Hematology

From the Department of Surgery, Washington University School of Medicine, St. Louis, MO.

Abstract

Background: Patients undergoing colorectal surgery are at high risk for postoperative venous thromboembolism (VTE). Early ambulation has been encouraged to lower rates of VTE, but evidence demonstrating its effectiveness outside of a bundle is limited.

Objective: To create a multidisciplinary ambulation protocol in an effort to reduce postoperative VTE.

Methods: A single-center, retrospective, comparative study of patients who underwent colectomy or proctectomy was conducted. Outcomes of patients operated on prior to protocol implementation were compared with a cohort after implementation. The intervention studied was the implementation of a multidisciplinary ambulation protocol. The primary endpoint was postoperative VTE.

Results: There was no difference between the pre-intervention group (n = 1762) and the postintervention group (n = 253) in terms of sex, race, origin, emergency status, operative time, and the majority of medical comorbidities (with the exception of smoking status and congestive heart failure). After the protocol was implemented, ambulation rates on postoperative days 0, 1, and 2 improved from 36.4%, 47.3%, and 50.2% to 36.8%, 74.7%, and 82.6%, respectively The VTE rate in the pre-intervention group was 2.7% versus a rate of 0.4% in the postintervention group (P = 0.02).

Conclusion: Creation of an ambulation protocol is associated with a significant reduction in VTE. Commitment from patients, families, nurses, physician extenders, and physicians is critical to the success of the program.

Keywords: VTE; pulmonary embolism; deep vein thrombosis; postoperative; quality improvement.

Postoperative venous thromboembolism (VTE) is a significant source of morbidity, mortality, and cost.^1,2 Colorectal surgery patients are at particularly high risk for VTE due to positioning during surgery, pelvic dissection, and other conditions often found in these patients, such as cancer and inflammatory bowel disease.³ A National Surgical Quality Improvement Program (NSQIP) analysis demonstrated an overall rate of VTE in colorectal surgery patients of 2.4%, although other studies have demonstrated rates up to 9%, even in those receiving appropriate chemoprophylaxis.^4-6 Many of these VTEs occur in the postdischarge setting. In a NSQIP study of colorectal surgery patients, the rate of VTE between discharge and 30 days was 0.47%.⁷ The cost burdenfor a postoperative VTE has been estimated to be more than $18,000.⁸

Studies from NSQIP have identified multiple factors associated with VTE in colorectal surgery patients, but NSQIP does not record ambulation as a standard variable.⁹ Multiple strategies have been implemented to reduce postoperative VTE. Often, these studies focus on increasing compliance with appropriate chemoprophylaxis, risk stratification, or bundling multiple strategies.^10,11 However, despite the fact that postsurgical ambulation is widely encouraged and recommended by the American Society of Colon and Rectal Surgeons clinical practice guidelines, there is little evidence demonstrating the role of ambulation alone in the reduction of VTE.^4,12 The purpose of this study was to create a multidisciplinary protocol to increase postoperative ambulation and evaluate its effect on VTE.

Methods

Setting

This study was conducted at a single academic tertiary care center.

Patients and Outcome Measures

All patients undergoing colectomy or proctectomy by surgeons in the section of colon and rectal surgery at a single institution between January 2011 and March 2017 were included. Colectomy and proctectomy were defined by CPT codes 44140, 44141, 44143, 44144, 44145, 44146, 44147, 44150, 44151, 44155, 44156, 44157, 44158, 44160, 44204, 44205, 44206, 44207, 44208, 44210, 44211, 44212, 44213, 45110, 45111, 45112, 45113, 45114, 45116, 45119, 45120, 45121, 45123, 45126, 45160, 45395, and 45397. The primary outcome of VTE within 30 days, including deep venous thrombosis (DVT) and pulmonary embolism (PE), was measured using institution-specific data from NSQIP in both the pre-intervention and postintervention setting. The occurrence of both DVT and PE in 1 patient was counted as a single event of VTE. Ambulation rate on postoperative day (POD) 0, 1, and 2 was calculated by NSQIP in the pre-intervention setting (our institution-specific NSQIP recorded ambulation data for an unrelated project) and by review of the electronic health record in the postintervention setting, as this institution-specific variable was no longer being collected. Ambulation was defined as getting out of bed and taking at least 1 step. The threshold for ambulating each day was once on POD 0 and twice on PODs 1 and 2. Patients with missing ambulation data were excluded from the analysis. Both prior to and throughout the intervention, all patients were given VTE chemoprophylaxis with either low-dose unfractionated heparin or low-molecular-weight heparin prior to induction of anesthesia, with chemoprophylaxis extending an additional 21 days after discharge (unless specifically contraindicated); sequential compression devices; and standard orders to ambulate 3 times daily from POD 0 as part of the standard Enhanced Recovery After Surgery protocol.

Analysis

Statistical analysis was performed using univariate analysis. Chi-square test and univariate logistic regression were used to determine the association between ambulation rates and VTE in the pre-intervention group. Chi-square test was also used to compare ambulation and VTE rates between the pre-intervention and postintervention groups. Plan-Do-Study-Act (PDSA) cycle fidelity (the degree to which a PDSA cycle is carried out in accordance with the guiding principles of its use) was measured by recording the ambulation rates both before and after the intervention.¹³ Statistical analysis was performed using SAS Version 9.4 (SAS Institute, Cary, NC). This study was reviewed by the Washington University School of Medicine Institutional Review Board and deemed to be quality improvement, not human subjects research, and therefore did not require formal approval.

 

 

Baseline Outcome Rates

A total of 1762 patients were identified during the pre-intervention period. The overall VTE rate in the pre-intervention group was 2.7% (n = 48), with 39 DVTs (2.2%) and 13 PEs (0.7%). Pre-intervention ambulation data were available on 590 patients. Baseline ambulation rates on PODs 0, 1, and 2 were 36.4% (213/590), 47.3% (279/590), and 50.2% (296/590), respectively. Patients who did not ambulate on POD 0 had a VTE rate of 4.3%, as compared to 0.9% in those who did ambulate (Table 1). Patients who did not ambulate twice on POD 1 had a VTE rate of 4.8%, compared to 1.1% in those who did ambulate (odds ratio [OR], 4.66; 95% confidence interval [CI], 1.34 to 16.28). Patients who did not ambulate twice on POD 2 had a VTE rate of 5.4%, compared to 0.7% in those who did. Finally, those who ambulated twice on both PODs 1 and 2 had a 0% rate of VTE, compared to 4.9% in those who did not ambulate on both PODs.

Ambulation Protocol

After baseline outcome rates had been established, a multidisciplinary team of medical assistants, nurses, nurse practitioners, and physicians worked together to identify all processes that involved postoperative ambulation. Given the significant differences in VTE rates between patients who ambulated and those that did not, we created a multidisciplinary ambulation protocol using the PDSA method.¹⁴ Multiple points of patient contact were chosen for intervention, and the ambulation protocol was implemented in June 2018 and continued for 7 months.

Patients were observed from their initial office visit with a surgeon, during the preoperative education encounter, and in the operating room and on the surgical ward until discharge. Representatives from multiple disciplines who encountered patients at various times in the process, including medical assistants, patient care technicians, nurses, nurse practitioners, physical therapists, and physicians, participated in a kick-off meeting to identify difficulties they encounter when encouraging patient ambulation. The following 4 areas were identified.

Barriers to Patient Ambulation

Patient Expectations. Patients did not appear to have a clear expectation of what their ambulation goals were postoperatively, despite the fact that each patient is given an operative pathway booklet that includes their goals for each day, including ambulation. The consensus was that patients were overwhelmed with the amount of information and, oftentimes, the severity of their diagnosis, so the information regarding ambulation was not retained. Nurses commented that patients frequently stated that they did not think their surgeon wanted them to get out of bed postoperatively.

Electronic Orders. There was confusion within the nursing staff regarding orders in the electronic health record compared to physician expectations. Orders stated patients should ambulate 3 times daily, but did not specify on which postoperative day this should start. Often, nursing verbal sign-out from the post-anesthesia care unit (PACU) would be an order for bedrest, despite no clear origin of this order. This created confusion among the nursing staff as to what the appropriate ambulation orders should be.

Nursing Workflow. The initial state of the nursing workflow was not conducive to evaluating for, or assisting with, ambulation. With no set time to assist and evaluate patients for ambulation, it turned into a task nurses needed to accomplish when they had extra time. With increasing demands of charting in the electronic health record, nurses often had to skip ambulation in order to accomplish other tasks.

Family Expectations. In addition to patient expectations, family members often had expectations that were not congruent with the planned postoperative course. Nurses stated family members would often tell them that they did not feel that their family member should be ambulating so soon after surgery. Often these family members had not attended preoperative education sessions with the patient. This was compounded by the uncertainty among the nursing staff regarding what exactly the ambulation orders were.

Interventions

Targeted interventions were created to address these 4 barriers to ambulation identified by staff.

Preoperative Education. Although all elective patients received a printed operative pathway booklet describing daily goals, including ambulation, patients still did not have a sufficient understanding of what was expected of them. The education session was modified to increase the time spent on both the expectation for and the rationale behind ambulation. That section of the education session ended with a verbal commitment and read-back of the expectations for ambulation by the patient.

Clarification of Electronic Orders. Postoperative orders within the colorectal standard pathway were changed, including specific time frames and frequency, to match the information provided in the patient education booklet. These orders were for ambulation within 4 hours of arrival to the floor, and the orders also noted that no patient should be on bedrest unless explicitly stated. From POD 1, all patients were to ambulate at least twice daily for the remainder of the hospital stay (patients were encouraged to walk 4 times daily, but we set a minimum expectation of twice daily for the order set). These orders were clarified with in-person meetings with the nursing staff and leadership from the PACU and the colorectal surgical ward.

Adjusted Nursing Workflow. Nurses were interviewed and asked to create a plan regarding how they could better incorporate ambulation into their daily workflow. Ambulation assessment was incorporated into the twice-per-shift recording of vital signs and patient safety assessment. This was recorded into the electronic health record at the same time as the patients’ vital signs. This allowed nurses to keep track of which patients would need extra assistance in ambulation and which patients were doing well on their own with the assistance of family. It also helped focus the resources of physical therapy and the single ambulation technician on the floor and to assist patients who needed more assistance.

Creation of Ambulation Encouragement Signs. The authors discovered that despite patients being told preoperatively about ambulation expectations, friends and family are not always included in these conversations. As nurses frequently cited both patients and family as reasons patients thought they should not walk, multiple signs inviting patients to take an active role in their recovery by ambulating were created and placed around the unit. The signs outlined the expectations of being out of bed and taking at least 1 step on the day of surgery and walking at least 4 times per day thereafter. In addition, we addressed frequently asked questions around issues such as walking with intravenous poles and urinary catheters. The posters were signed by all staff colorectal surgeons.

Results

Over the course of 7 months (June 2018 to December 2018), 253 postintervention patients were identified (Table 2). There was no difference between the pre-intervention group (n = 1762) and the postintervention group in terms of sex, race, origin, emergency status, operative time, and the majority of medical comorbidities (with the exception of smoking status and congestive heart failure). The postintervention group was slightly older (60 versus 57 years) and had a higher percentage of patients with an American Society of Anesthesiologists physical status score greater than 2 (66.8% versus 51.2%). The postintervention group also had higher rates of both malignancy (53.4% versus 33.3%) and inflammatory bowel disease (18.2% versus 14.4%).

The fidelity of the PDSA cycle was measured by pre-intervention and postintervention ambulation rates. Ambulation rates on POD 0, 1, and 2 improved from 36.4%, 47.3%, and 50.2% to 36.8%, 74.7%, and 82.6%, respectively (Table 3). The VTE rate decreased from 2.7% to 0.4% (P = 0.02), with 1 DVT and 0 PEs. It should be noted that the only patient who developed a VTE postintervention did not ambulate on PODs 0, 1, or 2.

Discussion

Postoperative VTE is a severe complication for postoperative colorectal surgery patients. Previous studies have demonstrated that increasing ambulation is associated with a lower rate of overall complications, and, when incorporated into a bundle, is associated with decreased rates of VTE.^11,15 However, this is the first study to our knowledge demonstrating that creation of an ambulation protocol alone is associated with a decrease in VTE.

Analysis of pre-intervention data demonstrated a strong association between ambulation and an absence of VTE. No patient who ambulated on PODs 0, 1, and 2 developed a VTE. Based on those results, we moved forward with creating the ambulation protocol. While ambulation stayed stable on POD 0, there were 60% and 65% increases on PODs 1 and 2, respectively. Nurses cited late arrival to the floor for second and third start cases as the primary difficulty in getting patients to ambulate more on POD 0.

We believe the key to the success of the ambulation protocol was its multidisciplinary nature. Certainly, the easiest way to create an ambulation protocol is to change the postoperative orders to state patients must walk 4 times per day. However, if the nursing staff is unable or unwilling to carry out these orders, the orders serve little purpose. In order to make lasting changes, all stakeholders in the process must be identified. In our case, stakeholders included surgery and nursing leadership, surgeons, nurse practitioners, nurses, medical assistants, physical therapists, patient care technicians, and patients. This is where we utilized kaizen, a core principle of Lean methodology that empowers employees at the level of the work being carried out to propose ideas for improvement.¹⁶ From the beginning of the patient experience, the health care practitioners who were carrying out each step of the process were best able to identify the problems and create solutions. In addition, stakeholders were given regular updates regarding how their efforts were increasing ambulation rates and the results at the end of the study period.

This study also demonstrates that, in a health care system increasingly focused on both quality and cost, significant improvements in quality can be made without increasing cost or resource utilization. Early in the process, it was proposed that the only way to increase the ambulation rate would be to increase the number of physical therapists, nurses, and nursing assistants. However, after identifying the root causes of the problem, the solutions had more to do with improving workflow and fixing problem areas identified by the staff.

In addition to having a positive effect on the outcome studied, collaborative projects such as this between physicians and nurses may lead to increased nursing job satisfaction. A meta-analysis of 31 studies identified nurse-physician collaboration and autonomy as 2 factors that correlate most strongly with nursing satisfaction.¹⁷ A Cochrane review also suggests that practice-based interprofessional collaboration may lead to improved health care processes and outcomes.¹⁸

This study has several limitations. Pre-intervention ambulation rates were abstracted from institution-specific NSQIP data, and missing data were excluded from analysis. Also, due to the retrospective collection of the pre-intervention data, the distance of ambulation could not be quantified. The bar for ambulation is low, as patients were only required to get out of bed and walk 1 step. However, we feel that getting out of bed and taking even 1 step is substantially better than complete bedrest. It is likely that once patients cross the threshold of taking 1 step, they are more likely to ambulate. An area of future study may be to more precisely define the relationship between the quantity of ambulation in steps and its effect on VTE. Finally, we acknowledge that while there is no direct increase in costs, implementing an ambulation protocol does take time from all who participate in the project.

Conclusion

Creation of an ambulation protocol is associated with a decrease in postoperative VTE rates in colorectal surgery patients. A multidisciplinary approach is critical to identify the underlying problems and propose effective solutions. Further studies are required to better correlate the distance of ambulation and its effect on VTE. However, this study shows that even a minimum of 1 step is associated with decreased VTE rates.

Corresponding author: Aneel Damle, MD, MBA, Colon & Rectal Surgery Associates, 3433 Broadway St. NE, Suite 115, Minneapolis, MN 55413; adamle@CRSAL.org.

Financial disclosures: None.

From the Department of Surgery, Washington University School of Medicine, St. Louis, MO.

Abstract

Background: Patients undergoing colorectal surgery are at high risk for postoperative venous thromboembolism (VTE). Early ambulation has been encouraged to lower rates of VTE, but evidence demonstrating its effectiveness outside of a bundle is limited.

Objective: To create a multidisciplinary ambulation protocol in an effort to reduce postoperative VTE.

Methods: A single-center, retrospective, comparative study of patients who underwent colectomy or proctectomy was conducted. Outcomes of patients operated on prior to protocol implementation were compared with a cohort after implementation. The intervention studied was the implementation of a multidisciplinary ambulation protocol. The primary endpoint was postoperative VTE.

Results: There was no difference between the pre-intervention group (n = 1762) and the postintervention group (n = 253) in terms of sex, race, origin, emergency status, operative time, and the majority of medical comorbidities (with the exception of smoking status and congestive heart failure). After the protocol was implemented, ambulation rates on postoperative days 0, 1, and 2 improved from 36.4%, 47.3%, and 50.2% to 36.8%, 74.7%, and 82.6%, respectively The VTE rate in the pre-intervention group was 2.7% versus a rate of 0.4% in the postintervention group (P = 0.02).

Conclusion: Creation of an ambulation protocol is associated with a significant reduction in VTE. Commitment from patients, families, nurses, physician extenders, and physicians is critical to the success of the program.

Keywords: VTE; pulmonary embolism; deep vein thrombosis; postoperative; quality improvement.

Postoperative venous thromboembolism (VTE) is a significant source of morbidity, mortality, and cost.^1,2 Colorectal surgery patients are at particularly high risk for VTE due to positioning during surgery, pelvic dissection, and other conditions often found in these patients, such as cancer and inflammatory bowel disease.³ A National Surgical Quality Improvement Program (NSQIP) analysis demonstrated an overall rate of VTE in colorectal surgery patients of 2.4%, although other studies have demonstrated rates up to 9%, even in those receiving appropriate chemoprophylaxis.^4-6 Many of these VTEs occur in the postdischarge setting. In a NSQIP study of colorectal surgery patients, the rate of VTE between discharge and 30 days was 0.47%.⁷ The cost burdenfor a postoperative VTE has been estimated to be more than $18,000.⁸

Studies from NSQIP have identified multiple factors associated with VTE in colorectal surgery patients, but NSQIP does not record ambulation as a standard variable.⁹ Multiple strategies have been implemented to reduce postoperative VTE. Often, these studies focus on increasing compliance with appropriate chemoprophylaxis, risk stratification, or bundling multiple strategies.^10,11 However, despite the fact that postsurgical ambulation is widely encouraged and recommended by the American Society of Colon and Rectal Surgeons clinical practice guidelines, there is little evidence demonstrating the role of ambulation alone in the reduction of VTE.^4,12 The purpose of this study was to create a multidisciplinary protocol to increase postoperative ambulation and evaluate its effect on VTE.

Methods

Setting

This study was conducted at a single academic tertiary care center.

