was lost to follow-up, and 6 (9%) for unspecified reasons.

The 5 adverse events leading to withdrawal included renal failure (n=2), worsening pulmonary disorder (n=1), paralyzing sciatica (n=1), and shortness of breath and pain (n=1). 

“Eight patients died on study,” Dr Kumar said, “none thought to be related to the drug.”

Adverse events

The toxicity profile was primarily hematologic and gastrointestinal.

All patients experienced an adverse event of any grade, and 45 (68%) had a grade 3 or 4 event.

“I wanted to highlight that the majority of the gastrointestinal and non-hematologic toxicity we saw were grades 1 and 2,” Dr Kumar pointed out, “and could be managed symptomatically or with dose modifications.”

Grade 3-4 hematologic adverse events included thrombocytopenia (26%), neutropenia (21%), anemia (14%), leukopenia (14%), and lymphopenia (15%).

Grade 3-4 non-hematologic adverse events included nausea (3%), diarrhea (3%), fatigue (5%), back pain (8%), and vomiting (3%).

Serious adverse events occurring in 2% or more of patients included pneumonia (8%), sepsis (5%), pain, pyrexia, cough, and hypotension (3% each).

Two patients had dose-limiting toxicities of abdominal pain and nausea at the 600 mg dose.

No events of tumor lysis syndrome (TLS) were reported.  Dr Kumar explained that this may have been the case because patients thought to be at high risk for TLS were mandated to be in the hospital and observed for early tumor lysis in the initial part of the study.

Response

The ORR was 21% in all patients, including a stringent complete response (sCR) of 3% and a CR of 4%.

“But what was really striking was the response rate that we observed in the 30 patients with translocation 11;14,” Dr Kumar said. “The overall response rate was 40%, with 14% of the patients having complete response or better [stringent CR] and 13% of the patients with very good partial response.”

The 36 patients without t(11;14) had a 6% ORR, 3% sCR, and 3% very good partial response.

“If you look at the response rates based on the type of therapy they were coming off or the drugs they were refractory to, the response rate is very similar across all these patient subgroups, irrespective of what groups of drugs they were refractory to,” he added.

Time to progression for all patients was about 2.5 months. For patients with the translocation, it was about 6.6 months.

“Responses were fairly durable among those who had a response,” Dr Kumar said, “considering these are patients with a median of 5 prior lines of therapy.”

Duration of response for patients with t(11;14) was close to 10 months.

Biomarker analysis

The underlying biology for the response was the BCL-2 to BCL-2L1 ratio, as the investigators had observed in the cell lines.

So they analyzed the BCL-2 gene expression ratio in 24 of the 30 patients with t(11;14).

The investigators used droplet digital PCR performed on CD138-selected bone marrow mononuclear cells collected at baseline.

Nine patients had a high ratio, and their ORR was 88%. Fifteen patients had a low ratio, and their ORR was 20%.

Median time to progression for patients with a high ratio was about 12 months. For those with a low ratio, it was about 9 months.

 

Median change in M protein for patients with t(11;14) was –53%, compared to +11% in the patients without the translocation.

The investigators recommend additional studies with venetoclax in MM, including those with alternative combination therapies.

Venetoclax is being developed by AbbVie, in partnership with Genentech and Roche. This study was sponsored by AbbVie.

*Data in the abstract differ from the presentation.

SAN DIEGO—Venetoclax, the oral BCL-2 inhibitor approved by the US Food and Drug Administration to treat chronic lymphocytic leukemia (CLL) patients with 17p deletion, is also showing activity in multiple myeloma (MM) patients, particularly those with t(11;14).

Final results of a phase 1 study showed venetoclax to be safe as monotherapy in relapsed or refractory MM, producing a response rate of 40% in patients with the translocation and 21% overall.

Preliminary results of the study were presented at the 2015 ASH Annual Meeting, and final results were presented at the 2016 ASH Annual Meeting.

“So I think we have a drug that potentially can change the outcome of a lot of patients with myeloma,” Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota, said during the presentation of the findings at ASH (abstract 488*).

“[It] also opens the possibility of being combined with a variety of other therapeutics that we have in this disease today.”

