Patrice Wendling

ORLANDO – The one-two punch of combining the programmed cell death-1 (PD-1) inhibitor pembrolizumab with the immunomodulatory drug lenalidomide and low-dose dexamethasone produced responses in 76% of 17 heavily pretreated patients with relapsed or refractory multiple myeloma in the KEYNOTE-023 study.

This included four very good partial responses (24%) and nine partial responses (53%).

In nine lenalidomide-refractory patients, the overall response rate was 56%, including two very good partial responses (22%) and three partial responses (33%).

The efficacy results are preliminary, but support the continued development of pembrolizumab (Keytruda) in patients with multiple myeloma, Dr. Jesús San Miguel of Clinica Universidad de Navarra, Pamplona, Spain, said at the annual meeting of the American Society of Hematology.

Patrice Wendling/Frontline Medical News

He closed his presentation with two illustrative cases highlighting a rapid response lasting more than a year and a half in a 49-year-old man with myeloma triple-refractory to autologous stem cell transplant (ASCT), lenalidomide (Revlimid), and dexamethasone.

The second case involved a patient with double-refractory myeloma and extramedullary disease who achieved a stringent complete response after two cycles of fourth-line pembrolizumab that was associated with a “striking” reduction in lesion volume on computed tomography scans, he said.

The median duration of response among the 17 evaluable patients was 9.7 months.

The median time to first response was 1.2 months (range 1.0 months to 6.5 months). But some patients require more time and, interestingly, the quality of the response was upgraded in 11% with continued treatment, Dr. San Miguel said.

The rationale for combining PD-1 inhibitors with immunomodulatory drugs (IMiD) lies in recent research showing that lenalidomide reduces PD-ligand 1 and PD-1 expression on multiple myeloma cells as well as on T and myeloid-derived suppressor cells, he explained. In addition, lenalidomide enhances checkpoint blockade–induced effector cytokine production in multiple myeloma bone marrow and induces cytotoxicity against myeloma cells.

“Lenalidomide will increase the number of T cells and the T-cell activation and anti-PD-1 will release the brake in order to allow these activated T cells to interact with the tumor,” Dr. San Miguel said.

Patients enrolled in KEYSTONE-023 were heavily pretreated, with 26% previously exposed to pomalidomide, 76% refractory to lenalidomide, 80% refractory to their last line of therapy, and 86% having undergone prior ASCT. Half the patients were double, triple, or quadruple refractory, he noted.

The study (Abstract 505) was designed to identify the maximum tolerated dose (MTD) of pembrolizumab and to assess its safety and tolerability when given with lenalidomide and dexamethasone in patients with multiple myeloma failing at least two prior lines of therapy including a proteasome inhibitor and an IMiD. Their median age was 62 years; 64% were male.

In the dose-determination stage, three of six patients treated with pembrolizumab 2 mg/kg plus lenalidomide 25 mg and dexamethasone 40 mg experienced dose-limiting toxicities that resolved without treatment discontinuation.

After dose adjustments, a “flat dose” of pembrolizumab 200 mg given every other week in a rapid 30-minute intravenous infusion without premedication with lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg weekly did not cause any dose-limiting toxicities and was identified as the final MTD, Dr. San Miguel said.

The regimen is to continue for 24 months or until tumor progression or excessive side effects and was carried forward into the dose-expansion stage in 33 additional patients with a median follow-up of 48 days.

Among all 50 patients evaluable for safety, 72% experienced at least one treatment-related adverse event of any grade and 46% (23/50 patients) had grade 3/4 adverse events including neutropenia (22%), thrombocytopenia and anemia (8% each), hyperglycemia (6%), and fatigue, muscle spasms, and diarrhea (2% each).

The adverse events were consistent with the individual drug safety profiles, but “the incidence may be underestimated due to the limited drug exposure,” Dr. San Miguel cautioned.

Immune-mediated adverse events included two cases each of hyper- and hypothyroidism, one case of thyroiditis, and one grade 2 adrenal insufficiency. No cases of colitis or pneumonitis were reported. No dose modifications or treatment discontinuations were required to mange the immune-related side effects, he said. No treatment-related deaths occurred.

In a second study reported during the same oral myeloma session, pneumonitis cropped up in 10% of heavily pretreated patients with relapsed multiple myeloma receiving a slightly different regimen of pembrolizumab plus the IMiD pomalidomide (Pomalyst) and dexamethasone. The overall response rate in the phase II study was 60% among 27 evaluable patients and 55% in those double-refractory to IMiDs and proteasome inhibitors.

[email protected]

ORLANDO – The one-two punch of combining the programmed cell death-1 (PD-1) inhibitor pembrolizumab with the immunomodulatory drug lenalidomide and low-dose dexamethasone produced responses in 76% of 17 heavily pretreated patients with relapsed or refractory multiple myeloma in the KEYNOTE-023 study.

This included four very good partial responses (24%) and nine partial responses (53%).

In nine lenalidomide-refractory patients, the overall response rate was 56%, including two very good partial responses (22%) and three partial responses (33%).

The efficacy results are preliminary, but support the continued development of pembrolizumab (Keytruda) in patients with multiple myeloma, Dr. Jesús San Miguel of Clinica Universidad de Navarra, Pamplona, Spain, said at the annual meeting of the American Society of Hematology.

Patrice Wendling/Frontline Medical News

He closed his presentation with two illustrative cases highlighting a rapid response lasting more than a year and a half in a 49-year-old man with myeloma triple-refractory to autologous stem cell transplant (ASCT), lenalidomide (Revlimid), and dexamethasone.

The second case involved a patient with double-refractory myeloma and extramedullary disease who achieved a stringent complete response after two cycles of fourth-line pembrolizumab that was associated with a “striking” reduction in lesion volume on computed tomography scans, he said.

The median duration of response among the 17 evaluable patients was 9.7 months.

The median time to first response was 1.2 months (range 1.0 months to 6.5 months). But some patients require more time and, interestingly, the quality of the response was upgraded in 11% with continued treatment, Dr. San Miguel said.

The rationale for combining PD-1 inhibitors with immunomodulatory drugs (IMiD) lies in recent research showing that lenalidomide reduces PD-ligand 1 and PD-1 expression on multiple myeloma cells as well as on T and myeloid-derived suppressor cells, he explained. In addition, lenalidomide enhances checkpoint blockade–induced effector cytokine production in multiple myeloma bone marrow and induces cytotoxicity against myeloma cells.

“Lenalidomide will increase the number of T cells and the T-cell activation and anti-PD-1 will release the brake in order to allow these activated T cells to interact with the tumor,” Dr. San Miguel said.

Patients enrolled in KEYSTONE-023 were heavily pretreated, with 26% previously exposed to pomalidomide, 76% refractory to lenalidomide, 80% refractory to their last line of therapy, and 86% having undergone prior ASCT. Half the patients were double, triple, or quadruple refractory, he noted.

The study (Abstract 505) was designed to identify the maximum tolerated dose (MTD) of pembrolizumab and to assess its safety and tolerability when given with lenalidomide and dexamethasone in patients with multiple myeloma failing at least two prior lines of therapy including a proteasome inhibitor and an IMiD. Their median age was 62 years; 64% were male.

In the dose-determination stage, three of six patients treated with pembrolizumab 2 mg/kg plus lenalidomide 25 mg and dexamethasone 40 mg experienced dose-limiting toxicities that resolved without treatment discontinuation.

After dose adjustments, a “flat dose” of pembrolizumab 200 mg given every other week in a rapid 30-minute intravenous infusion without premedication with lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg weekly did not cause any dose-limiting toxicities and was identified as the final MTD, Dr. San Miguel said.

The regimen is to continue for 24 months or until tumor progression or excessive side effects and was carried forward into the dose-expansion stage in 33 additional patients with a median follow-up of 48 days.

Among all 50 patients evaluable for safety, 72% experienced at least one treatment-related adverse event of any grade and 46% (23/50 patients) had grade 3/4 adverse events including neutropenia (22%), thrombocytopenia and anemia (8% each), hyperglycemia (6%), and fatigue, muscle spasms, and diarrhea (2% each).

The adverse events were consistent with the individual drug safety profiles, but “the incidence may be underestimated due to the limited drug exposure,” Dr. San Miguel cautioned.

Immune-mediated adverse events included two cases each of hyper- and hypothyroidism, one case of thyroiditis, and one grade 2 adrenal insufficiency. No cases of colitis or pneumonitis were reported. No dose modifications or treatment discontinuations were required to mange the immune-related side effects, he said. No treatment-related deaths occurred.

In a second study reported during the same oral myeloma session, pneumonitis cropped up in 10% of heavily pretreated patients with relapsed multiple myeloma receiving a slightly different regimen of pembrolizumab plus the IMiD pomalidomide (Pomalyst) and dexamethasone. The overall response rate in the phase II study was 60% among 27 evaluable patients and 55% in those double-refractory to IMiDs and proteasome inhibitors.

[email protected]

ORLANDO – The one-two punch of combining the programmed cell death-1 (PD-1) inhibitor pembrolizumab with the immunomodulatory drug lenalidomide and low-dose dexamethasone produced responses in 76% of 17 heavily pretreated patients with relapsed or refractory multiple myeloma in the KEYNOTE-023 study.

This included four very good partial responses (24%) and nine partial responses (53%).

In nine lenalidomide-refractory patients, the overall response rate was 56%, including two very good partial responses (22%) and three partial responses (33%).

The efficacy results are preliminary, but support the continued development of pembrolizumab (Keytruda) in patients with multiple myeloma, Dr. Jesús San Miguel of Clinica Universidad de Navarra, Pamplona, Spain, said at the annual meeting of the American Society of Hematology.

Patrice Wendling/Frontline Medical News

He closed his presentation with two illustrative cases highlighting a rapid response lasting more than a year and a half in a 49-year-old man with myeloma triple-refractory to autologous stem cell transplant (ASCT), lenalidomide (Revlimid), and dexamethasone.

The second case involved a patient with double-refractory myeloma and extramedullary disease who achieved a stringent complete response after two cycles of fourth-line pembrolizumab that was associated with a “striking” reduction in lesion volume on computed tomography scans, he said.

The median duration of response among the 17 evaluable patients was 9.7 months.

The median time to first response was 1.2 months (range 1.0 months to 6.5 months). But some patients require more time and, interestingly, the quality of the response was upgraded in 11% with continued treatment, Dr. San Miguel said.

The rationale for combining PD-1 inhibitors with immunomodulatory drugs (IMiD) lies in recent research showing that lenalidomide reduces PD-ligand 1 and PD-1 expression on multiple myeloma cells as well as on T and myeloid-derived suppressor cells, he explained. In addition, lenalidomide enhances checkpoint blockade–induced effector cytokine production in multiple myeloma bone marrow and induces cytotoxicity against myeloma cells.

“Lenalidomide will increase the number of T cells and the T-cell activation and anti-PD-1 will release the brake in order to allow these activated T cells to interact with the tumor,” Dr. San Miguel said.

Patients enrolled in KEYSTONE-023 were heavily pretreated, with 26% previously exposed to pomalidomide, 76% refractory to lenalidomide, 80% refractory to their last line of therapy, and 86% having undergone prior ASCT. Half the patients were double, triple, or quadruple refractory, he noted.

The study (Abstract 505) was designed to identify the maximum tolerated dose (MTD) of pembrolizumab and to assess its safety and tolerability when given with lenalidomide and dexamethasone in patients with multiple myeloma failing at least two prior lines of therapy including a proteasome inhibitor and an IMiD. Their median age was 62 years; 64% were male.

In the dose-determination stage, three of six patients treated with pembrolizumab 2 mg/kg plus lenalidomide 25 mg and dexamethasone 40 mg experienced dose-limiting toxicities that resolved without treatment discontinuation.

After dose adjustments, a “flat dose” of pembrolizumab 200 mg given every other week in a rapid 30-minute intravenous infusion without premedication with lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg weekly did not cause any dose-limiting toxicities and was identified as the final MTD, Dr. San Miguel said.

The regimen is to continue for 24 months or until tumor progression or excessive side effects and was carried forward into the dose-expansion stage in 33 additional patients with a median follow-up of 48 days.

Among all 50 patients evaluable for safety, 72% experienced at least one treatment-related adverse event of any grade and 46% (23/50 patients) had grade 3/4 adverse events including neutropenia (22%), thrombocytopenia and anemia (8% each), hyperglycemia (6%), and fatigue, muscle spasms, and diarrhea (2% each).

The adverse events were consistent with the individual drug safety profiles, but “the incidence may be underestimated due to the limited drug exposure,” Dr. San Miguel cautioned.

Immune-mediated adverse events included two cases each of hyper- and hypothyroidism, one case of thyroiditis, and one grade 2 adrenal insufficiency. No cases of colitis or pneumonitis were reported. No dose modifications or treatment discontinuations were required to mange the immune-related side effects, he said. No treatment-related deaths occurred.