Patients and Outcome Measures

All patients undergoing colectomy or proctectomy by surgeons in the section of colon and rectal surgery at a single institution between January 2011 and March 2017 were included. Colectomy and proctectomy were defined by CPT codes 44140, 44141, 44143, 44144, 44145, 44146, 44147, 44150, 44151, 44155, 44156, 44157, 44158, 44160, 44204, 44205, 44206, 44207, 44208, 44210, 44211, 44212, 44213, 45110, 45111, 45112, 45113, 45114, 45116, 45119, 45120, 45121, 45123, 45126, 45160, 45395, and 45397. The primary outcome of VTE within 30 days, including deep venous thrombosis (DVT) and pulmonary embolism (PE), was measured using institution-specific data from NSQIP in both the pre-intervention and postintervention setting. The occurrence of both DVT and PE in 1 patient was counted as a single event of VTE. Ambulation rate on postoperative day (POD) 0, 1, and 2 was calculated by NSQIP in the pre-intervention setting (our institution-specific NSQIP recorded ambulation data for an unrelated project) and by review of the electronic health record in the postintervention setting, as this institution-specific variable was no longer being collected. Ambulation was defined as getting out of bed and taking at least 1 step. The threshold for ambulating each day was once on POD 0 and twice on PODs 1 and 2. Patients with missing ambulation data were excluded from the analysis. Both prior to and throughout the intervention, all patients were given VTE chemoprophylaxis with either low-dose unfractionated heparin or low-molecular-weight heparin prior to induction of anesthesia, with chemoprophylaxis extending an additional 21 days after discharge (unless specifically contraindicated); sequential compression devices; and standard orders to ambulate 3 times daily from POD 0 as part of the standard Enhanced Recovery After Surgery protocol.

Analysis

Statistical analysis was performed using univariate analysis. Chi-square test and univariate logistic regression were used to determine the association between ambulation rates and VTE in the pre-intervention group. Chi-square test was also used to compare ambulation and VTE rates between the pre-intervention and postintervention groups. Plan-Do-Study-Act (PDSA) cycle fidelity (the degree to which a PDSA cycle is carried out in accordance with the guiding principles of its use) was measured by recording the ambulation rates both before and after the intervention.¹³ Statistical analysis was performed using SAS Version 9.4 (SAS Institute, Cary, NC). This study was reviewed by the Washington University School of Medicine Institutional Review Board and deemed to be quality improvement, not human subjects research, and therefore did not require formal approval.

 

 

Baseline Outcome Rates

A total of 1762 patients were identified during the pre-intervention period. The overall VTE rate in the pre-intervention group was 2.7% (n = 48), with 39 DVTs (2.2%) and 13 PEs (0.7%). Pre-intervention ambulation data were available on 590 patients. Baseline ambulation rates on PODs 0, 1, and 2 were 36.4% (213/590), 47.3% (279/590), and 50.2% (296/590), respectively. Patients who did not ambulate on POD 0 had a VTE rate of 4.3%, as compared to 0.9% in those who did ambulate (Table 1). Patients who did not ambulate twice on POD 1 had a VTE rate of 4.8%, compared to 1.1% in those who did ambulate (odds ratio [OR], 4.66; 95% confidence interval [CI], 1.34 to 16.28). Patients who did not ambulate twice on POD 2 had a VTE rate of 5.4%, compared to 0.7% in those who did. Finally, those who ambulated twice on both PODs 1 and 2 had a 0% rate of VTE, compared to 4.9% in those who did not ambulate on both PODs.

Ambulation Protocol

After baseline outcome rates had been established, a multidisciplinary team of medical assistants, nurses, nurse practitioners, and physicians worked together to identify all processes that involved postoperative ambulation. Given the significant differences in VTE rates between patients who ambulated and those that did not, we created a multidisciplinary ambulation protocol using the PDSA method.¹⁴ Multiple points of patient contact were chosen for intervention, and the ambulation protocol was implemented in June 2018 and continued for 7 months.

Patients were observed from their initial office visit with a surgeon, during the preoperative education encounter, and in the operating room and on the surgical ward until discharge. Representatives from multiple disciplines who encountered patients at various times in the process, including medical assistants, patient care technicians, nurses, nurse practitioners, physical therapists, and physicians, participated in a kick-off meeting to identify difficulties they encounter when encouraging patient ambulation. The following 4 areas were identified.

Barriers to Patient Ambulation

Patient Expectations. Patients did not appear to have a clear expectation of what their ambulation goals were postoperatively, despite the fact that each patient is given an operative pathway booklet that includes their goals for each day, including ambulation. The consensus was that patients were overwhelmed with the amount of information and, oftentimes, the severity of their diagnosis, so the information regarding ambulation was not retained. Nurses commented that patients frequently stated that they did not think their surgeon wanted them to get out of bed postoperatively.

Electronic Orders. There was confusion within the nursing staff regarding orders in the electronic health record compared to physician expectations. Orders stated patients should ambulate 3 times daily, but did not specify on which postoperative day this should start. Often, nursing verbal sign-out from the post-anesthesia care unit (PACU) would be an order for bedrest, despite no clear origin of this order. This created confusion among the nursing staff as to what the appropriate ambulation orders should be.

Nursing Workflow. The initial state of the nursing workflow was not conducive to evaluating for, or assisting with, ambulation. With no set time to assist and evaluate patients for ambulation, it turned into a task nurses needed to accomplish when they had extra time. With increasing demands of charting in the electronic health record, nurses often had to skip ambulation in order to accomplish other tasks.

Family Expectations. In addition to patient expectations, family members often had expectations that were not congruent with the planned postoperative course. Nurses stated family members would often tell them that they did not feel that their family member should be ambulating so soon after surgery. Often these family members had not attended preoperative education sessions with the patient. This was compounded by the uncertainty among the nursing staff regarding what exactly the ambulation orders were.

Interventions

Targeted interventions were created to address these 4 barriers to ambulation identified by staff.

Preoperative Education. Although all elective patients received a printed operative pathway booklet describing daily goals, including ambulation, patients still did not have a sufficient understanding of what was expected of them. The education session was modified to increase the time spent on both the expectation for and the rationale behind ambulation. That section of the education session ended with a verbal commitment and read-back of the expectations for ambulation by the patient.

Clarification of Electronic Orders. Postoperative orders within the colorectal standard pathway were changed, including specific time frames and frequency, to match the information provided in the patient education booklet. These orders were for ambulation within 4 hours of arrival to the floor, and the orders also noted that no patient should be on bedrest unless explicitly stated. From POD 1, all patients were to ambulate at least twice daily for the remainder of the hospital stay (patients were encouraged to walk 4 times daily, but we set a minimum expectation of twice daily for the order set). These orders were clarified with in-person meetings with the nursing staff and leadership from the PACU and the colorectal surgical ward.

Adjusted Nursing Workflow. Nurses were interviewed and asked to create a plan regarding how they could better incorporate ambulation into their daily workflow. Ambulation assessment was incorporated into the twice-per-shift recording of vital signs and patient safety assessment. This was recorded into the electronic health record at the same time as the patients’ vital signs. This allowed nurses to keep track of which patients would need extra assistance in ambulation and which patients were doing well on their own with the assistance of family. It also helped focus the resources of physical therapy and the single ambulation technician on the floor and to assist patients who needed more assistance.

Creation of Ambulation Encouragement Signs. The authors discovered that despite patients being told preoperatively about ambulation expectations, friends and family are not always included in these conversations. As nurses frequently cited both patients and family as reasons patients thought they should not walk, multiple signs inviting patients to take an active role in their recovery by ambulating were created and placed around the unit. The signs outlined the expectations of being out of bed and taking at least 1 step on the day of surgery and walking at least 4 times per day thereafter. In addition, we addressed frequently asked questions around issues such as walking with intravenous poles and urinary catheters. The posters were signed by all staff colorectal surgeons.

Results

Over the course of 7 months (June 2018 to December 2018), 253 postintervention patients were identified (Table 2). There was no difference between the pre-intervention group (n = 1762) and the postintervention group in terms of sex, race, origin, emergency status, operative time, and the majority of medical comorbidities (with the exception of smoking status and congestive heart failure). The postintervention group was slightly older (60 versus 57 years) and had a higher percentage of patients with an American Society of Anesthesiologists physical status score greater than 2 (66.8% versus 51.2%). The postintervention group also had higher rates of both malignancy (53.4% versus 33.3%) and inflammatory bowel disease (18.2% versus 14.4%).

The fidelity of the PDSA cycle was measured by pre-intervention and postintervention ambulation rates. Ambulation rates on POD 0, 1, and 2 improved from 36.4%, 47.3%, and 50.2% to 36.8%, 74.7%, and 82.6%, respectively (Table 3). The VTE rate decreased from 2.7% to 0.4% (P = 0.02), with 1 DVT and 0 PEs. It should be noted that the only patient who developed a VTE postintervention did not ambulate on PODs 0, 1, or 2.

Discussion

Postoperative VTE is a severe complication for postoperative colorectal surgery patients. Previous studies have demonstrated that increasing ambulation is associated with a lower rate of overall complications, and, when incorporated into a bundle, is associated with decreased rates of VTE.^11,15 However, this is the first study to our knowledge demonstrating that creation of an ambulation protocol alone is associated with a decrease in VTE.

Analysis of pre-intervention data demonstrated a strong association between ambulation and an absence of VTE. No patient who ambulated on PODs 0, 1, and 2 developed a VTE. Based on those results, we moved forward with creating the ambulation protocol. While ambulation stayed stable on POD 0, there were 60% and 65% increases on PODs 1 and 2, respectively. Nurses cited late arrival to the floor for second and third start cases as the primary difficulty in getting patients to ambulate more on POD 0.

We believe the key to the success of the ambulation protocol was its multidisciplinary nature. Certainly, the easiest way to create an ambulation protocol is to change the postoperative orders to state patients must walk 4 times per day. However, if the nursing staff is unable or unwilling to carry out these orders, the orders serve little purpose. In order to make lasting changes, all stakeholders in the process must be identified. In our case, stakeholders included surgery and nursing leadership, surgeons, nurse practitioners, nurses, medical assistants, physical therapists, patient care technicians, and patients. This is where we utilized kaizen, a core principle of Lean methodology that empowers employees at the level of the work being carried out to propose ideas for improvement.¹⁶ From the beginning of the patient experience, the health care practitioners who were carrying out each step of the process were best able to identify the problems and create solutions. In addition, stakeholders were given regular updates regarding how their efforts were increasing ambulation rates and the results at the end of the study period.

This study also demonstrates that, in a health care system increasingly focused on both quality and cost, significant improvements in quality can be made without increasing cost or resource utilization. Early in the process, it was proposed that the only way to increase the ambulation rate would be to increase the number of physical therapists, nurses, and nursing assistants. However, after identifying the root causes of the problem, the solutions had more to do with improving workflow and fixing problem areas identified by the staff.

In addition to having a positive effect on the outcome studied, collaborative projects such as this between physicians and nurses may lead to increased nursing job satisfaction. A meta-analysis of 31 studies identified nurse-physician collaboration and autonomy as 2 factors that correlate most strongly with nursing satisfaction.¹⁷ A Cochrane review also suggests that practice-based interprofessional collaboration may lead to improved health care processes and outcomes.¹⁸

This study has several limitations. Pre-intervention ambulation rates were abstracted from institution-specific NSQIP data, and missing data were excluded from analysis. Also, due to the retrospective collection of the pre-intervention data, the distance of ambulation could not be quantified. The bar for ambulation is low, as patients were only required to get out of bed and walk 1 step. However, we feel that getting out of bed and taking even 1 step is substantially better than complete bedrest. It is likely that once patients cross the threshold of taking 1 step, they are more likely to ambulate. An area of future study may be to more precisely define the relationship between the quantity of ambulation in steps and its effect on VTE. Finally, we acknowledge that while there is no direct increase in costs, implementing an ambulation protocol does take time from all who participate in the project.

Conclusion

Creation of an ambulation protocol is associated with a decrease in postoperative VTE rates in colorectal surgery patients. A multidisciplinary approach is critical to identify the underlying problems and propose effective solutions. Further studies are required to better correlate the distance of ambulation and its effect on VTE. However, this study shows that even a minimum of 1 step is associated with decreased VTE rates.

Corresponding author: Aneel Damle, MD, MBA, Colon & Rectal Surgery Associates, 3433 Broadway St. NE, Suite 115, Minneapolis, MN 55413; adamle@CRSAL.org.

Financial disclosures: None.

From the Department of Surgery, Washington University School of Medicine, St. Louis, MO.

Abstract

Background: Patients undergoing colorectal surgery are at high risk for postoperative venous thromboembolism (VTE). Early ambulation has been encouraged to lower rates of VTE, but evidence demonstrating its effectiveness outside of a bundle is limited.

Objective: To create a multidisciplinary ambulation protocol in an effort to reduce postoperative VTE.

Methods: A single-center, retrospective, comparative study of patients who underwent colectomy or proctectomy was conducted. Outcomes of patients operated on prior to protocol implementation were compared with a cohort after implementation. The intervention studied was the implementation of a multidisciplinary ambulation protocol. The primary endpoint was postoperative VTE.

Results: There was no difference between the pre-intervention group (n = 1762) and the postintervention group (n = 253) in terms of sex, race, origin, emergency status, operative time, and the majority of medical comorbidities (with the exception of smoking status and congestive heart failure). After the protocol was implemented, ambulation rates on postoperative days 0, 1, and 2 improved from 36.4%, 47.3%, and 50.2% to 36.8%, 74.7%, and 82.6%, respectively The VTE rate in the pre-intervention group was 2.7% versus a rate of 0.4% in the postintervention group (P = 0.02).

Conclusion: Creation of an ambulation protocol is associated with a significant reduction in VTE. Commitment from patients, families, nurses, physician extenders, and physicians is critical to the success of the program.

Keywords: VTE; pulmonary embolism; deep vein thrombosis; postoperative; quality improvement.

Postoperative venous thromboembolism (VTE) is a significant source of morbidity, mortality, and cost.^1,2 Colorectal surgery patients are at particularly high risk for VTE due to positioning during surgery, pelvic dissection, and other conditions often found in these patients, such as cancer and inflammatory bowel disease.³ A National Surgical Quality Improvement Program (NSQIP) analysis demonstrated an overall rate of VTE in colorectal surgery patients of 2.4%, although other studies have demonstrated rates up to 9%, even in those receiving appropriate chemoprophylaxis.^4-6 Many of these VTEs occur in the postdischarge setting. In a NSQIP study of colorectal surgery patients, the rate of VTE between discharge and 30 days was 0.47%.⁷ The cost burdenfor a postoperative VTE has been estimated to be more than $18,000.⁸

Studies from NSQIP have identified multiple factors associated with VTE in colorectal surgery patients, but NSQIP does not record ambulation as a standard variable.⁹ Multiple strategies have been implemented to reduce postoperative VTE. Often, these studies focus on increasing compliance with appropriate chemoprophylaxis, risk stratification, or bundling multiple strategies.^10,11 However, despite the fact that postsurgical ambulation is widely encouraged and recommended by the American Society of Colon and Rectal Surgeons clinical practice guidelines, there is little evidence demonstrating the role of ambulation alone in the reduction of VTE.^4,12 The purpose of this study was to create a multidisciplinary protocol to increase postoperative ambulation and evaluate its effect on VTE.

Methods

Setting

This study was conducted at a single academic tertiary care center.

Patients and Outcome Measures

All patients undergoing colectomy or proctectomy by surgeons in the section of colon and rectal surgery at a single institution between January 2011 and March 2017 were included. Colectomy and proctectomy were defined by CPT codes 44140, 44141, 44143, 44144, 44145, 44146, 44147, 44150, 44151, 44155, 44156, 44157, 44158, 44160, 44204, 44205, 44206, 44207, 44208, 44210, 44211, 44212, 44213, 45110, 45111, 45112, 45113, 45114, 45116, 45119, 45120, 45121, 45123, 45126, 45160, 45395, and 45397. The primary outcome of VTE within 30 days, including deep venous thrombosis (DVT) and pulmonary embolism (PE), was measured using institution-specific data from NSQIP in both the pre-intervention and postintervention setting. The occurrence of both DVT and PE in 1 patient was counted as a single event of VTE. Ambulation rate on postoperative day (POD) 0, 1, and 2 was calculated by NSQIP in the pre-intervention setting (our institution-specific NSQIP recorded ambulation data for an unrelated project) and by review of the electronic health record in the postintervention setting, as this institution-specific variable was no longer being collected. Ambulation was defined as getting out of bed and taking at least 1 step. The threshold for ambulating each day was once on POD 0 and twice on PODs 1 and 2. Patients with missing ambulation data were excluded from the analysis. Both prior to and throughout the intervention, all patients were given VTE chemoprophylaxis with either low-dose unfractionated heparin or low-molecular-weight heparin prior to induction of anesthesia, with chemoprophylaxis extending an additional 21 days after discharge (unless specifically contraindicated); sequential compression devices; and standard orders to ambulate 3 times daily from POD 0 as part of the standard Enhanced Recovery After Surgery protocol.

Analysis

Statistical analysis was performed using univariate analysis. Chi-square test and univariate logistic regression were used to determine the association between ambulation rates and VTE in the pre-intervention group. Chi-square test was also used to compare ambulation and VTE rates between the pre-intervention and postintervention groups. Plan-Do-Study-Act (PDSA) cycle fidelity (the degree to which a PDSA cycle is carried out in accordance with the guiding principles of its use) was measured by recording the ambulation rates both before and after the intervention.¹³ Statistical analysis was performed using SAS Version 9.4 (SAS Institute, Cary, NC). This study was reviewed by the Washington University School of Medicine Institutional Review Board and deemed to be quality improvement, not human subjects research, and therefore did not require formal approval.

 

 

Baseline Outcome Rates

A total of 1762 patients were identified during the pre-intervention period. The overall VTE rate in the pre-intervention group was 2.7% (n = 48), with 39 DVTs (2.2%) and 13 PEs (0.7%). Pre-intervention ambulation data were available on 590 patients. Baseline ambulation rates on PODs 0, 1, and 2 were 36.4% (213/590), 47.3% (279/590), and 50.2% (296/590), respectively. Patients who did not ambulate on POD 0 had a VTE rate of 4.3%, as compared to 0.9% in those who did ambulate (Table 1). Patients who did not ambulate twice on POD 1 had a VTE rate of 4.8%, compared to 1.1% in those who did ambulate (odds ratio [OR], 4.66; 95% confidence interval [CI], 1.34 to 16.28). Patients who did not ambulate twice on POD 2 had a VTE rate of 5.4%, compared to 0.7% in those who did. Finally, those who ambulated twice on both PODs 1 and 2 had a 0% rate of VTE, compared to 4.9% in those who did not ambulate on both PODs.

