Jen Smith

SAN FRANCISCO—New research indicates that extending anticoagulant therapy to 2 years can reduce the risk of recurrent venous thromboembolism (VTE) without increasing major bleeding, but this benefit only lasts while patients are receiving the therapy.

In the PADIS-PE study, patients with a first episode of symptomatic, unprovoked pulmonary embolism (PE) received 6 months of treatment with a vitamin K antagonist (VKA), followed by 18 months of warfarin or placebo.

Patients who received warfarin had a 77% reduction in the relative risk of recurrent VTE or major bleeding while they received treatment. But an additional 2 years of follow-up showed that this benefit was lost once patients stopped anticoagulation.

Francis Couturaud, MD, PhD, of the Brest University Hospital Center in Brest, France, presented these data at the 2014 ASH Annual Meeting as LBA-3.*

He and his colleagues randomized patients to receive warfarin (n=184) or placebo (n=187) for 18 months after their intial VKA treatment. Patients were followed for an additional 24 months after treatment ended.

Most baseline characteristics were similar between the treatment arms, although there was a significantly higher percentage of females in the warfarin arm.

“[Overall,] the mean age was below 60, [and] the mean BMI [body mass index] was below 30,” Dr Couturaud noted. “About 4% of patients had previous cancer [that had been] resolved for more than 2 years, 8% had previous distal DVT [deep vein thrombosis] or superficial venous thrombosis, a quarter of women were on estrogen-containing pills, and about one-third had an associated proximal DVT at the time of PE diagnosis.”

“Before the randomization, the mean duration of VKA [therapy] was 6 months, and the mean percentage of time within the therapeutic range was 70. At inclusion, about one-third of patients had residual perfusion defect, about 15% had residual DVT, the mean D-dimer level was below 500 μg/L, and about 27% had thrombophilia.”

Results

The study’s primary outcome was the composite of recurrent VTE or major bleeding during the 18-month treatment period. Significantly fewer patients met this endpoint in the warfarin arm than in the placebo arm—6 (3.3%) and 25 (13.5%), respectively (hazard ratio [HR]=0.23, P=0.0004).

Likewise, the number of patients with recurrent VTE at 18 months was significantly lower in the warfarin arm than in the placebo arm—3 (1.7%) and 25 (13.5%), respectively (HR=0.11, P<0.0001).

On the other hand, there was no significant difference in the rate of major bleeding between the treatment arms at 18 months. Four patients (2.2%) had major bleeding in the warfarin arm, as did 1 (0.5%) in the placebo arm (HR=4.07, P=0.18).

At 42 months, there was no significant difference between the treatment arms with regard to the composite outcome, the rate of recurrent VTE, or the rate of major bleeding.

The composite outcome occurred in 33 (20.8%) patients in the warfarin arm and 42 (24%) in the placebo arm (HR=0.74, P=0.19). Recurrent VTE occurred in 28 (17.9%) and 39 patients (22.1%), respectively (HR=0.67, P=0.10). And major bleeding occurred in 6 (3.5%) and 5 patients (3%), respectively (HR=1.12, P=0.71).

“[E]xtending anticoagulation for 18 additional months was associated with a major relative risk reduction of 77% of recurrent VTE or major bleeding during the treatment period,” Dr Couturaud said in summary. “However, this benefit was lost during a long-term follow-up of 2 years after stopping anticoagulation.”

“In addition, recurrent VTE occurred in 80% of cases as recurrent PE and in 90% of cases as unprovoked VTE. So additional investigations are needed to identify subgroups of patients at lower risk who may not need indefinite anticoagulation.”

This study was sponsored by Brest University Hospital. Investigators received research funding from Actelion Pharmaceuticals, GlaxoSmithKline, Bristol-Myers Squibb, Boehringer Ingelheim, Sanofi, LEO Pharma, and Bayer.

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—New research indicates that extending anticoagulant therapy to 2 years can reduce the risk of recurrent venous thromboembolism (VTE) without increasing major bleeding, but this benefit only lasts while patients are receiving the therapy.

In the PADIS-PE study, patients with a first episode of symptomatic, unprovoked pulmonary embolism (PE) received 6 months of treatment with a vitamin K antagonist (VKA), followed by 18 months of warfarin or placebo.

Patients who received warfarin had a 77% reduction in the relative risk of recurrent VTE or major bleeding while they received treatment. But an additional 2 years of follow-up showed that this benefit was lost once patients stopped anticoagulation.

Francis Couturaud, MD, PhD, of the Brest University Hospital Center in Brest, France, presented these data at the 2014 ASH Annual Meeting as LBA-3.*

He and his colleagues randomized patients to receive warfarin (n=184) or placebo (n=187) for 18 months after their intial VKA treatment. Patients were followed for an additional 24 months after treatment ended.

Most baseline characteristics were similar between the treatment arms, although there was a significantly higher percentage of females in the warfarin arm.

“[Overall,] the mean age was below 60, [and] the mean BMI [body mass index] was below 30,” Dr Couturaud noted. “About 4% of patients had previous cancer [that had been] resolved for more than 2 years, 8% had previous distal DVT [deep vein thrombosis] or superficial venous thrombosis, a quarter of women were on estrogen-containing pills, and about one-third had an associated proximal DVT at the time of PE diagnosis.”

“Before the randomization, the mean duration of VKA [therapy] was 6 months, and the mean percentage of time within the therapeutic range was 70. At inclusion, about one-third of patients had residual perfusion defect, about 15% had residual DVT, the mean D-dimer level was below 500 μg/L, and about 27% had thrombophilia.”

Results

The study’s primary outcome was the composite of recurrent VTE or major bleeding during the 18-month treatment period. Significantly fewer patients met this endpoint in the warfarin arm than in the placebo arm—6 (3.3%) and 25 (13.5%), respectively (hazard ratio [HR]=0.23, P=0.0004).

Likewise, the number of patients with recurrent VTE at 18 months was significantly lower in the warfarin arm than in the placebo arm—3 (1.7%) and 25 (13.5%), respectively (HR=0.11, P<0.0001).

On the other hand, there was no significant difference in the rate of major bleeding between the treatment arms at 18 months. Four patients (2.2%) had major bleeding in the warfarin arm, as did 1 (0.5%) in the placebo arm (HR=4.07, P=0.18).

At 42 months, there was no significant difference between the treatment arms with regard to the composite outcome, the rate of recurrent VTE, or the rate of major bleeding.

The composite outcome occurred in 33 (20.8%) patients in the warfarin arm and 42 (24%) in the placebo arm (HR=0.74, P=0.19). Recurrent VTE occurred in 28 (17.9%) and 39 patients (22.1%), respectively (HR=0.67, P=0.10). And major bleeding occurred in 6 (3.5%) and 5 patients (3%), respectively (HR=1.12, P=0.71).

“[E]xtending anticoagulation for 18 additional months was associated with a major relative risk reduction of 77% of recurrent VTE or major bleeding during the treatment period,” Dr Couturaud said in summary. “However, this benefit was lost during a long-term follow-up of 2 years after stopping anticoagulation.”

“In addition, recurrent VTE occurred in 80% of cases as recurrent PE and in 90% of cases as unprovoked VTE. So additional investigations are needed to identify subgroups of patients at lower risk who may not need indefinite anticoagulation.”

This study was sponsored by Brest University Hospital. Investigators received research funding from Actelion Pharmaceuticals, GlaxoSmithKline, Bristol-Myers Squibb, Boehringer Ingelheim, Sanofi, LEO Pharma, and Bayer.

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—New research indicates that extending anticoagulant therapy to 2 years can reduce the risk of recurrent venous thromboembolism (VTE) without increasing major bleeding, but this benefit only lasts while patients are receiving the therapy.

In the PADIS-PE study, patients with a first episode of symptomatic, unprovoked pulmonary embolism (PE) received 6 months of treatment with a vitamin K antagonist (VKA), followed by 18 months of warfarin or placebo.

Patients who received warfarin had a 77% reduction in the relative risk of recurrent VTE or major bleeding while they received treatment. But an additional 2 years of follow-up showed that this benefit was lost once patients stopped anticoagulation.

Francis Couturaud, MD, PhD, of the Brest University Hospital Center in Brest, France, presented these data at the 2014 ASH Annual Meeting as LBA-3.*

He and his colleagues randomized patients to receive warfarin (n=184) or placebo (n=187) for 18 months after their intial VKA treatment. Patients were followed for an additional 24 months after treatment ended.

Most baseline characteristics were similar between the treatment arms, although there was a significantly higher percentage of females in the warfarin arm.

“[Overall,] the mean age was below 60, [and] the mean BMI [body mass index] was below 30,” Dr Couturaud noted. “About 4% of patients had previous cancer [that had been] resolved for more than 2 years, 8% had previous distal DVT [deep vein thrombosis] or superficial venous thrombosis, a quarter of women were on estrogen-containing pills, and about one-third had an associated proximal DVT at the time of PE diagnosis.”

“Before the randomization, the mean duration of VKA [therapy] was 6 months, and the mean percentage of time within the therapeutic range was 70. At inclusion, about one-third of patients had residual perfusion defect, about 15% had residual DVT, the mean D-dimer level was below 500 μg/L, and about 27% had thrombophilia.”

Results

The study’s primary outcome was the composite of recurrent VTE or major bleeding during the 18-month treatment period. Significantly fewer patients met this endpoint in the warfarin arm than in the placebo arm—6 (3.3%) and 25 (13.5%), respectively (hazard ratio [HR]=0.23, P=0.0004).