In a second study reported during the same oral myeloma session, pneumonitis cropped up in 10% of heavily pretreated patients with relapsed multiple myeloma receiving a slightly different regimen of pembrolizumab plus the IMiD pomalidomide (Pomalyst) and dexamethasone. The overall response rate in the phase II study was 60% among 27 evaluable patients and 55% in those double-refractory to IMiDs and proteasome inhibitors.

[email protected]

CHICAGO – Following a few simple steps can help patients with peripheral artery disease (PAD) get off on the right foot with a home-based exercise program.

“There is growing evidence that PAD patients can walk for exercise at home and improve their walking performance,” Dr. Mary McDermott said at a symposium on vascular surgery sponsored by Northwestern University.

Getting them to do so, however, can be challenging. Patients with peripheral artery disease have greater functional impairment and are at higher risk for cardiovascular disease than is the general population. They also frequently limit their activity to avoid leg problems, as their PAD progresses.

“It’s hard enough to get patients without peripheral artery disease to exercise. As a general internist, I’m well aware of that,” she said. “It’s even more difficult when walking is so painful and uncomfortable.”

At present, the American College of Cardiology/American Heart Association practice guidelines for the management of patients with PAD do not recommend advising patients with PAD to go home and walk.

The guidelines were published in 2005, however, and since 2011, three of four randomized clinical trials of home-based exercise programs have shown a significant gain in walking endurance in patients with PAD, Dr. McDermott of Northwestern University in Chicago, observed.

The most hands-off of these trials showed that patients with symptomatic PAD randomized to a supervised exercise program did the best at treadmill walking, but the home-exercise group who received a step monitor and in-person feedback just once per month did significantly better than did controls assigned light resistance training. Moreover, the home-exercise group had greater change in 6-minute walk distances than either of the other groups (J Am Heart Assoc. 2014 Oct;3[5]:e001107).

“I think the reason for this is that the home-based group was walking outside or perhaps in a mall and getting better at walking over ground,” Dr. McDermott. “The treadmill group was walking only on the treadmill.”

Supervised treadmill exercise may seem like an easier prescription to write, but it faces two major barriers, she said. Most medical insurers, including Medicare, do not pay for supervised exercise for people with PAD and intermittent claudication, and most PAD patients don’t participate. The burden of traveling to an exercise center three times weekly, week after week, to participate can be overwhelming.

“For all of these reasons, we really need to develop home-based exercise programs that work,” Dr. McDermott said.

Based on the successful trials, home-based programs should include monitoring, group support, and goal setting. Dr. McDermott and her colleagues added cognitive-behavioral therapy to group support in the Group Oriented Arterial Leg Study (GOALS), resulting in significant improvement in 6-minute walk distance at 6 months, physical activity over 7 days, and self-perception of walking endurance and speed among home walkers (JAMA. 2013 Jul 3;310[1]:57-65).

Before embarking on any home-exercise program, all patients with PAD should undergo a baseline cardiac stress test to rule out coronary artery ischemia, she cautioned. This also serves to identify any coronary ischemia that may develop during the new walking program.

Once this is performed, Dr. McDermott recommends clinicians:

• Advise patients to walk 5 days per week.

“This may seem like a lot, but it’s important to have them see this as part of their daily routine; just something they get in the habit of doing,” she said.

• Start with 10-15 minutes of walking per exercise session. Tailor the program to the individual patient.

• Walk to maximal leg pain or onset of ischemic pain. Stopping to rest is acceptable.

“A lot of patients, I find, have questions, “ ‘I can’t do this.’ ‘How can this be beneficial?’ So just letting them know that if they just walk and stop, walk and stop, and start with just 10 minutes of that and increase this over time, they really can see improvement,” Dr. McDermott said.

• Increase the walk time by 5 minutes each week.

Increase the duration until the patient is walking at least 30 minutes per session and preferably 45-50 minutes per session, excluding rest periods, she said.

• Advise patients to write down their walking goals.

Specify where they will walk, when they will walk, and the duration of walking to improve compliance, which can slip following hospitalizations or when patients experience acute illness.

• Have patients self-monitor, but also check in with someone for support.

“It doesn’t have to be a nurse,” Dr. McDermott said. “In our studies, we’ve used bachelor’s degree-level people, but told them what to look for. They can do this and the patient feels there is someone they’re accountable to.”

Dr. McDermott and her colleagues are testing the boundaries of support in the ongoing HONOR trial, which includes four weekly visits to an exercise center in phase I to meet the telephone coach, learn to use a Fitbit monitor, and learn the behavioral skills necessary for long-term adherence. Phase II, however, is entirely home based and includes only Fitbit self-monitoring, regular telephone calls from the coach for feedback, use of the study website, and optional group telephone calls.

The bottom line with any program is for patients to understand it must be indefinite to maintain improvement.

“Unfortunately, if they don’t stick with it, they will slide back,” she cautioned.

Dr. McDermott reported research funding from the National Institutes of Health, the Patient-Centered Outcomes Research Institute (PCORI), and Novartis.

[email protected]

CHICAGO – Following a few simple steps can help patients with peripheral artery disease (PAD) get off on the right foot with a home-based exercise program.

“There is growing evidence that PAD patients can walk for exercise at home and improve their walking performance,” Dr. Mary McDermott said at a symposium on vascular surgery sponsored by Northwestern University.

Getting them to do so, however, can be challenging. Patients with peripheral artery disease have greater functional impairment and are at higher risk for cardiovascular disease than is the general population. They also frequently limit their activity to avoid leg problems, as their PAD progresses.

“It’s hard enough to get patients without peripheral artery disease to exercise. As a general internist, I’m well aware of that,” she said. “It’s even more difficult when walking is so painful and uncomfortable.”

At present, the American College of Cardiology/American Heart Association practice guidelines for the management of patients with PAD do not recommend advising patients with PAD to go home and walk.

The guidelines were published in 2005, however, and since 2011, three of four randomized clinical trials of home-based exercise programs have shown a significant gain in walking endurance in patients with PAD, Dr. McDermott of Northwestern University in Chicago, observed.

The most hands-off of these trials showed that patients with symptomatic PAD randomized to a supervised exercise program did the best at treadmill walking, but the home-exercise group who received a step monitor and in-person feedback just once per month did significantly better than did controls assigned light resistance training. Moreover, the home-exercise group had greater change in 6-minute walk distances than either of the other groups (J Am Heart Assoc. 2014 Oct;3[5]:e001107).

“I think the reason for this is that the home-based group was walking outside or perhaps in a mall and getting better at walking over ground,” Dr. McDermott. “The treadmill group was walking only on the treadmill.”

Supervised treadmill exercise may seem like an easier prescription to write, but it faces two major barriers, she said. Most medical insurers, including Medicare, do not pay for supervised exercise for people with PAD and intermittent claudication, and most PAD patients don’t participate. The burden of traveling to an exercise center three times weekly, week after week, to participate can be overwhelming.

“For all of these reasons, we really need to develop home-based exercise programs that work,” Dr. McDermott said.

Based on the successful trials, home-based programs should include monitoring, group support, and goal setting. Dr. McDermott and her colleagues added cognitive-behavioral therapy to group support in the Group Oriented Arterial Leg Study (GOALS), resulting in significant improvement in 6-minute walk distance at 6 months, physical activity over 7 days, and self-perception of walking endurance and speed among home walkers (JAMA. 2013 Jul 3;310[1]:57-65).

Before embarking on any home-exercise program, all patients with PAD should undergo a baseline cardiac stress test to rule out coronary artery ischemia, she cautioned. This also serves to identify any coronary ischemia that may develop during the new walking program.

Once this is performed, Dr. McDermott recommends clinicians:

• Advise patients to walk 5 days per week.

“This may seem like a lot, but it’s important to have them see this as part of their daily routine; just something they get in the habit of doing,” she said.

• Start with 10-15 minutes of walking per exercise session. Tailor the program to the individual patient.

• Walk to maximal leg pain or onset of ischemic pain. Stopping to rest is acceptable.

“A lot of patients, I find, have questions, “ ‘I can’t do this.’ ‘How can this be beneficial?’ So just letting them know that if they just walk and stop, walk and stop, and start with just 10 minutes of that and increase this over time, they really can see improvement,” Dr. McDermott said.

• Increase the walk time by 5 minutes each week.

Increase the duration until the patient is walking at least 30 minutes per session and preferably 45-50 minutes per session, excluding rest periods, she said.

• Advise patients to write down their walking goals.

Specify where they will walk, when they will walk, and the duration of walking to improve compliance, which can slip following hospitalizations or when patients experience acute illness.

• Have patients self-monitor, but also check in with someone for support.

“It doesn’t have to be a nurse,” Dr. McDermott said. “In our studies, we’ve used bachelor’s degree-level people, but told them what to look for. They can do this and the patient feels there is someone they’re accountable to.”

Dr. McDermott and her colleagues are testing the boundaries of support in the ongoing HONOR trial, which includes four weekly visits to an exercise center in phase I to meet the telephone coach, learn to use a Fitbit monitor, and learn the behavioral skills necessary for long-term adherence. Phase II, however, is entirely home based and includes only Fitbit self-monitoring, regular telephone calls from the coach for feedback, use of the study website, and optional group telephone calls.

The bottom line with any program is for patients to understand it must be indefinite to maintain improvement.

“Unfortunately, if they don’t stick with it, they will slide back,” she cautioned.

Dr. McDermott reported research funding from the National Institutes of Health, the Patient-Centered Outcomes Research Institute (PCORI), and Novartis.

[email protected]

CHICAGO – Following a few simple steps can help patients with peripheral artery disease (PAD) get off on the right foot with a home-based exercise program.

“There is growing evidence that PAD patients can walk for exercise at home and improve their walking performance,” Dr. Mary McDermott said at a symposium on vascular surgery sponsored by Northwestern University.

Getting them to do so, however, can be challenging. Patients with peripheral artery disease have greater functional impairment and are at higher risk for cardiovascular disease than is the general population. They also frequently limit their activity to avoid leg problems, as their PAD progresses.

“It’s hard enough to get patients without peripheral artery disease to exercise. As a general internist, I’m well aware of that,” she said. “It’s even more difficult when walking is so painful and uncomfortable.”

At present, the American College of Cardiology/American Heart Association practice guidelines for the management of patients with PAD do not recommend advising patients with PAD to go home and walk.

The guidelines were published in 2005, however, and since 2011, three of four randomized clinical trials of home-based exercise programs have shown a significant gain in walking endurance in patients with PAD, Dr. McDermott of Northwestern University in Chicago, observed.

The most hands-off of these trials showed that patients with symptomatic PAD randomized to a supervised exercise program did the best at treadmill walking, but the home-exercise group who received a step monitor and in-person feedback just once per month did significantly better than did controls assigned light resistance training. Moreover, the home-exercise group had greater change in 6-minute walk distances than either of the other groups (J Am Heart Assoc. 2014 Oct;3[5]:e001107).

“I think the reason for this is that the home-based group was walking outside or perhaps in a mall and getting better at walking over ground,” Dr. McDermott. “The treadmill group was walking only on the treadmill.”

Supervised treadmill exercise may seem like an easier prescription to write, but it faces two major barriers, she said. Most medical insurers, including Medicare, do not pay for supervised exercise for people with PAD and intermittent claudication, and most PAD patients don’t participate. The burden of traveling to an exercise center three times weekly, week after week, to participate can be overwhelming.

“For all of these reasons, we really need to develop home-based exercise programs that work,” Dr. McDermott said.

Based on the successful trials, home-based programs should include monitoring, group support, and goal setting. Dr. McDermott and her colleagues added cognitive-behavioral therapy to group support in the Group Oriented Arterial Leg Study (GOALS), resulting in significant improvement in 6-minute walk distance at 6 months, physical activity over 7 days, and self-perception of walking endurance and speed among home walkers (JAMA. 2013 Jul 3;310[1]:57-65).

Before embarking on any home-exercise program, all patients with PAD should undergo a baseline cardiac stress test to rule out coronary artery ischemia, she cautioned. This also serves to identify any coronary ischemia that may develop during the new walking program.

Once this is performed, Dr. McDermott recommends clinicians:

• Advise patients to walk 5 days per week.

“This may seem like a lot, but it’s important to have them see this as part of their daily routine; just something they get in the habit of doing,” she said.

• Start with 10-15 minutes of walking per exercise session. Tailor the program to the individual patient.

• Walk to maximal leg pain or onset of ischemic pain. Stopping to rest is acceptable.

“A lot of patients, I find, have questions, “ ‘I can’t do this.’ ‘How can this be beneficial?’ So just letting them know that if they just walk and stop, walk and stop, and start with just 10 minutes of that and increase this over time, they really can see improvement,” Dr. McDermott said.

• Increase the walk time by 5 minutes each week.

Increase the duration until the patient is walking at least 30 minutes per session and preferably 45-50 minutes per session, excluding rest periods, she said.

• Advise patients to write down their walking goals.

Specify where they will walk, when they will walk, and the duration of walking to improve compliance, which can slip following hospitalizations or when patients experience acute illness.