Ambulation Protocol

After baseline outcome rates had been established, a multidisciplinary team of medical assistants, nurses, nurse practitioners, and physicians worked together to identify all processes that involved postoperative ambulation. Given the significant differences in VTE rates between patients who ambulated and those that did not, we created a multidisciplinary ambulation protocol using the PDSA method.¹⁴ Multiple points of patient contact were chosen for intervention, and the ambulation protocol was implemented in June 2018 and continued for 7 months.

Patients were observed from their initial office visit with a surgeon, during the preoperative education encounter, and in the operating room and on the surgical ward until discharge. Representatives from multiple disciplines who encountered patients at various times in the process, including medical assistants, patient care technicians, nurses, nurse practitioners, physical therapists, and physicians, participated in a kick-off meeting to identify difficulties they encounter when encouraging patient ambulation. The following 4 areas were identified.

Barriers to Patient Ambulation

Patient Expectations. Patients did not appear to have a clear expectation of what their ambulation goals were postoperatively, despite the fact that each patient is given an operative pathway booklet that includes their goals for each day, including ambulation. The consensus was that patients were overwhelmed with the amount of information and, oftentimes, the severity of their diagnosis, so the information regarding ambulation was not retained. Nurses commented that patients frequently stated that they did not think their surgeon wanted them to get out of bed postoperatively.

Electronic Orders. There was confusion within the nursing staff regarding orders in the electronic health record compared to physician expectations. Orders stated patients should ambulate 3 times daily, but did not specify on which postoperative day this should start. Often, nursing verbal sign-out from the post-anesthesia care unit (PACU) would be an order for bedrest, despite no clear origin of this order. This created confusion among the nursing staff as to what the appropriate ambulation orders should be.

Nursing Workflow. The initial state of the nursing workflow was not conducive to evaluating for, or assisting with, ambulation. With no set time to assist and evaluate patients for ambulation, it turned into a task nurses needed to accomplish when they had extra time. With increasing demands of charting in the electronic health record, nurses often had to skip ambulation in order to accomplish other tasks.

Family Expectations. In addition to patient expectations, family members often had expectations that were not congruent with the planned postoperative course. Nurses stated family members would often tell them that they did not feel that their family member should be ambulating so soon after surgery. Often these family members had not attended preoperative education sessions with the patient. This was compounded by the uncertainty among the nursing staff regarding what exactly the ambulation orders were.

Interventions

Targeted interventions were created to address these 4 barriers to ambulation identified by staff.

Preoperative Education. Although all elective patients received a printed operative pathway booklet describing daily goals, including ambulation, patients still did not have a sufficient understanding of what was expected of them. The education session was modified to increase the time spent on both the expectation for and the rationale behind ambulation. That section of the education session ended with a verbal commitment and read-back of the expectations for ambulation by the patient.

Clarification of Electronic Orders. Postoperative orders within the colorectal standard pathway were changed, including specific time frames and frequency, to match the information provided in the patient education booklet. These orders were for ambulation within 4 hours of arrival to the floor, and the orders also noted that no patient should be on bedrest unless explicitly stated. From POD 1, all patients were to ambulate at least twice daily for the remainder of the hospital stay (patients were encouraged to walk 4 times daily, but we set a minimum expectation of twice daily for the order set). These orders were clarified with in-person meetings with the nursing staff and leadership from the PACU and the colorectal surgical ward.

Adjusted Nursing Workflow. Nurses were interviewed and asked to create a plan regarding how they could better incorporate ambulation into their daily workflow. Ambulation assessment was incorporated into the twice-per-shift recording of vital signs and patient safety assessment. This was recorded into the electronic health record at the same time as the patients’ vital signs. This allowed nurses to keep track of which patients would need extra assistance in ambulation and which patients were doing well on their own with the assistance of family. It also helped focus the resources of physical therapy and the single ambulation technician on the floor and to assist patients who needed more assistance.

Creation of Ambulation Encouragement Signs. The authors discovered that despite patients being told preoperatively about ambulation expectations, friends and family are not always included in these conversations. As nurses frequently cited both patients and family as reasons patients thought they should not walk, multiple signs inviting patients to take an active role in their recovery by ambulating were created and placed around the unit. The signs outlined the expectations of being out of bed and taking at least 1 step on the day of surgery and walking at least 4 times per day thereafter. In addition, we addressed frequently asked questions around issues such as walking with intravenous poles and urinary catheters. The posters were signed by all staff colorectal surgeons.

Results

Over the course of 7 months (June 2018 to December 2018), 253 postintervention patients were identified (Table 2). There was no difference between the pre-intervention group (n = 1762) and the postintervention group in terms of sex, race, origin, emergency status, operative time, and the majority of medical comorbidities (with the exception of smoking status and congestive heart failure). The postintervention group was slightly older (60 versus 57 years) and had a higher percentage of patients with an American Society of Anesthesiologists physical status score greater than 2 (66.8% versus 51.2%). The postintervention group also had higher rates of both malignancy (53.4% versus 33.3%) and inflammatory bowel disease (18.2% versus 14.4%).

The fidelity of the PDSA cycle was measured by pre-intervention and postintervention ambulation rates. Ambulation rates on POD 0, 1, and 2 improved from 36.4%, 47.3%, and 50.2% to 36.8%, 74.7%, and 82.6%, respectively (Table 3). The VTE rate decreased from 2.7% to 0.4% (P = 0.02), with 1 DVT and 0 PEs. It should be noted that the only patient who developed a VTE postintervention did not ambulate on PODs 0, 1, or 2.

Discussion

Postoperative VTE is a severe complication for postoperative colorectal surgery patients. Previous studies have demonstrated that increasing ambulation is associated with a lower rate of overall complications, and, when incorporated into a bundle, is associated with decreased rates of VTE.^11,15 However, this is the first study to our knowledge demonstrating that creation of an ambulation protocol alone is associated with a decrease in VTE.

Analysis of pre-intervention data demonstrated a strong association between ambulation and an absence of VTE. No patient who ambulated on PODs 0, 1, and 2 developed a VTE. Based on those results, we moved forward with creating the ambulation protocol. While ambulation stayed stable on POD 0, there were 60% and 65% increases on PODs 1 and 2, respectively. Nurses cited late arrival to the floor for second and third start cases as the primary difficulty in getting patients to ambulate more on POD 0.

We believe the key to the success of the ambulation protocol was its multidisciplinary nature. Certainly, the easiest way to create an ambulation protocol is to change the postoperative orders to state patients must walk 4 times per day. However, if the nursing staff is unable or unwilling to carry out these orders, the orders serve little purpose. In order to make lasting changes, all stakeholders in the process must be identified. In our case, stakeholders included surgery and nursing leadership, surgeons, nurse practitioners, nurses, medical assistants, physical therapists, patient care technicians, and patients. This is where we utilized kaizen, a core principle of Lean methodology that empowers employees at the level of the work being carried out to propose ideas for improvement.¹⁶ From the beginning of the patient experience, the health care practitioners who were carrying out each step of the process were best able to identify the problems and create solutions. In addition, stakeholders were given regular updates regarding how their efforts were increasing ambulation rates and the results at the end of the study period.

This study also demonstrates that, in a health care system increasingly focused on both quality and cost, significant improvements in quality can be made without increasing cost or resource utilization. Early in the process, it was proposed that the only way to increase the ambulation rate would be to increase the number of physical therapists, nurses, and nursing assistants. However, after identifying the root causes of the problem, the solutions had more to do with improving workflow and fixing problem areas identified by the staff.

In addition to having a positive effect on the outcome studied, collaborative projects such as this between physicians and nurses may lead to increased nursing job satisfaction. A meta-analysis of 31 studies identified nurse-physician collaboration and autonomy as 2 factors that correlate most strongly with nursing satisfaction.¹⁷ A Cochrane review also suggests that practice-based interprofessional collaboration may lead to improved health care processes and outcomes.¹⁸

This study has several limitations. Pre-intervention ambulation rates were abstracted from institution-specific NSQIP data, and missing data were excluded from analysis. Also, due to the retrospective collection of the pre-intervention data, the distance of ambulation could not be quantified. The bar for ambulation is low, as patients were only required to get out of bed and walk 1 step. However, we feel that getting out of bed and taking even 1 step is substantially better than complete bedrest. It is likely that once patients cross the threshold of taking 1 step, they are more likely to ambulate. An area of future study may be to more precisely define the relationship between the quantity of ambulation in steps and its effect on VTE. Finally, we acknowledge that while there is no direct increase in costs, implementing an ambulation protocol does take time from all who participate in the project.

Conclusion

Creation of an ambulation protocol is associated with a decrease in postoperative VTE rates in colorectal surgery patients. A multidisciplinary approach is critical to identify the underlying problems and propose effective solutions. Further studies are required to better correlate the distance of ambulation and its effect on VTE. However, this study shows that even a minimum of 1 step is associated with decreased VTE rates.

Corresponding author: Aneel Damle, MD, MBA, Colon & Rectal Surgery Associates, 3433 Broadway St. NE, Suite 115, Minneapolis, MN 55413; adamle@CRSAL.org.

Financial disclosures: None.

The Food and Drug Administration granted accelerated approval to brexucabtagene autoleucel (Tecartus, Kite Pharma), the first approved chimeric antigen receptor (CAR) T cell therapy for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL).

The new agent is the second approved CAR T cell product developed by Kite and follows the 2017 approval of axicabtagene ciloleucel (Yescarta) for diffuse large B-cell lymphoma.

“Despite promising advances, there are still major gaps in treatment for patients with MCL who progress following initial therapy,” investigator Michael Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston, said in a company statement. “Many patients have high-risk disease and are more likely to keep progressing, even after subsequent treatments.”

In the same press statement, Meghan Gutierrez, chief executive officer, Lymphoma Research Foundation, said: “This approval marks the first CAR T cell therapy approved for mantle cell lymphoma patients and represents a new frontier in the treatment of this disease.”

The approval of the single-infusion therapy is based on efficacy and safety data from the ongoing, single-arm ZUMA-2 pivotal trial, which enrolled 74 adult patients. All patients had previously received anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 antibody therapy and a Bruton tyrosine kinase inhibitor (ibrutinib or acalabrutinib).

In the trial, there was an objective response rate, which was the primary outcome measure, of 87% among 60 patients who were evaluable for efficacy analysis; 62% had a complete response. 

Among all patients, follow-up was at least 6 months after their first objective disease response. Median duration of response has not yet been reached.

In terms of adverse events, 18% of the 82 patients evaluable for safety experienced > grade 3 cytokine release syndrome and 37% experienced neurologic events, per the company statement. The most common (≥ 10%) grade 3 or higher adverse reactions were anemia, neutropenia, thrombocytopenia, hypotension, hypophosphatemia, encephalopathy, leukopenia, hypoxia, pyrexia, hyponatremia, hypertension, infection-pathogen unspecified, pneumonia, hypocalcemia, and lymphopenia.

Brexucabtagene autoleucel will be manufactured in Kite’s facility in California. In the pivotal trial, there was a 96% manufacturing success rate and a median manufacturing turnaround time of 15 days from leukapheresis to product delivery.  
 

A version of this article originally appeared on Medscape.com.

The Food and Drug Administration granted accelerated approval to brexucabtagene autoleucel (Tecartus, Kite Pharma), the first approved chimeric antigen receptor (CAR) T cell therapy for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL).

The new agent is the second approved CAR T cell product developed by Kite and follows the 2017 approval of axicabtagene ciloleucel (Yescarta) for diffuse large B-cell lymphoma.

“Despite promising advances, there are still major gaps in treatment for patients with MCL who progress following initial therapy,” investigator Michael Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston, said in a company statement. “Many patients have high-risk disease and are more likely to keep progressing, even after subsequent treatments.”

In the same press statement, Meghan Gutierrez, chief executive officer, Lymphoma Research Foundation, said: “This approval marks the first CAR T cell therapy approved for mantle cell lymphoma patients and represents a new frontier in the treatment of this disease.”

The approval of the single-infusion therapy is based on efficacy and safety data from the ongoing, single-arm ZUMA-2 pivotal trial, which enrolled 74 adult patients. All patients had previously received anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 antibody therapy and a Bruton tyrosine kinase inhibitor (ibrutinib or acalabrutinib).

In the trial, there was an objective response rate, which was the primary outcome measure, of 87% among 60 patients who were evaluable for efficacy analysis; 62% had a complete response. 

Among all patients, follow-up was at least 6 months after their first objective disease response. Median duration of response has not yet been reached.

In terms of adverse events, 18% of the 82 patients evaluable for safety experienced > grade 3 cytokine release syndrome and 37% experienced neurologic events, per the company statement. The most common (≥ 10%) grade 3 or higher adverse reactions were anemia, neutropenia, thrombocytopenia, hypotension, hypophosphatemia, encephalopathy, leukopenia, hypoxia, pyrexia, hyponatremia, hypertension, infection-pathogen unspecified, pneumonia, hypocalcemia, and lymphopenia.

Brexucabtagene autoleucel will be manufactured in Kite’s facility in California. In the pivotal trial, there was a 96% manufacturing success rate and a median manufacturing turnaround time of 15 days from leukapheresis to product delivery.  
 

A version of this article originally appeared on Medscape.com.

The Food and Drug Administration granted accelerated approval to brexucabtagene autoleucel (Tecartus, Kite Pharma), the first approved chimeric antigen receptor (CAR) T cell therapy for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL).

The new agent is the second approved CAR T cell product developed by Kite and follows the 2017 approval of axicabtagene ciloleucel (Yescarta) for diffuse large B-cell lymphoma.

“Despite promising advances, there are still major gaps in treatment for patients with MCL who progress following initial therapy,” investigator Michael Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston, said in a company statement. “Many patients have high-risk disease and are more likely to keep progressing, even after subsequent treatments.”

In the same press statement, Meghan Gutierrez, chief executive officer, Lymphoma Research Foundation, said: “This approval marks the first CAR T cell therapy approved for mantle cell lymphoma patients and represents a new frontier in the treatment of this disease.”

The approval of the single-infusion therapy is based on efficacy and safety data from the ongoing, single-arm ZUMA-2 pivotal trial, which enrolled 74 adult patients. All patients had previously received anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 antibody therapy and a Bruton tyrosine kinase inhibitor (ibrutinib or acalabrutinib).

In the trial, there was an objective response rate, which was the primary outcome measure, of 87% among 60 patients who were evaluable for efficacy analysis; 62% had a complete response. 

Among all patients, follow-up was at least 6 months after their first objective disease response. Median duration of response has not yet been reached.

In terms of adverse events, 18% of the 82 patients evaluable for safety experienced > grade 3 cytokine release syndrome and 37% experienced neurologic events, per the company statement. The most common (≥ 10%) grade 3 or higher adverse reactions were anemia, neutropenia, thrombocytopenia, hypotension, hypophosphatemia, encephalopathy, leukopenia, hypoxia, pyrexia, hyponatremia, hypertension, infection-pathogen unspecified, pneumonia, hypocalcemia, and lymphopenia.

Brexucabtagene autoleucel will be manufactured in Kite’s facility in California. In the pivotal trial, there was a 96% manufacturing success rate and a median manufacturing turnaround time of 15 days from leukapheresis to product delivery.  
 

A version of this article originally appeared on Medscape.com.

SPK-8011, an investigational adeno-associated virus (AAV)–mediated gene therapy for hemophilia A, provides stable and durable factor VIII expression with no major safety concerns, according to findings at least 2 years after a single treatment in patients from a phase 1/2 trial.

The first 5 of 14 adult men with hemophilia A and who had factor VIII (FVIII) activity of 2% or less before treatment with SPK-8011 (at single doses of either 5 × 10^{11 or 1} × 10¹² vg/kg), showed no development of FVIII inhibitors or evidence of FVIII cellular immune response at 106-142 weeks’ follow-up after vector infusion, according to Lindsey A. George, MD, at the International Society of Thrombosis and Haemostasis 2020 virtual congress.

At follow-up, the two who had received a 5 × 10¹¹ vg/kg dose had FVIII activity of 6.9%-8.4%, and the three in the 1 × 10¹² vg/kg cohort had FVIII activity of 5.2%-19.8%, said Dr. George, of the Children’s Hospital of Philadelphia.

Overall, 12 of the 14 patients in the study had sustained FVIII expression, including 7 of 9 who received the highest SPK-8011 dose of 2 × 10¹² vg/kg. In the 12 with sustained expression, a “remarkable” 91% reduction in the annualized bleeding rate from the year prior to vs. the year after vector infusion was observed, she said.

“Similarly, looking at number of factor infusions before vector infusion relative to the number of factor infusions after vector infusion ... [there was] evidence of remarkable preliminary efficacy,” she added, noting a 96% reduction in factor consumption.

The findings are of note because, while clinical studies of Spark Therapeutic’s SPK-8011 product in hemophilia B and preclinical models in hemophilia A showed promising reductions in bleeds and stable, durable levels of FVIII expression after therapy, the first successful clinical trial of an AAV-mediated gene therapy in hemophilia A – the BioMarin AAV serotype 5 human FVIII-SQ (valoctocogene roxaparvovec) – showed an unexpected decline in FVIII expression at 1, 2, 3, and 4 years.

“This may be particularly relevant in the context of development of multi-serotype AAV neutralizing antibodies (NAb) following AAV vector administration,” Dr. George said, referencing a small study in which she and her colleagues showed long-term persistence of cross-reactive AAV NAb. The findings of that study, which is currently in press in Molecular Therapy, “suggest that repeat AAV vector infusion is unlikely to be possible with current methods.”

Initial results from the SPK-8011 study were presented at the 2018 American Society of Hematology annual meeting. No major safety issues have emerged since those data were presented at ASH; no deaths have occurred, and none of the patients developed FVIII inhibitors.

Treatment-related adverse events were limited to an infusion reaction in one patient, which resolved completely, and liver enzyme elevations in three patients, which also resolved. One serious adverse event – a grade 2 transaminitis that resulted in elective hospitalization for intravenous steroid administration, also resolved.