Likewise, the number of patients with recurrent VTE at 18 months was significantly lower in the warfarin arm than in the placebo arm—3 (1.7%) and 25 (13.5%), respectively (HR=0.11, P<0.0001).

On the other hand, there was no significant difference in the rate of major bleeding between the treatment arms at 18 months. Four patients (2.2%) had major bleeding in the warfarin arm, as did 1 (0.5%) in the placebo arm (HR=4.07, P=0.18).

At 42 months, there was no significant difference between the treatment arms with regard to the composite outcome, the rate of recurrent VTE, or the rate of major bleeding.

The composite outcome occurred in 33 (20.8%) patients in the warfarin arm and 42 (24%) in the placebo arm (HR=0.74, P=0.19). Recurrent VTE occurred in 28 (17.9%) and 39 patients (22.1%), respectively (HR=0.67, P=0.10). And major bleeding occurred in 6 (3.5%) and 5 patients (3%), respectively (HR=1.12, P=0.71).

“[E]xtending anticoagulation for 18 additional months was associated with a major relative risk reduction of 77% of recurrent VTE or major bleeding during the treatment period,” Dr Couturaud said in summary. “However, this benefit was lost during a long-term follow-up of 2 years after stopping anticoagulation.”

“In addition, recurrent VTE occurred in 80% of cases as recurrent PE and in 90% of cases as unprovoked VTE. So additional investigations are needed to identify subgroups of patients at lower risk who may not need indefinite anticoagulation.”

This study was sponsored by Brest University Hospital. Investigators received research funding from Actelion Pharmaceuticals, GlaxoSmithKline, Bristol-Myers Squibb, Boehringer Ingelheim, Sanofi, LEO Pharma, and Bayer.

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—Pharmaceutical-grade L-glutamine can reduce the risk of complications in patients with sickle cell disease (SCD), according to new research.

In a phase 3 study of more than 200 patients, those who received L-glutamine saw a reduction in sickle cell crises, hospitalizations, and the incidence of acute chest syndrome (ACS) when compared to patients who received placebo.

In addition, L-glutamine appeared to have a synergistic effect with hydroxyurea.

Yutaka Niihara, MD, of Emmaus Medical, Inc., in Torrance, California, presented these results at the 2014 ASH Annual Meeting (abstract 86*). Emmaus Medical produced the pharmaceutical-grade L-glutamine used in the study.

Dr Niihara noted that nicotinamide adenine dinucleotide (NAD) is an important physiological antioxidant in red blood cells. But in sickled red blood cells, NAD redox potential is significantly compromised.

So he and his colleagues hypothesized that glutamine, a precursor for NAD, can improve NAD redox potential and modify the destructive effect of increased oxidation and the pathophysiology of SCD. They also theorized that glutamine will decrease the frequency of vaso-occlusive crises.

To test their theories, the researchers enrolled 230 patients from 31 different sites on a phase 3 trial. Patients had sickle cell anemia (SS) or sickle B⁰ thalassemia. They were 5 years of age or older, and some were receiving hydroxyurea.

Patients were randomized 2:1 to receive L-glutamine at 0.3 g/kg twice daily (maximum 30 g/day) or placebo (maltodextrin) at 0.3 g/kg twice daily for 48 weeks. The researchers had discovered high variation in the quality of over-the-counter L-glutamine, so they used pharmaceutical-grade L-glutamine only.

In all, 152 patients received L-glutamine, and 78 received placebo. Demographics and baseline characteristics were similar between the two treatment arms.

The median age was 19 (range, 5-57) in the L-glutamine arm and 17 (range, 5-58) in the placebo arm. There were more females than males in both arms—52% and 57.7%, respectively. And most patients in both arms had sickle cell anemia—89.5% and 91%, respectively.

Safety and efficacy

Dr Niihara said there were no serious adverse events attributable to L-glutamine and no dose modifications due to toxicity.

There were more gastrointestinal events (such as constipation and flatulence) in the L-glutamine arm (8.6%) than in the placebo arm (5.2%). But there was no difference in other adverse events between the two arms.

The study’s primary endpoint was the frequency of painful sickle cell crises. Patients in the L-glutamine arm had 25% fewer crises than patients in the placebo arm (P=0.008).

In patients aged 18 and younger, the median number of sickle cell crises was 3 in the L-glutamine arm and 4 in the placebo arm (P<0.001). The numbers were the same in patients older than 18 (P<0.001) and among patients receiving hydroxyurea (P<0.001).

“Those patients, even though they were on hydroxyurea, they have shown improvements [with L-glutamine],” Dr Niihara said. “And it appears there is some synergistic effect . . ., certainly more than just an additive effect.”

Dr Niihara also noted that patients who received placebo took less than 2 months to experience a first sickle cell crisis, but, for patients on L-glutamine, it took almost 3 months before they had a first crisis. The time to a first crisis was a median of 87 days in the L-glutamine arm and 54 days in the placebo arm (P=0.010).

The study’s secondary endpoint was the frequency of hospitalizations. Compared to patients in the placebo arm, those in the L-glutamine arm had a 33% reduction in hospitalizations (P=0.005) and a 41% reduction in the length of hospital stay (P=0.022).

The researchers also looked at the incidence of ACS and found that L-glutamine was associated with a 58% reduction in ACS. The incidence was 26.9% in the placebo arm and 11.9% in the L-glutamine arm (P=0.006).

“We observed this cascade improvement [with L-glutamine],” Dr Niihara noted. “And what we mean [by that] is that, with glutamine, there is less chance of having painful crises, but if patients have to have crises, they have less chance of being hospitalized. And if they have to be hospitalized, their stays in the hospital are shorter. And, again, if they have to be hospitalized, there’s less chance of them going to the ICU with acute chest syndrome.”

Dr Niihara said the researchers’ next steps are to investigate L-glutamine in a clinical setting, in patients younger than 5 years old, in pregnant women, and as part of combination therapy.

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—Pharmaceutical-grade L-glutamine can reduce the risk of complications in patients with sickle cell disease (SCD), according to new research.

In a phase 3 study of more than 200 patients, those who received L-glutamine saw a reduction in sickle cell crises, hospitalizations, and the incidence of acute chest syndrome (ACS) when compared to patients who received placebo.

In addition, L-glutamine appeared to have a synergistic effect with hydroxyurea.

Yutaka Niihara, MD, of Emmaus Medical, Inc., in Torrance, California, presented these results at the 2014 ASH Annual Meeting (abstract 86*). Emmaus Medical produced the pharmaceutical-grade L-glutamine used in the study.

Dr Niihara noted that nicotinamide adenine dinucleotide (NAD) is an important physiological antioxidant in red blood cells. But in sickled red blood cells, NAD redox potential is significantly compromised.

So he and his colleagues hypothesized that glutamine, a precursor for NAD, can improve NAD redox potential and modify the destructive effect of increased oxidation and the pathophysiology of SCD. They also theorized that glutamine will decrease the frequency of vaso-occlusive crises.

To test their theories, the researchers enrolled 230 patients from 31 different sites on a phase 3 trial. Patients had sickle cell anemia (SS) or sickle B⁰ thalassemia. They were 5 years of age or older, and some were receiving hydroxyurea.

Patients were randomized 2:1 to receive L-glutamine at 0.3 g/kg twice daily (maximum 30 g/day) or placebo (maltodextrin) at 0.3 g/kg twice daily for 48 weeks. The researchers had discovered high variation in the quality of over-the-counter L-glutamine, so they used pharmaceutical-grade L-glutamine only.

In all, 152 patients received L-glutamine, and 78 received placebo. Demographics and baseline characteristics were similar between the two treatment arms.

The median age was 19 (range, 5-57) in the L-glutamine arm and 17 (range, 5-58) in the placebo arm. There were more females than males in both arms—52% and 57.7%, respectively. And most patients in both arms had sickle cell anemia—89.5% and 91%, respectively.

Safety and efficacy

Dr Niihara said there were no serious adverse events attributable to L-glutamine and no dose modifications due to toxicity.

There were more gastrointestinal events (such as constipation and flatulence) in the L-glutamine arm (8.6%) than in the placebo arm (5.2%). But there was no difference in other adverse events between the two arms.

The study’s primary endpoint was the frequency of painful sickle cell crises. Patients in the L-glutamine arm had 25% fewer crises than patients in the placebo arm (P=0.008).

In patients aged 18 and younger, the median number of sickle cell crises was 3 in the L-glutamine arm and 4 in the placebo arm (P<0.001). The numbers were the same in patients older than 18 (P<0.001) and among patients receiving hydroxyurea (P<0.001).

“Those patients, even though they were on hydroxyurea, they have shown improvements [with L-glutamine],” Dr Niihara said. “And it appears there is some synergistic effect . . ., certainly more than just an additive effect.”

Dr Niihara also noted that patients who received placebo took less than 2 months to experience a first sickle cell crisis, but, for patients on L-glutamine, it took almost 3 months before they had a first crisis. The time to a first crisis was a median of 87 days in the L-glutamine arm and 54 days in the placebo arm (P=0.010).

The study’s secondary endpoint was the frequency of hospitalizations. Compared to patients in the placebo arm, those in the L-glutamine arm had a 33% reduction in hospitalizations (P=0.005) and a 41% reduction in the length of hospital stay (P=0.022).

The researchers also looked at the incidence of ACS and found that L-glutamine was associated with a 58% reduction in ACS. The incidence was 26.9% in the placebo arm and 11.9% in the L-glutamine arm (P=0.006).