• Have patients self-monitor, but also check in with someone for support.

“It doesn’t have to be a nurse,” Dr. McDermott said. “In our studies, we’ve used bachelor’s degree-level people, but told them what to look for. They can do this and the patient feels there is someone they’re accountable to.”

Dr. McDermott and her colleagues are testing the boundaries of support in the ongoing HONOR trial, which includes four weekly visits to an exercise center in phase I to meet the telephone coach, learn to use a Fitbit monitor, and learn the behavioral skills necessary for long-term adherence. Phase II, however, is entirely home based and includes only Fitbit self-monitoring, regular telephone calls from the coach for feedback, use of the study website, and optional group telephone calls.

The bottom line with any program is for patients to understand it must be indefinite to maintain improvement.

“Unfortunately, if they don’t stick with it, they will slide back,” she cautioned.

Dr. McDermott reported research funding from the National Institutes of Health, the Patient-Centered Outcomes Research Institute (PCORI), and Novartis.

[email protected]

ORLANDO – Chimeric antigen receptor (CAR) T cells targeting BCMA eradicated myeloma cells in a patient with a heavy burden of chemotherapy-resistant multiple myeloma.

The patient had received three prior myeloma therapies and relapsed with myeloma making up more than 90% of his bone marrow cells just 3 months after autologous transplant.

CD138-positive plasma cells were completely absent, however, one month after infusion of CAR T cells directed against the B-cell maturation antigen (BCMA), and remain undetectable 14 weeks after infusion.

“We have demonstrated for the first time that CAR T cells can have powerful activity against measurable multiple myeloma,” Dr. James N. Kochenderfer of the National Cancer Institute in Bethesda, Md., said at the annual meeting of the American Society of Hematology.

A second patient, who had five prior lines of myeloma therapy and myeloma in 80% of his bone marrow cells, also experienced a dramatic reduction in myeloma, resulting so far in a partial response. The patient has returned to full-time work and myeloma cells continue to decrease 6 weeks after infusion.

The two ongoing responses, however, were associated with the most severe clinical signs of cytokine release syndrome in the late-breaking abstract study (LBA-1), Dr. Kochenderfer said.

The complete responder experienced cytokine release toxicities including fever, tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase that resolved. The patient was also platelet transfusion-dependent for 9 weeks after infusion and a baseline absolute neutrophil count of less than 500 microliters remained at that level for 40 days after infusion. All symptoms resolved within two weeks, he said.

The ongoing partial responder experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia and all completely resolved.

Both patients had much higher serum levels of interleukin-6 than the other patients, he noted.

Both patients also received the highest dose level of anti-BCMA CAR T cells. Going forward, that dose will now only be administered to patients with less than 50% bone marrow plasma cells, Dr. Kochenderfer said.

Other responses among the 12 patients treated thus far include 1 transient very good partial response of 8-week duration, 1 transient partial response lasting 2 weeks, and 8 responses of stable disease.

While three new drugs (elotuzumab, daratumumab, ixazomib) were approved for the treatment of multiple myeloma in the month of November alone, this is early days for CAR T-cell therapy in multiple myeloma.

“Almost all of the CAR T-cell work has been in B-cell malignancies, acute lymphocytic leukemia, and chronic lymphocytic leukemia, so is this the right antigen, we don’t know? Is this the right construct, we don’t know? But there’s clearly activity and that is very exciting,” session comoderator Dr. David P. Steensma of the Dana-Farber Cancer Institute in Boston, said in an interview.

Dana-Farber is conducting a CAR T cell trial in myeloma using a different target and NKG2D ligands. Other centers are also using CAR T cells with different targets. “So maybe other targets would have different results and a better safety profile,” he added.

BCMA is an appropriate target for CAR T cell therapy for multiple reasons, Dr. Kochenderfer said. Multiple myeloma is still an incurable disease and BCMA, a member of the tumor necrosis factor superfamily, is uniformly expressed in 60% to 70% of cases.

Preclinical studies by the team also show that BCMA is not detectable in normal human tissues, but is selectively expressed only in bone marrow, lymphoid organs, and organs known to have plasma cells in their lamina propria and by plasma cells and a small fraction of B cells.

The investigators genetically modified autologous T cells to express an anti-BCMA CAR and ligated it into a replication-incompetent gamma retrovirus. The T cells were stimulated with the anti-CD3 monoclonal antibody OKT3 before transduction, with the entire culture process taking 9 days from start to finish. T cells expressing this CAR recognize BCMA with great specificity, Dr. Kochenderfer observed.

The 12 patients received 300 mg/m² of cyclophosphamide and 30 mg/m² of fludarabine (Fludara) daily for 3 days before a single infusion of anti-BCMA CAR at dose levels of 0.3 x 10⁶ to 9 x 10⁶ T cells/kg. All patients had at least 3 prior therapies and normal organ function. Five had amyloid light chain only, 4 had immunoglobulin gamma disease, and 4 patients, including the complete responder, had immunoglobulin alpha disease.

It’s unclear why only a few patients responded to the CAR T cells, but dose level was likely a big factor and there is a lot of patient variability with T-cell therapies, Dr. Kochenderfer said at a press briefing.

“I wish we knew exactly why some patients respond and some don’t,” he added. “The CAR T cells have shown remarkable activity against really previously refractory diseases like acute lymphocytic leukemia,” noted Dr. George Daley of Harvard Medical School, Boston, in an interview at the meeting. “There’s been a lot of excitement that maybe we can extend the principles that work in leukemia to other types of diseases.”

The study is still ongoing and accruing patients, but a multicenter trial is also being initiated in myeloma with Bluebird Bio using “a closely related, but slightly different CAR,” Dr. Kochenderfer said.

[email protected]

ORLANDO – Chimeric antigen receptor (CAR) T cells targeting BCMA eradicated myeloma cells in a patient with a heavy burden of chemotherapy-resistant multiple myeloma.

The patient had received three prior myeloma therapies and relapsed with myeloma making up more than 90% of his bone marrow cells just 3 months after autologous transplant.

CD138-positive plasma cells were completely absent, however, one month after infusion of CAR T cells directed against the B-cell maturation antigen (BCMA), and remain undetectable 14 weeks after infusion.

“We have demonstrated for the first time that CAR T cells can have powerful activity against measurable multiple myeloma,” Dr. James N. Kochenderfer of the National Cancer Institute in Bethesda, Md., said at the annual meeting of the American Society of Hematology.

A second patient, who had five prior lines of myeloma therapy and myeloma in 80% of his bone marrow cells, also experienced a dramatic reduction in myeloma, resulting so far in a partial response. The patient has returned to full-time work and myeloma cells continue to decrease 6 weeks after infusion.

The two ongoing responses, however, were associated with the most severe clinical signs of cytokine release syndrome in the late-breaking abstract study (LBA-1), Dr. Kochenderfer said.

The complete responder experienced cytokine release toxicities including fever, tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase that resolved. The patient was also platelet transfusion-dependent for 9 weeks after infusion and a baseline absolute neutrophil count of less than 500 microliters remained at that level for 40 days after infusion. All symptoms resolved within two weeks, he said.

The ongoing partial responder experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia and all completely resolved.

Both patients had much higher serum levels of interleukin-6 than the other patients, he noted.

Both patients also received the highest dose level of anti-BCMA CAR T cells. Going forward, that dose will now only be administered to patients with less than 50% bone marrow plasma cells, Dr. Kochenderfer said.

Other responses among the 12 patients treated thus far include 1 transient very good partial response of 8-week duration, 1 transient partial response lasting 2 weeks, and 8 responses of stable disease.

While three new drugs (elotuzumab, daratumumab, ixazomib) were approved for the treatment of multiple myeloma in the month of November alone, this is early days for CAR T-cell therapy in multiple myeloma.

“Almost all of the CAR T-cell work has been in B-cell malignancies, acute lymphocytic leukemia, and chronic lymphocytic leukemia, so is this the right antigen, we don’t know? Is this the right construct, we don’t know? But there’s clearly activity and that is very exciting,” session comoderator Dr. David P. Steensma of the Dana-Farber Cancer Institute in Boston, said in an interview.

Dana-Farber is conducting a CAR T cell trial in myeloma using a different target and NKG2D ligands. Other centers are also using CAR T cells with different targets. “So maybe other targets would have different results and a better safety profile,” he added.

BCMA is an appropriate target for CAR T cell therapy for multiple reasons, Dr. Kochenderfer said. Multiple myeloma is still an incurable disease and BCMA, a member of the tumor necrosis factor superfamily, is uniformly expressed in 60% to 70% of cases.

Preclinical studies by the team also show that BCMA is not detectable in normal human tissues, but is selectively expressed only in bone marrow, lymphoid organs, and organs known to have plasma cells in their lamina propria and by plasma cells and a small fraction of B cells.

The investigators genetically modified autologous T cells to express an anti-BCMA CAR and ligated it into a replication-incompetent gamma retrovirus. The T cells were stimulated with the anti-CD3 monoclonal antibody OKT3 before transduction, with the entire culture process taking 9 days from start to finish. T cells expressing this CAR recognize BCMA with great specificity, Dr. Kochenderfer observed.

The 12 patients received 300 mg/m² of cyclophosphamide and 30 mg/m² of fludarabine (Fludara) daily for 3 days before a single infusion of anti-BCMA CAR at dose levels of 0.3 x 10⁶ to 9 x 10⁶ T cells/kg. All patients had at least 3 prior therapies and normal organ function. Five had amyloid light chain only, 4 had immunoglobulin gamma disease, and 4 patients, including the complete responder, had immunoglobulin alpha disease.

It’s unclear why only a few patients responded to the CAR T cells, but dose level was likely a big factor and there is a lot of patient variability with T-cell therapies, Dr. Kochenderfer said at a press briefing.

“I wish we knew exactly why some patients respond and some don’t,” he added. “The CAR T cells have shown remarkable activity against really previously refractory diseases like acute lymphocytic leukemia,” noted Dr. George Daley of Harvard Medical School, Boston, in an interview at the meeting. “There’s been a lot of excitement that maybe we can extend the principles that work in leukemia to other types of diseases.”

The study is still ongoing and accruing patients, but a multicenter trial is also being initiated in myeloma with Bluebird Bio using “a closely related, but slightly different CAR,” Dr. Kochenderfer said.

[email protected]

ORLANDO – Chimeric antigen receptor (CAR) T cells targeting BCMA eradicated myeloma cells in a patient with a heavy burden of chemotherapy-resistant multiple myeloma.

The patient had received three prior myeloma therapies and relapsed with myeloma making up more than 90% of his bone marrow cells just 3 months after autologous transplant.

CD138-positive plasma cells were completely absent, however, one month after infusion of CAR T cells directed against the B-cell maturation antigen (BCMA), and remain undetectable 14 weeks after infusion.

“We have demonstrated for the first time that CAR T cells can have powerful activity against measurable multiple myeloma,” Dr. James N. Kochenderfer of the National Cancer Institute in Bethesda, Md., said at the annual meeting of the American Society of Hematology.

A second patient, who had five prior lines of myeloma therapy and myeloma in 80% of his bone marrow cells, also experienced a dramatic reduction in myeloma, resulting so far in a partial response. The patient has returned to full-time work and myeloma cells continue to decrease 6 weeks after infusion.

The two ongoing responses, however, were associated with the most severe clinical signs of cytokine release syndrome in the late-breaking abstract study (LBA-1), Dr. Kochenderfer said.

The complete responder experienced cytokine release toxicities including fever, tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase that resolved. The patient was also platelet transfusion-dependent for 9 weeks after infusion and a baseline absolute neutrophil count of less than 500 microliters remained at that level for 40 days after infusion. All symptoms resolved within two weeks, he said.

The ongoing partial responder experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia and all completely resolved.

Both patients had much higher serum levels of interleukin-6 than the other patients, he noted.

Both patients also received the highest dose level of anti-BCMA CAR T cells. Going forward, that dose will now only be administered to patients with less than 50% bone marrow plasma cells, Dr. Kochenderfer said.

Other responses among the 12 patients treated thus far include 1 transient very good partial response of 8-week duration, 1 transient partial response lasting 2 weeks, and 8 responses of stable disease.

While three new drugs (elotuzumab, daratumumab, ixazomib) were approved for the treatment of multiple myeloma in the month of November alone, this is early days for CAR T-cell therapy in multiple myeloma.

“Almost all of the CAR T-cell work has been in B-cell malignancies, acute lymphocytic leukemia, and chronic lymphocytic leukemia, so is this the right antigen, we don’t know? Is this the right construct, we don’t know? But there’s clearly activity and that is very exciting,” session comoderator Dr. David P. Steensma of the Dana-Farber Cancer Institute in Boston, said in an interview.

Dana-Farber is conducting a CAR T cell trial in myeloma using a different target and NKG2D ligands. Other centers are also using CAR T cells with different targets. “So maybe other targets would have different results and a better safety profile,” he added.