With respect to vector clearance, there was “no evidence of vector in either saliva, semen, serum, urine, or peripheral blood mononuclear cells by 6 weeks after vector infusion,” Dr. George said.

One-stage assay determination of FVIII activity showed that activity greater than 10% permits an absolute bleeding rate (ABR) of less than 1%, which is consistent with hemophilia natural history studies. Therefore “these data support that FVIII activity that is approximately greater than 10% “may be adequate to either eliminate or achieve an ABR of less than 1,” she said.

“With respect to assay discrepancy, our data at least preliminarily support that the one-stage assay determinant of hepatocyte-derived FVIII correlates with clinical phenotype,” she added.

The findings in the first five patients demonstrate preliminary stability of FVIII expression at follow up between 2 and 3.3 years, she said.

Further, of the nine patients who received the 2 × 10¹² vg/kg dose, seven had sustained FVIII expression at about 1.5 years, five of the seven had no bleeds, and two lost FVIII expression and returned to prophylaxis uneventfully, she noted.

“The future directions of this work are ultimately to explore the optimal vector dose and immunosuppression regimens to achieve predictable, safe, efficacious, and durable FVIII expression,” she said.

Asked during a question and answer period about potential reasons for the differences in durability seen with SBK-8011 versus valoctocogene roxaparvovec, Dr. George said they remain unclear but could be related to differences in vector doses and manufacturing platforms.

Emerging data may allow for better comparisons, she added.

Session moderator Sebastien Lacroix-Desmazes, MD, of Centre de Recherche des Cordeliers, Paris, further asked about plans to optimize the immunosuppression regimen.

Plans are indeed in the works to identify the optimal immunosuppression regimen and to optimize immunosuppression in this trial, Dr. George said, noting that Spark Therapeutics “has outlined a plan to further investigate this in phase 1/2 trial before progressing into phase 3 study.”

Spark Therapeutic sponsored the SPK-8011 study. Dr. George disclosed consulting and/or data safety monitoring board activity for Pfizer and AvroBio.

sworcester@mdedge.com

SOURCE: George L et al. 2020 ISTH Congress, Abstract OC 03.5.

SPK-8011, an investigational adeno-associated virus (AAV)–mediated gene therapy for hemophilia A, provides stable and durable factor VIII expression with no major safety concerns, according to findings at least 2 years after a single treatment in patients from a phase 1/2 trial.

The first 5 of 14 adult men with hemophilia A and who had factor VIII (FVIII) activity of 2% or less before treatment with SPK-8011 (at single doses of either 5 × 10^{11 or 1} × 10¹² vg/kg), showed no development of FVIII inhibitors or evidence of FVIII cellular immune response at 106-142 weeks’ follow-up after vector infusion, according to Lindsey A. George, MD, at the International Society of Thrombosis and Haemostasis 2020 virtual congress.

At follow-up, the two who had received a 5 × 10¹¹ vg/kg dose had FVIII activity of 6.9%-8.4%, and the three in the 1 × 10¹² vg/kg cohort had FVIII activity of 5.2%-19.8%, said Dr. George, of the Children’s Hospital of Philadelphia.

Overall, 12 of the 14 patients in the study had sustained FVIII expression, including 7 of 9 who received the highest SPK-8011 dose of 2 × 10¹² vg/kg. In the 12 with sustained expression, a “remarkable” 91% reduction in the annualized bleeding rate from the year prior to vs. the year after vector infusion was observed, she said.

“Similarly, looking at number of factor infusions before vector infusion relative to the number of factor infusions after vector infusion ... [there was] evidence of remarkable preliminary efficacy,” she added, noting a 96% reduction in factor consumption.

The findings are of note because, while clinical studies of Spark Therapeutic’s SPK-8011 product in hemophilia B and preclinical models in hemophilia A showed promising reductions in bleeds and stable, durable levels of FVIII expression after therapy, the first successful clinical trial of an AAV-mediated gene therapy in hemophilia A – the BioMarin AAV serotype 5 human FVIII-SQ (valoctocogene roxaparvovec) – showed an unexpected decline in FVIII expression at 1, 2, 3, and 4 years.

“This may be particularly relevant in the context of development of multi-serotype AAV neutralizing antibodies (NAb) following AAV vector administration,” Dr. George said, referencing a small study in which she and her colleagues showed long-term persistence of cross-reactive AAV NAb. The findings of that study, which is currently in press in Molecular Therapy, “suggest that repeat AAV vector infusion is unlikely to be possible with current methods.”

Initial results from the SPK-8011 study were presented at the 2018 American Society of Hematology annual meeting. No major safety issues have emerged since those data were presented at ASH; no deaths have occurred, and none of the patients developed FVIII inhibitors.

Treatment-related adverse events were limited to an infusion reaction in one patient, which resolved completely, and liver enzyme elevations in three patients, which also resolved. One serious adverse event – a grade 2 transaminitis that resulted in elective hospitalization for intravenous steroid administration, also resolved.

With respect to vector clearance, there was “no evidence of vector in either saliva, semen, serum, urine, or peripheral blood mononuclear cells by 6 weeks after vector infusion,” Dr. George said.

One-stage assay determination of FVIII activity showed that activity greater than 10% permits an absolute bleeding rate (ABR) of less than 1%, which is consistent with hemophilia natural history studies. Therefore “these data support that FVIII activity that is approximately greater than 10% “may be adequate to either eliminate or achieve an ABR of less than 1,” she said.

“With respect to assay discrepancy, our data at least preliminarily support that the one-stage assay determinant of hepatocyte-derived FVIII correlates with clinical phenotype,” she added.

The findings in the first five patients demonstrate preliminary stability of FVIII expression at follow up between 2 and 3.3 years, she said.

Further, of the nine patients who received the 2 × 10¹² vg/kg dose, seven had sustained FVIII expression at about 1.5 years, five of the seven had no bleeds, and two lost FVIII expression and returned to prophylaxis uneventfully, she noted.

“The future directions of this work are ultimately to explore the optimal vector dose and immunosuppression regimens to achieve predictable, safe, efficacious, and durable FVIII expression,” she said.

Asked during a question and answer period about potential reasons for the differences in durability seen with SBK-8011 versus valoctocogene roxaparvovec, Dr. George said they remain unclear but could be related to differences in vector doses and manufacturing platforms.

Emerging data may allow for better comparisons, she added.

Session moderator Sebastien Lacroix-Desmazes, MD, of Centre de Recherche des Cordeliers, Paris, further asked about plans to optimize the immunosuppression regimen.

Plans are indeed in the works to identify the optimal immunosuppression regimen and to optimize immunosuppression in this trial, Dr. George said, noting that Spark Therapeutics “has outlined a plan to further investigate this in phase 1/2 trial before progressing into phase 3 study.”

Spark Therapeutic sponsored the SPK-8011 study. Dr. George disclosed consulting and/or data safety monitoring board activity for Pfizer and AvroBio.

sworcester@mdedge.com

SOURCE: George L et al. 2020 ISTH Congress, Abstract OC 03.5.

SPK-8011, an investigational adeno-associated virus (AAV)–mediated gene therapy for hemophilia A, provides stable and durable factor VIII expression with no major safety concerns, according to findings at least 2 years after a single treatment in patients from a phase 1/2 trial.

The first 5 of 14 adult men with hemophilia A and who had factor VIII (FVIII) activity of 2% or less before treatment with SPK-8011 (at single doses of either 5 × 10^{11 or 1} × 10¹² vg/kg), showed no development of FVIII inhibitors or evidence of FVIII cellular immune response at 106-142 weeks’ follow-up after vector infusion, according to Lindsey A. George, MD, at the International Society of Thrombosis and Haemostasis 2020 virtual congress.

At follow-up, the two who had received a 5 × 10¹¹ vg/kg dose had FVIII activity of 6.9%-8.4%, and the three in the 1 × 10¹² vg/kg cohort had FVIII activity of 5.2%-19.8%, said Dr. George, of the Children’s Hospital of Philadelphia.

Overall, 12 of the 14 patients in the study had sustained FVIII expression, including 7 of 9 who received the highest SPK-8011 dose of 2 × 10¹² vg/kg. In the 12 with sustained expression, a “remarkable” 91% reduction in the annualized bleeding rate from the year prior to vs. the year after vector infusion was observed, she said.

“Similarly, looking at number of factor infusions before vector infusion relative to the number of factor infusions after vector infusion ... [there was] evidence of remarkable preliminary efficacy,” she added, noting a 96% reduction in factor consumption.

The findings are of note because, while clinical studies of Spark Therapeutic’s SPK-8011 product in hemophilia B and preclinical models in hemophilia A showed promising reductions in bleeds and stable, durable levels of FVIII expression after therapy, the first successful clinical trial of an AAV-mediated gene therapy in hemophilia A – the BioMarin AAV serotype 5 human FVIII-SQ (valoctocogene roxaparvovec) – showed an unexpected decline in FVIII expression at 1, 2, 3, and 4 years.

“This may be particularly relevant in the context of development of multi-serotype AAV neutralizing antibodies (NAb) following AAV vector administration,” Dr. George said, referencing a small study in which she and her colleagues showed long-term persistence of cross-reactive AAV NAb. The findings of that study, which is currently in press in Molecular Therapy, “suggest that repeat AAV vector infusion is unlikely to be possible with current methods.”

Initial results from the SPK-8011 study were presented at the 2018 American Society of Hematology annual meeting. No major safety issues have emerged since those data were presented at ASH; no deaths have occurred, and none of the patients developed FVIII inhibitors.

Treatment-related adverse events were limited to an infusion reaction in one patient, which resolved completely, and liver enzyme elevations in three patients, which also resolved. One serious adverse event – a grade 2 transaminitis that resulted in elective hospitalization for intravenous steroid administration, also resolved.

With respect to vector clearance, there was “no evidence of vector in either saliva, semen, serum, urine, or peripheral blood mononuclear cells by 6 weeks after vector infusion,” Dr. George said.

One-stage assay determination of FVIII activity showed that activity greater than 10% permits an absolute bleeding rate (ABR) of less than 1%, which is consistent with hemophilia natural history studies. Therefore “these data support that FVIII activity that is approximately greater than 10% “may be adequate to either eliminate or achieve an ABR of less than 1,” she said.

“With respect to assay discrepancy, our data at least preliminarily support that the one-stage assay determinant of hepatocyte-derived FVIII correlates with clinical phenotype,” she added.

The findings in the first five patients demonstrate preliminary stability of FVIII expression at follow up between 2 and 3.3 years, she said.

Further, of the nine patients who received the 2 × 10¹² vg/kg dose, seven had sustained FVIII expression at about 1.5 years, five of the seven had no bleeds, and two lost FVIII expression and returned to prophylaxis uneventfully, she noted.

“The future directions of this work are ultimately to explore the optimal vector dose and immunosuppression regimens to achieve predictable, safe, efficacious, and durable FVIII expression,” she said.

Asked during a question and answer period about potential reasons for the differences in durability seen with SBK-8011 versus valoctocogene roxaparvovec, Dr. George said they remain unclear but could be related to differences in vector doses and manufacturing platforms.

Emerging data may allow for better comparisons, she added.

Session moderator Sebastien Lacroix-Desmazes, MD, of Centre de Recherche des Cordeliers, Paris, further asked about plans to optimize the immunosuppression regimen.

Plans are indeed in the works to identify the optimal immunosuppression regimen and to optimize immunosuppression in this trial, Dr. George said, noting that Spark Therapeutics “has outlined a plan to further investigate this in phase 1/2 trial before progressing into phase 3 study.”

Spark Therapeutic sponsored the SPK-8011 study. Dr. George disclosed consulting and/or data safety monitoring board activity for Pfizer and AvroBio.

sworcester@mdedge.com

SOURCE: George L et al. 2020 ISTH Congress, Abstract OC 03.5.

Systemic or hematopoietic stem cell transplantation (HSCT) treatment of HIV-positive lymphoma patients resulted in improved outcomes, compared with nonsystemic treatment, according to the results of a large database study.

Researchers Thejus T. Jayakrishnan, MD, and colleagues examined patients with lymphoma diagnosed between 2004 and 2015 from the National Cancer Database. Patients were categorized as HIV positive and HIV negative. First-line lymphoma treatment was categorized as no systemic therapy reported, systemic therapy, or HSCT. Multivariate analysis was used to predict treatment and survival, according to Dr. Jayakrishnan, a resident at the department of internal medicine, Allegheny Health Network, Pittsburgh.

A total of 11,160 HIV-positive vs. 349,607 HIV-negative patients were analyzed, including mostly men, with a comorbidity index of 0. The most common lymphoma among HIV-positive patients was diffuse large B-cell lymphoma, according to the report in Clinical Lymphoma, Myeloma & Leukemia.

Among HIV-positive patients, 792 had no systemic treatment, 10,328 underwent systemic treatment, and 40 received HSCT treatment. The results showed that treatment of HIV-positive lymphoma patients resulted in improved outcomes: 3-year overall survival was 43.6% for nonsystemic treatment versus 58.1% for systemic (hazard ratio, 0.56; 95% confidence interval, 0.52-0.61; P < .005) versus 62.2% for HSCT therapy (HR, 0.42; 95% CI, 0.14-1.3; P = .08), the lack of significance in the latter could be caused in part by the small number of patients treated. Outcomes for both treatment regimens were lower, however, compared with non-HIV patients.

“The present study demonstrates improvement in survival outcomes for HIV-positive patients with lymphoma with treatments when feasible, but these outcomes are poor when compared to HIV-negative patients,” the researchers concluded.

The authors reported that they had no conflicts of interest.

mlesney@mdedge.com

SOURCE: Jayakrishnan TT et al. Clin Lymph Myeloma Leuk. 2020 Feb 20. doi: 10.1016/j.clml.2020.06.003.

Systemic or hematopoietic stem cell transplantation (HSCT) treatment of HIV-positive lymphoma patients resulted in improved outcomes, compared with nonsystemic treatment, according to the results of a large database study.

Researchers Thejus T. Jayakrishnan, MD, and colleagues examined patients with lymphoma diagnosed between 2004 and 2015 from the National Cancer Database. Patients were categorized as HIV positive and HIV negative. First-line lymphoma treatment was categorized as no systemic therapy reported, systemic therapy, or HSCT. Multivariate analysis was used to predict treatment and survival, according to Dr. Jayakrishnan, a resident at the department of internal medicine, Allegheny Health Network, Pittsburgh.

A total of 11,160 HIV-positive vs. 349,607 HIV-negative patients were analyzed, including mostly men, with a comorbidity index of 0. The most common lymphoma among HIV-positive patients was diffuse large B-cell lymphoma, according to the report in Clinical Lymphoma, Myeloma & Leukemia.

Among HIV-positive patients, 792 had no systemic treatment, 10,328 underwent systemic treatment, and 40 received HSCT treatment. The results showed that treatment of HIV-positive lymphoma patients resulted in improved outcomes: 3-year overall survival was 43.6% for nonsystemic treatment versus 58.1% for systemic (hazard ratio, 0.56; 95% confidence interval, 0.52-0.61; P < .005) versus 62.2% for HSCT therapy (HR, 0.42; 95% CI, 0.14-1.3; P = .08), the lack of significance in the latter could be caused in part by the small number of patients treated. Outcomes for both treatment regimens were lower, however, compared with non-HIV patients.

“The present study demonstrates improvement in survival outcomes for HIV-positive patients with lymphoma with treatments when feasible, but these outcomes are poor when compared to HIV-negative patients,” the researchers concluded.

The authors reported that they had no conflicts of interest.

mlesney@mdedge.com

SOURCE: Jayakrishnan TT et al. Clin Lymph Myeloma Leuk. 2020 Feb 20. doi: 10.1016/j.clml.2020.06.003.

Systemic or hematopoietic stem cell transplantation (HSCT) treatment of HIV-positive lymphoma patients resulted in improved outcomes, compared with nonsystemic treatment, according to the results of a large database study.

Researchers Thejus T. Jayakrishnan, MD, and colleagues examined patients with lymphoma diagnosed between 2004 and 2015 from the National Cancer Database. Patients were categorized as HIV positive and HIV negative. First-line lymphoma treatment was categorized as no systemic therapy reported, systemic therapy, or HSCT. Multivariate analysis was used to predict treatment and survival, according to Dr. Jayakrishnan, a resident at the department of internal medicine, Allegheny Health Network, Pittsburgh.

A total of 11,160 HIV-positive vs. 349,607 HIV-negative patients were analyzed, including mostly men, with a comorbidity index of 0. The most common lymphoma among HIV-positive patients was diffuse large B-cell lymphoma, according to the report in Clinical Lymphoma, Myeloma & Leukemia.

Among HIV-positive patients, 792 had no systemic treatment, 10,328 underwent systemic treatment, and 40 received HSCT treatment. The results showed that treatment of HIV-positive lymphoma patients resulted in improved outcomes: 3-year overall survival was 43.6% for nonsystemic treatment versus 58.1% for systemic (hazard ratio, 0.56; 95% confidence interval, 0.52-0.61; P < .005) versus 62.2% for HSCT therapy (HR, 0.42; 95% CI, 0.14-1.3; P = .08), the lack of significance in the latter could be caused in part by the small number of patients treated. Outcomes for both treatment regimens were lower, however, compared with non-HIV patients.

“The present study demonstrates improvement in survival outcomes for HIV-positive patients with lymphoma with treatments when feasible, but these outcomes are poor when compared to HIV-negative patients,” the researchers concluded.

The authors reported that they had no conflicts of interest.

mlesney@mdedge.com

SOURCE: Jayakrishnan TT et al. Clin Lymph Myeloma Leuk. 2020 Feb 20. doi: 10.1016/j.clml.2020.06.003.

Physician consensus and a broadly effective treatment for heavy menstrual bleeding was not found among young patients with inherited platelet function disorders, according to the results of a retrospective chart review reported in the Journal of Pediatric and Adolescent Gynecology.

Heavy menstrual bleeding (HMB) in girls with inherited platelet function disorders (IPFD) can be difficult to control despite ongoing follow-up and treatment changes, reported Christine M. Pennesi, MD, of the University of Michigan, Ann Arbor, and colleagues.

They assessed 34 young women and girls (ages 9-25 years) diagnosed with IPFDs referred to gynecology and/or hematology at a tertiary care hospital between 2006 and 2018.

Billing codes were used to determine hormonal or nonhormonal treatments, and outcomes over a 1- to 2-year period were collected. The initial treatment was defined as the first treatment prescribed after referral. The primary outcome was treatment failure, defined as a change in treatment method because of continued bleeding.