“We observed this cascade improvement [with L-glutamine],” Dr Niihara noted. “And what we mean [by that] is that, with glutamine, there is less chance of having painful crises, but if patients have to have crises, they have less chance of being hospitalized. And if they have to be hospitalized, their stays in the hospital are shorter. And, again, if they have to be hospitalized, there’s less chance of them going to the ICU with acute chest syndrome.”

Dr Niihara said the researchers’ next steps are to investigate L-glutamine in a clinical setting, in patients younger than 5 years old, in pregnant women, and as part of combination therapy.

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—Pharmaceutical-grade L-glutamine can reduce the risk of complications in patients with sickle cell disease (SCD), according to new research.

In a phase 3 study of more than 200 patients, those who received L-glutamine saw a reduction in sickle cell crises, hospitalizations, and the incidence of acute chest syndrome (ACS) when compared to patients who received placebo.

In addition, L-glutamine appeared to have a synergistic effect with hydroxyurea.

Yutaka Niihara, MD, of Emmaus Medical, Inc., in Torrance, California, presented these results at the 2014 ASH Annual Meeting (abstract 86*). Emmaus Medical produced the pharmaceutical-grade L-glutamine used in the study.

Dr Niihara noted that nicotinamide adenine dinucleotide (NAD) is an important physiological antioxidant in red blood cells. But in sickled red blood cells, NAD redox potential is significantly compromised.

So he and his colleagues hypothesized that glutamine, a precursor for NAD, can improve NAD redox potential and modify the destructive effect of increased oxidation and the pathophysiology of SCD. They also theorized that glutamine will decrease the frequency of vaso-occlusive crises.

To test their theories, the researchers enrolled 230 patients from 31 different sites on a phase 3 trial. Patients had sickle cell anemia (SS) or sickle B⁰ thalassemia. They were 5 years of age or older, and some were receiving hydroxyurea.

Patients were randomized 2:1 to receive L-glutamine at 0.3 g/kg twice daily (maximum 30 g/day) or placebo (maltodextrin) at 0.3 g/kg twice daily for 48 weeks. The researchers had discovered high variation in the quality of over-the-counter L-glutamine, so they used pharmaceutical-grade L-glutamine only.

In all, 152 patients received L-glutamine, and 78 received placebo. Demographics and baseline characteristics were similar between the two treatment arms.

The median age was 19 (range, 5-57) in the L-glutamine arm and 17 (range, 5-58) in the placebo arm. There were more females than males in both arms—52% and 57.7%, respectively. And most patients in both arms had sickle cell anemia—89.5% and 91%, respectively.

Safety and efficacy

Dr Niihara said there were no serious adverse events attributable to L-glutamine and no dose modifications due to toxicity.

There were more gastrointestinal events (such as constipation and flatulence) in the L-glutamine arm (8.6%) than in the placebo arm (5.2%). But there was no difference in other adverse events between the two arms.

The study’s primary endpoint was the frequency of painful sickle cell crises. Patients in the L-glutamine arm had 25% fewer crises than patients in the placebo arm (P=0.008).

In patients aged 18 and younger, the median number of sickle cell crises was 3 in the L-glutamine arm and 4 in the placebo arm (P<0.001). The numbers were the same in patients older than 18 (P<0.001) and among patients receiving hydroxyurea (P<0.001).

“Those patients, even though they were on hydroxyurea, they have shown improvements [with L-glutamine],” Dr Niihara said. “And it appears there is some synergistic effect . . ., certainly more than just an additive effect.”

Dr Niihara also noted that patients who received placebo took less than 2 months to experience a first sickle cell crisis, but, for patients on L-glutamine, it took almost 3 months before they had a first crisis. The time to a first crisis was a median of 87 days in the L-glutamine arm and 54 days in the placebo arm (P=0.010).

The study’s secondary endpoint was the frequency of hospitalizations. Compared to patients in the placebo arm, those in the L-glutamine arm had a 33% reduction in hospitalizations (P=0.005) and a 41% reduction in the length of hospital stay (P=0.022).

The researchers also looked at the incidence of ACS and found that L-glutamine was associated with a 58% reduction in ACS. The incidence was 26.9% in the placebo arm and 11.9% in the L-glutamine arm (P=0.006).

“We observed this cascade improvement [with L-glutamine],” Dr Niihara noted. “And what we mean [by that] is that, with glutamine, there is less chance of having painful crises, but if patients have to have crises, they have less chance of being hospitalized. And if they have to be hospitalized, their stays in the hospital are shorter. And, again, if they have to be hospitalized, there’s less chance of them going to the ICU with acute chest syndrome.”

Dr Niihara said the researchers’ next steps are to investigate L-glutamine in a clinical setting, in patients younger than 5 years old, in pregnant women, and as part of combination therapy.

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—Follicular lymphoma (FL) patients who receive high-dose therapy with autologous stem cell transplant (HDT/ASCT) after they’ve responded to chemotherapy can achieve long-term cancer-free survival, new research suggests.

The study showed that many patients transplanted in complete remission (CR) did not relapse and could be considered cured.

Patients transplanted in their first CR fared the best, as median progression-free survival (PFS) and overall survival (OS) times were not reached.

But even patients transplanted in their second/third CR or in their first partial remission (PR) survived a median of 15 years or more, although their PFS times were shorter, at about 14 years and 3 years, respectively.

Carlos Grande García, MD, of Hospital Universitario 12 de Octubre in Madrid, Spain, presented these results at the 2014 ASH Annual Meeting (abstract 675.)*

“In follicular lymphoma patients, intensification with high-dose therapy and autologous stem cell support offers an advantage in terms of progression-free survival in comparison with conventional chemo,” he said. “But, so far, no randomized studies have yet shown any overall survival advantage.”

“Follicular lymphoma has a long natural course, and most patients have received different salvage therapies. Probably, this is why the available phase 3 studies have had insufficient time to confirm the impact on OS.”

To investigate the impact of HDT/ASCT on OS, Dr Grande García and his colleagues conducted a retrospective study of 655 FL patients who received HDT/ASCT from 1989 to 2007. Patients with histological transformation, those undergoing a second transplant, and those with a follow-up of less than 7 years were excluded.

Patient characteristics

The median follow-up was 12 years from HDT/ASCT and 14.4 years from diagnosis. At diagnosis, the median patient age was 47, 49.6% of patients were male, and 90% had stage III/IV disease.

According to FLIPI, 33% of patients were good risk, 36% were intermediate risk, and 31% were poor risk. According to FLIPI-2, the percentages were 22%, 38%, and 40%, respectively. Thirty percent of patients had received rituximab prior to HDT/ASCT.

Thirty-one percent of patients (n=203) were in their first CR at the time of transplant, 43% of whom required more than one line of therapy to reach first CR.

Thirty-one percent of patients (n=202) were in second or third CR, 21.5% (n=149) were in first PR, 12.5% (n=81) were in sensitive relapse (defined as a response other than CR or first PR), and 5% (n=29) had overt disease (which included untreated relapsed disease, first refractory disease, and second refractory disease).

Patients received a variety of conditioning regimens, including total-body irradiation plus cyclophosphamide, BEAM (carmustine, etoposide, cytarabine, and melphalan), BEAC (carmustine, etoposide, cytarabine, and cyclophosphamide), and other regimens. They received stem cells from peripheral blood (81%), bone marrow (14%), or both sources (5%).

There were 4 graft failures and 17 early toxic deaths. Thirty-one percent of patients experienced grade 3/4 hematologic toxicities.

PFS and OS

In all patients, the median PFS was 9.25 years, and the median OS was 19.5 years.

When the researchers looked at outcomes according to patients’ status at transplant, they found the median OS and PFS were not reached among patients in first CR. At a median follow-up of 12.75 years, the OS rate was 72%, and the PFS rate was 68%.

“Beginning at 10 years from transplantation, only 6 patients have died,” Dr Grande García noted, “one from disease progression, 3 from second malignancy, [and] 2 from unrelated causes.”

For patients in second or third CR, the median OS was not reached, and the median PFS was 13.9 years. For those in first PR, the median OS was 15 years, and the median PFS was 2.6 years.

For patients with sensitive disease, the median OS was 5.1 years, and the median PFS was 2 years. For those with overt disease, the median OS was 4.4 years, and the median PFS was 0.5 years.

In multivariate analysis, the following characteristics were significant predictors of OS: being older than 47 years of age (hazard ratio [HR]=1.74, P=0.0001), female sex (HR=0.58, P=0.00004), status at HDT/ASCT (HR=2.06, P<10^-5), and receipt of rituximab prior to HDT/ASCT (HR=0.61, P=0.004).

Significant predictors of PFS included age (HR=1.34, P=0.01), sex (HR=0.64, P<10^-5), status at HDT/ASCT (HR=2.15, P<10^-5), and rituximab use (HR=0.67, P=0.003).

For patients transplanted in first CR, only sex was a significant predictor of PFS (HR=0.48, P=0.008) and OS (HR=0.43, P=0.007).

Secondary malignancies

Overall, 13% of patients developed secondary malignancies, of which 46% were solid neoplasias, 44% were myelodysplastic syndromes/acute myeloid leukemias, and 10% were other malignancies.

The incidence of secondary malignancies at 10 years was 3.5%, and the median time from HDT/ASCT to diagnosis was 16 years. There were no significant differences in the rate of secondary malignancy according to a patient’s status at HDT/ASCT or according to the use of rituximab.