BCMA is an appropriate target for CAR T cell therapy for multiple reasons, Dr. Kochenderfer said. Multiple myeloma is still an incurable disease and BCMA, a member of the tumor necrosis factor superfamily, is uniformly expressed in 60% to 70% of cases.

Preclinical studies by the team also show that BCMA is not detectable in normal human tissues, but is selectively expressed only in bone marrow, lymphoid organs, and organs known to have plasma cells in their lamina propria and by plasma cells and a small fraction of B cells.

The investigators genetically modified autologous T cells to express an anti-BCMA CAR and ligated it into a replication-incompetent gamma retrovirus. The T cells were stimulated with the anti-CD3 monoclonal antibody OKT3 before transduction, with the entire culture process taking 9 days from start to finish. T cells expressing this CAR recognize BCMA with great specificity, Dr. Kochenderfer observed.

The 12 patients received 300 mg/m² of cyclophosphamide and 30 mg/m² of fludarabine (Fludara) daily for 3 days before a single infusion of anti-BCMA CAR at dose levels of 0.3 x 10⁶ to 9 x 10⁶ T cells/kg. All patients had at least 3 prior therapies and normal organ function. Five had amyloid light chain only, 4 had immunoglobulin gamma disease, and 4 patients, including the complete responder, had immunoglobulin alpha disease.

It’s unclear why only a few patients responded to the CAR T cells, but dose level was likely a big factor and there is a lot of patient variability with T-cell therapies, Dr. Kochenderfer said at a press briefing.

“I wish we knew exactly why some patients respond and some don’t,” he added. “The CAR T cells have shown remarkable activity against really previously refractory diseases like acute lymphocytic leukemia,” noted Dr. George Daley of Harvard Medical School, Boston, in an interview at the meeting. “There’s been a lot of excitement that maybe we can extend the principles that work in leukemia to other types of diseases.”

The study is still ongoing and accruing patients, but a multicenter trial is also being initiated in myeloma with Bluebird Bio using “a closely related, but slightly different CAR,” Dr. Kochenderfer said.

[email protected]

ORLANDO – Patients with acute myeloid leukemia (AML) initially treated at an academic center lived significantly longer than those treated at nonacademic centers, a database analysis shows.

Median overall survival increased from 7 months at a nonacademic center to 12.6 months at an academic center (P less than .001).

One-year overall survival rates were also significantly better at 51% vs. 39% (P less than .001).

Patrice Wendling/Frontline Medical News

The difference remained significant even after controlling for important confounders including age, comorbidity burden, receipt of chemotherapy, transplant, and delay between diagnosis and treatment, Mr. Smith Giri reported at the annual meeting of the American Society of Hematology.

“From a policy perspective, it may be useful to know whether these results are due to higher volume of cases, more advanced technology, expanded role of specialists, or greater, round-the-clock availability of resident physicians,” said Mr. Giri of the University of Tennessee Health Science Center in Memphis.

Prior studies in cancer have suggested better overall survival among breast cancer patients treated at academic centers, but this is the first study looking at outcomes in AML, the most common acute leukemia in adults.

Using the National Cancer Database Participant User File, the investigators identified 7,823 patients with AML who received their initial therapy at the reporting facility from 1998 to 2011. The database collects information from more than 1,500 Commission on Cancer (CoC)–accredited facilities. Of the 7,823 patients, 4,681 (60%) were treated at an AC (academic/research program) and 3,142 at a non-AC (community cancer program/comprehensive community cancer program).

Patients treated at an AC were significantly younger than those treated at a non-AC (median 62 years vs. 67 years), tended to be of nonwhite race, less educated, have a lower income, and more comorbidities.

Receipt of chemotherapy (97.4% vs. 94.5%) and transplant (9% vs. 2.4%) were significantly higher at an AC than a non-AC (both P less than .001).

Kaplan Meier survival curves suggested disparate survival curves between the two groups, mainly within the first 5 years of follow-up (P less than .001), Mr. Giri said.

In multivariate model analysis, the non-AC group had significantly worse risk adjusted 30-day mortality than the AC group (odds ratio, 1.52; 95% confidence interval 1.33-1.74; P less than .001) and worse overall survival (hazard ratio, 1.13; 95% CI 1.07-1.19; P less than .001).

The study (Ab. 533) findings should be interpreted with caution because of its limitations, including the lack of information on AML risk type in the database, the fact that administrative datasets are prone to coding errors, and because the analysis did not adjust for hospital volume, which has been shown to affect survival, he said. Also, because there are more than 3,500 non–Coc approved hospitals, the sample may not be representative of overall U.S. hospitals.

During a discussion of the results, Mr. Giri acknowledged that patients treated at academic centers may have greater access to clinical trials and experimental agents. Future analyses should also distinguish patients with a diagnosis of acute promyelocytic leukemia, a distinct subset of AML.

[email protected]

ORLANDO – Patients with acute myeloid leukemia (AML) initially treated at an academic center lived significantly longer than those treated at nonacademic centers, a database analysis shows.

Median overall survival increased from 7 months at a nonacademic center to 12.6 months at an academic center (P less than .001).

One-year overall survival rates were also significantly better at 51% vs. 39% (P less than .001).

Patrice Wendling/Frontline Medical News

The difference remained significant even after controlling for important confounders including age, comorbidity burden, receipt of chemotherapy, transplant, and delay between diagnosis and treatment, Mr. Smith Giri reported at the annual meeting of the American Society of Hematology.

“From a policy perspective, it may be useful to know whether these results are due to higher volume of cases, more advanced technology, expanded role of specialists, or greater, round-the-clock availability of resident physicians,” said Mr. Giri of the University of Tennessee Health Science Center in Memphis.

Prior studies in cancer have suggested better overall survival among breast cancer patients treated at academic centers, but this is the first study looking at outcomes in AML, the most common acute leukemia in adults.

Using the National Cancer Database Participant User File, the investigators identified 7,823 patients with AML who received their initial therapy at the reporting facility from 1998 to 2011. The database collects information from more than 1,500 Commission on Cancer (CoC)–accredited facilities. Of the 7,823 patients, 4,681 (60%) were treated at an AC (academic/research program) and 3,142 at a non-AC (community cancer program/comprehensive community cancer program).

Patients treated at an AC were significantly younger than those treated at a non-AC (median 62 years vs. 67 years), tended to be of nonwhite race, less educated, have a lower income, and more comorbidities.

Receipt of chemotherapy (97.4% vs. 94.5%) and transplant (9% vs. 2.4%) were significantly higher at an AC than a non-AC (both P less than .001).

Kaplan Meier survival curves suggested disparate survival curves between the two groups, mainly within the first 5 years of follow-up (P less than .001), Mr. Giri said.

In multivariate model analysis, the non-AC group had significantly worse risk adjusted 30-day mortality than the AC group (odds ratio, 1.52; 95% confidence interval 1.33-1.74; P less than .001) and worse overall survival (hazard ratio, 1.13; 95% CI 1.07-1.19; P less than .001).

The study (Ab. 533) findings should be interpreted with caution because of its limitations, including the lack of information on AML risk type in the database, the fact that administrative datasets are prone to coding errors, and because the analysis did not adjust for hospital volume, which has been shown to affect survival, he said. Also, because there are more than 3,500 non–Coc approved hospitals, the sample may not be representative of overall U.S. hospitals.

During a discussion of the results, Mr. Giri acknowledged that patients treated at academic centers may have greater access to clinical trials and experimental agents. Future analyses should also distinguish patients with a diagnosis of acute promyelocytic leukemia, a distinct subset of AML.

[email protected]

ORLANDO – Patients with acute myeloid leukemia (AML) initially treated at an academic center lived significantly longer than those treated at nonacademic centers, a database analysis shows.

Median overall survival increased from 7 months at a nonacademic center to 12.6 months at an academic center (P less than .001).

One-year overall survival rates were also significantly better at 51% vs. 39% (P less than .001).

Patrice Wendling/Frontline Medical News

The difference remained significant even after controlling for important confounders including age, comorbidity burden, receipt of chemotherapy, transplant, and delay between diagnosis and treatment, Mr. Smith Giri reported at the annual meeting of the American Society of Hematology.

“From a policy perspective, it may be useful to know whether these results are due to higher volume of cases, more advanced technology, expanded role of specialists, or greater, round-the-clock availability of resident physicians,” said Mr. Giri of the University of Tennessee Health Science Center in Memphis.

Prior studies in cancer have suggested better overall survival among breast cancer patients treated at academic centers, but this is the first study looking at outcomes in AML, the most common acute leukemia in adults.

Using the National Cancer Database Participant User File, the investigators identified 7,823 patients with AML who received their initial therapy at the reporting facility from 1998 to 2011. The database collects information from more than 1,500 Commission on Cancer (CoC)–accredited facilities. Of the 7,823 patients, 4,681 (60%) were treated at an AC (academic/research program) and 3,142 at a non-AC (community cancer program/comprehensive community cancer program).

Patients treated at an AC were significantly younger than those treated at a non-AC (median 62 years vs. 67 years), tended to be of nonwhite race, less educated, have a lower income, and more comorbidities.

Receipt of chemotherapy (97.4% vs. 94.5%) and transplant (9% vs. 2.4%) were significantly higher at an AC than a non-AC (both P less than .001).

Kaplan Meier survival curves suggested disparate survival curves between the two groups, mainly within the first 5 years of follow-up (P less than .001), Mr. Giri said.

In multivariate model analysis, the non-AC group had significantly worse risk adjusted 30-day mortality than the AC group (odds ratio, 1.52; 95% confidence interval 1.33-1.74; P less than .001) and worse overall survival (hazard ratio, 1.13; 95% CI 1.07-1.19; P less than .001).

The study (Ab. 533) findings should be interpreted with caution because of its limitations, including the lack of information on AML risk type in the database, the fact that administrative datasets are prone to coding errors, and because the analysis did not adjust for hospital volume, which has been shown to affect survival, he said. Also, because there are more than 3,500 non–Coc approved hospitals, the sample may not be representative of overall U.S. hospitals.

During a discussion of the results, Mr. Giri acknowledged that patients treated at academic centers may have greater access to clinical trials and experimental agents. Future analyses should also distinguish patients with a diagnosis of acute promyelocytic leukemia, a distinct subset of AML.

[email protected]

CHICAGO – A high neutrophil to lymphocyte ratio on days 2 and 5 of surgical ICU hospitalization independently predicts increased mortality in critically ill trauma patients, an award-winning study showed.

The risk of death was two times higher for patients with a neutrophil to lymphocyte ratio (NLR) of at least 10.45 on day 2 (adjusted hazard ratio, 2.07; 95% confidence interval, 1.38-3.13; P = .001) and 5.7 times higher for those with an NLR of at least 7.91 on day 5 (adjusted HR, 5.79; 95% CI, 2.93-11.44; P less than .001) in a multivariate analysis, after adjustment for age 65 years or older, male sex, a systolic blood pressure of 90 mm Hg or less, a Glasgow Coma Scale (GCS) score of 8 or less, an Injury Severity Score (ISS) of at least 25, and operation on admission.

Patrice Wendling/Frontline Medical News

“The neutrophil to lymphocyte ratio is easily accessible, the calculation is simple, it adds no additional costs, and virtually all critically ill patients will have these labs,” study author Dr. Evren Dilektasli said at the American College of Surgeons annual clinical congress.

The simple calculation has been shown to be useful in the diagnosis of appendicitis and to be associated with overall survivalin metastatic colorectal cancer, but its association with mortality in trauma patients is not known, he said.

The retrospective cohort comprised 1,356 trauma patients, at least 16 years old, admitted to the Los Angeles County–University of Southern California Medical Center surgical ICU between January 2013 and January 2014. The median NLR was calculated for each day of the surgical ICU stay. At baseline, 16% of patients had an ISS of at least 25, 16.5% had a GCS of 8 or less, 4.5% had a systolic BP of 90 mm Hg or less, 74.3% were male, 23.7% were aged 65 or older, and 86% had a blunt injury. The most common operations on admission were laparotomy (39.6%) and craniectomy/craniotomy (20.7%).

In receiver operating characteristic (ROC) analysis for the first 10 days of hospitalization, the area under the curve (AUC) values for predicting mortality were between 0.55 on day 1 and a high of 0.79 on day 5, Dr. Dilektasli reported.

Starting from day 2 to day 10, the AUCs were statistically significant for predicting mortality.

The NLRs on day 2 (AUC, 0.73; P less than .001) and day 5 (AUC, 0.79; P less than .001) were selected in order to adjust for the clinical probability of early and late complications, he said.

Subsequent ROC curve analysis revealed an NLR cutoff of 10.45 on day 2 (AUC, 0.73; sensitivity, 73.2%; specificity, 61.8%) and a cutoff of 7.91 on day 5 (AUC, 0.79; sensitivity, 82.8%; specificity, 65.2%).