The majority (56%) of patients failed initial treatment (n = 19); among all 34 individuals followed in the study, an average of 2.7 total treatments were required.

Six patients (18%) remained uncontrolled despite numerous treatment changes (mean treatment changes, four; range, two to seven), and two patients (6%) remained uncontrolled because of noncompliance with treatment.

Overall, the researchers identified a 18% failure rate of successfully treatment of HMB in young women and girls with IPFDs over a 2-year follow-up period.

Of the 26 women who achieved control of HMB within 2-year follow-up, 54% (n = 14) were on hormonal treatments, 27% (n = 7) on nonhormonal treatments, 12% (n = 3) on combined treatments, and 8% (n = 2) on no treatment at time of control, the authors stated.

“The heterogeneity in treatments that were described in this study, clearly demonstrate that, in selecting treatment methods for HMB in young women, other considerations are often in play. This includes patient preference and need for contraception. Some patients or parents may have personal or religious objections to hormonal methods or worry about hormones in this young age group,” the researchers speculated.

“Appropriate counseling in these patients should include that it would not be unexpected for a patient to need more than one treatment before control of bleeding is achieved. This may help to alleviate the fear of teenagers when continued bleeding occurs after starting their initial treatment,” Dr. Pennesi and colleagues concluded.

One of the authors participated in funded trials and received funding from several pharmaceutical companies. The others reported having no disclosures.

mlesney@mdedge.com

SOURCE: Pennesi CM et al. J Pediatr Adolesc Gynecol. 2020 Jun 22. doi: 10.1016/j.jpag.2020.06.019.

Physician consensus and a broadly effective treatment for heavy menstrual bleeding was not found among young patients with inherited platelet function disorders, according to the results of a retrospective chart review reported in the Journal of Pediatric and Adolescent Gynecology.

Heavy menstrual bleeding (HMB) in girls with inherited platelet function disorders (IPFD) can be difficult to control despite ongoing follow-up and treatment changes, reported Christine M. Pennesi, MD, of the University of Michigan, Ann Arbor, and colleagues.

They assessed 34 young women and girls (ages 9-25 years) diagnosed with IPFDs referred to gynecology and/or hematology at a tertiary care hospital between 2006 and 2018.

Billing codes were used to determine hormonal or nonhormonal treatments, and outcomes over a 1- to 2-year period were collected. The initial treatment was defined as the first treatment prescribed after referral. The primary outcome was treatment failure, defined as a change in treatment method because of continued bleeding.

The majority (56%) of patients failed initial treatment (n = 19); among all 34 individuals followed in the study, an average of 2.7 total treatments were required.

Six patients (18%) remained uncontrolled despite numerous treatment changes (mean treatment changes, four; range, two to seven), and two patients (6%) remained uncontrolled because of noncompliance with treatment.

Overall, the researchers identified a 18% failure rate of successfully treatment of HMB in young women and girls with IPFDs over a 2-year follow-up period.

Of the 26 women who achieved control of HMB within 2-year follow-up, 54% (n = 14) were on hormonal treatments, 27% (n = 7) on nonhormonal treatments, 12% (n = 3) on combined treatments, and 8% (n = 2) on no treatment at time of control, the authors stated.

“The heterogeneity in treatments that were described in this study, clearly demonstrate that, in selecting treatment methods for HMB in young women, other considerations are often in play. This includes patient preference and need for contraception. Some patients or parents may have personal or religious objections to hormonal methods or worry about hormones in this young age group,” the researchers speculated.

“Appropriate counseling in these patients should include that it would not be unexpected for a patient to need more than one treatment before control of bleeding is achieved. This may help to alleviate the fear of teenagers when continued bleeding occurs after starting their initial treatment,” Dr. Pennesi and colleagues concluded.

One of the authors participated in funded trials and received funding from several pharmaceutical companies. The others reported having no disclosures.

mlesney@mdedge.com

SOURCE: Pennesi CM et al. J Pediatr Adolesc Gynecol. 2020 Jun 22. doi: 10.1016/j.jpag.2020.06.019.

Physician consensus and a broadly effective treatment for heavy menstrual bleeding was not found among young patients with inherited platelet function disorders, according to the results of a retrospective chart review reported in the Journal of Pediatric and Adolescent Gynecology.

Heavy menstrual bleeding (HMB) in girls with inherited platelet function disorders (IPFD) can be difficult to control despite ongoing follow-up and treatment changes, reported Christine M. Pennesi, MD, of the University of Michigan, Ann Arbor, and colleagues.

They assessed 34 young women and girls (ages 9-25 years) diagnosed with IPFDs referred to gynecology and/or hematology at a tertiary care hospital between 2006 and 2018.

Billing codes were used to determine hormonal or nonhormonal treatments, and outcomes over a 1- to 2-year period were collected. The initial treatment was defined as the first treatment prescribed after referral. The primary outcome was treatment failure, defined as a change in treatment method because of continued bleeding.

The majority (56%) of patients failed initial treatment (n = 19); among all 34 individuals followed in the study, an average of 2.7 total treatments were required.

Six patients (18%) remained uncontrolled despite numerous treatment changes (mean treatment changes, four; range, two to seven), and two patients (6%) remained uncontrolled because of noncompliance with treatment.

Overall, the researchers identified a 18% failure rate of successfully treatment of HMB in young women and girls with IPFDs over a 2-year follow-up period.

Of the 26 women who achieved control of HMB within 2-year follow-up, 54% (n = 14) were on hormonal treatments, 27% (n = 7) on nonhormonal treatments, 12% (n = 3) on combined treatments, and 8% (n = 2) on no treatment at time of control, the authors stated.

“The heterogeneity in treatments that were described in this study, clearly demonstrate that, in selecting treatment methods for HMB in young women, other considerations are often in play. This includes patient preference and need for contraception. Some patients or parents may have personal or religious objections to hormonal methods or worry about hormones in this young age group,” the researchers speculated.

“Appropriate counseling in these patients should include that it would not be unexpected for a patient to need more than one treatment before control of bleeding is achieved. This may help to alleviate the fear of teenagers when continued bleeding occurs after starting their initial treatment,” Dr. Pennesi and colleagues concluded.

One of the authors participated in funded trials and received funding from several pharmaceutical companies. The others reported having no disclosures.

mlesney@mdedge.com

SOURCE: Pennesi CM et al. J Pediatr Adolesc Gynecol. 2020 Jun 22. doi: 10.1016/j.jpag.2020.06.019.

Transitioning from parenteral bortezomib-based induction to all-oral ixazomib-lenalidomide-dexamethasone therapy increased proteasome inhibitor (PI)–based treatment adherence and duration, according to early results from a clinical trial designed to include patients representing the real-world U.S. multiple myeloma population.

The US MM-6 study was designed to evaluate a novel in-class therapy (iCT) transitioning approach from intravenous to oral treatment in the community-based setting with the aims of increasing PI-based treatment duration and adherence, maintaining health-related quality of life (HRQoL), and improving outcomes in a representative, real-world, community population of multiple myeloma patients, according to Sudhir Manda, MD, of Arizona Oncology/U.S. Oncology Research, Tucson, and colleagues.

Dr. Manda and colleagues reported on the early results of the US MM-6 trial (NCT03173092), which is a community-based, real-world, open-label, single-arm, phase 4 study of adult multiple myeloma patients who do not meet transplant-eligibility criteria, or for whom transplant would be delayed for 2 years or more, and who are receiving first-line bortezomib-based induction. All patients in the study had no evidence of progressive disease after three treatment cycles.

By the data cutoff for the reported analysis, 84 patients had been treated. The patients had a median age of 73 years; 49% were men; 15% black/African American; 10% Hispanic/Latino. A total of 62% of the patients remain on therapy, with a mean duration of total PI therapy of 10.1 months and of ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) of 7.3 months.

The overall response rate was 62% (complete response, 4%; very good partial response, 25%; partial response, 33%) after bortezomib-based induction and 70% (complete response, 26%; very good partial response, 29%; partial response, 15%) after induction to all-oral ixazomib-Rd.

“The use of this novel iCT approach from parenteral bortezomib-based to oral ixazomib-based therapy facilitates long-term PI-based treatment that is well tolerated in real-world, nontransplant [newly diagnosed multiple myeloma] patients,” according to Dr. Manda and colleagues. In addition, “preliminary findings indicate that the iCT approach results in promising efficacy and high medication adherence, with no adverse impact on patients’ HRQoL or treatment satisfaction.”

The study was sponsored by Millennium Pharmaceuticals. Four of the authors are employees of Millennium Pharmaceuticals and several authors disclosed relationships with various pharmaceutical companies, including Millennium Pharmaceuticals.

mlesney@mdedge.com

SOURCE: Manda S et al. Clin Lymphoma Myeloma Leuk. 2020 Jun 30. doi: 10.1016/j.clml.2020.06.024.

Transitioning from parenteral bortezomib-based induction to all-oral ixazomib-lenalidomide-dexamethasone therapy increased proteasome inhibitor (PI)–based treatment adherence and duration, according to early results from a clinical trial designed to include patients representing the real-world U.S. multiple myeloma population.

The US MM-6 study was designed to evaluate a novel in-class therapy (iCT) transitioning approach from intravenous to oral treatment in the community-based setting with the aims of increasing PI-based treatment duration and adherence, maintaining health-related quality of life (HRQoL), and improving outcomes in a representative, real-world, community population of multiple myeloma patients, according to Sudhir Manda, MD, of Arizona Oncology/U.S. Oncology Research, Tucson, and colleagues.

Dr. Manda and colleagues reported on the early results of the US MM-6 trial (NCT03173092), which is a community-based, real-world, open-label, single-arm, phase 4 study of adult multiple myeloma patients who do not meet transplant-eligibility criteria, or for whom transplant would be delayed for 2 years or more, and who are receiving first-line bortezomib-based induction. All patients in the study had no evidence of progressive disease after three treatment cycles.

By the data cutoff for the reported analysis, 84 patients had been treated. The patients had a median age of 73 years; 49% were men; 15% black/African American; 10% Hispanic/Latino. A total of 62% of the patients remain on therapy, with a mean duration of total PI therapy of 10.1 months and of ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) of 7.3 months.

The overall response rate was 62% (complete response, 4%; very good partial response, 25%; partial response, 33%) after bortezomib-based induction and 70% (complete response, 26%; very good partial response, 29%; partial response, 15%) after induction to all-oral ixazomib-Rd.

“The use of this novel iCT approach from parenteral bortezomib-based to oral ixazomib-based therapy facilitates long-term PI-based treatment that is well tolerated in real-world, nontransplant [newly diagnosed multiple myeloma] patients,” according to Dr. Manda and colleagues. In addition, “preliminary findings indicate that the iCT approach results in promising efficacy and high medication adherence, with no adverse impact on patients’ HRQoL or treatment satisfaction.”

The study was sponsored by Millennium Pharmaceuticals. Four of the authors are employees of Millennium Pharmaceuticals and several authors disclosed relationships with various pharmaceutical companies, including Millennium Pharmaceuticals.

mlesney@mdedge.com

SOURCE: Manda S et al. Clin Lymphoma Myeloma Leuk. 2020 Jun 30. doi: 10.1016/j.clml.2020.06.024.

Transitioning from parenteral bortezomib-based induction to all-oral ixazomib-lenalidomide-dexamethasone therapy increased proteasome inhibitor (PI)–based treatment adherence and duration, according to early results from a clinical trial designed to include patients representing the real-world U.S. multiple myeloma population.

The US MM-6 study was designed to evaluate a novel in-class therapy (iCT) transitioning approach from intravenous to oral treatment in the community-based setting with the aims of increasing PI-based treatment duration and adherence, maintaining health-related quality of life (HRQoL), and improving outcomes in a representative, real-world, community population of multiple myeloma patients, according to Sudhir Manda, MD, of Arizona Oncology/U.S. Oncology Research, Tucson, and colleagues.

Dr. Manda and colleagues reported on the early results of the US MM-6 trial (NCT03173092), which is a community-based, real-world, open-label, single-arm, phase 4 study of adult multiple myeloma patients who do not meet transplant-eligibility criteria, or for whom transplant would be delayed for 2 years or more, and who are receiving first-line bortezomib-based induction. All patients in the study had no evidence of progressive disease after three treatment cycles.

By the data cutoff for the reported analysis, 84 patients had been treated. The patients had a median age of 73 years; 49% were men; 15% black/African American; 10% Hispanic/Latino. A total of 62% of the patients remain on therapy, with a mean duration of total PI therapy of 10.1 months and of ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) of 7.3 months.

The overall response rate was 62% (complete response, 4%; very good partial response, 25%; partial response, 33%) after bortezomib-based induction and 70% (complete response, 26%; very good partial response, 29%; partial response, 15%) after induction to all-oral ixazomib-Rd.

“The use of this novel iCT approach from parenteral bortezomib-based to oral ixazomib-based therapy facilitates long-term PI-based treatment that is well tolerated in real-world, nontransplant [newly diagnosed multiple myeloma] patients,” according to Dr. Manda and colleagues. In addition, “preliminary findings indicate that the iCT approach results in promising efficacy and high medication adherence, with no adverse impact on patients’ HRQoL or treatment satisfaction.”

The study was sponsored by Millennium Pharmaceuticals. Four of the authors are employees of Millennium Pharmaceuticals and several authors disclosed relationships with various pharmaceutical companies, including Millennium Pharmaceuticals.

mlesney@mdedge.com

SOURCE: Manda S et al. Clin Lymphoma Myeloma Leuk. 2020 Jun 30. doi: 10.1016/j.clml.2020.06.024.

A striking clinical feature of illness from SARS-CoV-2 is a marked increase in thrombotic and microvascular complications, or COVID-19–associated coagulopathy (CAC).

A new study suggests endothelial cell injury plays a major role in the pathogenesis of CAC, and blood levels of soluble thrombomodulin correlate with mortality.

George Goshua, MD, of Yale University, New Haven, Conn., presented this study as a late-breaking abstract at the virtual annual congress of the European Hematology Association.

Dr. Goshua cited past research showing CAC to be highly prevalent among hospitalized patients. Venous thromboembolism was found in 17% to 69% of patients, despite thromboprophylaxis.^1-4 Arterial thrombosis has been seen in 3.6% to 4.0% of patients,^1-3 and autopsy findings have shown microvascular thrombosis in as many as 87% of patients.^5-7

For their study, Dr. Goshua and colleagues assessed endothelial cell damage, platelet activation, and hemostatic and fibrinolytic cascade effects of CAC.

The investigators measured markers of endothelial cell injury and platelet activation, plasminogen activation inhibitor 1 (PAI-1), and coagulation factors in stable and critically ill patients hospitalized with COVID-19. In addition, the team sought to identify biomarkers of mortality in hospitalized patients.

Dr. Goshua and colleagues studied 68 adults hospitalized for suspected COVID-19 – 48 in the ICU and 20 outside the ICU. Patients in the ICU received mechanical ventilation, while the non-ICU patients required supplemental oxygen (≤3 L/min per nasal cannula).

There were more men than women (69% vs. 31%) in the ICU population but not in the non-ICU population (40% vs. 60%). There were no statistically significant differences in age or comorbid conditions between the ICU and non-ICU patients.
 

Results and interpretation

Consistent with augmentation of the coagulation cascade – and as expected – D-dimer and thrombin-antithrombin levels were high in both the ICU and non-ICU populations, but levels were significantly higher (P < .001) among the ICU patients.

Endogenous anticoagulants (antithrombin and proteins C and S) and fibrinolytic enzymes (alpha 2-antiplasmin) were preserved, verifying that CAC is distinct from disseminated intravascular coagulation. Classic fibrinolysis did not occur, as PAI-1 was high in ICU and non-ICU patients, and lysis-30 was normal in nearly all ICU patients (96%).

Von Willebrand factor antigen and activity levels and factor VIII levels were markedly elevated in non-ICU and ICU patients, but they were significantly higher (P < .001) in the ICU cohort. This supports the hypothesis that endothelial cell damage and platelet activation play major roles in CAC.

Similarly, soluble P-selectin, which is shed from endothelial cells and platelets, was dramatically elevated in ICU patients in comparison with controls and non-ICU patients (P < .001 for both comparisons).

Levels of soluble thrombomodulin, which is released from endothelial cells, were not significantly different in ICU patients and controls. However, given thrombomodulin’s significant role in the coagulation cascade, Dr. Goshua and colleagues plotted receiver operating curves to see if soluble thrombomodulin levels were predictive of mortality.

The results showed that soluble thrombomodulin correlated with the probability of survival, both overall and in ICU patients. Soluble thrombomodulin levels greater than 3.26 ng/mL were associated with significantly worse survival in all patients (P = .0087) and ICU patients (P = .0309).
 

Influence on therapy

Laboratory perturbations were detected in both ICU and non-ICU patients, and otherwise healthy outpatients have exhibited potentially life-threatening CAC, according to Dr. Goshua.

These findings suggest the prothrombotic state occurs early in the pathogenesis of SARS-CoV-2 infection, is driven by platelet activation and endotheliopathy, and becomes more pronounced with worsening severity of infection.

The results of this study prompted a change in how Yale–New Haven Hospital manages COVID-19 patients. Patients without a clinical contraindication now receive aspirin at 81 mg daily in addition to the anticoagulation regimen typically used for all hospitalized COVID-19 patients.

Investigations regarding other medications that can influence platelet-endothelial cell interactions and modulate endothelial cell damage in CAC – such as dipyridamole, defibrotide, and eculizumab – are planned.
 

Challenges and unanswered questions

Virchow’s triad was described by the eminent German physician, Rudolf Virchow, MD, in the 19th century. It refers to the three broad categories of factors that can predispose patients to thrombosis — circulatory stasis, hypercoagulability, and endothelial injury.

Although all of these elements could be operative in CAC, the current study suggests platelet activation and endothelial cell injury in CAC may be of primary importance.

Because of the limited ability to test critically ill patients and concerns regarding exposure of additional hospital personnel to COVID-19 patients, the current report lacked clarity about the relationship of the detected laboratory abnormalities to confirmed thrombotic events.

It is unknown whether endothelial cells in different organs are damaged uniformly. It is also unclear if the laboratory abnormalities identified in this analysis can be used to monitor response to therapy, to guide follow-up management of discharged patients with CAC, or to identify infected outpatients who should receive prophylactic anticoagulation.