“The incidence of second malignancies is not higher than that reported in other series without transplantation,” Dr Grande García noted.

“[HDT/ASCT] is highly effective, even for patients with poor initial features. A significant number of patients transplanted in CR never relapse and may be considered cured.”

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—Follicular lymphoma (FL) patients who receive high-dose therapy with autologous stem cell transplant (HDT/ASCT) after they’ve responded to chemotherapy can achieve long-term cancer-free survival, new research suggests.

The study showed that many patients transplanted in complete remission (CR) did not relapse and could be considered cured.

Patients transplanted in their first CR fared the best, as median progression-free survival (PFS) and overall survival (OS) times were not reached.

But even patients transplanted in their second/third CR or in their first partial remission (PR) survived a median of 15 years or more, although their PFS times were shorter, at about 14 years and 3 years, respectively.

Carlos Grande García, MD, of Hospital Universitario 12 de Octubre in Madrid, Spain, presented these results at the 2014 ASH Annual Meeting (abstract 675.)*

“In follicular lymphoma patients, intensification with high-dose therapy and autologous stem cell support offers an advantage in terms of progression-free survival in comparison with conventional chemo,” he said. “But, so far, no randomized studies have yet shown any overall survival advantage.”

“Follicular lymphoma has a long natural course, and most patients have received different salvage therapies. Probably, this is why the available phase 3 studies have had insufficient time to confirm the impact on OS.”

To investigate the impact of HDT/ASCT on OS, Dr Grande García and his colleagues conducted a retrospective study of 655 FL patients who received HDT/ASCT from 1989 to 2007. Patients with histological transformation, those undergoing a second transplant, and those with a follow-up of less than 7 years were excluded.

Patient characteristics

The median follow-up was 12 years from HDT/ASCT and 14.4 years from diagnosis. At diagnosis, the median patient age was 47, 49.6% of patients were male, and 90% had stage III/IV disease.

According to FLIPI, 33% of patients were good risk, 36% were intermediate risk, and 31% were poor risk. According to FLIPI-2, the percentages were 22%, 38%, and 40%, respectively. Thirty percent of patients had received rituximab prior to HDT/ASCT.

Thirty-one percent of patients (n=203) were in their first CR at the time of transplant, 43% of whom required more than one line of therapy to reach first CR.

Thirty-one percent of patients (n=202) were in second or third CR, 21.5% (n=149) were in first PR, 12.5% (n=81) were in sensitive relapse (defined as a response other than CR or first PR), and 5% (n=29) had overt disease (which included untreated relapsed disease, first refractory disease, and second refractory disease).

Patients received a variety of conditioning regimens, including total-body irradiation plus cyclophosphamide, BEAM (carmustine, etoposide, cytarabine, and melphalan), BEAC (carmustine, etoposide, cytarabine, and cyclophosphamide), and other regimens. They received stem cells from peripheral blood (81%), bone marrow (14%), or both sources (5%).

There were 4 graft failures and 17 early toxic deaths. Thirty-one percent of patients experienced grade 3/4 hematologic toxicities.

PFS and OS

In all patients, the median PFS was 9.25 years, and the median OS was 19.5 years.

When the researchers looked at outcomes according to patients’ status at transplant, they found the median OS and PFS were not reached among patients in first CR. At a median follow-up of 12.75 years, the OS rate was 72%, and the PFS rate was 68%.

“Beginning at 10 years from transplantation, only 6 patients have died,” Dr Grande García noted, “one from disease progression, 3 from second malignancy, [and] 2 from unrelated causes.”

For patients in second or third CR, the median OS was not reached, and the median PFS was 13.9 years. For those in first PR, the median OS was 15 years, and the median PFS was 2.6 years.

For patients with sensitive disease, the median OS was 5.1 years, and the median PFS was 2 years. For those with overt disease, the median OS was 4.4 years, and the median PFS was 0.5 years.

In multivariate analysis, the following characteristics were significant predictors of OS: being older than 47 years of age (hazard ratio [HR]=1.74, P=0.0001), female sex (HR=0.58, P=0.00004), status at HDT/ASCT (HR=2.06, P<10^-5), and receipt of rituximab prior to HDT/ASCT (HR=0.61, P=0.004).

Significant predictors of PFS included age (HR=1.34, P=0.01), sex (HR=0.64, P<10^-5), status at HDT/ASCT (HR=2.15, P<10^-5), and rituximab use (HR=0.67, P=0.003).

For patients transplanted in first CR, only sex was a significant predictor of PFS (HR=0.48, P=0.008) and OS (HR=0.43, P=0.007).

Secondary malignancies

Overall, 13% of patients developed secondary malignancies, of which 46% were solid neoplasias, 44% were myelodysplastic syndromes/acute myeloid leukemias, and 10% were other malignancies.

The incidence of secondary malignancies at 10 years was 3.5%, and the median time from HDT/ASCT to diagnosis was 16 years. There were no significant differences in the rate of secondary malignancy according to a patient’s status at HDT/ASCT or according to the use of rituximab.

“The incidence of second malignancies is not higher than that reported in other series without transplantation,” Dr Grande García noted.

“[HDT/ASCT] is highly effective, even for patients with poor initial features. A significant number of patients transplanted in CR never relapse and may be considered cured.”

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—Follicular lymphoma (FL) patients who receive high-dose therapy with autologous stem cell transplant (HDT/ASCT) after they’ve responded to chemotherapy can achieve long-term cancer-free survival, new research suggests.

The study showed that many patients transplanted in complete remission (CR) did not relapse and could be considered cured.

Patients transplanted in their first CR fared the best, as median progression-free survival (PFS) and overall survival (OS) times were not reached.

But even patients transplanted in their second/third CR or in their first partial remission (PR) survived a median of 15 years or more, although their PFS times were shorter, at about 14 years and 3 years, respectively.

Carlos Grande García, MD, of Hospital Universitario 12 de Octubre in Madrid, Spain, presented these results at the 2014 ASH Annual Meeting (abstract 675.)*

“In follicular lymphoma patients, intensification with high-dose therapy and autologous stem cell support offers an advantage in terms of progression-free survival in comparison with conventional chemo,” he said. “But, so far, no randomized studies have yet shown any overall survival advantage.”

“Follicular lymphoma has a long natural course, and most patients have received different salvage therapies. Probably, this is why the available phase 3 studies have had insufficient time to confirm the impact on OS.”

To investigate the impact of HDT/ASCT on OS, Dr Grande García and his colleagues conducted a retrospective study of 655 FL patients who received HDT/ASCT from 1989 to 2007. Patients with histological transformation, those undergoing a second transplant, and those with a follow-up of less than 7 years were excluded.

Patient characteristics

The median follow-up was 12 years from HDT/ASCT and 14.4 years from diagnosis. At diagnosis, the median patient age was 47, 49.6% of patients were male, and 90% had stage III/IV disease.

According to FLIPI, 33% of patients were good risk, 36% were intermediate risk, and 31% were poor risk. According to FLIPI-2, the percentages were 22%, 38%, and 40%, respectively. Thirty percent of patients had received rituximab prior to HDT/ASCT.

Thirty-one percent of patients (n=203) were in their first CR at the time of transplant, 43% of whom required more than one line of therapy to reach first CR.

Thirty-one percent of patients (n=202) were in second or third CR, 21.5% (n=149) were in first PR, 12.5% (n=81) were in sensitive relapse (defined as a response other than CR or first PR), and 5% (n=29) had overt disease (which included untreated relapsed disease, first refractory disease, and second refractory disease).

Patients received a variety of conditioning regimens, including total-body irradiation plus cyclophosphamide, BEAM (carmustine, etoposide, cytarabine, and melphalan), BEAC (carmustine, etoposide, cytarabine, and cyclophosphamide), and other regimens. They received stem cells from peripheral blood (81%), bone marrow (14%), or both sources (5%).

There were 4 graft failures and 17 early toxic deaths. Thirty-one percent of patients experienced grade 3/4 hematologic toxicities.

PFS and OS

In all patients, the median PFS was 9.25 years, and the median OS was 19.5 years.

When the researchers looked at outcomes according to patients’ status at transplant, they found the median OS and PFS were not reached among patients in first CR. At a median follow-up of 12.75 years, the OS rate was 72%, and the PFS rate was 68%.

“Beginning at 10 years from transplantation, only 6 patients have died,” Dr Grande García noted, “one from disease progression, 3 from second malignancy, [and] 2 from unrelated causes.”

For patients in second or third CR, the median OS was not reached, and the median PFS was 13.9 years. For those in first PR, the median OS was 15 years, and the median PFS was 2.6 years.

For patients with sensitive disease, the median OS was 5.1 years, and the median PFS was 2 years. For those with overt disease, the median OS was 4.4 years, and the median PFS was 0.5 years.

In multivariate analysis, the following characteristics were significant predictors of OS: being older than 47 years of age (hazard ratio [HR]=1.74, P=0.0001), female sex (HR=0.58, P=0.00004), status at HDT/ASCT (HR=2.06, P<10^-5), and receipt of rituximab prior to HDT/ASCT (HR=0.61, P=0.004).

Significant predictors of PFS included age (HR=1.34, P=0.01), sex (HR=0.64, P<10^-5), status at HDT/ASCT (HR=2.15, P<10^-5), and rituximab use (HR=0.67, P=0.003).

For patients transplanted in first CR, only sex was a significant predictor of PFS (HR=0.48, P=0.008) and OS (HR=0.43, P=0.007).