A high NLR on day 2 (at least 10.45) versus a low NLR (less than 10.45) was associated with significantly more ventilator days (5 days vs. 3 days), a longer surgical ICU length of stay (5 days vs. 3 days), a longer hospital stay (11 days vs. 8 days), and greater mortality (18.3% vs. 4.8%; all P values less than .001), reported Dr. Dilektasli, who was a research fellow at USC at the time of the study and has returned to Turkey to continue his training.

On day 5, a high NLR (at least 7.91) versus a low NLR (less than 7.91) was associated with significantly more ventilator days (7 days vs. 4 days; P less than .001), a longer surgical ICU stay (9 days vs. 5 days; P less than .001), and increased mortality (20.4% vs. 2.8%; P less than .001), but not a longer hospital stay (17 days vs. 14 days; P = .119).

In Kaplan-Meier analysis, a significant difference was observed between the high and low NLR groups on day 2 (log rank P less than .001) and day 5 (log rank P less than .001), he said.

“NLR may be a promising tool for assessing the risk of in-hospital mortality,” Dr. Dilektasli concluded. “Prospective external validation is warranted in a larger heterogeneous trauma population.”

During a discussion of the study, it was noted that the ROC curves were impressive, but that other biologic markers known to be associated with poor survival such as C-reactive protein level and class II major hepatitis C expression should have been included in the analysis.

When asked whether any patients with a low NLR on day 2 went on to have a high NLR on day 5, Dr. Dilektasli said there were such patients and that they also had an increased risk of death.

The findings of the study, which earned an excellence in research award, are only an “observation” at this point and are not being used in clinical practice, he added.

The authors reported having no relevant financial conflicts of interest.

[email protected]

CHICAGO – A high neutrophil to lymphocyte ratio on days 2 and 5 of surgical ICU hospitalization independently predicts increased mortality in critically ill trauma patients, an award-winning study showed.

The risk of death was two times higher for patients with a neutrophil to lymphocyte ratio (NLR) of at least 10.45 on day 2 (adjusted hazard ratio, 2.07; 95% confidence interval, 1.38-3.13; P = .001) and 5.7 times higher for those with an NLR of at least 7.91 on day 5 (adjusted HR, 5.79; 95% CI, 2.93-11.44; P less than .001) in a multivariate analysis, after adjustment for age 65 years or older, male sex, a systolic blood pressure of 90 mm Hg or less, a Glasgow Coma Scale (GCS) score of 8 or less, an Injury Severity Score (ISS) of at least 25, and operation on admission.

Patrice Wendling/Frontline Medical News

“The neutrophil to lymphocyte ratio is easily accessible, the calculation is simple, it adds no additional costs, and virtually all critically ill patients will have these labs,” study author Dr. Evren Dilektasli said at the American College of Surgeons annual clinical congress.

The simple calculation has been shown to be useful in the diagnosis of appendicitis and to be associated with overall survivalin metastatic colorectal cancer, but its association with mortality in trauma patients is not known, he said.

The retrospective cohort comprised 1,356 trauma patients, at least 16 years old, admitted to the Los Angeles County–University of Southern California Medical Center surgical ICU between January 2013 and January 2014. The median NLR was calculated for each day of the surgical ICU stay. At baseline, 16% of patients had an ISS of at least 25, 16.5% had a GCS of 8 or less, 4.5% had a systolic BP of 90 mm Hg or less, 74.3% were male, 23.7% were aged 65 or older, and 86% had a blunt injury. The most common operations on admission were laparotomy (39.6%) and craniectomy/craniotomy (20.7%).

In receiver operating characteristic (ROC) analysis for the first 10 days of hospitalization, the area under the curve (AUC) values for predicting mortality were between 0.55 on day 1 and a high of 0.79 on day 5, Dr. Dilektasli reported.

Starting from day 2 to day 10, the AUCs were statistically significant for predicting mortality.

The NLRs on day 2 (AUC, 0.73; P less than .001) and day 5 (AUC, 0.79; P less than .001) were selected in order to adjust for the clinical probability of early and late complications, he said.

Subsequent ROC curve analysis revealed an NLR cutoff of 10.45 on day 2 (AUC, 0.73; sensitivity, 73.2%; specificity, 61.8%) and a cutoff of 7.91 on day 5 (AUC, 0.79; sensitivity, 82.8%; specificity, 65.2%).

A high NLR on day 2 (at least 10.45) versus a low NLR (less than 10.45) was associated with significantly more ventilator days (5 days vs. 3 days), a longer surgical ICU length of stay (5 days vs. 3 days), a longer hospital stay (11 days vs. 8 days), and greater mortality (18.3% vs. 4.8%; all P values less than .001), reported Dr. Dilektasli, who was a research fellow at USC at the time of the study and has returned to Turkey to continue his training.

On day 5, a high NLR (at least 7.91) versus a low NLR (less than 7.91) was associated with significantly more ventilator days (7 days vs. 4 days; P less than .001), a longer surgical ICU stay (9 days vs. 5 days; P less than .001), and increased mortality (20.4% vs. 2.8%; P less than .001), but not a longer hospital stay (17 days vs. 14 days; P = .119).

In Kaplan-Meier analysis, a significant difference was observed between the high and low NLR groups on day 2 (log rank P less than .001) and day 5 (log rank P less than .001), he said.

“NLR may be a promising tool for assessing the risk of in-hospital mortality,” Dr. Dilektasli concluded. “Prospective external validation is warranted in a larger heterogeneous trauma population.”

During a discussion of the study, it was noted that the ROC curves were impressive, but that other biologic markers known to be associated with poor survival such as C-reactive protein level and class II major hepatitis C expression should have been included in the analysis.

When asked whether any patients with a low NLR on day 2 went on to have a high NLR on day 5, Dr. Dilektasli said there were such patients and that they also had an increased risk of death.

The findings of the study, which earned an excellence in research award, are only an “observation” at this point and are not being used in clinical practice, he added.

The authors reported having no relevant financial conflicts of interest.

[email protected]

CHICAGO – A high neutrophil to lymphocyte ratio on days 2 and 5 of surgical ICU hospitalization independently predicts increased mortality in critically ill trauma patients, an award-winning study showed.

The risk of death was two times higher for patients with a neutrophil to lymphocyte ratio (NLR) of at least 10.45 on day 2 (adjusted hazard ratio, 2.07; 95% confidence interval, 1.38-3.13; P = .001) and 5.7 times higher for those with an NLR of at least 7.91 on day 5 (adjusted HR, 5.79; 95% CI, 2.93-11.44; P less than .001) in a multivariate analysis, after adjustment for age 65 years or older, male sex, a systolic blood pressure of 90 mm Hg or less, a Glasgow Coma Scale (GCS) score of 8 or less, an Injury Severity Score (ISS) of at least 25, and operation on admission.

Patrice Wendling/Frontline Medical News

“The neutrophil to lymphocyte ratio is easily accessible, the calculation is simple, it adds no additional costs, and virtually all critically ill patients will have these labs,” study author Dr. Evren Dilektasli said at the American College of Surgeons annual clinical congress.

The simple calculation has been shown to be useful in the diagnosis of appendicitis and to be associated with overall survivalin metastatic colorectal cancer, but its association with mortality in trauma patients is not known, he said.

The retrospective cohort comprised 1,356 trauma patients, at least 16 years old, admitted to the Los Angeles County–University of Southern California Medical Center surgical ICU between January 2013 and January 2014. The median NLR was calculated for each day of the surgical ICU stay. At baseline, 16% of patients had an ISS of at least 25, 16.5% had a GCS of 8 or less, 4.5% had a systolic BP of 90 mm Hg or less, 74.3% were male, 23.7% were aged 65 or older, and 86% had a blunt injury. The most common operations on admission were laparotomy (39.6%) and craniectomy/craniotomy (20.7%).

In receiver operating characteristic (ROC) analysis for the first 10 days of hospitalization, the area under the curve (AUC) values for predicting mortality were between 0.55 on day 1 and a high of 0.79 on day 5, Dr. Dilektasli reported.

Starting from day 2 to day 10, the AUCs were statistically significant for predicting mortality.

The NLRs on day 2 (AUC, 0.73; P less than .001) and day 5 (AUC, 0.79; P less than .001) were selected in order to adjust for the clinical probability of early and late complications, he said.

Subsequent ROC curve analysis revealed an NLR cutoff of 10.45 on day 2 (AUC, 0.73; sensitivity, 73.2%; specificity, 61.8%) and a cutoff of 7.91 on day 5 (AUC, 0.79; sensitivity, 82.8%; specificity, 65.2%).

A high NLR on day 2 (at least 10.45) versus a low NLR (less than 10.45) was associated with significantly more ventilator days (5 days vs. 3 days), a longer surgical ICU length of stay (5 days vs. 3 days), a longer hospital stay (11 days vs. 8 days), and greater mortality (18.3% vs. 4.8%; all P values less than .001), reported Dr. Dilektasli, who was a research fellow at USC at the time of the study and has returned to Turkey to continue his training.

On day 5, a high NLR (at least 7.91) versus a low NLR (less than 7.91) was associated with significantly more ventilator days (7 days vs. 4 days; P less than .001), a longer surgical ICU stay (9 days vs. 5 days; P less than .001), and increased mortality (20.4% vs. 2.8%; P less than .001), but not a longer hospital stay (17 days vs. 14 days; P = .119).

In Kaplan-Meier analysis, a significant difference was observed between the high and low NLR groups on day 2 (log rank P less than .001) and day 5 (log rank P less than .001), he said.

“NLR may be a promising tool for assessing the risk of in-hospital mortality,” Dr. Dilektasli concluded. “Prospective external validation is warranted in a larger heterogeneous trauma population.”

During a discussion of the study, it was noted that the ROC curves were impressive, but that other biologic markers known to be associated with poor survival such as C-reactive protein level and class II major hepatitis C expression should have been included in the analysis.

When asked whether any patients with a low NLR on day 2 went on to have a high NLR on day 5, Dr. Dilektasli said there were such patients and that they also had an increased risk of death.

The findings of the study, which earned an excellence in research award, are only an “observation” at this point and are not being used in clinical practice, he added.

The authors reported having no relevant financial conflicts of interest.

[email protected]

ORLANDO – Partnering the PD-1 antibody pembrolizumab with pomalidomide and dexamethasone induced responses in 60% of 27 patients with heavily pretreated relapsed and/or refractory multiple myeloma in a phase II trial.

This included 1 stringent complete response, 4 very good partial responses (VGPR), and 11 partial responses (PR). Eight patients had stable disease and 3 progressed.

Further, the overall response rate was 55% (2 VGPR, 9 PR) in patients double-refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) and 50% (1 VGPR and 5 PR) in those with high-risk cytogenetics.

“The regimen shows promising anti-myeloma activity in heavily pretreated patients” and had a “predictable and manageable side-effect profile,” Dr. Asraf Badros of University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, said at the annual meeting of the American Society of Hematology.

The investigators hypothesized that blocking signaling of the programmed cell death protein 1 (PD-1) and its ligand PD-L1 with pembrolizumab (Keytruda) would activate multiple myeloma-specific cytotoxic T cells that could be further enhanced by the immunomodulator pomalidomide (Pomalyst).

The primary goal of the ongoing study is to establish the safety of the combination therapy.

In all, 33 patients received 28-day cycles of pembrolizumab 200 mg intravenous every 2 weeks plus pomalidomide 4 mg daily for 21 days and dexamethasone 40 mg weekly (20 mg for patients older than 70 years). After 24 months, responders will continue pomalidomide and dexamethasone alone until progression.

At enrollment, patients had to have relapsed and/or refractory disease after at least two lines of prior therapy including an IMiD and a PI, an ECOG performance status of less than 2, and adequate organ function.

Key exclusion criteria are an active autoimmune disease requiring systemic treatment or a history of severe autoimmune disease such as interstitial lung disease or active, non-infectious pneumonitis.

Patients received a median of three prior lines of therapy, 67% had prior autologous transplant, 89% were refractory to lenalidomide, and 70% were double-refractory to both IMiDs and PIs. The median age was 65 years (range 42-81 years), 73% were male, and 42% had high-risk deletion 17p and/or a translocation of chromosomes 14 and 16 [t(14;16)].

The median number of cycles was six and median follow-up short at 7.4 months.

The most common adverse events reported in 10% of all grades were fatigue and hypoglycemia, mostly grades 1 and 2.

The most serious adverse events in the study were pneumonia and infection, including one death due to sepsis, Dr. Badros said. Two other patients died as a result of disease progression and one because of a cardiac event.

“We reported a lot, actually, of immune-related adverse events,” he said.

In 10% of patients, the investigators noted pneumonitis, one of which was grade 3, as well as hyperthyroidism and autoimmune hepatitis. Pembrolizumab was not stopped and the pneumonitis was treated with steroids until symptoms resolved. Patients resumed the assigned doses, though one patient withdrew consent.

The pneumonitis did not appear to be associated with prior therapy and it “responded extremely quickly and well to the steroids, indicating it might be a cytokine release issue,” Dr. Badros said.