Venetoclax induces cell death in MM cell lines, particularly those positive for t(11;14). The translocation correlates with higher ratios of BCL-2 to MCL-1 and BCL-2 to MCL-2L1 (BCL-X_L) mRNA. BCL-2 and MCL-1 promote survival of MM cells.

Study design and enrollment

The phase 1, open-label, multicenter study was designed to determine the best tolerated dose of venetoclax.

Secondary and exploratory objectives included overall response rate (ORR), time to progression, duration of response, and predictive biomarkers.

Patients had to have previously treated MM with measurable disease, ECOG status of 0 or 1, and adequate organ function.

They were excluded if they had an active infection, a history of significant renal, neurologic, psychiatric, endocrine, immunologic, cardiovascular, or hepatic disease within 6 months of study entry, or a history of other active malignancies within 3 years of study entry.

The study called for a 2-week lead-in period of venetoclax with weekly dose escalation. Four different dose cohorts were evaluated—300 mg, 600 mg, 900 mg, and 1200 mg.

Thirty patients were enrolled during the lead-in period, and 36 additional patients enrolled at the maximum evaluated dose of 1200 mg in the safety expansion cohort, for a total of 66 patients.

Patients were treated on a 21-day cycle with daily venetoclax. They could also receive dexamethasone to continue on the study if they progressed while receiving the monotherapy.

Patient characteristics

Patient characteristics were “similar to what you would see in relapsed/refractory multiple myloma,” Dr Kumar said.

Median age was 63 (range, 31–79), and most (62%) were ISS stage II/III.

“I want to draw your attention to two features here,” Dr Kumar said.

“Thirty patients, or 46% of the patients, had 11;14 translocation, and that reflects the interest in this drug for this particular class of patients.”

Twelve patients (18%) had 17p deletion, 32 (48%) had 13q deletion, and 27 (41%) were hyperdiploid.

“What is most striking in this cohort of patients,” Dr Kumar added, “is the fact that the median number of prior lines of therapy was 5, with some as high as 15 prior lines of therapy.”

Seventy percent were refractory to bortezomib, 77% refractory to lenalidomide, and 61% refractory to both. Fifty-two patients (79%) were refractory to their last prior therapy.

Patient disposition

At the time of data cutoff on August 19, 2016, 11 patients (17%) were still active on the study.

The median time on study was 3.3 months (range, 0.2–27), median time on venetoclax monotherapy was 2.5 months (range, 0.2–25), and median time on venetoclax plus dexamethasone was 1.4 months (range, 1–13). Seventeen patients received the combination after disease progression.

Fifty-five patients (83%) discontinued treatment, 41 (62%) because of disease progression, 5 (8%) because of adverse events, 2 (3%) withdrew consent, 1 (2%) was lost to follow-up, and 6 (9%) for unspecified reasons.

The 5 adverse events leading to withdrawal included renal failure (n=2), worsening pulmonary disorder (n=1), paralyzing sciatica (n=1), and shortness of breath and pain (n=1). 

“Eight patients died on study,” Dr Kumar said, “none thought to be related to the drug.”

Adverse events

The toxicity profile was primarily hematologic and gastrointestinal.

All patients experienced an adverse event of any grade, and 45 (68%) had a grade 3 or 4 event.

“I wanted to highlight that the majority of the gastrointestinal and non-hematologic toxicity we saw were grades 1 and 2,” Dr Kumar pointed out, “and could be managed symptomatically or with dose modifications.”

Grade 3-4 hematologic adverse events included thrombocytopenia (26%), neutropenia (21%), anemia (14%), leukopenia (14%), and lymphopenia (15%).

Grade 3-4 non-hematologic adverse events included nausea (3%), diarrhea (3%), fatigue (5%), back pain (8%), and vomiting (3%).

Serious adverse events occurring in 2% or more of patients included pneumonia (8%), sepsis (5%), pain, pyrexia, cough, and hypotension (3% each).

Two patients had dose-limiting toxicities of abdominal pain and nausea at the 600 mg dose.

No events of tumor lysis syndrome (TLS) were reported.  Dr Kumar explained that this may have been the case because patients thought to be at high risk for TLS were mandated to be in the hospital and observed for early tumor lysis in the initial part of the study.