Secondary malignancies

Overall, 13% of patients developed secondary malignancies, of which 46% were solid neoplasias, 44% were myelodysplastic syndromes/acute myeloid leukemias, and 10% were other malignancies.

The incidence of secondary malignancies at 10 years was 3.5%, and the median time from HDT/ASCT to diagnosis was 16 years. There were no significant differences in the rate of secondary malignancy according to a patient’s status at HDT/ASCT or according to the use of rituximab.

“The incidence of second malignancies is not higher than that reported in other series without transplantation,” Dr Grande García noted.

“[HDT/ASCT] is highly effective, even for patients with poor initial features. A significant number of patients transplanted in CR never relapse and may be considered cured.”

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—New research suggests complex metaphase karyotype (CKT) is a stronger predictor of inferior outcome than 17p deletion in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who are treated with the BTK inhibitor ibrutinib.

The study showed that CKT, defined as 3 or more distinct chromosomal abnormalities, was independently associated with inferior event-free survival (EFS) and overall survival (OS), but del(17p) was not.

According to investigators, this suggests that del(17p) patients without CKT could be managed with long-term ibrutinib and close monitoring, as these patients have similar outcomes as patients without del(17p).

However, patients with CKT will likely require treatment-intensification strategies after ibrutinib-based therapy.

“We believe that patients with a complex karyotype represent an ideal group in whom to study novel treatment approaches, including ibrutinib-based combination regimens and/or consolidated approaches after initial ibrutinib response,” said investigator Philip A. Thompson, MBBS, of the University of Texas MD Anderson Cancer Center in Houston.

Dr Thompson presented his group’s findings at the 2014 ASH Annual Meeting as abstract 22.* Investigators involved in this study received research funding or consultancy fees from Pharmacyclics, Inc., makers of ibrutinib.

Patient characteristics

Dr Thompson and his colleagues analyzed 100 patients with relapsed/refractory CLL who received treatment with ibrutinib-based regimens—50 with ibrutinib alone, 36 with ibrutinib and rituximab, and 14 with ibrutinib, rituximab, and bendamustine.

The median age was 65 (range, 35-83), patients received a median of 2 prior therapies (range, 1-12), and 19% were fludarabine-refractory. Sixty percent of patients had Rai stage III-IV disease, 52% had bulky adenopathy, 81% had unmutated IGHV, and 56% had β2-microglobulin ≥ 4.0 mg/L.

FISH was available for 94 patients, and metaphase analysis was available for 65 patients. Forty-two percent (27/65) of patients had CKT, 28% (26/94) had del(11q), and 48% (45/94) had del(17p).

Of the 45 patients who had del(17p), 23 also had CKT. And of the 49 patients who did not have del(17p), 4 had CKT.

Event-free survival

The median follow-up in surviving patients was 27 months (range, 11-48). Eight patients had planned allogeneic stem cell transplant and were censored for the EFS analysis.

“As has been shown previously, patients with 17p deletion by FISH did have inferior event-free survival,” Dr Thompson said. “And when we looked at those patients with complex metaphase karyotype, there was a highly significant inferior event-free survival in these patients, compared to those with complex karyotype.”

EFS was 78% in patients with neither del(17p) nor del(11q), 69% in patients with del(11q), and 60% in patients with del(17p) (P=0.014).

EFS was 82% in patients without CKT and 44% in those with CKT (P<0.0001). In patients with del(17p), EFS was 78% in those without CKT and 48% in those with CKT (P=0.047).

In patients without CKT, EFS was 79% in those without del(17p) or del(11q), 90% in those with del(11q), and 78% in those with del(17p) (P=0.516).

“Interestingly, when we looked at the events that occurred in those patients without complex karyotype, none were due to CLL progression or Richter’s transformation,” Dr Thompson said.

In multivariable analysis, CKT was significantly associated with EFS (P=0.011), but del(17p) was not (P=0.887).

Overall survival

There was no significant difference in OS according to the presence of del(17p) or del(11q). OS was 87% in patients with neither del(17p) nor del(11q), 81% in patients with del(11q), and 67% in patients with del(17p) (P=0.054).

However, there was a significant difference in OS for patients with and without CKT. OS was 82% in patients without CKT and 56% in patients with CKT (P=0.006).

Among patients without CKT, OS was 84% in those with neither del(17p) nor del(11q), 80% in those with del(11q), and 78% in those with del(17p) (P=0.52).

In multivariable analysis, OS was significantly associated with CKT (P=0.011) and fludarabine-refractory disease (P=0.004) but not del(17p) (P=0.981).

“So, in summary, complex karyotype appears to be a more important predictor of outcomes in patients with relapsed or refractory CLL treated with ibrutinib-based regimens than the presence of del(17p) by FISH,” Dr Thompson said.

“Patients without complex karyotype have a low rate of disease progression, including those who have del(17p). Most progressions during ibrutinib therapy occur late, beyond the 12-month time point, but survival is short after disease progression.”

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—New research suggests complex metaphase karyotype (CKT) is a stronger predictor of inferior outcome than 17p deletion in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who are treated with the BTK inhibitor ibrutinib.

The study showed that CKT, defined as 3 or more distinct chromosomal abnormalities, was independently associated with inferior event-free survival (EFS) and overall survival (OS), but del(17p) was not.

According to investigators, this suggests that del(17p) patients without CKT could be managed with long-term ibrutinib and close monitoring, as these patients have similar outcomes as patients without del(17p).

However, patients with CKT will likely require treatment-intensification strategies after ibrutinib-based therapy.

“We believe that patients with a complex karyotype represent an ideal group in whom to study novel treatment approaches, including ibrutinib-based combination regimens and/or consolidated approaches after initial ibrutinib response,” said investigator Philip A. Thompson, MBBS, of the University of Texas MD Anderson Cancer Center in Houston.

Dr Thompson presented his group’s findings at the 2014 ASH Annual Meeting as abstract 22.* Investigators involved in this study received research funding or consultancy fees from Pharmacyclics, Inc., makers of ibrutinib.

Patient characteristics

Dr Thompson and his colleagues analyzed 100 patients with relapsed/refractory CLL who received treatment with ibrutinib-based regimens—50 with ibrutinib alone, 36 with ibrutinib and rituximab, and 14 with ibrutinib, rituximab, and bendamustine.

The median age was 65 (range, 35-83), patients received a median of 2 prior therapies (range, 1-12), and 19% were fludarabine-refractory. Sixty percent of patients had Rai stage III-IV disease, 52% had bulky adenopathy, 81% had unmutated IGHV, and 56% had β2-microglobulin ≥ 4.0 mg/L.

FISH was available for 94 patients, and metaphase analysis was available for 65 patients. Forty-two percent (27/65) of patients had CKT, 28% (26/94) had del(11q), and 48% (45/94) had del(17p).

Of the 45 patients who had del(17p), 23 also had CKT. And of the 49 patients who did not have del(17p), 4 had CKT.

Event-free survival

The median follow-up in surviving patients was 27 months (range, 11-48). Eight patients had planned allogeneic stem cell transplant and were censored for the EFS analysis.

“As has been shown previously, patients with 17p deletion by FISH did have inferior event-free survival,” Dr Thompson said. “And when we looked at those patients with complex metaphase karyotype, there was a highly significant inferior event-free survival in these patients, compared to those with complex karyotype.”

EFS was 78% in patients with neither del(17p) nor del(11q), 69% in patients with del(11q), and 60% in patients with del(17p) (P=0.014).

EFS was 82% in patients without CKT and 44% in those with CKT (P<0.0001). In patients with del(17p), EFS was 78% in those without CKT and 48% in those with CKT (P=0.047).

In patients without CKT, EFS was 79% in those without del(17p) or del(11q), 90% in those with del(11q), and 78% in those with del(17p) (P=0.516).

“Interestingly, when we looked at the events that occurred in those patients without complex karyotype, none were due to CLL progression or Richter’s transformation,” Dr Thompson said.

In multivariable analysis, CKT was significantly associated with EFS (P=0.011), but del(17p) was not (P=0.887).

Overall survival

There was no significant difference in OS according to the presence of del(17p) or del(11q). OS was 87% in patients with neither del(17p) nor del(11q), 81% in patients with del(11q), and 67% in patients with del(17p) (P=0.054).

However, there was a significant difference in OS for patients with and without CKT. OS was 82% in patients without CKT and 56% in patients with CKT (P=0.006).

Among patients without CKT, OS was 84% in those with neither del(17p) nor del(11q), 80% in those with del(11q), and 78% in those with del(17p) (P=0.52).

In multivariable analysis, OS was significantly associated with CKT (P=0.011) and fludarabine-refractory disease (P=0.004) but not del(17p) (P=0.981).

“So, in summary, complex karyotype appears to be a more important predictor of outcomes in patients with relapsed or refractory CLL treated with ibrutinib-based regimens than the presence of del(17p) by FISH,” Dr Thompson said.

“Patients without complex karyotype have a low rate of disease progression, including those who have del(17p). Most progressions during ibrutinib therapy occur late, beyond the 12-month time point, but survival is short after disease progression.”

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—New research suggests complex metaphase karyotype (CKT) is a stronger predictor of inferior outcome than 17p deletion in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who are treated with the BTK inhibitor ibrutinib.

The study showed that CKT, defined as 3 or more distinct chromosomal abnormalities, was independently associated with inferior event-free survival (EFS) and overall survival (OS), but del(17p) was not.