Five patients required pomalidomide dose reductions due to neutropenia in two, and one case each of rash, palpitations, and fatigue. After the septic death, antibiotic prophylaxis was started in all patients, he said.

A total of 22 patients remain on study, with 7 patients discontinuing because of disease progression.

Given the short follow-up, it is “too early to talk about progression-free and overall-survival, but the signal we are getting is quite impressive,” Dr. Badros said.

The investigators also tried to look at PD-L1 expression in bone marrow samples collected at screening and on day 1 of cycle 3. No PD-L1 expression was found on plasma cells in the first patient, about 40% expression in the second, and 100% expression in the third, which is consistent with the heterogeneity of PD-L1 expression reported previously in the literature, Dr. Badros said. PD-L1 expression on bone marrow biopsies was very hard to standardize and they are exploring various methods to assess the impact of fixation and decalcification on level of expression, he added.

Dr. Badros disclosed off-label use of pembrolizumab and no relevant conflicts of interest.

[email protected]

ORLANDO – Partnering the PD-1 antibody pembrolizumab with pomalidomide and dexamethasone induced responses in 60% of 27 patients with heavily pretreated relapsed and/or refractory multiple myeloma in a phase II trial.

This included 1 stringent complete response, 4 very good partial responses (VGPR), and 11 partial responses (PR). Eight patients had stable disease and 3 progressed.

Further, the overall response rate was 55% (2 VGPR, 9 PR) in patients double-refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) and 50% (1 VGPR and 5 PR) in those with high-risk cytogenetics.

“The regimen shows promising anti-myeloma activity in heavily pretreated patients” and had a “predictable and manageable side-effect profile,” Dr. Asraf Badros of University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, said at the annual meeting of the American Society of Hematology.

The investigators hypothesized that blocking signaling of the programmed cell death protein 1 (PD-1) and its ligand PD-L1 with pembrolizumab (Keytruda) would activate multiple myeloma-specific cytotoxic T cells that could be further enhanced by the immunomodulator pomalidomide (Pomalyst).

The primary goal of the ongoing study is to establish the safety of the combination therapy.

In all, 33 patients received 28-day cycles of pembrolizumab 200 mg intravenous every 2 weeks plus pomalidomide 4 mg daily for 21 days and dexamethasone 40 mg weekly (20 mg for patients older than 70 years). After 24 months, responders will continue pomalidomide and dexamethasone alone until progression.

At enrollment, patients had to have relapsed and/or refractory disease after at least two lines of prior therapy including an IMiD and a PI, an ECOG performance status of less than 2, and adequate organ function.

Key exclusion criteria are an active autoimmune disease requiring systemic treatment or a history of severe autoimmune disease such as interstitial lung disease or active, non-infectious pneumonitis.

Patients received a median of three prior lines of therapy, 67% had prior autologous transplant, 89% were refractory to lenalidomide, and 70% were double-refractory to both IMiDs and PIs. The median age was 65 years (range 42-81 years), 73% were male, and 42% had high-risk deletion 17p and/or a translocation of chromosomes 14 and 16 [t(14;16)].

The median number of cycles was six and median follow-up short at 7.4 months.

The most common adverse events reported in 10% of all grades were fatigue and hypoglycemia, mostly grades 1 and 2.

The most serious adverse events in the study were pneumonia and infection, including one death due to sepsis, Dr. Badros said. Two other patients died as a result of disease progression and one because of a cardiac event.

“We reported a lot, actually, of immune-related adverse events,” he said.

In 10% of patients, the investigators noted pneumonitis, one of which was grade 3, as well as hyperthyroidism and autoimmune hepatitis. Pembrolizumab was not stopped and the pneumonitis was treated with steroids until symptoms resolved. Patients resumed the assigned doses, though one patient withdrew consent.

The pneumonitis did not appear to be associated with prior therapy and it “responded extremely quickly and well to the steroids, indicating it might be a cytokine release issue,” Dr. Badros said.

Five patients required pomalidomide dose reductions due to neutropenia in two, and one case each of rash, palpitations, and fatigue. After the septic death, antibiotic prophylaxis was started in all patients, he said.

A total of 22 patients remain on study, with 7 patients discontinuing because of disease progression.

Given the short follow-up, it is “too early to talk about progression-free and overall-survival, but the signal we are getting is quite impressive,” Dr. Badros said.

The investigators also tried to look at PD-L1 expression in bone marrow samples collected at screening and on day 1 of cycle 3. No PD-L1 expression was found on plasma cells in the first patient, about 40% expression in the second, and 100% expression in the third, which is consistent with the heterogeneity of PD-L1 expression reported previously in the literature, Dr. Badros said. PD-L1 expression on bone marrow biopsies was very hard to standardize and they are exploring various methods to assess the impact of fixation and decalcification on level of expression, he added.

Dr. Badros disclosed off-label use of pembrolizumab and no relevant conflicts of interest.

[email protected]

ORLANDO – Partnering the PD-1 antibody pembrolizumab with pomalidomide and dexamethasone induced responses in 60% of 27 patients with heavily pretreated relapsed and/or refractory multiple myeloma in a phase II trial.

This included 1 stringent complete response, 4 very good partial responses (VGPR), and 11 partial responses (PR). Eight patients had stable disease and 3 progressed.

Further, the overall response rate was 55% (2 VGPR, 9 PR) in patients double-refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) and 50% (1 VGPR and 5 PR) in those with high-risk cytogenetics.

“The regimen shows promising anti-myeloma activity in heavily pretreated patients” and had a “predictable and manageable side-effect profile,” Dr. Asraf Badros of University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, said at the annual meeting of the American Society of Hematology.

The investigators hypothesized that blocking signaling of the programmed cell death protein 1 (PD-1) and its ligand PD-L1 with pembrolizumab (Keytruda) would activate multiple myeloma-specific cytotoxic T cells that could be further enhanced by the immunomodulator pomalidomide (Pomalyst).

The primary goal of the ongoing study is to establish the safety of the combination therapy.

In all, 33 patients received 28-day cycles of pembrolizumab 200 mg intravenous every 2 weeks plus pomalidomide 4 mg daily for 21 days and dexamethasone 40 mg weekly (20 mg for patients older than 70 years). After 24 months, responders will continue pomalidomide and dexamethasone alone until progression.

At enrollment, patients had to have relapsed and/or refractory disease after at least two lines of prior therapy including an IMiD and a PI, an ECOG performance status of less than 2, and adequate organ function.

Key exclusion criteria are an active autoimmune disease requiring systemic treatment or a history of severe autoimmune disease such as interstitial lung disease or active, non-infectious pneumonitis.

Patients received a median of three prior lines of therapy, 67% had prior autologous transplant, 89% were refractory to lenalidomide, and 70% were double-refractory to both IMiDs and PIs. The median age was 65 years (range 42-81 years), 73% were male, and 42% had high-risk deletion 17p and/or a translocation of chromosomes 14 and 16 [t(14;16)].

The median number of cycles was six and median follow-up short at 7.4 months.

The most common adverse events reported in 10% of all grades were fatigue and hypoglycemia, mostly grades 1 and 2.

The most serious adverse events in the study were pneumonia and infection, including one death due to sepsis, Dr. Badros said. Two other patients died as a result of disease progression and one because of a cardiac event.

“We reported a lot, actually, of immune-related adverse events,” he said.

In 10% of patients, the investigators noted pneumonitis, one of which was grade 3, as well as hyperthyroidism and autoimmune hepatitis. Pembrolizumab was not stopped and the pneumonitis was treated with steroids until symptoms resolved. Patients resumed the assigned doses, though one patient withdrew consent.

The pneumonitis did not appear to be associated with prior therapy and it “responded extremely quickly and well to the steroids, indicating it might be a cytokine release issue,” Dr. Badros said.

Five patients required pomalidomide dose reductions due to neutropenia in two, and one case each of rash, palpitations, and fatigue. After the septic death, antibiotic prophylaxis was started in all patients, he said.

A total of 22 patients remain on study, with 7 patients discontinuing because of disease progression.

Given the short follow-up, it is “too early to talk about progression-free and overall-survival, but the signal we are getting is quite impressive,” Dr. Badros said.

The investigators also tried to look at PD-L1 expression in bone marrow samples collected at screening and on day 1 of cycle 3. No PD-L1 expression was found on plasma cells in the first patient, about 40% expression in the second, and 100% expression in the third, which is consistent with the heterogeneity of PD-L1 expression reported previously in the literature, Dr. Badros said. PD-L1 expression on bone marrow biopsies was very hard to standardize and they are exploring various methods to assess the impact of fixation and decalcification on level of expression, he added.

Dr. Badros disclosed off-label use of pembrolizumab and no relevant conflicts of interest.

[email protected]

ORLANDO – Reduced-intensity conditioning regimens failed to show a significant survival benefit over high-intensity regimens in myelodysplastic syndrome or acute myeloid leukemia in the phase III MAVERICK trial.

Pretransplant reduced intensity conditioning (RIC) also resulted in a significantly higher risk of relapse and inferior relapse-free survival vs. myeloablative conditioning (MAC).

The findings, reported in the late-breaking abstract (LBA-8) session at the annual meeting of the American Society of Hematology, generated a lively debate over the study construct and whether its conclusion that MAC remain “the treatment of choice” in appropriate candidates should be applied to both diseases.

Session comoderator Dr. David P. Steensma, a myelodysplasia physician at the Dana-Farber Cancer Institute in Boston, said in an interview that the data will not change his practice and that physicians should continue to “push the envelope” and provide as intense a conditioning regimen as their patients can tolerate.

“The take-home message is that using a reduced conditioning regimen whatever your choice might be, even though it is gentler on the patient and may be easier for them to go through the transplant, the biggest risk is still the disease, the underlying leukemia or myelodysplasia coming back. And the benefit from reduced intensity is not enough to outweigh that risk.”

To sort out this complex trial, we spoke with study author Dr. Bart L. Scott of the Fred Hutchinson Cancer Research Center at the University of Washington, Seattle.

[email protected]

ORLANDO – Reduced-intensity conditioning regimens failed to show a significant survival benefit over high-intensity regimens in myelodysplastic syndrome or acute myeloid leukemia in the phase III MAVERICK trial.

Pretransplant reduced intensity conditioning (RIC) also resulted in a significantly higher risk of relapse and inferior relapse-free survival vs. myeloablative conditioning (MAC).

The findings, reported in the late-breaking abstract (LBA-8) session at the annual meeting of the American Society of Hematology, generated a lively debate over the study construct and whether its conclusion that MAC remain “the treatment of choice” in appropriate candidates should be applied to both diseases.

Session comoderator Dr. David P. Steensma, a myelodysplasia physician at the Dana-Farber Cancer Institute in Boston, said in an interview that the data will not change his practice and that physicians should continue to “push the envelope” and provide as intense a conditioning regimen as their patients can tolerate.

“The take-home message is that using a reduced conditioning regimen whatever your choice might be, even though it is gentler on the patient and may be easier for them to go through the transplant, the biggest risk is still the disease, the underlying leukemia or myelodysplasia coming back. And the benefit from reduced intensity is not enough to outweigh that risk.”

To sort out this complex trial, we spoke with study author Dr. Bart L. Scott of the Fred Hutchinson Cancer Research Center at the University of Washington, Seattle.

[email protected]

ORLANDO – Reduced-intensity conditioning regimens failed to show a significant survival benefit over high-intensity regimens in myelodysplastic syndrome or acute myeloid leukemia in the phase III MAVERICK trial.

Pretransplant reduced intensity conditioning (RIC) also resulted in a significantly higher risk of relapse and inferior relapse-free survival vs. myeloablative conditioning (MAC).

The findings, reported in the late-breaking abstract (LBA-8) session at the annual meeting of the American Society of Hematology, generated a lively debate over the study construct and whether its conclusion that MAC remain “the treatment of choice” in appropriate candidates should be applied to both diseases.

Session comoderator Dr. David P. Steensma, a myelodysplasia physician at the Dana-Farber Cancer Institute in Boston, said in an interview that the data will not change his practice and that physicians should continue to “push the envelope” and provide as intense a conditioning regimen as their patients can tolerate.

“The take-home message is that using a reduced conditioning regimen whatever your choice might be, even though it is gentler on the patient and may be easier for them to go through the transplant, the biggest risk is still the disease, the underlying leukemia or myelodysplasia coming back. And the benefit from reduced intensity is not enough to outweigh that risk.”

To sort out this complex trial, we spoke with study author Dr. Bart L. Scott of the Fred Hutchinson Cancer Research Center at the University of Washington, Seattle.

[email protected]

ORLANDO – Adding rituximab to standard intensive chemotherapy significantly improved event-free survival in adults with Philadelphia-negative, CD20-positive B-cell precursor acute lymphoblastic leukemia in the phase III GRAALL-R 2005 study.