The mechanism by which SARS-CoV-2 injures endothelial cells is not explained by these data. Neutrophil defensins and other prothrombotic peptides or markers of inflammation could play key roles in pathogenesis, assessment of disease severity, or monitoring for therapeutic efficacy.

Today, we have more sophisticated diagnostic tools than Dr. Virchow had. We also have the ability to record and rapidly disseminate information globally. Still, with regard to the COVID-19 pandemic, clinicians face many of the same challenges that confronted Dr. Virchow in his era.

The analysis conducted by Dr. Goshua and colleagues goes a long way toward elucidating some of the mechanisms and therapeutic targets to meet these challenges.

Dr. Goshua disclosed no conflicts of interest.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Goshua G et al. EHA Congress. Abstract LB2605.

References

1. Klok FA et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis. Thromb Res. 2020;191:148-50. doi: 10.1016/j.thromres.2020.04.041.

2. Thomas W et al. Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom. Thromb Res. 2020;191:76-7. doi: 10.1016/j.thromres.2020.04.028

3. Lodigiani C et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020;191:9-14. doi: 10.1016/j.thromres.2020.04.024

4. Llitjos JF et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients [published online ahead of print, 2020 Apr 22]. J Thromb Haemost. 2020;10.1111/jth.14869. doi: 10.1111/jth.14869

5. Carsana L et al. Pulmonary post-mortem findings in a large series of COVID-19 cases from Northern Italy. medRxiv 2020.04.19.20054262; doi: 10.1101/2020.04.19.20054262v1.

6. Menter T et al. Post-mortem examination of COVID19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction [published online ahead of print, 2020 May 4]. Histopathology. 2020;10.1111/his.14134. doi: 10.1111/his.14134

7. Lax SF, et al. Pulmonary arterial thrombosis in COVID-19 with fatal outcome: Results from a prospective, single-center, clinicopathologic case series [published online ahead of print, 2020 May 14]. Ann Intern Med. 2020;M20-2566. doi: 10.7326/M20-2566.

A striking clinical feature of illness from SARS-CoV-2 is a marked increase in thrombotic and microvascular complications, or COVID-19–associated coagulopathy (CAC).

A new study suggests endothelial cell injury plays a major role in the pathogenesis of CAC, and blood levels of soluble thrombomodulin correlate with mortality.

George Goshua, MD, of Yale University, New Haven, Conn., presented this study as a late-breaking abstract at the virtual annual congress of the European Hematology Association.

Dr. Goshua cited past research showing CAC to be highly prevalent among hospitalized patients. Venous thromboembolism was found in 17% to 69% of patients, despite thromboprophylaxis.^1-4 Arterial thrombosis has been seen in 3.6% to 4.0% of patients,^1-3 and autopsy findings have shown microvascular thrombosis in as many as 87% of patients.^5-7

For their study, Dr. Goshua and colleagues assessed endothelial cell damage, platelet activation, and hemostatic and fibrinolytic cascade effects of CAC.

The investigators measured markers of endothelial cell injury and platelet activation, plasminogen activation inhibitor 1 (PAI-1), and coagulation factors in stable and critically ill patients hospitalized with COVID-19. In addition, the team sought to identify biomarkers of mortality in hospitalized patients.

Dr. Goshua and colleagues studied 68 adults hospitalized for suspected COVID-19 – 48 in the ICU and 20 outside the ICU. Patients in the ICU received mechanical ventilation, while the non-ICU patients required supplemental oxygen (≤3 L/min per nasal cannula).

There were more men than women (69% vs. 31%) in the ICU population but not in the non-ICU population (40% vs. 60%). There were no statistically significant differences in age or comorbid conditions between the ICU and non-ICU patients.
 

Results and interpretation

Consistent with augmentation of the coagulation cascade – and as expected – D-dimer and thrombin-antithrombin levels were high in both the ICU and non-ICU populations, but levels were significantly higher (P < .001) among the ICU patients.

Endogenous anticoagulants (antithrombin and proteins C and S) and fibrinolytic enzymes (alpha 2-antiplasmin) were preserved, verifying that CAC is distinct from disseminated intravascular coagulation. Classic fibrinolysis did not occur, as PAI-1 was high in ICU and non-ICU patients, and lysis-30 was normal in nearly all ICU patients (96%).

Von Willebrand factor antigen and activity levels and factor VIII levels were markedly elevated in non-ICU and ICU patients, but they were significantly higher (P < .001) in the ICU cohort. This supports the hypothesis that endothelial cell damage and platelet activation play major roles in CAC.

Similarly, soluble P-selectin, which is shed from endothelial cells and platelets, was dramatically elevated in ICU patients in comparison with controls and non-ICU patients (P < .001 for both comparisons).

Levels of soluble thrombomodulin, which is released from endothelial cells, were not significantly different in ICU patients and controls. However, given thrombomodulin’s significant role in the coagulation cascade, Dr. Goshua and colleagues plotted receiver operating curves to see if soluble thrombomodulin levels were predictive of mortality.

The results showed that soluble thrombomodulin correlated with the probability of survival, both overall and in ICU patients. Soluble thrombomodulin levels greater than 3.26 ng/mL were associated with significantly worse survival in all patients (P = .0087) and ICU patients (P = .0309).
 

Influence on therapy

Laboratory perturbations were detected in both ICU and non-ICU patients, and otherwise healthy outpatients have exhibited potentially life-threatening CAC, according to Dr. Goshua.

These findings suggest the prothrombotic state occurs early in the pathogenesis of SARS-CoV-2 infection, is driven by platelet activation and endotheliopathy, and becomes more pronounced with worsening severity of infection.

The results of this study prompted a change in how Yale–New Haven Hospital manages COVID-19 patients. Patients without a clinical contraindication now receive aspirin at 81 mg daily in addition to the anticoagulation regimen typically used for all hospitalized COVID-19 patients.

Investigations regarding other medications that can influence platelet-endothelial cell interactions and modulate endothelial cell damage in CAC – such as dipyridamole, defibrotide, and eculizumab – are planned.
 

Challenges and unanswered questions

Virchow’s triad was described by the eminent German physician, Rudolf Virchow, MD, in the 19th century. It refers to the three broad categories of factors that can predispose patients to thrombosis — circulatory stasis, hypercoagulability, and endothelial injury.

Although all of these elements could be operative in CAC, the current study suggests platelet activation and endothelial cell injury in CAC may be of primary importance.

Because of the limited ability to test critically ill patients and concerns regarding exposure of additional hospital personnel to COVID-19 patients, the current report lacked clarity about the relationship of the detected laboratory abnormalities to confirmed thrombotic events.

It is unknown whether endothelial cells in different organs are damaged uniformly. It is also unclear if the laboratory abnormalities identified in this analysis can be used to monitor response to therapy, to guide follow-up management of discharged patients with CAC, or to identify infected outpatients who should receive prophylactic anticoagulation.

The mechanism by which SARS-CoV-2 injures endothelial cells is not explained by these data. Neutrophil defensins and other prothrombotic peptides or markers of inflammation could play key roles in pathogenesis, assessment of disease severity, or monitoring for therapeutic efficacy.

Today, we have more sophisticated diagnostic tools than Dr. Virchow had. We also have the ability to record and rapidly disseminate information globally. Still, with regard to the COVID-19 pandemic, clinicians face many of the same challenges that confronted Dr. Virchow in his era.

The analysis conducted by Dr. Goshua and colleagues goes a long way toward elucidating some of the mechanisms and therapeutic targets to meet these challenges.

Dr. Goshua disclosed no conflicts of interest.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Goshua G et al. EHA Congress. Abstract LB2605.

References

1. Klok FA et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis. Thromb Res. 2020;191:148-50. doi: 10.1016/j.thromres.2020.04.041.

2. Thomas W et al. Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom. Thromb Res. 2020;191:76-7. doi: 10.1016/j.thromres.2020.04.028

3. Lodigiani C et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020;191:9-14. doi: 10.1016/j.thromres.2020.04.024

4. Llitjos JF et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients [published online ahead of print, 2020 Apr 22]. J Thromb Haemost. 2020;10.1111/jth.14869. doi: 10.1111/jth.14869

5. Carsana L et al. Pulmonary post-mortem findings in a large series of COVID-19 cases from Northern Italy. medRxiv 2020.04.19.20054262; doi: 10.1101/2020.04.19.20054262v1.

6. Menter T et al. Post-mortem examination of COVID19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction [published online ahead of print, 2020 May 4]. Histopathology. 2020;10.1111/his.14134. doi: 10.1111/his.14134

7. Lax SF, et al. Pulmonary arterial thrombosis in COVID-19 with fatal outcome: Results from a prospective, single-center, clinicopathologic case series [published online ahead of print, 2020 May 14]. Ann Intern Med. 2020;M20-2566. doi: 10.7326/M20-2566.

A striking clinical feature of illness from SARS-CoV-2 is a marked increase in thrombotic and microvascular complications, or COVID-19–associated coagulopathy (CAC).

A new study suggests endothelial cell injury plays a major role in the pathogenesis of CAC, and blood levels of soluble thrombomodulin correlate with mortality.

George Goshua, MD, of Yale University, New Haven, Conn., presented this study as a late-breaking abstract at the virtual annual congress of the European Hematology Association.

Dr. Goshua cited past research showing CAC to be highly prevalent among hospitalized patients. Venous thromboembolism was found in 17% to 69% of patients, despite thromboprophylaxis.^1-4 Arterial thrombosis has been seen in 3.6% to 4.0% of patients,^1-3 and autopsy findings have shown microvascular thrombosis in as many as 87% of patients.^5-7

For their study, Dr. Goshua and colleagues assessed endothelial cell damage, platelet activation, and hemostatic and fibrinolytic cascade effects of CAC.

The investigators measured markers of endothelial cell injury and platelet activation, plasminogen activation inhibitor 1 (PAI-1), and coagulation factors in stable and critically ill patients hospitalized with COVID-19. In addition, the team sought to identify biomarkers of mortality in hospitalized patients.

Dr. Goshua and colleagues studied 68 adults hospitalized for suspected COVID-19 – 48 in the ICU and 20 outside the ICU. Patients in the ICU received mechanical ventilation, while the non-ICU patients required supplemental oxygen (≤3 L/min per nasal cannula).

There were more men than women (69% vs. 31%) in the ICU population but not in the non-ICU population (40% vs. 60%). There were no statistically significant differences in age or comorbid conditions between the ICU and non-ICU patients.
 

Results and interpretation

Consistent with augmentation of the coagulation cascade – and as expected – D-dimer and thrombin-antithrombin levels were high in both the ICU and non-ICU populations, but levels were significantly higher (P < .001) among the ICU patients.

Endogenous anticoagulants (antithrombin and proteins C and S) and fibrinolytic enzymes (alpha 2-antiplasmin) were preserved, verifying that CAC is distinct from disseminated intravascular coagulation. Classic fibrinolysis did not occur, as PAI-1 was high in ICU and non-ICU patients, and lysis-30 was normal in nearly all ICU patients (96%).

Von Willebrand factor antigen and activity levels and factor VIII levels were markedly elevated in non-ICU and ICU patients, but they were significantly higher (P < .001) in the ICU cohort. This supports the hypothesis that endothelial cell damage and platelet activation play major roles in CAC.

Similarly, soluble P-selectin, which is shed from endothelial cells and platelets, was dramatically elevated in ICU patients in comparison with controls and non-ICU patients (P < .001 for both comparisons).

Levels of soluble thrombomodulin, which is released from endothelial cells, were not significantly different in ICU patients and controls. However, given thrombomodulin’s significant role in the coagulation cascade, Dr. Goshua and colleagues plotted receiver operating curves to see if soluble thrombomodulin levels were predictive of mortality.

The results showed that soluble thrombomodulin correlated with the probability of survival, both overall and in ICU patients. Soluble thrombomodulin levels greater than 3.26 ng/mL were associated with significantly worse survival in all patients (P = .0087) and ICU patients (P = .0309).
 

Influence on therapy

Laboratory perturbations were detected in both ICU and non-ICU patients, and otherwise healthy outpatients have exhibited potentially life-threatening CAC, according to Dr. Goshua.

These findings suggest the prothrombotic state occurs early in the pathogenesis of SARS-CoV-2 infection, is driven by platelet activation and endotheliopathy, and becomes more pronounced with worsening severity of infection.

The results of this study prompted a change in how Yale–New Haven Hospital manages COVID-19 patients. Patients without a clinical contraindication now receive aspirin at 81 mg daily in addition to the anticoagulation regimen typically used for all hospitalized COVID-19 patients.

Investigations regarding other medications that can influence platelet-endothelial cell interactions and modulate endothelial cell damage in CAC – such as dipyridamole, defibrotide, and eculizumab – are planned.
 

Challenges and unanswered questions

Virchow’s triad was described by the eminent German physician, Rudolf Virchow, MD, in the 19th century. It refers to the three broad categories of factors that can predispose patients to thrombosis — circulatory stasis, hypercoagulability, and endothelial injury.

Although all of these elements could be operative in CAC, the current study suggests platelet activation and endothelial cell injury in CAC may be of primary importance.

Because of the limited ability to test critically ill patients and concerns regarding exposure of additional hospital personnel to COVID-19 patients, the current report lacked clarity about the relationship of the detected laboratory abnormalities to confirmed thrombotic events.

It is unknown whether endothelial cells in different organs are damaged uniformly. It is also unclear if the laboratory abnormalities identified in this analysis can be used to monitor response to therapy, to guide follow-up management of discharged patients with CAC, or to identify infected outpatients who should receive prophylactic anticoagulation.

The mechanism by which SARS-CoV-2 injures endothelial cells is not explained by these data. Neutrophil defensins and other prothrombotic peptides or markers of inflammation could play key roles in pathogenesis, assessment of disease severity, or monitoring for therapeutic efficacy.

Today, we have more sophisticated diagnostic tools than Dr. Virchow had. We also have the ability to record and rapidly disseminate information globally. Still, with regard to the COVID-19 pandemic, clinicians face many of the same challenges that confronted Dr. Virchow in his era.

The analysis conducted by Dr. Goshua and colleagues goes a long way toward elucidating some of the mechanisms and therapeutic targets to meet these challenges.

Dr. Goshua disclosed no conflicts of interest.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Goshua G et al. EHA Congress. Abstract LB2605.

References

1. Klok FA et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis. Thromb Res. 2020;191:148-50. doi: 10.1016/j.thromres.2020.04.041.

2. Thomas W et al. Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom. Thromb Res. 2020;191:76-7. doi: 10.1016/j.thromres.2020.04.028

3. Lodigiani C et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020;191:9-14. doi: 10.1016/j.thromres.2020.04.024

4. Llitjos JF et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients [published online ahead of print, 2020 Apr 22]. J Thromb Haemost. 2020;10.1111/jth.14869. doi: 10.1111/jth.14869

5. Carsana L et al. Pulmonary post-mortem findings in a large series of COVID-19 cases from Northern Italy. medRxiv 2020.04.19.20054262; doi: 10.1101/2020.04.19.20054262v1.

6. Menter T et al. Post-mortem examination of COVID19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction [published online ahead of print, 2020 May 4]. Histopathology. 2020;10.1111/his.14134. doi: 10.1111/his.14134

7. Lax SF, et al. Pulmonary arterial thrombosis in COVID-19 with fatal outcome: Results from a prospective, single-center, clinicopathologic case series [published online ahead of print, 2020 May 14]. Ann Intern Med. 2020;M20-2566. doi: 10.7326/M20-2566.

The use of CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin, was tied to long-term remission and survival in older patients with newly diagnosed high-risk or secondary acute myeloid leukemia (AML), according to final results of a phase 3 study.

As part of the American Society of Clinical Oncology virtual scientific program, Jeffrey E. Lancet, MD, of the Moffitt Cancer Center in Tampa, Fla., presented the 5-year final data from a trial comparing CPX-351 vs. the conventional 7+3 regimen of cytarabine and daunorubicin in more than 300 older adult patients (age 60-75 years) with newly diagnosed high-risk or secondary AML. Early mortality rates for CPX-351 vs. 7+3 were 6% vs. 11% at Day 30 and 14% vs. 21% at day 60, respectively.

The final 5-year follow-up results had a median follow-up of just greater than 60 months, and maintained the improved median overall survival previously observed in the trial with CPX-351 (153 patients), compared with 7+3 (155 patients), Dr. Lancet reported.

Allogeneic hematopoietic stem cell transplant was received by 35% of the patients in the CPX-351 arm and 25% of patients in the 7+3 arm. The median overall survival after transplant was not reached for the CPX-351 arm, compared with 10.3 months with the 7+3 treated patients.

Remission, either complete remission or complete remission with incomplete neutrophil or platelet recovery, was achieved by 48% of patients in the CPX-351 arm and 33% of patients in the 7+3 arm, according to the results of the 5-year follow-up. In addition, among all patients who achieved remission, median overall survival was longer with CPX-351 than with 7+3, and the Kaplan-Meier estimated survival rate was higher for CPX-351 at both 3 years and 5 years.

At 5 years of follow-up, 81% of patients in the CPX-351 arm and 93% of patients in the 7+3 arm had died, with similar causes cited in each arm. Progressive leukemia was the most common primary cause of death in both treatment arms, according to Dr. Lancet.

“The final 5-year follow-up results from this phase 3 study support the prior evidence that CPX-351 has the ability to produce or contribute to long-term remission and survival in older patients with newly diagnosed high-risk or secondary AML,” Dr. Lancet concluded.

CPX-351 (Vyxeos) has been approved by the Food and Drug Administration and the European Medicines Agency for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplastic syndrome–related changes.

The study was funded by Jazz Pharmaceuticals. Dr. Lancet disclosed that he has a consulting or advisory role for Agios, Daiichi Sankyo, Jazz Pharmaceuticals, and Pfizer.

mlesney@mdedge.com

SOURCE: Lancet JE et al. ASCO 2020, Abstract 7510.

The use of CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin, was tied to long-term remission and survival in older patients with newly diagnosed high-risk or secondary acute myeloid leukemia (AML), according to final results of a phase 3 study.

As part of the American Society of Clinical Oncology virtual scientific program, Jeffrey E. Lancet, MD, of the Moffitt Cancer Center in Tampa, Fla., presented the 5-year final data from a trial comparing CPX-351 vs. the conventional 7+3 regimen of cytarabine and daunorubicin in more than 300 older adult patients (age 60-75 years) with newly diagnosed high-risk or secondary AML. Early mortality rates for CPX-351 vs. 7+3 were 6% vs. 11% at Day 30 and 14% vs. 21% at day 60, respectively.