According to investigators, this suggests that del(17p) patients without CKT could be managed with long-term ibrutinib and close monitoring, as these patients have similar outcomes as patients without del(17p).

However, patients with CKT will likely require treatment-intensification strategies after ibrutinib-based therapy.

“We believe that patients with a complex karyotype represent an ideal group in whom to study novel treatment approaches, including ibrutinib-based combination regimens and/or consolidated approaches after initial ibrutinib response,” said investigator Philip A. Thompson, MBBS, of the University of Texas MD Anderson Cancer Center in Houston.

Dr Thompson presented his group’s findings at the 2014 ASH Annual Meeting as abstract 22.* Investigators involved in this study received research funding or consultancy fees from Pharmacyclics, Inc., makers of ibrutinib.

Patient characteristics

Dr Thompson and his colleagues analyzed 100 patients with relapsed/refractory CLL who received treatment with ibrutinib-based regimens—50 with ibrutinib alone, 36 with ibrutinib and rituximab, and 14 with ibrutinib, rituximab, and bendamustine.

The median age was 65 (range, 35-83), patients received a median of 2 prior therapies (range, 1-12), and 19% were fludarabine-refractory. Sixty percent of patients had Rai stage III-IV disease, 52% had bulky adenopathy, 81% had unmutated IGHV, and 56% had β2-microglobulin ≥ 4.0 mg/L.

FISH was available for 94 patients, and metaphase analysis was available for 65 patients. Forty-two percent (27/65) of patients had CKT, 28% (26/94) had del(11q), and 48% (45/94) had del(17p).

Of the 45 patients who had del(17p), 23 also had CKT. And of the 49 patients who did not have del(17p), 4 had CKT.

Event-free survival

The median follow-up in surviving patients was 27 months (range, 11-48). Eight patients had planned allogeneic stem cell transplant and were censored for the EFS analysis.

“As has been shown previously, patients with 17p deletion by FISH did have inferior event-free survival,” Dr Thompson said. “And when we looked at those patients with complex metaphase karyotype, there was a highly significant inferior event-free survival in these patients, compared to those with complex karyotype.”

EFS was 78% in patients with neither del(17p) nor del(11q), 69% in patients with del(11q), and 60% in patients with del(17p) (P=0.014).

EFS was 82% in patients without CKT and 44% in those with CKT (P<0.0001). In patients with del(17p), EFS was 78% in those without CKT and 48% in those with CKT (P=0.047).

In patients without CKT, EFS was 79% in those without del(17p) or del(11q), 90% in those with del(11q), and 78% in those with del(17p) (P=0.516).

“Interestingly, when we looked at the events that occurred in those patients without complex karyotype, none were due to CLL progression or Richter’s transformation,” Dr Thompson said.

In multivariable analysis, CKT was significantly associated with EFS (P=0.011), but del(17p) was not (P=0.887).

Overall survival

There was no significant difference in OS according to the presence of del(17p) or del(11q). OS was 87% in patients with neither del(17p) nor del(11q), 81% in patients with del(11q), and 67% in patients with del(17p) (P=0.054).

However, there was a significant difference in OS for patients with and without CKT. OS was 82% in patients without CKT and 56% in patients with CKT (P=0.006).

Among patients without CKT, OS was 84% in those with neither del(17p) nor del(11q), 80% in those with del(11q), and 78% in those with del(17p) (P=0.52).

In multivariable analysis, OS was significantly associated with CKT (P=0.011) and fludarabine-refractory disease (P=0.004) but not del(17p) (P=0.981).

“So, in summary, complex karyotype appears to be a more important predictor of outcomes in patients with relapsed or refractory CLL treated with ibrutinib-based regimens than the presence of del(17p) by FISH,” Dr Thompson said.

“Patients without complex karyotype have a low rate of disease progression, including those who have del(17p). Most progressions during ibrutinib therapy occur late, beyond the 12-month time point, but survival is short after disease progression.”

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—Low-molecular-weight heparin (LMWH) should replace warfarin as thromboprophylaxis in cancer patients, according to a speaker at the 2014 ASH Annual Meeting.

Results of the phase 3 CATCH trial showed that long-term treatment with the LMWH tinzaparin was associated with a 35% lower risk of recurrent venous thromboembolism (VTE) when compared to warfarin, although the difference between the treatment arms was not statistically significant.

Patients who received tinzaparin did have a significantly lower risk of symptomatic deep vein thrombosis (DVT) and clinically relevant, non-major bleeding.

However, there was no difference between the treatment arms with regard to major bleeding or overall mortality.

Agnes Y.Y. Lee, MD, of the University of British Columbia and Vancouver Coastal Health in British Columbia, Canada, presented these results at ASH as LBA-2.*

“CATCH is the largest randomized trial studying treatment of cancer-associated thrombosis,” she said. “It provides confirmatory data for improved efficacy of low-molecular-weight heparin over warfarin.”

The trial included 900 cancer patients from 164 centers around the world. The mean patient age was 59 (range, 18-89), and 59% were female. The most common cancers were gynecologic, colorectal, upper gastrointestinal, and lung.

Patients were stratified by geographic region, tumor characteristics, and history of VTE. They were randomized to receive tinzaparin at 175 IU/kg once daily for 6 months (n=449) or initial tinzaparin at 175 IU/kg once daily for 5 to 10 days overlapped and followed by dose-adjusted warfarin for 6 months (n=451).

In all, 416 patients completed treatment with tinzaparin, and 401 completed warfarin treatment. The patients were followed up to 6 months or death, whichever came first.

Efficacy data 

The primary efficacy outcome was recurrent VTE, which included symptomatic DVT and/or pulmonary embolism (PE), incidental proximal DVT and/or PE, and fatal PE.

The rate of recurrent VTE was 7.2% in the tinzaparin arm and 10.5% in the warfarin arm (hazard ratio [HR]=0.65, P=0.07). This represents a 35% reduction in recurrent VTE with the LMWH.

In the per-protocol analysis, the rates of recurrent VTE were 8.3% and 12.7%, respectively (HR=0.62), which translates to a 38% reduction in recurrent VTE with tinzaparin.

“Pre-specified efficacy analyses further showed that tinzaparin significantly reduced symptomatic, recurrent DVT by 52%,” Dr Lee noted. “There were very few symptomatic PEs, equal numbers of fatal PEs occurred in each arm, and there were only 2 incidental thrombotic events, both in the warfarin arm.”

Symptomatic, non-fatal DVT occurred in 12 patients (2.7%) in the tinzaparin arm and 24 (5.3%) in the warfarin arm (HR=0.48, P=0.04). Symptomatic, non-fatal PE occurred in 3 patients (0.7%) and 2 patients (0.4%), respectively. And fatal PE occurred in 17 patients (3.8%) in each arm (HR=0.96).

“We were clearly disappointed that our primary efficacy outcome did not achieve statistical significance,” Dr Lee said. “But our sample size was based on an estimated recurrent [VTE] rate of 12.6% in the warfarin group, and we only saw a 10% [sic] recurrence. So, basically, our study was slightly underpowered to achieve statistical significance.”

“I think that, given the symptomatic DVT results, as well as the per-protocol analysis, in additon to all the previous data on low-molecular-weight heparin, this is still very strong confirmatory data that low-molecular-weight heparin is more effective than warfarin therapy in treating cancer patients with thrombosis.”

Safety and mortality

The primary safety endpoint was major bleeding, which occurred in 2.9% of patients in the tinzaparin arm and 2.6% in the warfarin arm (HR=0.89).

The rate of clinically relevant, non-major bleeding was 11.1% and 16.2%, respectively (HR=0.69, P=0.03).

“Tinzaparin reduced the rate of clinically relevant, non-major bleeding by 31%,” Dr Lee noted.

On the other hand, there was no significant difference between the arms with regard to 180-day overall mortality, which was 34.2% in the tinzaparin arm and 32.3% in the warfarin arm (HR=1.08).

This research was sponsored by LEO Pharma, the company developing tinzaparin (Innohep).

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—Low-molecular-weight heparin (LMWH) should replace warfarin as thromboprophylaxis in cancer patients, according to a speaker at the 2014 ASH Annual Meeting.

Results of the phase 3 CATCH trial showed that long-term treatment with the LMWH tinzaparin was associated with a 35% lower risk of recurrent venous thromboembolism (VTE) when compared to warfarin, although the difference between the treatment arms was not statistically significant.

Patients who received tinzaparin did have a significantly lower risk of symptomatic deep vein thrombosis (DVT) and clinically relevant, non-major bleeding.

However, there was no difference between the treatment arms with regard to major bleeding or overall mortality.

Agnes Y.Y. Lee, MD, of the University of British Columbia and Vancouver Coastal Health in British Columbia, Canada, presented these results at ASH as LBA-2.*

“CATCH is the largest randomized trial studying treatment of cancer-associated thrombosis,” she said. “It provides confirmatory data for improved efficacy of low-molecular-weight heparin over warfarin.”

The trial included 900 cancer patients from 164 centers around the world. The mean patient age was 59 (range, 18-89), and 59% were female. The most common cancers were gynecologic, colorectal, upper gastrointestinal, and lung.

Patients were stratified by geographic region, tumor characteristics, and history of VTE. They were randomized to receive tinzaparin at 175 IU/kg once daily for 6 months (n=449) or initial tinzaparin at 175 IU/kg once daily for 5 to 10 days overlapped and followed by dose-adjusted warfarin for 6 months (n=451).

In all, 416 patients completed treatment with tinzaparin, and 401 completed warfarin treatment. The patients were followed up to 6 months or death, whichever came first.