Response

The ORR was 21% in all patients, including a stringent complete response (sCR) of 3% and a CR of 4%.

“But what was really striking was the response rate that we observed in the 30 patients with translocation 11;14,” Dr Kumar said. “The overall response rate was 40%, with 14% of the patients having complete response or better [stringent CR] and 13% of the patients with very good partial response.”

The 36 patients without t(11;14) had a 6% ORR, 3% sCR, and 3% very good partial response.

“If you look at the response rates based on the type of therapy they were coming off or the drugs they were refractory to, the response rate is very similar across all these patient subgroups, irrespective of what groups of drugs they were refractory to,” he added.

Time to progression for all patients was about 2.5 months. For patients with the translocation, it was about 6.6 months.

“Responses were fairly durable among those who had a response,” Dr Kumar said, “considering these are patients with a median of 5 prior lines of therapy.”

Duration of response for patients with t(11;14) was close to 10 months.

Biomarker analysis

The underlying biology for the response was the BCL-2 to BCL-2L1 ratio, as the investigators had observed in the cell lines.

So they analyzed the BCL-2 gene expression ratio in 24 of the 30 patients with t(11;14).

The investigators used droplet digital PCR performed on CD138-selected bone marrow mononuclear cells collected at baseline.

Nine patients had a high ratio, and their ORR was 88%. Fifteen patients had a low ratio, and their ORR was 20%.

Median time to progression for patients with a high ratio was about 12 months. For those with a low ratio, it was about 9 months.

 

Median change in M protein for patients with t(11;14) was –53%, compared to +11% in the patients without the translocation.

The investigators recommend additional studies with venetoclax in MM, including those with alternative combination therapies.

Venetoclax is being developed by AbbVie, in partnership with Genentech and Roche. This study was sponsored by AbbVie.

*Data in the abstract differ from the presentation.

SAN DIEGO—Venetoclax, the oral BCL-2 inhibitor approved by the US Food and Drug Administration to treat chronic lymphocytic leukemia (CLL) patients with 17p deletion, is also showing activity in multiple myeloma (MM) patients, particularly those with t(11;14).

Final results of a phase 1 study showed venetoclax to be safe as monotherapy in relapsed or refractory MM, producing a response rate of 40% in patients with the translocation and 21% overall.

Preliminary results of the study were presented at the 2015 ASH Annual Meeting, and final results were presented at the 2016 ASH Annual Meeting.

“So I think we have a drug that potentially can change the outcome of a lot of patients with myeloma,” Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota, said during the presentation of the findings at ASH (abstract 488*).

“[It] also opens the possibility of being combined with a variety of other therapeutics that we have in this disease today.”

Venetoclax induces cell death in MM cell lines, particularly those positive for t(11;14). The translocation correlates with higher ratios of BCL-2 to MCL-1 and BCL-2 to MCL-2L1 (BCL-X_L) mRNA. BCL-2 and MCL-1 promote survival of MM cells.

Study design and enrollment

The phase 1, open-label, multicenter study was designed to determine the best tolerated dose of venetoclax.

Secondary and exploratory objectives included overall response rate (ORR), time to progression, duration of response, and predictive biomarkers.

Patients had to have previously treated MM with measurable disease, ECOG status of 0 or 1, and adequate organ function.

They were excluded if they had an active infection, a history of significant renal, neurologic, psychiatric, endocrine, immunologic, cardiovascular, or hepatic disease within 6 months of study entry, or a history of other active malignancies within 3 years of study entry.

The study called for a 2-week lead-in period of venetoclax with weekly dose escalation. Four different dose cohorts were evaluated—300 mg, 600 mg, 900 mg, and 1200 mg.

Thirty patients were enrolled during the lead-in period, and 36 additional patients enrolled at the maximum evaluated dose of 1200 mg in the safety expansion cohort, for a total of 66 patients.

Patients were treated on a 21-day cycle with daily venetoclax. They could also receive dexamethasone to continue on the study if they progressed while receiving the monotherapy.

Patient characteristics

Patient characteristics were “similar to what you would see in relapsed/refractory multiple myloma,” Dr Kumar said.