Rituximab (Rituxan) is already being used to improve outcomes in patients with lymphoma, and non-randomized data support addition of the anti-CD20 monoclonal antibody to chemotherapy in B-cell precursor (BCP) ALL, where the CD20 antigen is expressed in 30% to 40% of patients at diagnosis.

In the randomized GRAALL-R 2005, 2-year event-free survival (EFS) was 65% in the rituximab arm vs. 52% in the control arm (hazard ratio, 0.66; P = .038).

Patrice Wendling/Frontline Medical News

This difference is not explained by the early response rates, which were very close in both arms after one or two induction courses (92% vs. 90%; P = .63), Dr. Sébastien Maury, Hôpital Henri Mondor in Créteil, France, said during the plenary session at the annual meeting of the American Society of Hematology (Ab. 1).

The beneficial effect of rituximab, however, was clearly related to the cumulative incidence of relapse at 18% with vs. 32% without rituximab (HR, 0.52; P = .017).

Despite this advantage, overall survival was similar between patients given chemotherapy with and without rituximab (71% vs. 64%; HR, 0.70; P = .095), he said.

After censoring for patients not receiving allogeneic stem cell transplant in first complete remission, however, rituximab significantly prolonged 2-year EFS (HR, 0.59; P = .021) as well as overall survival (HR, 0.55; P = .018), Dr. Maury said.

“We thus recommend that the addition of rituximab become a new standard of care for these patients, although some aspects including the definition of the optimal dose needs to be determined in further studies,” he concluded.

Dr. Adele Fielding of University College London, who introduced the study at the meeting, said, “For me, the prior knowledge that the drug can be safely already added to chemotherapy in other settings provides profound comfort in a disease in which so many people are already damaged by the current therapies we offer.”

Also, of importance is the potential relevance of rituximab in patients in whom CD20 is present on fewer than 20% of blasts at diagnosis.

Key questions that remain in rituximab therapy of ALL beyond overall benefit include early and late toxicities and how best to judge response and when, she said. Synergies with other agents and the mechanism of action will also require clarification, especially which effector cells are relevant to ensure that agents are not used with rituximab that destroy the optimal chance for response.

“Finally, the cost of introducing novel agents cannot be ignored, even in well-developed economies, and I am hopeful that the cost of this drug will be variable for many countries and many patients.” Dr. Fielding said.

Study details

A total of 220 patients, aged 18-59 years, with newly diagnosed CD20-positive Ph-negative BCP-ALL were randomized to the pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) chemotherapy protocol with or without rituximab 375 mg/m² given during induction (day 1 and 7), salvage reinduction when needed (day 1 and 7), consolidation blocks (6 infusions), late intensification (day 1 and 7, and the first year of maintenance [6 infusions], for a total of 16-18 infusions. Allogeneic stem cell transplant (SCT) was offered after consolidation blocks 1 or 2 to patients with one or more high-risk criteria and an available donor. CD20-positivity was defined as expression of CD20 in more than 20% of leukemia blasts.

Eleven patients were excluded from the analysis because of non–ineligibility criteria, leaving 209 patients in the modified intent-to-treat analysis. Their median age was 40.2 years and 67% had high-risk ALL.

Rates of postinduction minimal residual disease less than 10^–4 were 65% and 61% in the rituximab and control arms among 85 evaluable patients(P = .82), and rates of postconsolidation minimal residual disease less than 10^–4 were 91% and 82% among 80 evaluable patients (P = .31), Dr. Maury reported.

Notably, more patients in the rituximab arm received allogeneic SCT in their first complete remission (34% vs. 20%; P = .029).

The cumulative incidence of death in first complete remission was 12% in both arms.

In multivariate analysis, rituximab impacted EFS, together with age, central nervous system involvement, white blood cells, or CD20 expression at diagnosis. A preferential effect with rituximab was seen in patients with high CD20 levels that deserves further evaluation, he observed.

There was no difference in the incidence of adverse events between the rituximab and control arms, although there was a trend for more infectious events with rituximab (71 events vs. 55 events), Dr. Maury said.

Allergic events – all but one from aspergillosis – were significantly more common in the control arm (2 events vs. 14 events; P = .002).

The Group for Research in Adult Acute Lymphoblastic Leukemia sponsored the study. Dr. Maury reported having no disclosures.

[email protected]

ORLANDO – Adding rituximab to standard intensive chemotherapy significantly improved event-free survival in adults with Philadelphia-negative, CD20-positive B-cell precursor acute lymphoblastic leukemia in the phase III GRAALL-R 2005 study.

Rituximab (Rituxan) is already being used to improve outcomes in patients with lymphoma, and non-randomized data support addition of the anti-CD20 monoclonal antibody to chemotherapy in B-cell precursor (BCP) ALL, where the CD20 antigen is expressed in 30% to 40% of patients at diagnosis.

In the randomized GRAALL-R 2005, 2-year event-free survival (EFS) was 65% in the rituximab arm vs. 52% in the control arm (hazard ratio, 0.66; P = .038).

Patrice Wendling/Frontline Medical News

This difference is not explained by the early response rates, which were very close in both arms after one or two induction courses (92% vs. 90%; P = .63), Dr. Sébastien Maury, Hôpital Henri Mondor in Créteil, France, said during the plenary session at the annual meeting of the American Society of Hematology (Ab. 1).

The beneficial effect of rituximab, however, was clearly related to the cumulative incidence of relapse at 18% with vs. 32% without rituximab (HR, 0.52; P = .017).

Despite this advantage, overall survival was similar between patients given chemotherapy with and without rituximab (71% vs. 64%; HR, 0.70; P = .095), he said.

After censoring for patients not receiving allogeneic stem cell transplant in first complete remission, however, rituximab significantly prolonged 2-year EFS (HR, 0.59; P = .021) as well as overall survival (HR, 0.55; P = .018), Dr. Maury said.

“We thus recommend that the addition of rituximab become a new standard of care for these patients, although some aspects including the definition of the optimal dose needs to be determined in further studies,” he concluded.

Dr. Adele Fielding of University College London, who introduced the study at the meeting, said, “For me, the prior knowledge that the drug can be safely already added to chemotherapy in other settings provides profound comfort in a disease in which so many people are already damaged by the current therapies we offer.”

Also, of importance is the potential relevance of rituximab in patients in whom CD20 is present on fewer than 20% of blasts at diagnosis.

Key questions that remain in rituximab therapy of ALL beyond overall benefit include early and late toxicities and how best to judge response and when, she said. Synergies with other agents and the mechanism of action will also require clarification, especially which effector cells are relevant to ensure that agents are not used with rituximab that destroy the optimal chance for response.

“Finally, the cost of introducing novel agents cannot be ignored, even in well-developed economies, and I am hopeful that the cost of this drug will be variable for many countries and many patients.” Dr. Fielding said.

Study details

A total of 220 patients, aged 18-59 years, with newly diagnosed CD20-positive Ph-negative BCP-ALL were randomized to the pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) chemotherapy protocol with or without rituximab 375 mg/m² given during induction (day 1 and 7), salvage reinduction when needed (day 1 and 7), consolidation blocks (6 infusions), late intensification (day 1 and 7, and the first year of maintenance [6 infusions], for a total of 16-18 infusions. Allogeneic stem cell transplant (SCT) was offered after consolidation blocks 1 or 2 to patients with one or more high-risk criteria and an available donor. CD20-positivity was defined as expression of CD20 in more than 20% of leukemia blasts.

Eleven patients were excluded from the analysis because of non–ineligibility criteria, leaving 209 patients in the modified intent-to-treat analysis. Their median age was 40.2 years and 67% had high-risk ALL.

Rates of postinduction minimal residual disease less than 10^–4 were 65% and 61% in the rituximab and control arms among 85 evaluable patients(P = .82), and rates of postconsolidation minimal residual disease less than 10^–4 were 91% and 82% among 80 evaluable patients (P = .31), Dr. Maury reported.

Notably, more patients in the rituximab arm received allogeneic SCT in their first complete remission (34% vs. 20%; P = .029).

The cumulative incidence of death in first complete remission was 12% in both arms.

In multivariate analysis, rituximab impacted EFS, together with age, central nervous system involvement, white blood cells, or CD20 expression at diagnosis. A preferential effect with rituximab was seen in patients with high CD20 levels that deserves further evaluation, he observed.

There was no difference in the incidence of adverse events between the rituximab and control arms, although there was a trend for more infectious events with rituximab (71 events vs. 55 events), Dr. Maury said.

Allergic events – all but one from aspergillosis – were significantly more common in the control arm (2 events vs. 14 events; P = .002).

The Group for Research in Adult Acute Lymphoblastic Leukemia sponsored the study. Dr. Maury reported having no disclosures.

[email protected]

ORLANDO – Adding rituximab to standard intensive chemotherapy significantly improved event-free survival in adults with Philadelphia-negative, CD20-positive B-cell precursor acute lymphoblastic leukemia in the phase III GRAALL-R 2005 study.

Rituximab (Rituxan) is already being used to improve outcomes in patients with lymphoma, and non-randomized data support addition of the anti-CD20 monoclonal antibody to chemotherapy in B-cell precursor (BCP) ALL, where the CD20 antigen is expressed in 30% to 40% of patients at diagnosis.

In the randomized GRAALL-R 2005, 2-year event-free survival (EFS) was 65% in the rituximab arm vs. 52% in the control arm (hazard ratio, 0.66; P = .038).

Patrice Wendling/Frontline Medical News

This difference is not explained by the early response rates, which were very close in both arms after one or two induction courses (92% vs. 90%; P = .63), Dr. Sébastien Maury, Hôpital Henri Mondor in Créteil, France, said during the plenary session at the annual meeting of the American Society of Hematology (Ab. 1).

The beneficial effect of rituximab, however, was clearly related to the cumulative incidence of relapse at 18% with vs. 32% without rituximab (HR, 0.52; P = .017).

Despite this advantage, overall survival was similar between patients given chemotherapy with and without rituximab (71% vs. 64%; HR, 0.70; P = .095), he said.

After censoring for patients not receiving allogeneic stem cell transplant in first complete remission, however, rituximab significantly prolonged 2-year EFS (HR, 0.59; P = .021) as well as overall survival (HR, 0.55; P = .018), Dr. Maury said.

“We thus recommend that the addition of rituximab become a new standard of care for these patients, although some aspects including the definition of the optimal dose needs to be determined in further studies,” he concluded.

Dr. Adele Fielding of University College London, who introduced the study at the meeting, said, “For me, the prior knowledge that the drug can be safely already added to chemotherapy in other settings provides profound comfort in a disease in which so many people are already damaged by the current therapies we offer.”

Also, of importance is the potential relevance of rituximab in patients in whom CD20 is present on fewer than 20% of blasts at diagnosis.

Key questions that remain in rituximab therapy of ALL beyond overall benefit include early and late toxicities and how best to judge response and when, she said. Synergies with other agents and the mechanism of action will also require clarification, especially which effector cells are relevant to ensure that agents are not used with rituximab that destroy the optimal chance for response.

“Finally, the cost of introducing novel agents cannot be ignored, even in well-developed economies, and I am hopeful that the cost of this drug will be variable for many countries and many patients.” Dr. Fielding said.

Study details

A total of 220 patients, aged 18-59 years, with newly diagnosed CD20-positive Ph-negative BCP-ALL were randomized to the pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) chemotherapy protocol with or without rituximab 375 mg/m² given during induction (day 1 and 7), salvage reinduction when needed (day 1 and 7), consolidation blocks (6 infusions), late intensification (day 1 and 7, and the first year of maintenance [6 infusions], for a total of 16-18 infusions. Allogeneic stem cell transplant (SCT) was offered after consolidation blocks 1 or 2 to patients with one or more high-risk criteria and an available donor. CD20-positivity was defined as expression of CD20 in more than 20% of leukemia blasts.

Eleven patients were excluded from the analysis because of non–ineligibility criteria, leaving 209 patients in the modified intent-to-treat analysis. Their median age was 40.2 years and 67% had high-risk ALL.

Rates of postinduction minimal residual disease less than 10^–4 were 65% and 61% in the rituximab and control arms among 85 evaluable patients(P = .82), and rates of postconsolidation minimal residual disease less than 10^–4 were 91% and 82% among 80 evaluable patients (P = .31), Dr. Maury reported.

Notably, more patients in the rituximab arm received allogeneic SCT in their first complete remission (34% vs. 20%; P = .029).

The cumulative incidence of death in first complete remission was 12% in both arms.

In multivariate analysis, rituximab impacted EFS, together with age, central nervous system involvement, white blood cells, or CD20 expression at diagnosis. A preferential effect with rituximab was seen in patients with high CD20 levels that deserves further evaluation, he observed.

There was no difference in the incidence of adverse events between the rituximab and control arms, although there was a trend for more infectious events with rituximab (71 events vs. 55 events), Dr. Maury said.

Allergic events – all but one from aspergillosis – were significantly more common in the control arm (2 events vs. 14 events; P = .002).

The Group for Research in Adult Acute Lymphoblastic Leukemia sponsored the study. Dr. Maury reported having no disclosures.