Efficacy data 

The primary efficacy outcome was recurrent VTE, which included symptomatic DVT and/or pulmonary embolism (PE), incidental proximal DVT and/or PE, and fatal PE.

The rate of recurrent VTE was 7.2% in the tinzaparin arm and 10.5% in the warfarin arm (hazard ratio [HR]=0.65, P=0.07). This represents a 35% reduction in recurrent VTE with the LMWH.

In the per-protocol analysis, the rates of recurrent VTE were 8.3% and 12.7%, respectively (HR=0.62), which translates to a 38% reduction in recurrent VTE with tinzaparin.

“Pre-specified efficacy analyses further showed that tinzaparin significantly reduced symptomatic, recurrent DVT by 52%,” Dr Lee noted. “There were very few symptomatic PEs, equal numbers of fatal PEs occurred in each arm, and there were only 2 incidental thrombotic events, both in the warfarin arm.”

Symptomatic, non-fatal DVT occurred in 12 patients (2.7%) in the tinzaparin arm and 24 (5.3%) in the warfarin arm (HR=0.48, P=0.04). Symptomatic, non-fatal PE occurred in 3 patients (0.7%) and 2 patients (0.4%), respectively. And fatal PE occurred in 17 patients (3.8%) in each arm (HR=0.96).

“We were clearly disappointed that our primary efficacy outcome did not achieve statistical significance,” Dr Lee said. “But our sample size was based on an estimated recurrent [VTE] rate of 12.6% in the warfarin group, and we only saw a 10% [sic] recurrence. So, basically, our study was slightly underpowered to achieve statistical significance.”

“I think that, given the symptomatic DVT results, as well as the per-protocol analysis, in additon to all the previous data on low-molecular-weight heparin, this is still very strong confirmatory data that low-molecular-weight heparin is more effective than warfarin therapy in treating cancer patients with thrombosis.”

Safety and mortality

The primary safety endpoint was major bleeding, which occurred in 2.9% of patients in the tinzaparin arm and 2.6% in the warfarin arm (HR=0.89).

The rate of clinically relevant, non-major bleeding was 11.1% and 16.2%, respectively (HR=0.69, P=0.03).

“Tinzaparin reduced the rate of clinically relevant, non-major bleeding by 31%,” Dr Lee noted.

On the other hand, there was no significant difference between the arms with regard to 180-day overall mortality, which was 34.2% in the tinzaparin arm and 32.3% in the warfarin arm (HR=1.08).

This research was sponsored by LEO Pharma, the company developing tinzaparin (Innohep).

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—Low-molecular-weight heparin (LMWH) should replace warfarin as thromboprophylaxis in cancer patients, according to a speaker at the 2014 ASH Annual Meeting.

Results of the phase 3 CATCH trial showed that long-term treatment with the LMWH tinzaparin was associated with a 35% lower risk of recurrent venous thromboembolism (VTE) when compared to warfarin, although the difference between the treatment arms was not statistically significant.

Patients who received tinzaparin did have a significantly lower risk of symptomatic deep vein thrombosis (DVT) and clinically relevant, non-major bleeding.

However, there was no difference between the treatment arms with regard to major bleeding or overall mortality.

Agnes Y.Y. Lee, MD, of the University of British Columbia and Vancouver Coastal Health in British Columbia, Canada, presented these results at ASH as LBA-2.*

“CATCH is the largest randomized trial studying treatment of cancer-associated thrombosis,” she said. “It provides confirmatory data for improved efficacy of low-molecular-weight heparin over warfarin.”

The trial included 900 cancer patients from 164 centers around the world. The mean patient age was 59 (range, 18-89), and 59% were female. The most common cancers were gynecologic, colorectal, upper gastrointestinal, and lung.

Patients were stratified by geographic region, tumor characteristics, and history of VTE. They were randomized to receive tinzaparin at 175 IU/kg once daily for 6 months (n=449) or initial tinzaparin at 175 IU/kg once daily for 5 to 10 days overlapped and followed by dose-adjusted warfarin for 6 months (n=451).

In all, 416 patients completed treatment with tinzaparin, and 401 completed warfarin treatment. The patients were followed up to 6 months or death, whichever came first.

Efficacy data 

The primary efficacy outcome was recurrent VTE, which included symptomatic DVT and/or pulmonary embolism (PE), incidental proximal DVT and/or PE, and fatal PE.

The rate of recurrent VTE was 7.2% in the tinzaparin arm and 10.5% in the warfarin arm (hazard ratio [HR]=0.65, P=0.07). This represents a 35% reduction in recurrent VTE with the LMWH.

In the per-protocol analysis, the rates of recurrent VTE were 8.3% and 12.7%, respectively (HR=0.62), which translates to a 38% reduction in recurrent VTE with tinzaparin.

“Pre-specified efficacy analyses further showed that tinzaparin significantly reduced symptomatic, recurrent DVT by 52%,” Dr Lee noted. “There were very few symptomatic PEs, equal numbers of fatal PEs occurred in each arm, and there were only 2 incidental thrombotic events, both in the warfarin arm.”

Symptomatic, non-fatal DVT occurred in 12 patients (2.7%) in the tinzaparin arm and 24 (5.3%) in the warfarin arm (HR=0.48, P=0.04). Symptomatic, non-fatal PE occurred in 3 patients (0.7%) and 2 patients (0.4%), respectively. And fatal PE occurred in 17 patients (3.8%) in each arm (HR=0.96).

“We were clearly disappointed that our primary efficacy outcome did not achieve statistical significance,” Dr Lee said. “But our sample size was based on an estimated recurrent [VTE] rate of 12.6% in the warfarin group, and we only saw a 10% [sic] recurrence. So, basically, our study was slightly underpowered to achieve statistical significance.”

“I think that, given the symptomatic DVT results, as well as the per-protocol analysis, in additon to all the previous data on low-molecular-weight heparin, this is still very strong confirmatory data that low-molecular-weight heparin is more effective than warfarin therapy in treating cancer patients with thrombosis.”

Safety and mortality

The primary safety endpoint was major bleeding, which occurred in 2.9% of patients in the tinzaparin arm and 2.6% in the warfarin arm (HR=0.89).

The rate of clinically relevant, non-major bleeding was 11.1% and 16.2%, respectively (HR=0.69, P=0.03).

“Tinzaparin reduced the rate of clinically relevant, non-major bleeding by 31%,” Dr Lee noted.

On the other hand, there was no significant difference between the arms with regard to 180-day overall mortality, which was 34.2% in the tinzaparin arm and 32.3% in the warfarin arm (HR=1.08).

This research was sponsored by LEO Pharma, the company developing tinzaparin (Innohep).

*Information in the abstract differs from that presented at the meeting.

Doctor examines child with

sickle cell disease

Credit: St. Jude Hospital

SAN FRANCISCO—Magnesium does not improve outcomes in children hospitalized for sickle cell pain crises, results of the MAGiC study suggest.

Researchers hypothesized that magnesium—a known vasodilator, anti-inflammatory, and pain reliever—could alter the pathophysiology of pain crises.

However, when compared to normal saline, intravenous (IV) magnesium did not shorten hospital stays, lessen opioid use, or improve patients’ quality of life.

David C. Brousseau, MD, of the Medical College of Wisconsin and the Children’s Hospital of Wisconsin in Milwaukee, presented the results of this study at the 2014 ASH Annual Meeting (abstract 88).

Dr Brousseau noted that vasoocclusive crises are the most common acute complication of sickle cell disease and the most frequent cause of acute care or emergency department visits and hospitalizations. But recent changes in treatment have been minimal, with the judicious use of IV fluid and IV opioids being the mainstays of therapy.

“There have been few multicenter clinical trials evaluating new treatments, in part, due to a long history of difficulty with enrollment in interventional trials for sickle cell crises,” he continued. “These enrollment difficulties have been due to an inability to consent or to consent in a timely manner, leading to delayed initiation of study drug.”

With the MAGiC trial, Dr Brousseau and his colleagues sought to overcome this problem through a collaboration between pediatric emergency medicine physicians and pediatric hematologists.

In this randomized, double-blind trial, the researchers compared IV magnesium to normal saline. They enrolled children ages 4 to 21, with hemoglobin SS or hemoglobin SB° thalassemia, who were hospitalized after failing emergency department management for pain.

A total of 208 children were enrolled at 8 study sites over 3 years. Four children were excluded before receiving treatment, so 101 were randomized to receive magnesium and 103 to saline.

The children received 40 mg/kg of IV magnesium every 8 hours for a total of 6 doses or normal saline of an equivalent volume (1 mL/kg).

The treatment groups were well-balanced, with similar baseline age, sex, genotype, weight, history of acute chest syndrome or asthma, previous hospitalizations within the past 3 years, use of hydroxyurea, and days of pain prior to arrival.

The median time from the first emergency department opioid to the first study drug infusion was 7.3 hours in the magnesium group and 7.5 hours in the saline group.

For the study’s primary outcome, the researchers assessed patients’ length of stay from the first study drug infusion until 12 hours after the last IV opioid dose or the time of discharge, whichever came first.

“Approximately 50% of children [overall] met the study endpoint within 52 hours, and 25% met the study endpoint within 24 hours of the first drug infusion,” Dr Brousseau noted.

And there was no significant difference in the median length of stay between the treatment arms—56 hours in the magnesium arm and 47 hours in the placebo arm (P=0.264).