Median age was 63 (range, 31–79), and most (62%) were ISS stage II/III.

“I want to draw your attention to two features here,” Dr Kumar said.

“Thirty patients, or 46% of the patients, had 11;14 translocation, and that reflects the interest in this drug for this particular class of patients.”

Twelve patients (18%) had 17p deletion, 32 (48%) had 13q deletion, and 27 (41%) were hyperdiploid.

“What is most striking in this cohort of patients,” Dr Kumar added, “is the fact that the median number of prior lines of therapy was 5, with some as high as 15 prior lines of therapy.”

Seventy percent were refractory to bortezomib, 77% refractory to lenalidomide, and 61% refractory to both. Fifty-two patients (79%) were refractory to their last prior therapy.

Patient disposition

At the time of data cutoff on August 19, 2016, 11 patients (17%) were still active on the study.

The median time on study was 3.3 months (range, 0.2–27), median time on venetoclax monotherapy was 2.5 months (range, 0.2–25), and median time on venetoclax plus dexamethasone was 1.4 months (range, 1–13). Seventeen patients received the combination after disease progression.

Fifty-five patients (83%) discontinued treatment, 41 (62%) because of disease progression, 5 (8%) because of adverse events, 2 (3%) withdrew consent, 1 (2%) was lost to follow-up, and 6 (9%) for unspecified reasons.

The 5 adverse events leading to withdrawal included renal failure (n=2), worsening pulmonary disorder (n=1), paralyzing sciatica (n=1), and shortness of breath and pain (n=1). 

“Eight patients died on study,” Dr Kumar said, “none thought to be related to the drug.”

Adverse events

The toxicity profile was primarily hematologic and gastrointestinal.

All patients experienced an adverse event of any grade, and 45 (68%) had a grade 3 or 4 event.

“I wanted to highlight that the majority of the gastrointestinal and non-hematologic toxicity we saw were grades 1 and 2,” Dr Kumar pointed out, “and could be managed symptomatically or with dose modifications.”

Grade 3-4 hematologic adverse events included thrombocytopenia (26%), neutropenia (21%), anemia (14%), leukopenia (14%), and lymphopenia (15%).

Grade 3-4 non-hematologic adverse events included nausea (3%), diarrhea (3%), fatigue (5%), back pain (8%), and vomiting (3%).

Serious adverse events occurring in 2% or more of patients included pneumonia (8%), sepsis (5%), pain, pyrexia, cough, and hypotension (3% each).

Two patients had dose-limiting toxicities of abdominal pain and nausea at the 600 mg dose.

No events of tumor lysis syndrome (TLS) were reported.  Dr Kumar explained that this may have been the case because patients thought to be at high risk for TLS were mandated to be in the hospital and observed for early tumor lysis in the initial part of the study.

Response

The ORR was 21% in all patients, including a stringent complete response (sCR) of 3% and a CR of 4%.

“But what was really striking was the response rate that we observed in the 30 patients with translocation 11;14,” Dr Kumar said. “The overall response rate was 40%, with 14% of the patients having complete response or better [stringent CR] and 13% of the patients with very good partial response.”

The 36 patients without t(11;14) had a 6% ORR, 3% sCR, and 3% very good partial response.

“If you look at the response rates based on the type of therapy they were coming off or the drugs they were refractory to, the response rate is very similar across all these patient subgroups, irrespective of what groups of drugs they were refractory to,” he added.

Time to progression for all patients was about 2.5 months. For patients with the translocation, it was about 6.6 months.

“Responses were fairly durable among those who had a response,” Dr Kumar said, “considering these are patients with a median of 5 prior lines of therapy.”

Duration of response for patients with t(11;14) was close to 10 months.

Biomarker analysis

The underlying biology for the response was the BCL-2 to BCL-2L1 ratio, as the investigators had observed in the cell lines.

So they analyzed the BCL-2 gene expression ratio in 24 of the 30 patients with t(11;14).

The investigators used droplet digital PCR performed on CD138-selected bone marrow mononuclear cells collected at baseline.

Nine patients had a high ratio, and their ORR was 88%. Fifteen patients had a low ratio, and their ORR was 20%.

Median time to progression for patients with a high ratio was about 12 months. For those with a low ratio, it was about 9 months.