The final 5-year follow-up results had a median follow-up of just greater than 60 months, and maintained the improved median overall survival previously observed in the trial with CPX-351 (153 patients), compared with 7+3 (155 patients), Dr. Lancet reported.

Allogeneic hematopoietic stem cell transplant was received by 35% of the patients in the CPX-351 arm and 25% of patients in the 7+3 arm. The median overall survival after transplant was not reached for the CPX-351 arm, compared with 10.3 months with the 7+3 treated patients.

Remission, either complete remission or complete remission with incomplete neutrophil or platelet recovery, was achieved by 48% of patients in the CPX-351 arm and 33% of patients in the 7+3 arm, according to the results of the 5-year follow-up. In addition, among all patients who achieved remission, median overall survival was longer with CPX-351 than with 7+3, and the Kaplan-Meier estimated survival rate was higher for CPX-351 at both 3 years and 5 years.

At 5 years of follow-up, 81% of patients in the CPX-351 arm and 93% of patients in the 7+3 arm had died, with similar causes cited in each arm. Progressive leukemia was the most common primary cause of death in both treatment arms, according to Dr. Lancet.

“The final 5-year follow-up results from this phase 3 study support the prior evidence that CPX-351 has the ability to produce or contribute to long-term remission and survival in older patients with newly diagnosed high-risk or secondary AML,” Dr. Lancet concluded.

CPX-351 (Vyxeos) has been approved by the Food and Drug Administration and the European Medicines Agency for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplastic syndrome–related changes.

The study was funded by Jazz Pharmaceuticals. Dr. Lancet disclosed that he has a consulting or advisory role for Agios, Daiichi Sankyo, Jazz Pharmaceuticals, and Pfizer.

mlesney@mdedge.com

SOURCE: Lancet JE et al. ASCO 2020, Abstract 7510.

The use of CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin, was tied to long-term remission and survival in older patients with newly diagnosed high-risk or secondary acute myeloid leukemia (AML), according to final results of a phase 3 study.

As part of the American Society of Clinical Oncology virtual scientific program, Jeffrey E. Lancet, MD, of the Moffitt Cancer Center in Tampa, Fla., presented the 5-year final data from a trial comparing CPX-351 vs. the conventional 7+3 regimen of cytarabine and daunorubicin in more than 300 older adult patients (age 60-75 years) with newly diagnosed high-risk or secondary AML. Early mortality rates for CPX-351 vs. 7+3 were 6% vs. 11% at Day 30 and 14% vs. 21% at day 60, respectively.

The final 5-year follow-up results had a median follow-up of just greater than 60 months, and maintained the improved median overall survival previously observed in the trial with CPX-351 (153 patients), compared with 7+3 (155 patients), Dr. Lancet reported.

Allogeneic hematopoietic stem cell transplant was received by 35% of the patients in the CPX-351 arm and 25% of patients in the 7+3 arm. The median overall survival after transplant was not reached for the CPX-351 arm, compared with 10.3 months with the 7+3 treated patients.

Remission, either complete remission or complete remission with incomplete neutrophil or platelet recovery, was achieved by 48% of patients in the CPX-351 arm and 33% of patients in the 7+3 arm, according to the results of the 5-year follow-up. In addition, among all patients who achieved remission, median overall survival was longer with CPX-351 than with 7+3, and the Kaplan-Meier estimated survival rate was higher for CPX-351 at both 3 years and 5 years.

At 5 years of follow-up, 81% of patients in the CPX-351 arm and 93% of patients in the 7+3 arm had died, with similar causes cited in each arm. Progressive leukemia was the most common primary cause of death in both treatment arms, according to Dr. Lancet.

“The final 5-year follow-up results from this phase 3 study support the prior evidence that CPX-351 has the ability to produce or contribute to long-term remission and survival in older patients with newly diagnosed high-risk or secondary AML,” Dr. Lancet concluded.

CPX-351 (Vyxeos) has been approved by the Food and Drug Administration and the European Medicines Agency for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplastic syndrome–related changes.

The study was funded by Jazz Pharmaceuticals. Dr. Lancet disclosed that he has a consulting or advisory role for Agios, Daiichi Sankyo, Jazz Pharmaceuticals, and Pfizer.

mlesney@mdedge.com

SOURCE: Lancet JE et al. ASCO 2020, Abstract 7510.

At about 18 months’ follow-up in treatment naive acute myelogenous leukemia (AML) patients who were 75 years or older or otherwise unfit for intensive chemotherapy, median overall survival (OS) was 8.4 months when they were randomized to low-dose cytarabine (LDAC) plus the BCL-2 inhibitor venetoclax versus 4.1 months with LDAC plus placebo. The results from the phase 3 trial were reported at the virtual annual congress of the European Hematology Association.

The combination also improved rates of remission, event-free survival, and patient reported outcomes and lessened transfusion requirements. Adverse events were manageable.

The findings position venetoclax add-on with LDAC “as a potential new standard of care” for untreated patients ineligible for intensive chemotherapy, lead investigator Andrew Wei, MD, PhD, an AML researcher at Monash University, Melbourne, said at the meeting.

The study addresses a substantial unmet need. The median age at AML diagnosis is over 68 years old and comorbidities such as heart failure and reduced creatinine clearance are common, which make the risk of toxicity with standard chemotherapy too high. Single-agent alternatives are of limited benefit, so Dr. Wei’s group and others are looking for better options to plug the treatment gap when standard chemotherapy is contraindicated.

Several combinations are under investigation, including LDAC plus venetoclax, which appears to have a synergistic effect greater than either agent on its own, Dr. Wei and colleagues explained in their journal report, which was published online to coincide with his presentation (Blood. 2020 Jun 11;135(24):2137-45).

“A challenging AML population”

In the study, 143 patients were randomized to oral venetoclax 600 mg daily and 68 to placebo in 28-day cycles, on a background of LDAC 20 mg/m² administered subcutaneously on days 1-10 of each cycle.

“This study enrolled a challenging AML population, with nearly 60% age ≥75 years and a high proportion of patients with secondary disease (38%), prior hypomethylating agent (HMA) treatment (20%), poor cytogenetic risk (32%), and TP53 mutations (15%), which are known factors associated with dismal prognosis in AML,” the investigators noted in their report.

There was a numerical benefit in OS at 12 months – the preplanned primary outcome – but it was not statistically significant. At 18 months, however, and after adjustment for a higher rate of secondary AML in the venetoclax arm and other confounders in a post hoc analysis, survival differences reached significance. The 4.3-month OS benefit with the combination translated into a 30% reduction in the risk of death (hazard ratio, 0.70; 95% confidence interval, 0.50-0.99; P = .04)

Survival outcomes “were particularly promising for patient subgroups with NPM1- (median OS, not reached) and IDH1/2-mutant AML (median OS, 19.4 months),” the team noted.

Complete remission (CR) were 48% in the venetoclax arm, compared with 13% in the placebo group, and 34% of venetoclax patients versus 3% of placebo patients went into remission after their first cycle. Venetoclax subjects also had longer median event free survival (4.7 months vs. 2 months); higher rates of red blood cell and platelet transfusion independence (37% vs. 16%); and higher rates of cytometric minimal residual disease levels below 0.1% (6% vs. 1%).

The findings correlated with “strong improvements” in patient-reported outcomes, including fatigue and quality of life, the investigators reported.
 

Risk mitigation

Grade 3 or higher adverse events (AEs) included febrile neutropenia (32% in the venetoclax arm versus 29% in the placebo group), neutropenia (47% venetoclax vs. 16% placebo), thrombocytopenia (45% vs. 37%), and anemia (25% vs. 22%). The eight cases of tumor lysis syndrome (TLS) were all in the venetoclax arm. Grade 3 or higher bleeding was higher in the venetoclax arm (11% versus 7%), but the incidence of fatal bleeding was similar between the groups (1.4% venetoclax versus 1.5%).

“Although the venetoclax arm showed modest increases in hematologic AEs, the rate of AEs leading to treatment discontinuation (24% vs. 25%) and the rate of serious AEs such as pneumonia” and sepsis “were nearly identical between” the arms, the team said.

The combination “is more myelosuppressive,” but the effects “were mostly mitigated by venetoclax dose interruptions and reductions.” To mitigate the TLS risk, patients were hospitalized for TLS evaluation and prophylaxis during the 4-day venetoclax ramp-up in the first treatment cycle and for 24 hours after the 600-mg target was reached. “I think this is an extremely important measure to avoid this small but important complication,” Dr. Wei said at the meeting.
 

A moderate step forward

Dr. Lowenberg and Dr. Huls noted in their commentary that, despite the favorable outcomes, “the results are still sobering with a rapid drop of the survival curves to values of [around] 25% or less within 18 months, and event-free survival rates even falling to considerably lower levels.”

Also, there was a “weak correlation between the relatively wide differences in comparative CR/CRi rates and the much smaller differences in survival,” perhaps “due to a limited depth of the complete responses following venetoclax-LDAC therapy or the early development of therapeutic resistance,” they said.

The commentary also noted another option, adding the hedgehog pathway inhibitor glasdegib, instead of venetoclax, to LDAC. It also improved survival in a similar randomized study in unfit AML and high-risk myelodysplastic syndrome patients, from a median survival of 4.9 months with LDAC alone to 8.8 months with the combination (Leukemia. 2019 Feb;33(2):379-389. doi: 10.1038/s41375-018-0312-9).
 

Dueling regimens

Another alternative approach – venetoclax plus the HMA agent azacitidine – garnered a lot of attention at the meeting when it was reported that the combination had a median overall survival of 14.7 months, versus 9.6 months with azacitidine alone, in patients ineligible for intensive chemotherapy. CR/CRi rates were 66% with the combination, versus 28%.

“It seems like the results were better with the combination of venetoclax and azacitidine” than venetoclax plus LDAC, said Gunnar Juliusson, MD, PhD, of Lund (Sweden) University, who moderated Dr. Wei’s presentation.

He wanted to know if there was a way to identify patients who would do better on one regimen versus the other and was curious about the fact that the azacitidine study used a dose of 400 mg venetoclax, instead of 600 mg.

Dr. Wei noted the high incidence of poor prognostic factors in his study, including prior HMA treatment in 20%, but also that “we don’t know for sure” if there’s a clinically meaningful benefit with the higher dose.

He also said the optimal number of venetoclax cycles for best response is unknown. For now, treatment is “recommend until either [disease] progression, dose intolerance, or patient or physician preference,” he noted. Venetoclax subjects in his study had a median of four treatment cycles versus two in the placebo group. Combination patients in the azacitidine study had a median of seven cycles versus 4.5 with placebo.

Venetoclax already carries an indication in the United States in combination with azacitidine, decitabine, or LDAC for newly-diagnosed AML in adults 75 years or older or who have comorbidities that preclude use of intensive induction chemotherapy, at a daily dosage of 400 mg with HMAs and 600 mg with LDAC.

Labeling notes that “continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.”

Both venetoclax trials were sponsored by the drug’s maker, AbbVie, which was involved with data interpretation and other matters. Dr. Wei is a consultant for and receives research funding from the company and also receives royalty payments in relation to venetoclax. The commentators did not have any competing financial interests. Disclosures, if any, were not reported for Dr. Juliusson.
 

aotto@mdedge.com

SOURCE: Wei AH et al. EHA Congress, Abstract S136.

At about 18 months’ follow-up in treatment naive acute myelogenous leukemia (AML) patients who were 75 years or older or otherwise unfit for intensive chemotherapy, median overall survival (OS) was 8.4 months when they were randomized to low-dose cytarabine (LDAC) plus the BCL-2 inhibitor venetoclax versus 4.1 months with LDAC plus placebo. The results from the phase 3 trial were reported at the virtual annual congress of the European Hematology Association.

The combination also improved rates of remission, event-free survival, and patient reported outcomes and lessened transfusion requirements. Adverse events were manageable.

The findings position venetoclax add-on with LDAC “as a potential new standard of care” for untreated patients ineligible for intensive chemotherapy, lead investigator Andrew Wei, MD, PhD, an AML researcher at Monash University, Melbourne, said at the meeting.

The study addresses a substantial unmet need. The median age at AML diagnosis is over 68 years old and comorbidities such as heart failure and reduced creatinine clearance are common, which make the risk of toxicity with standard chemotherapy too high. Single-agent alternatives are of limited benefit, so Dr. Wei’s group and others are looking for better options to plug the treatment gap when standard chemotherapy is contraindicated.

Several combinations are under investigation, including LDAC plus venetoclax, which appears to have a synergistic effect greater than either agent on its own, Dr. Wei and colleagues explained in their journal report, which was published online to coincide with his presentation (Blood. 2020 Jun 11;135(24):2137-45).

“A challenging AML population”

In the study, 143 patients were randomized to oral venetoclax 600 mg daily and 68 to placebo in 28-day cycles, on a background of LDAC 20 mg/m² administered subcutaneously on days 1-10 of each cycle.

“This study enrolled a challenging AML population, with nearly 60% age ≥75 years and a high proportion of patients with secondary disease (38%), prior hypomethylating agent (HMA) treatment (20%), poor cytogenetic risk (32%), and TP53 mutations (15%), which are known factors associated with dismal prognosis in AML,” the investigators noted in their report.

There was a numerical benefit in OS at 12 months – the preplanned primary outcome – but it was not statistically significant. At 18 months, however, and after adjustment for a higher rate of secondary AML in the venetoclax arm and other confounders in a post hoc analysis, survival differences reached significance. The 4.3-month OS benefit with the combination translated into a 30% reduction in the risk of death (hazard ratio, 0.70; 95% confidence interval, 0.50-0.99; P = .04)

Survival outcomes “were particularly promising for patient subgroups with NPM1- (median OS, not reached) and IDH1/2-mutant AML (median OS, 19.4 months),” the team noted.

Complete remission (CR) were 48% in the venetoclax arm, compared with 13% in the placebo group, and 34% of venetoclax patients versus 3% of placebo patients went into remission after their first cycle. Venetoclax subjects also had longer median event free survival (4.7 months vs. 2 months); higher rates of red blood cell and platelet transfusion independence (37% vs. 16%); and higher rates of cytometric minimal residual disease levels below 0.1% (6% vs. 1%).

The findings correlated with “strong improvements” in patient-reported outcomes, including fatigue and quality of life, the investigators reported.
 

Risk mitigation

Grade 3 or higher adverse events (AEs) included febrile neutropenia (32% in the venetoclax arm versus 29% in the placebo group), neutropenia (47% venetoclax vs. 16% placebo), thrombocytopenia (45% vs. 37%), and anemia (25% vs. 22%). The eight cases of tumor lysis syndrome (TLS) were all in the venetoclax arm. Grade 3 or higher bleeding was higher in the venetoclax arm (11% versus 7%), but the incidence of fatal bleeding was similar between the groups (1.4% venetoclax versus 1.5%).

“Although the venetoclax arm showed modest increases in hematologic AEs, the rate of AEs leading to treatment discontinuation (24% vs. 25%) and the rate of serious AEs such as pneumonia” and sepsis “were nearly identical between” the arms, the team said.

The combination “is more myelosuppressive,” but the effects “were mostly mitigated by venetoclax dose interruptions and reductions.” To mitigate the TLS risk, patients were hospitalized for TLS evaluation and prophylaxis during the 4-day venetoclax ramp-up in the first treatment cycle and for 24 hours after the 600-mg target was reached. “I think this is an extremely important measure to avoid this small but important complication,” Dr. Wei said at the meeting.
 

A moderate step forward

Dr. Lowenberg and Dr. Huls noted in their commentary that, despite the favorable outcomes, “the results are still sobering with a rapid drop of the survival curves to values of [around] 25% or less within 18 months, and event-free survival rates even falling to considerably lower levels.”

Also, there was a “weak correlation between the relatively wide differences in comparative CR/CRi rates and the much smaller differences in survival,” perhaps “due to a limited depth of the complete responses following venetoclax-LDAC therapy or the early development of therapeutic resistance,” they said.

The commentary also noted another option, adding the hedgehog pathway inhibitor glasdegib, instead of venetoclax, to LDAC. It also improved survival in a similar randomized study in unfit AML and high-risk myelodysplastic syndrome patients, from a median survival of 4.9 months with LDAC alone to 8.8 months with the combination (Leukemia. 2019 Feb;33(2):379-389. doi: 10.1038/s41375-018-0312-9).
 

Dueling regimens

Another alternative approach – venetoclax plus the HMA agent azacitidine – garnered a lot of attention at the meeting when it was reported that the combination had a median overall survival of 14.7 months, versus 9.6 months with azacitidine alone, in patients ineligible for intensive chemotherapy. CR/CRi rates were 66% with the combination, versus 28%.

“It seems like the results were better with the combination of venetoclax and azacitidine” than venetoclax plus LDAC, said Gunnar Juliusson, MD, PhD, of Lund (Sweden) University, who moderated Dr. Wei’s presentation.

He wanted to know if there was a way to identify patients who would do better on one regimen versus the other and was curious about the fact that the azacitidine study used a dose of 400 mg venetoclax, instead of 600 mg.

Dr. Wei noted the high incidence of poor prognostic factors in his study, including prior HMA treatment in 20%, but also that “we don’t know for sure” if there’s a clinically meaningful benefit with the higher dose.

He also said the optimal number of venetoclax cycles for best response is unknown. For now, treatment is “recommend until either [disease] progression, dose intolerance, or patient or physician preference,” he noted. Venetoclax subjects in his study had a median of four treatment cycles versus two in the placebo group. Combination patients in the azacitidine study had a median of seven cycles versus 4.5 with placebo.

Venetoclax already carries an indication in the United States in combination with azacitidine, decitabine, or LDAC for newly-diagnosed AML in adults 75 years or older or who have comorbidities that preclude use of intensive induction chemotherapy, at a daily dosage of 400 mg with HMAs and 600 mg with LDAC.

Labeling notes that “continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.”

Both venetoclax trials were sponsored by the drug’s maker, AbbVie, which was involved with data interpretation and other matters. Dr. Wei is a consultant for and receives research funding from the company and also receives royalty payments in relation to venetoclax. The commentators did not have any competing financial interests. Disclosures, if any, were not reported for Dr. Juliusson.
 

aotto@mdedge.com

SOURCE: Wei AH et al. EHA Congress, Abstract S136.