[email protected]

ORLANDO – Monotherapy with ibrutinib (Imbruvica) prolonged survival longer than did standard chemotherapy using chlorambucil (Leukeran) in the front-line treatment of older patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in the phase III RESONATE-2 study.

Co–drug developers Pharmacyclics and Janssen Biotech announced this summer that ibrutinib, an orally bioavailable, small-molecule inhibitor of Bruton’s tyrosine kinase, had achieved its primary and secondary endpoints.

Courtesy: Neil Osterweil

But the first full look at the data at the annual meeting of the American Society of Hematology showed ibrutinib reduced the risk of progression or death by 84% by independent review compared with chlorambucil, which has been a standard first-line therapy in older CLL patients.

The results were simultaneously published in the New England Journal of Medicine (doi: 10.1056/NEJMoa1509388).

With a median follow-up of 18.4 months, median progression-free survival (PFS) had not been reached with ibrutinib vs. 19 months with chlorambucil (hazard ratio, 0.16; P less than .001).

By investigator assessment, ibrutinib reduced the risk of progression by 91%, with an 18-month PFS rate of 94% vs. 45% with chlorambucil (HR, 0.09; P less than .001).

The PFS benefit with ibrutinib was consistent regardless of patient age, Rai stage, ECOG (Eastern Cooperative Oncology Group) status, bulky disease, and importantly, such high-risk markers as chromosome 11q deletion and unmutated immunoglobulin heavy chain variable (IGHV) mutation status, study author Dr. Alessandra Tedeschi, of Hospital Niguarda Cà Granda, Milan, , said at a press briefing highlighting the study (Ab. 485).

In addition, ibrutinib led to an 84% reduction in the risk of death compared with chlorambucil (HR, 0.16; P = .001). The 24-month overall survival rate was 98% with ibrutinib versus 85% with chlorambucil.

Single-agent ibrutinib was approved in 2014 for patients with CLL who had received at least one prior therapy and for all patients with the deleterious 17p deletion on the basis of the phase III RESONATE trial in relapsed or refractory CLL.

Three-year follow-up in the phase II PCYC-1102 study signaled a benefit with ibrutinib in treatment-naive CLL, showing an overall response rate of 84%, 30-month PFS of 96%, and overall survival rate of 97% in a subset of 31 patients at least 65 years old (Blood. 2015 Apr 16;125[16]:2497-506).

“The phase III RESONATE-2 trial confirms the efficacy of ibrutinib in treatment-naive CLL patients, leading to a 91% reduction in risk of progression and 84% reduction in risk of death when compared to chlorambucil,” Dr. Tedeschi said.

In all, 269 patients, median age of 73 years, were evenly randomized to once-daily ibrutinib 420 mg until progression or unacceptable toxicity or chlorambucil 0.5 mg/kg (up to a maximum of 0.8 mg/kg) on days 1 and 15 of a 28-day cycle for up to 12 cycles. Patients with the deleterious 17p deletion were excluded, as single-agent chlorambucil is not effective in this population.

Ibrutinib significantly improved bone marrow function, as reflected by a sustained increase in hemoglobin and platelets.

“This is very important in this category of elderly patients, in whom bone marrow failure is the most common cause of morbidity,” Dr. Tedeschi said.

There were 3 deaths on the ibrutinib arm and 17 on the chlorambucil arm.

The majority of patients (87%) in this older population with frequent comorbidities was able to continue on oral, once-daily ibrutinib with a median of 1.5 years of follow-up, she said.

The most common adverse events on ibrutinib were grade one diarrhea, fatigue, cough, and nausea that did not result in treatment discontinuation. On the chlorambucil arm, fatigue nausea, vomiting, and cytopenias occurred more frequently than with ibrutinib.

Grade 3 maculopapular rash occurred in 3% with ibrutinib and 2% with chlorambucil, she said.

Ibrutinib was associated with higher and not insignificant rates of atrial fibrillation and major hemorrhage compared with chlorambucil, said Dr. Brian T. Hill of the Taussig Cancer Institute at the Cleveland Clinic, who was not involved in the study. In our interview, Dr. Hill also questions the relevance today of chlorambucil monotherapy as the comparator arm in RESONATE-2.

Pharmacyclics, which is jointly developing ibrutinib with Janssen Biotech, sponsored the study. Dr. Tedeschi reported having nothing to disclose. Several coauthors reported relationships with Pharmacyclics and Janssen.

[email protected]

ORLANDO – Monotherapy with ibrutinib (Imbruvica) prolonged survival longer than did standard chemotherapy using chlorambucil (Leukeran) in the front-line treatment of older patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in the phase III RESONATE-2 study.

Co–drug developers Pharmacyclics and Janssen Biotech announced this summer that ibrutinib, an orally bioavailable, small-molecule inhibitor of Bruton’s tyrosine kinase, had achieved its primary and secondary endpoints.

Courtesy: Neil Osterweil

But the first full look at the data at the annual meeting of the American Society of Hematology showed ibrutinib reduced the risk of progression or death by 84% by independent review compared with chlorambucil, which has been a standard first-line therapy in older CLL patients.

The results were simultaneously published in the New England Journal of Medicine (doi: 10.1056/NEJMoa1509388).

With a median follow-up of 18.4 months, median progression-free survival (PFS) had not been reached with ibrutinib vs. 19 months with chlorambucil (hazard ratio, 0.16; P less than .001).

By investigator assessment, ibrutinib reduced the risk of progression by 91%, with an 18-month PFS rate of 94% vs. 45% with chlorambucil (HR, 0.09; P less than .001).

The PFS benefit with ibrutinib was consistent regardless of patient age, Rai stage, ECOG (Eastern Cooperative Oncology Group) status, bulky disease, and importantly, such high-risk markers as chromosome 11q deletion and unmutated immunoglobulin heavy chain variable (IGHV) mutation status, study author Dr. Alessandra Tedeschi, of Hospital Niguarda Cà Granda, Milan, , said at a press briefing highlighting the study (Ab. 485).

In addition, ibrutinib led to an 84% reduction in the risk of death compared with chlorambucil (HR, 0.16; P = .001). The 24-month overall survival rate was 98% with ibrutinib versus 85% with chlorambucil.

Single-agent ibrutinib was approved in 2014 for patients with CLL who had received at least one prior therapy and for all patients with the deleterious 17p deletion on the basis of the phase III RESONATE trial in relapsed or refractory CLL.

Three-year follow-up in the phase II PCYC-1102 study signaled a benefit with ibrutinib in treatment-naive CLL, showing an overall response rate of 84%, 30-month PFS of 96%, and overall survival rate of 97% in a subset of 31 patients at least 65 years old (Blood. 2015 Apr 16;125[16]:2497-506).

“The phase III RESONATE-2 trial confirms the efficacy of ibrutinib in treatment-naive CLL patients, leading to a 91% reduction in risk of progression and 84% reduction in risk of death when compared to chlorambucil,” Dr. Tedeschi said.

In all, 269 patients, median age of 73 years, were evenly randomized to once-daily ibrutinib 420 mg until progression or unacceptable toxicity or chlorambucil 0.5 mg/kg (up to a maximum of 0.8 mg/kg) on days 1 and 15 of a 28-day cycle for up to 12 cycles. Patients with the deleterious 17p deletion were excluded, as single-agent chlorambucil is not effective in this population.

Ibrutinib significantly improved bone marrow function, as reflected by a sustained increase in hemoglobin and platelets.

“This is very important in this category of elderly patients, in whom bone marrow failure is the most common cause of morbidity,” Dr. Tedeschi said.

There were 3 deaths on the ibrutinib arm and 17 on the chlorambucil arm.

The majority of patients (87%) in this older population with frequent comorbidities was able to continue on oral, once-daily ibrutinib with a median of 1.5 years of follow-up, she said.

The most common adverse events on ibrutinib were grade one diarrhea, fatigue, cough, and nausea that did not result in treatment discontinuation. On the chlorambucil arm, fatigue nausea, vomiting, and cytopenias occurred more frequently than with ibrutinib.

Grade 3 maculopapular rash occurred in 3% with ibrutinib and 2% with chlorambucil, she said.

Ibrutinib was associated with higher and not insignificant rates of atrial fibrillation and major hemorrhage compared with chlorambucil, said Dr. Brian T. Hill of the Taussig Cancer Institute at the Cleveland Clinic, who was not involved in the study. In our interview, Dr. Hill also questions the relevance today of chlorambucil monotherapy as the comparator arm in RESONATE-2.

Pharmacyclics, which is jointly developing ibrutinib with Janssen Biotech, sponsored the study. Dr. Tedeschi reported having nothing to disclose. Several coauthors reported relationships with Pharmacyclics and Janssen.

[email protected]

ORLANDO – Monotherapy with ibrutinib (Imbruvica) prolonged survival longer than did standard chemotherapy using chlorambucil (Leukeran) in the front-line treatment of older patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in the phase III RESONATE-2 study.

Co–drug developers Pharmacyclics and Janssen Biotech announced this summer that ibrutinib, an orally bioavailable, small-molecule inhibitor of Bruton’s tyrosine kinase, had achieved its primary and secondary endpoints.

Courtesy: Neil Osterweil

But the first full look at the data at the annual meeting of the American Society of Hematology showed ibrutinib reduced the risk of progression or death by 84% by independent review compared with chlorambucil, which has been a standard first-line therapy in older CLL patients.

The results were simultaneously published in the New England Journal of Medicine (doi: 10.1056/NEJMoa1509388).

With a median follow-up of 18.4 months, median progression-free survival (PFS) had not been reached with ibrutinib vs. 19 months with chlorambucil (hazard ratio, 0.16; P less than .001).

By investigator assessment, ibrutinib reduced the risk of progression by 91%, with an 18-month PFS rate of 94% vs. 45% with chlorambucil (HR, 0.09; P less than .001).

The PFS benefit with ibrutinib was consistent regardless of patient age, Rai stage, ECOG (Eastern Cooperative Oncology Group) status, bulky disease, and importantly, such high-risk markers as chromosome 11q deletion and unmutated immunoglobulin heavy chain variable (IGHV) mutation status, study author Dr. Alessandra Tedeschi, of Hospital Niguarda Cà Granda, Milan, , said at a press briefing highlighting the study (Ab. 485).

In addition, ibrutinib led to an 84% reduction in the risk of death compared with chlorambucil (HR, 0.16; P = .001). The 24-month overall survival rate was 98% with ibrutinib versus 85% with chlorambucil.

Single-agent ibrutinib was approved in 2014 for patients with CLL who had received at least one prior therapy and for all patients with the deleterious 17p deletion on the basis of the phase III RESONATE trial in relapsed or refractory CLL.

Three-year follow-up in the phase II PCYC-1102 study signaled a benefit with ibrutinib in treatment-naive CLL, showing an overall response rate of 84%, 30-month PFS of 96%, and overall survival rate of 97% in a subset of 31 patients at least 65 years old (Blood. 2015 Apr 16;125[16]:2497-506).

“The phase III RESONATE-2 trial confirms the efficacy of ibrutinib in treatment-naive CLL patients, leading to a 91% reduction in risk of progression and 84% reduction in risk of death when compared to chlorambucil,” Dr. Tedeschi said.

In all, 269 patients, median age of 73 years, were evenly randomized to once-daily ibrutinib 420 mg until progression or unacceptable toxicity or chlorambucil 0.5 mg/kg (up to a maximum of 0.8 mg/kg) on days 1 and 15 of a 28-day cycle for up to 12 cycles. Patients with the deleterious 17p deletion were excluded, as single-agent chlorambucil is not effective in this population.

Ibrutinib significantly improved bone marrow function, as reflected by a sustained increase in hemoglobin and platelets.

“This is very important in this category of elderly patients, in whom bone marrow failure is the most common cause of morbidity,” Dr. Tedeschi said.

There were 3 deaths on the ibrutinib arm and 17 on the chlorambucil arm.

The majority of patients (87%) in this older population with frequent comorbidities was able to continue on oral, once-daily ibrutinib with a median of 1.5 years of follow-up, she said.

The most common adverse events on ibrutinib were grade one diarrhea, fatigue, cough, and nausea that did not result in treatment discontinuation. On the chlorambucil arm, fatigue nausea, vomiting, and cytopenias occurred more frequently than with ibrutinib.

Grade 3 maculopapular rash occurred in 3% with ibrutinib and 2% with chlorambucil, she said.

Ibrutinib was associated with higher and not insignificant rates of atrial fibrillation and major hemorrhage compared with chlorambucil, said Dr. Brian T. Hill of the Taussig Cancer Institute at the Cleveland Clinic, who was not involved in the study. In our interview, Dr. Hill also questions the relevance today of chlorambucil monotherapy as the comparator arm in RESONATE-2.

Pharmacyclics, which is jointly developing ibrutinib with Janssen Biotech, sponsored the study. Dr. Tedeschi reported having nothing to disclose. Several coauthors reported relationships with Pharmacyclics and Janssen.

[email protected]