 

Median change in M protein for patients with t(11;14) was –53%, compared to +11% in the patients without the translocation.

The investigators recommend additional studies with venetoclax in MM, including those with alternative combination therapies.

Venetoclax is being developed by AbbVie, in partnership with Genentech and Roche. This study was sponsored by AbbVie.

*Data in the abstract differ from the presentation.

Researchers say they have uncovered one potential reason why it has been difficult to generate protective immunity against the early liver stage of malaria infection in regions where the incidence of malaria is high.

Their research, conducted in mice and published in Cell Reports, suggests that exposure to the blood stage of malaria infection inhibits the formation of the protective immune cells (and their antibodies) that can prevent liver-stage infection.

“The blood stage of malaria infection has a very profound impact on the liver stage immune response, and that impact had never been dissected and visualized at this level,” said study author Marion Pepper, PhD, of the University of Washington School of Medicine in Seattle.

“These studies really suggest that you need a vaccine that is protective against both stages of infection to effectively prevent malaria.”

To track how the blood stage of malaria infection overpowers the liver-stage immune response, Dr Pepper and her colleagues infected 2 groups of mice with different forms of malaria parasites.

One group of mice was infected with Plasmodium yoelii wild-type sporozoites, which complete the pre-erythrocytic stage of infection and establish a blood-stage infection.

The other group was infected with a genetically attenuated Plasmodium yoelii parasite that arrests late in liver stage development and does not cause blood-stage infection.

Six days after infection, the researchers found the levels of antibodies were significantly lower in the mice with the blood stage infection than in mice that only had the parasite targeted to the liver.

To understand this discrepancy, the team tracked the differentiation of Plasmodium liver stage-specific B cells. B cells can differentiate into antibody-secreting early effector cells or long-lived memory cells, both of which contribute to protection against malaria.

The researchers discovered that, 14 days after infection, the B cells in the blood-stage-infected mice never went through the necessary changes to make rapidly responsive memory cells.

However, in the mice that received the liver-stage attenuated version of the parasite, the B cells were still able to differentiate and create the necessary antibodies and memory cells for an effective immune response.

“This work really highlights the importance of looking at antigen-specific B cells,” Dr Pepper said. “These data also suggest that if you’re getting a vaccine while you have an ongoing blood-stage infection, there is a chance that the vaccine will not generate good memory cells because the blood stage disrupts all the processes that are involved in making that immunological memory.”

Dr Pepper and her colleagues are now looking into the possibility of treatment to solve this problem.

The team found that when they treated the second stage of the infection with the anti-malarial drug atovaquone, the B cells were able to create the optimally responsive memory cells.

For now, the researchers hope their work can be used to answer immediate questions about the efficacy of malaria vaccines in regions that are most significantly affected by the disease.

“Malaria has evolved with us throughout human existence and therefore has some potent immune evasion strategies,” Dr Pepper said. “We really tried to tease apart some of the factors that could be driving the loss of protective immunity during natural infection and with current vaccine strategies in areas of high malaria transmission.”

“Our next step is to compare malaria-specific B cells after vaccination or natural infection in humans so we can translate these findings and start to determine how to solve this problem.”

Researchers say they have uncovered one potential reason why it has been difficult to generate protective immunity against the early liver stage of malaria infection in regions where the incidence of malaria is high.

Their research, conducted in mice and published in Cell Reports, suggests that exposure to the blood stage of malaria infection inhibits the formation of the protective immune cells (and their antibodies) that can prevent liver-stage infection.

“The blood stage of malaria infection has a very profound impact on the liver stage immune response, and that impact had never been dissected and visualized at this level,” said study author Marion Pepper, PhD, of the University of Washington School of Medicine in Seattle.

“These studies really suggest that you need a vaccine that is protective against both stages of infection to effectively prevent malaria.”

To track how the blood stage of malaria infection overpowers the liver-stage immune response, Dr Pepper and her colleagues infected 2 groups of mice with different forms of malaria parasites.

One group of mice was infected with Plasmodium yoelii wild-type sporozoites, which complete the pre-erythrocytic stage of infection and establish a blood-stage infection.