At about 18 months’ follow-up in treatment naive acute myelogenous leukemia (AML) patients who were 75 years or older or otherwise unfit for intensive chemotherapy, median overall survival (OS) was 8.4 months when they were randomized to low-dose cytarabine (LDAC) plus the BCL-2 inhibitor venetoclax versus 4.1 months with LDAC plus placebo. The results from the phase 3 trial were reported at the virtual annual congress of the European Hematology Association.

The combination also improved rates of remission, event-free survival, and patient reported outcomes and lessened transfusion requirements. Adverse events were manageable.

The findings position venetoclax add-on with LDAC “as a potential new standard of care” for untreated patients ineligible for intensive chemotherapy, lead investigator Andrew Wei, MD, PhD, an AML researcher at Monash University, Melbourne, said at the meeting.

The study addresses a substantial unmet need. The median age at AML diagnosis is over 68 years old and comorbidities such as heart failure and reduced creatinine clearance are common, which make the risk of toxicity with standard chemotherapy too high. Single-agent alternatives are of limited benefit, so Dr. Wei’s group and others are looking for better options to plug the treatment gap when standard chemotherapy is contraindicated.

Several combinations are under investigation, including LDAC plus venetoclax, which appears to have a synergistic effect greater than either agent on its own, Dr. Wei and colleagues explained in their journal report, which was published online to coincide with his presentation (Blood. 2020 Jun 11;135(24):2137-45).

“A challenging AML population”

In the study, 143 patients were randomized to oral venetoclax 600 mg daily and 68 to placebo in 28-day cycles, on a background of LDAC 20 mg/m² administered subcutaneously on days 1-10 of each cycle.

“This study enrolled a challenging AML population, with nearly 60% age ≥75 years and a high proportion of patients with secondary disease (38%), prior hypomethylating agent (HMA) treatment (20%), poor cytogenetic risk (32%), and TP53 mutations (15%), which are known factors associated with dismal prognosis in AML,” the investigators noted in their report.

There was a numerical benefit in OS at 12 months – the preplanned primary outcome – but it was not statistically significant. At 18 months, however, and after adjustment for a higher rate of secondary AML in the venetoclax arm and other confounders in a post hoc analysis, survival differences reached significance. The 4.3-month OS benefit with the combination translated into a 30% reduction in the risk of death (hazard ratio, 0.70; 95% confidence interval, 0.50-0.99; P = .04)

Survival outcomes “were particularly promising for patient subgroups with NPM1- (median OS, not reached) and IDH1/2-mutant AML (median OS, 19.4 months),” the team noted.

Complete remission (CR) were 48% in the venetoclax arm, compared with 13% in the placebo group, and 34% of venetoclax patients versus 3% of placebo patients went into remission after their first cycle. Venetoclax subjects also had longer median event free survival (4.7 months vs. 2 months); higher rates of red blood cell and platelet transfusion independence (37% vs. 16%); and higher rates of cytometric minimal residual disease levels below 0.1% (6% vs. 1%).

The findings correlated with “strong improvements” in patient-reported outcomes, including fatigue and quality of life, the investigators reported.
 

Risk mitigation

Grade 3 or higher adverse events (AEs) included febrile neutropenia (32% in the venetoclax arm versus 29% in the placebo group), neutropenia (47% venetoclax vs. 16% placebo), thrombocytopenia (45% vs. 37%), and anemia (25% vs. 22%). The eight cases of tumor lysis syndrome (TLS) were all in the venetoclax arm. Grade 3 or higher bleeding was higher in the venetoclax arm (11% versus 7%), but the incidence of fatal bleeding was similar between the groups (1.4% venetoclax versus 1.5%).

“Although the venetoclax arm showed modest increases in hematologic AEs, the rate of AEs leading to treatment discontinuation (24% vs. 25%) and the rate of serious AEs such as pneumonia” and sepsis “were nearly identical between” the arms, the team said.

The combination “is more myelosuppressive,” but the effects “were mostly mitigated by venetoclax dose interruptions and reductions.” To mitigate the TLS risk, patients were hospitalized for TLS evaluation and prophylaxis during the 4-day venetoclax ramp-up in the first treatment cycle and for 24 hours after the 600-mg target was reached. “I think this is an extremely important measure to avoid this small but important complication,” Dr. Wei said at the meeting.
 

A moderate step forward

Dr. Lowenberg and Dr. Huls noted in their commentary that, despite the favorable outcomes, “the results are still sobering with a rapid drop of the survival curves to values of [around] 25% or less within 18 months, and event-free survival rates even falling to considerably lower levels.”

Also, there was a “weak correlation between the relatively wide differences in comparative CR/CRi rates and the much smaller differences in survival,” perhaps “due to a limited depth of the complete responses following venetoclax-LDAC therapy or the early development of therapeutic resistance,” they said.

The commentary also noted another option, adding the hedgehog pathway inhibitor glasdegib, instead of venetoclax, to LDAC. It also improved survival in a similar randomized study in unfit AML and high-risk myelodysplastic syndrome patients, from a median survival of 4.9 months with LDAC alone to 8.8 months with the combination (Leukemia. 2019 Feb;33(2):379-389. doi: 10.1038/s41375-018-0312-9).
 

Dueling regimens

Another alternative approach – venetoclax plus the HMA agent azacitidine – garnered a lot of attention at the meeting when it was reported that the combination had a median overall survival of 14.7 months, versus 9.6 months with azacitidine alone, in patients ineligible for intensive chemotherapy. CR/CRi rates were 66% with the combination, versus 28%.

“It seems like the results were better with the combination of venetoclax and azacitidine” than venetoclax plus LDAC, said Gunnar Juliusson, MD, PhD, of Lund (Sweden) University, who moderated Dr. Wei’s presentation.

He wanted to know if there was a way to identify patients who would do better on one regimen versus the other and was curious about the fact that the azacitidine study used a dose of 400 mg venetoclax, instead of 600 mg.

Dr. Wei noted the high incidence of poor prognostic factors in his study, including prior HMA treatment in 20%, but also that “we don’t know for sure” if there’s a clinically meaningful benefit with the higher dose.

He also said the optimal number of venetoclax cycles for best response is unknown. For now, treatment is “recommend until either [disease] progression, dose intolerance, or patient or physician preference,” he noted. Venetoclax subjects in his study had a median of four treatment cycles versus two in the placebo group. Combination patients in the azacitidine study had a median of seven cycles versus 4.5 with placebo.

Venetoclax already carries an indication in the United States in combination with azacitidine, decitabine, or LDAC for newly-diagnosed AML in adults 75 years or older or who have comorbidities that preclude use of intensive induction chemotherapy, at a daily dosage of 400 mg with HMAs and 600 mg with LDAC.

Labeling notes that “continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.”

Both venetoclax trials were sponsored by the drug’s maker, AbbVie, which was involved with data interpretation and other matters. Dr. Wei is a consultant for and receives research funding from the company and also receives royalty payments in relation to venetoclax. The commentators did not have any competing financial interests. Disclosures, if any, were not reported for Dr. Juliusson.
 

aotto@mdedge.com

SOURCE: Wei AH et al. EHA Congress, Abstract S136.

Azacitidine plus enasidenib improved complete and overall responses in newly diagnosed acute myelogenous leukemia with isocitrate dehydrogenase 2 gene mutations, compared with azacitidine alone, but it did not improve overall survival in an open-label, phase 2 trial reported at the virtual annual congress of the European Hematology Association.

“Given the very high cost of” enasidenib, and the lack of survival benefit, Gunnar Juliusson, MD, PhD, of Lund University, Sweden, who moderated the study presentation, wondered if it might make more sense to hold enasidenib in reserve until after progression on azacitidine.

“The challenge is going to be exactly” that, “trying to figure out [if] you use both things together” or in sequence. “You can look at it in both ways,” said lead investigator Courtney DiNardo, MD, associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston.

“We do know” that with enasidenib monotherapy, there’s “a decrement in the rates of remission and in the duration of response” and overall survival in the salvage setting, so there’s “a clear rationale to give it earlier rather than later,” but “I think this study in some ways provides a few more questions than it really answers,” she said at the meeting.

About 15% of AML patients have leukemogenic isocitrate dehydrogenase 2 (IDH2) mutations; enasidenib, an oral small molecule, inhibits the mutant enzyme. The older AML patients are, the more likely they are to have an IDH2 mutation, so the work “is relevant to our older chemotherapy ineligible population,” Dr. DiNardo said.

The trial was prompted by preclinical indications of synergy with azacitidine; alone, each agent has an overall response rate of about 30% in newly diagnosed AML, and a complete remission (CR) rate of about 20%, she explained.

Her team randomized 68 adults with newly diagnosed AML and an IDH2 mutation to enasidenib 100 mg daily on a 28-day cycle with subcutaneous azacitidine 75 mg/m² for 7 days during the cycle, and 33 others to just the azacitidine alone.

Their subjects were ineligible for intensive chemotherapy and had intermediate to poor risk cytogenetics. The median age was 75 years, and Eastern Cooperative Oncology Group performance scores were 2 or less.

The overall response rate was 71% with the combination and 42% in the azacitidine alone arm (P = .0064). Fifty-three percent of combination patients, but 12% of azacitidine alone subjects, had complete remissions (P = .0001). The median duration of response with combination therapy was 24.1 months, versus 12.1 months.

Enasidenib plus azacitidine subjects also had greater drops in mutant IDH2 variant allele frequency (median 83.4% versus 17.7%, P < .01) and levels of the downstream oncometabolite 2-hydroxyglutarate (97.8% versus 54.3%; P < .01).

However, median OS was 22 months in both arms (HR 0.99, 95% CI 0.52, 1.87, P = .97). Although median event-free survival favored the combination – 17.2 months versus 10.8 – the results were not statistically significant (HR 0.59, 95% CI 0.30, 1.17, P = .13).

A possible reason for the lack of survival benefit, Dr. DiNardo said, was that seven azacitidine-alone patients (21%) went on to enasidenib after leaving the study, most commonly for disease progression, which occurred in 31% of combination patients versus 52% in the azacitidine-alone arm.

Combination subjects had a median of 10 treatment cycles, vs. 7 in the azacitidine-alone group. Grade 3-4 adverse events included thrombocytopenia (37% combination, 19% azacitidine-alone), neutropenia (35% vs. 22%), anemia (19% vs. 22%), and febrile neutropenia (15% vs. 16%). Grade 3-4 infections were more common with azacitidine monotherapy (31% vs. 18%).

Twelve enasidenib/azacitidine subjects (18%) developed isocitrate dehydrogenase differentiation syndrome, a complication that carries a black box warning in enasidenib’s label.

The work was funded by enasidenib marketer Celgene. Dr. DiNardo is an adviser to, and receives research funding from, the company. Dr. Juliusson’s disclosures, if any, were not reported.
 

SOURCE: DiNardo CD et al. EHA Congress, abstract S139.

Azacitidine plus enasidenib improved complete and overall responses in newly diagnosed acute myelogenous leukemia with isocitrate dehydrogenase 2 gene mutations, compared with azacitidine alone, but it did not improve overall survival in an open-label, phase 2 trial reported at the virtual annual congress of the European Hematology Association.

“Given the very high cost of” enasidenib, and the lack of survival benefit, Gunnar Juliusson, MD, PhD, of Lund University, Sweden, who moderated the study presentation, wondered if it might make more sense to hold enasidenib in reserve until after progression on azacitidine.

“The challenge is going to be exactly” that, “trying to figure out [if] you use both things together” or in sequence. “You can look at it in both ways,” said lead investigator Courtney DiNardo, MD, associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston.

“We do know” that with enasidenib monotherapy, there’s “a decrement in the rates of remission and in the duration of response” and overall survival in the salvage setting, so there’s “a clear rationale to give it earlier rather than later,” but “I think this study in some ways provides a few more questions than it really answers,” she said at the meeting.

About 15% of AML patients have leukemogenic isocitrate dehydrogenase 2 (IDH2) mutations; enasidenib, an oral small molecule, inhibits the mutant enzyme. The older AML patients are, the more likely they are to have an IDH2 mutation, so the work “is relevant to our older chemotherapy ineligible population,” Dr. DiNardo said.

The trial was prompted by preclinical indications of synergy with azacitidine; alone, each agent has an overall response rate of about 30% in newly diagnosed AML, and a complete remission (CR) rate of about 20%, she explained.

Her team randomized 68 adults with newly diagnosed AML and an IDH2 mutation to enasidenib 100 mg daily on a 28-day cycle with subcutaneous azacitidine 75 mg/m² for 7 days during the cycle, and 33 others to just the azacitidine alone.

Their subjects were ineligible for intensive chemotherapy and had intermediate to poor risk cytogenetics. The median age was 75 years, and Eastern Cooperative Oncology Group performance scores were 2 or less.

The overall response rate was 71% with the combination and 42% in the azacitidine alone arm (P = .0064). Fifty-three percent of combination patients, but 12% of azacitidine alone subjects, had complete remissions (P = .0001). The median duration of response with combination therapy was 24.1 months, versus 12.1 months.

Enasidenib plus azacitidine subjects also had greater drops in mutant IDH2 variant allele frequency (median 83.4% versus 17.7%, P < .01) and levels of the downstream oncometabolite 2-hydroxyglutarate (97.8% versus 54.3%; P < .01).

However, median OS was 22 months in both arms (HR 0.99, 95% CI 0.52, 1.87, P = .97). Although median event-free survival favored the combination – 17.2 months versus 10.8 – the results were not statistically significant (HR 0.59, 95% CI 0.30, 1.17, P = .13).

A possible reason for the lack of survival benefit, Dr. DiNardo said, was that seven azacitidine-alone patients (21%) went on to enasidenib after leaving the study, most commonly for disease progression, which occurred in 31% of combination patients versus 52% in the azacitidine-alone arm.

Combination subjects had a median of 10 treatment cycles, vs. 7 in the azacitidine-alone group. Grade 3-4 adverse events included thrombocytopenia (37% combination, 19% azacitidine-alone), neutropenia (35% vs. 22%), anemia (19% vs. 22%), and febrile neutropenia (15% vs. 16%). Grade 3-4 infections were more common with azacitidine monotherapy (31% vs. 18%).

Twelve enasidenib/azacitidine subjects (18%) developed isocitrate dehydrogenase differentiation syndrome, a complication that carries a black box warning in enasidenib’s label.

The work was funded by enasidenib marketer Celgene. Dr. DiNardo is an adviser to, and receives research funding from, the company. Dr. Juliusson’s disclosures, if any, were not reported.
 

SOURCE: DiNardo CD et al. EHA Congress, abstract S139.

Azacitidine plus enasidenib improved complete and overall responses in newly diagnosed acute myelogenous leukemia with isocitrate dehydrogenase 2 gene mutations, compared with azacitidine alone, but it did not improve overall survival in an open-label, phase 2 trial reported at the virtual annual congress of the European Hematology Association.

“Given the very high cost of” enasidenib, and the lack of survival benefit, Gunnar Juliusson, MD, PhD, of Lund University, Sweden, who moderated the study presentation, wondered if it might make more sense to hold enasidenib in reserve until after progression on azacitidine.

“The challenge is going to be exactly” that, “trying to figure out [if] you use both things together” or in sequence. “You can look at it in both ways,” said lead investigator Courtney DiNardo, MD, associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston.

“We do know” that with enasidenib monotherapy, there’s “a decrement in the rates of remission and in the duration of response” and overall survival in the salvage setting, so there’s “a clear rationale to give it earlier rather than later,” but “I think this study in some ways provides a few more questions than it really answers,” she said at the meeting.

About 15% of AML patients have leukemogenic isocitrate dehydrogenase 2 (IDH2) mutations; enasidenib, an oral small molecule, inhibits the mutant enzyme. The older AML patients are, the more likely they are to have an IDH2 mutation, so the work “is relevant to our older chemotherapy ineligible population,” Dr. DiNardo said.

The trial was prompted by preclinical indications of synergy with azacitidine; alone, each agent has an overall response rate of about 30% in newly diagnosed AML, and a complete remission (CR) rate of about 20%, she explained.

Her team randomized 68 adults with newly diagnosed AML and an IDH2 mutation to enasidenib 100 mg daily on a 28-day cycle with subcutaneous azacitidine 75 mg/m² for 7 days during the cycle, and 33 others to just the azacitidine alone.

Their subjects were ineligible for intensive chemotherapy and had intermediate to poor risk cytogenetics. The median age was 75 years, and Eastern Cooperative Oncology Group performance scores were 2 or less.

The overall response rate was 71% with the combination and 42% in the azacitidine alone arm (P = .0064). Fifty-three percent of combination patients, but 12% of azacitidine alone subjects, had complete remissions (P = .0001). The median duration of response with combination therapy was 24.1 months, versus 12.1 months.

Enasidenib plus azacitidine subjects also had greater drops in mutant IDH2 variant allele frequency (median 83.4% versus 17.7%, P < .01) and levels of the downstream oncometabolite 2-hydroxyglutarate (97.8% versus 54.3%; P < .01).

However, median OS was 22 months in both arms (HR 0.99, 95% CI 0.52, 1.87, P = .97). Although median event-free survival favored the combination – 17.2 months versus 10.8 – the results were not statistically significant (HR 0.59, 95% CI 0.30, 1.17, P = .13).

A possible reason for the lack of survival benefit, Dr. DiNardo said, was that seven azacitidine-alone patients (21%) went on to enasidenib after leaving the study, most commonly for disease progression, which occurred in 31% of combination patients versus 52% in the azacitidine-alone arm.

Combination subjects had a median of 10 treatment cycles, vs. 7 in the azacitidine-alone group. Grade 3-4 adverse events included thrombocytopenia (37% combination, 19% azacitidine-alone), neutropenia (35% vs. 22%), anemia (19% vs. 22%), and febrile neutropenia (15% vs. 16%). Grade 3-4 infections were more common with azacitidine monotherapy (31% vs. 18%).

Twelve enasidenib/azacitidine subjects (18%) developed isocitrate dehydrogenase differentiation syndrome, a complication that carries a black box warning in enasidenib’s label.

The work was funded by enasidenib marketer Celgene. Dr. DiNardo is an adviser to, and receives research funding from, the company. Dr. Juliusson’s disclosures, if any, were not reported.
 

SOURCE: DiNardo CD et al. EHA Congress, abstract S139.