The other group was infected with a genetically attenuated Plasmodium yoelii parasite that arrests late in liver stage development and does not cause blood-stage infection.

Six days after infection, the researchers found the levels of antibodies were significantly lower in the mice with the blood stage infection than in mice that only had the parasite targeted to the liver.

To understand this discrepancy, the team tracked the differentiation of Plasmodium liver stage-specific B cells. B cells can differentiate into antibody-secreting early effector cells or long-lived memory cells, both of which contribute to protection against malaria.

The researchers discovered that, 14 days after infection, the B cells in the blood-stage-infected mice never went through the necessary changes to make rapidly responsive memory cells.

However, in the mice that received the liver-stage attenuated version of the parasite, the B cells were still able to differentiate and create the necessary antibodies and memory cells for an effective immune response.

“This work really highlights the importance of looking at antigen-specific B cells,” Dr Pepper said. “These data also suggest that if you’re getting a vaccine while you have an ongoing blood-stage infection, there is a chance that the vaccine will not generate good memory cells because the blood stage disrupts all the processes that are involved in making that immunological memory.”

Dr Pepper and her colleagues are now looking into the possibility of treatment to solve this problem.

The team found that when they treated the second stage of the infection with the anti-malarial drug atovaquone, the B cells were able to create the optimally responsive memory cells.

For now, the researchers hope their work can be used to answer immediate questions about the efficacy of malaria vaccines in regions that are most significantly affected by the disease.

“Malaria has evolved with us throughout human existence and therefore has some potent immune evasion strategies,” Dr Pepper said. “We really tried to tease apart some of the factors that could be driving the loss of protective immunity during natural infection and with current vaccine strategies in areas of high malaria transmission.”

“Our next step is to compare malaria-specific B cells after vaccination or natural infection in humans so we can translate these findings and start to determine how to solve this problem.”

Researchers say they have uncovered one potential reason why it has been difficult to generate protective immunity against the early liver stage of malaria infection in regions where the incidence of malaria is high.

Their research, conducted in mice and published in Cell Reports, suggests that exposure to the blood stage of malaria infection inhibits the formation of the protective immune cells (and their antibodies) that can prevent liver-stage infection.

“The blood stage of malaria infection has a very profound impact on the liver stage immune response, and that impact had never been dissected and visualized at this level,” said study author Marion Pepper, PhD, of the University of Washington School of Medicine in Seattle.

“These studies really suggest that you need a vaccine that is protective against both stages of infection to effectively prevent malaria.”

To track how the blood stage of malaria infection overpowers the liver-stage immune response, Dr Pepper and her colleagues infected 2 groups of mice with different forms of malaria parasites.

One group of mice was infected with Plasmodium yoelii wild-type sporozoites, which complete the pre-erythrocytic stage of infection and establish a blood-stage infection.

The other group was infected with a genetically attenuated Plasmodium yoelii parasite that arrests late in liver stage development and does not cause blood-stage infection.

Six days after infection, the researchers found the levels of antibodies were significantly lower in the mice with the blood stage infection than in mice that only had the parasite targeted to the liver.

To understand this discrepancy, the team tracked the differentiation of Plasmodium liver stage-specific B cells. B cells can differentiate into antibody-secreting early effector cells or long-lived memory cells, both of which contribute to protection against malaria.

The researchers discovered that, 14 days after infection, the B cells in the blood-stage-infected mice never went through the necessary changes to make rapidly responsive memory cells.

However, in the mice that received the liver-stage attenuated version of the parasite, the B cells were still able to differentiate and create the necessary antibodies and memory cells for an effective immune response.

“This work really highlights the importance of looking at antigen-specific B cells,” Dr Pepper said. “These data also suggest that if you’re getting a vaccine while you have an ongoing blood-stage infection, there is a chance that the vaccine will not generate good memory cells because the blood stage disrupts all the processes that are involved in making that immunological memory.”

Dr Pepper and her colleagues are now looking into the possibility of treatment to solve this problem.

The team found that when they treated the second stage of the infection with the anti-malarial drug atovaquone, the B cells were able to create the optimally responsive memory cells.

For now, the researchers hope their work can be used to answer immediate questions about the efficacy of malaria vaccines in regions that are most significantly affected by the disease.

“Malaria has evolved with us throughout human existence and therefore has some potent immune evasion strategies,” Dr Pepper said. “We really tried to tease apart some of the factors that could be driving the loss of protective immunity during natural infection and with current vaccine strategies in areas of high malaria transmission.”

“Our next step is to compare malaria-specific B cells after vaccination or natural infection in humans so we can translate these findings and start to determine how to solve this problem.”

Bendamustine hydrochloride (TREAKISYM®) has been approved in Japan as first-line treatment for patients with low-grade B-cell non-Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL).

The drug will now be available for adjunctive use with rituximab in these patients.

Bendamustine hydrochloride is already approved in Japan as monotherapy for relapsed or refractory low-grade B-cell NHL and MCL, as well as chronic lymphocytic leukemia.

Bendamustine hydrochloride is the subject of a licensing agreement concluded between Eisai Co., Ltd and SymBio Pharmaceuticals Limited. Under the licensing agreement, Eisai has been marketing the product since December 2010.

Bendamustine hydrochloride is available at doses of 25 mg and 100 mg for intravenous infusion. The recommended dosage and administration is as follows:

• For low-grade B-cell NHL and MCL

  • As first-line treatment

    When used adjunctively with rituximab, the usual adult dose of bendamustine hydrochloride is 90 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 28-day cycles.

  • For relapsed or refractory disease

    The usual adult dose of bendamustine hydrochloride is 120 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 21-day cycles.

• For chronic lymphocytic leukemia

  • The usual adult dose of bendamustine hydrochloride is 100 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 28-day cycles.

All of the aforementioned doses may be reduced appropriately according to the patient’s condition. 

Bendamustine hydrochloride (TREAKISYM®) has been approved in Japan as first-line treatment for patients with low-grade B-cell non-Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL).

The drug will now be available for adjunctive use with rituximab in these patients.

Bendamustine hydrochloride is already approved in Japan as monotherapy for relapsed or refractory low-grade B-cell NHL and MCL, as well as chronic lymphocytic leukemia.

Bendamustine hydrochloride is the subject of a licensing agreement concluded between Eisai Co., Ltd and SymBio Pharmaceuticals Limited. Under the licensing agreement, Eisai has been marketing the product since December 2010.

Bendamustine hydrochloride is available at doses of 25 mg and 100 mg for intravenous infusion. The recommended dosage and administration is as follows:

• For low-grade B-cell NHL and MCL

  • As first-line treatment

    When used adjunctively with rituximab, the usual adult dose of bendamustine hydrochloride is 90 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 28-day cycles.

  • For relapsed or refractory disease

    The usual adult dose of bendamustine hydrochloride is 120 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 21-day cycles.

• For chronic lymphocytic leukemia

  • The usual adult dose of bendamustine hydrochloride is 100 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 28-day cycles.

All of the aforementioned doses may be reduced appropriately according to the patient’s condition. 

Bendamustine hydrochloride (TREAKISYM®) has been approved in Japan as first-line treatment for patients with low-grade B-cell non-Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL).

The drug will now be available for adjunctive use with rituximab in these patients.

Bendamustine hydrochloride is already approved in Japan as monotherapy for relapsed or refractory low-grade B-cell NHL and MCL, as well as chronic lymphocytic leukemia.

Bendamustine hydrochloride is the subject of a licensing agreement concluded between Eisai Co., Ltd and SymBio Pharmaceuticals Limited. Under the licensing agreement, Eisai has been marketing the product since December 2010.

Bendamustine hydrochloride is available at doses of 25 mg and 100 mg for intravenous infusion. The recommended dosage and administration is as follows:

• For low-grade B-cell NHL and MCL

  • As first-line treatment

    When used adjunctively with rituximab, the usual adult dose of bendamustine hydrochloride is 90 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 28-day cycles.

  • For relapsed or refractory disease

    The usual adult dose of bendamustine hydrochloride is 120 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 21-day cycles.

• For chronic lymphocytic leukemia

  • The usual adult dose of bendamustine hydrochloride is 100 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 28-day cycles.

All of the aforementioned doses may be reduced appropriately according to the patient’s condition.