A secondary outcome was opioid use, recorded as morphine equivalents. There was no significant difference with this outcome, either. Patients in the magnesium arm received 1.46 mg/kg of morphine equivalents, compared to 1.28 mg/kg in the saline arm (P=0.12).

The researchers also assessed quality of life using the PedsQL sickle cell disease-specific module, fatigue module, and generic module. At 48 hours after the first infusion, there was no significant difference in quality of life scores between the treatment groups for any of the modules (P=0.17, 0.26, and 0.94, respectively). The same was true 1 week after discharge (P=0.55, 0.82, and 0.36, respectively).

As for safety, there was no significant difference between the treatment arms for most measures. However, patients in the magnesium arm were more likely to experience warmth upon infusion, at 26%, compared to 2% in the saline arm (P<0.01).

Acute chest syndrome occurred in 16% of patients in the magnesium arm and 14% in the saline arm (P=0.78). Hypotension occurred in 4% and 1%, respectively (P=0.39). And rehospitalization within 7 days occurred in 12% and 7%, respectively (P=0.11).

In closing, Dr Brousseau noted that, although the researchers did not prove their hypothesis correct, the MAGiC study was a success in one respect.

“Intravenous magnesium does not shorten length of stay, lessen opioid use, or improve quality of life in children hospitalized for sickle cell pain crises,” he said. “[However,] a collaboration between pediatric emergency department medicine physicians and pediatric hematologists allowed for successful enrollment in an acute intervention trial with a median time to first study drug of 7.5 hours.”

Doctor examines child with

sickle cell disease

Credit: St. Jude Hospital

SAN FRANCISCO—Magnesium does not improve outcomes in children hospitalized for sickle cell pain crises, results of the MAGiC study suggest.

Researchers hypothesized that magnesium—a known vasodilator, anti-inflammatory, and pain reliever—could alter the pathophysiology of pain crises.

However, when compared to normal saline, intravenous (IV) magnesium did not shorten hospital stays, lessen opioid use, or improve patients’ quality of life.

David C. Brousseau, MD, of the Medical College of Wisconsin and the Children’s Hospital of Wisconsin in Milwaukee, presented the results of this study at the 2014 ASH Annual Meeting (abstract 88).

Dr Brousseau noted that vasoocclusive crises are the most common acute complication of sickle cell disease and the most frequent cause of acute care or emergency department visits and hospitalizations. But recent changes in treatment have been minimal, with the judicious use of IV fluid and IV opioids being the mainstays of therapy.

“There have been few multicenter clinical trials evaluating new treatments, in part, due to a long history of difficulty with enrollment in interventional trials for sickle cell crises,” he continued. “These enrollment difficulties have been due to an inability to consent or to consent in a timely manner, leading to delayed initiation of study drug.”

With the MAGiC trial, Dr Brousseau and his colleagues sought to overcome this problem through a collaboration between pediatric emergency medicine physicians and pediatric hematologists.

In this randomized, double-blind trial, the researchers compared IV magnesium to normal saline. They enrolled children ages 4 to 21, with hemoglobin SS or hemoglobin SB° thalassemia, who were hospitalized after failing emergency department management for pain.

A total of 208 children were enrolled at 8 study sites over 3 years. Four children were excluded before receiving treatment, so 101 were randomized to receive magnesium and 103 to saline.

The children received 40 mg/kg of IV magnesium every 8 hours for a total of 6 doses or normal saline of an equivalent volume (1 mL/kg).

The treatment groups were well-balanced, with similar baseline age, sex, genotype, weight, history of acute chest syndrome or asthma, previous hospitalizations within the past 3 years, use of hydroxyurea, and days of pain prior to arrival.

The median time from the first emergency department opioid to the first study drug infusion was 7.3 hours in the magnesium group and 7.5 hours in the saline group.

For the study’s primary outcome, the researchers assessed patients’ length of stay from the first study drug infusion until 12 hours after the last IV opioid dose or the time of discharge, whichever came first.

“Approximately 50% of children [overall] met the study endpoint within 52 hours, and 25% met the study endpoint within 24 hours of the first drug infusion,” Dr Brousseau noted.

And there was no significant difference in the median length of stay between the treatment arms—56 hours in the magnesium arm and 47 hours in the placebo arm (P=0.264).

A secondary outcome was opioid use, recorded as morphine equivalents. There was no significant difference with this outcome, either. Patients in the magnesium arm received 1.46 mg/kg of morphine equivalents, compared to 1.28 mg/kg in the saline arm (P=0.12).

The researchers also assessed quality of life using the PedsQL sickle cell disease-specific module, fatigue module, and generic module. At 48 hours after the first infusion, there was no significant difference in quality of life scores between the treatment groups for any of the modules (P=0.17, 0.26, and 0.94, respectively). The same was true 1 week after discharge (P=0.55, 0.82, and 0.36, respectively).

As for safety, there was no significant difference between the treatment arms for most measures. However, patients in the magnesium arm were more likely to experience warmth upon infusion, at 26%, compared to 2% in the saline arm (P<0.01).

Acute chest syndrome occurred in 16% of patients in the magnesium arm and 14% in the saline arm (P=0.78). Hypotension occurred in 4% and 1%, respectively (P=0.39). And rehospitalization within 7 days occurred in 12% and 7%, respectively (P=0.11).

In closing, Dr Brousseau noted that, although the researchers did not prove their hypothesis correct, the MAGiC study was a success in one respect.

“Intravenous magnesium does not shorten length of stay, lessen opioid use, or improve quality of life in children hospitalized for sickle cell pain crises,” he said. “[However,] a collaboration between pediatric emergency department medicine physicians and pediatric hematologists allowed for successful enrollment in an acute intervention trial with a median time to first study drug of 7.5 hours.”

Doctor examines child with

sickle cell disease

Credit: St. Jude Hospital

SAN FRANCISCO—Magnesium does not improve outcomes in children hospitalized for sickle cell pain crises, results of the MAGiC study suggest.

Researchers hypothesized that magnesium—a known vasodilator, anti-inflammatory, and pain reliever—could alter the pathophysiology of pain crises.

However, when compared to normal saline, intravenous (IV) magnesium did not shorten hospital stays, lessen opioid use, or improve patients’ quality of life.

David C. Brousseau, MD, of the Medical College of Wisconsin and the Children’s Hospital of Wisconsin in Milwaukee, presented the results of this study at the 2014 ASH Annual Meeting (abstract 88).

Dr Brousseau noted that vasoocclusive crises are the most common acute complication of sickle cell disease and the most frequent cause of acute care or emergency department visits and hospitalizations. But recent changes in treatment have been minimal, with the judicious use of IV fluid and IV opioids being the mainstays of therapy.

“There have been few multicenter clinical trials evaluating new treatments, in part, due to a long history of difficulty with enrollment in interventional trials for sickle cell crises,” he continued. “These enrollment difficulties have been due to an inability to consent or to consent in a timely manner, leading to delayed initiation of study drug.”

With the MAGiC trial, Dr Brousseau and his colleagues sought to overcome this problem through a collaboration between pediatric emergency medicine physicians and pediatric hematologists.

In this randomized, double-blind trial, the researchers compared IV magnesium to normal saline. They enrolled children ages 4 to 21, with hemoglobin SS or hemoglobin SB° thalassemia, who were hospitalized after failing emergency department management for pain.

A total of 208 children were enrolled at 8 study sites over 3 years. Four children were excluded before receiving treatment, so 101 were randomized to receive magnesium and 103 to saline.

The children received 40 mg/kg of IV magnesium every 8 hours for a total of 6 doses or normal saline of an equivalent volume (1 mL/kg).

The treatment groups were well-balanced, with similar baseline age, sex, genotype, weight, history of acute chest syndrome or asthma, previous hospitalizations within the past 3 years, use of hydroxyurea, and days of pain prior to arrival.

The median time from the first emergency department opioid to the first study drug infusion was 7.3 hours in the magnesium group and 7.5 hours in the saline group.

For the study’s primary outcome, the researchers assessed patients’ length of stay from the first study drug infusion until 12 hours after the last IV opioid dose or the time of discharge, whichever came first.

“Approximately 50% of children [overall] met the study endpoint within 52 hours, and 25% met the study endpoint within 24 hours of the first drug infusion,” Dr Brousseau noted.

And there was no significant difference in the median length of stay between the treatment arms—56 hours in the magnesium arm and 47 hours in the placebo arm (P=0.264).

A secondary outcome was opioid use, recorded as morphine equivalents. There was no significant difference with this outcome, either. Patients in the magnesium arm received 1.46 mg/kg of morphine equivalents, compared to 1.28 mg/kg in the saline arm (P=0.12).

The researchers also assessed quality of life using the PedsQL sickle cell disease-specific module, fatigue module, and generic module. At 48 hours after the first infusion, there was no significant difference in quality of life scores between the treatment groups for any of the modules (P=0.17, 0.26, and 0.94, respectively). The same was true 1 week after discharge (P=0.55, 0.82, and 0.36, respectively).

As for safety, there was no significant difference between the treatment arms for most measures. However, patients in the magnesium arm were more likely to experience warmth upon infusion, at 26%, compared to 2% in the saline arm (P<0.01).

Acute chest syndrome occurred in 16% of patients in the magnesium arm and 14% in the saline arm (P=0.78). Hypotension occurred in 4% and 1%, respectively (P=0.39). And rehospitalization within 7 days occurred in 12% and 7%, respectively (P=0.11).

In closing, Dr Brousseau noted that, although the researchers did not prove their hypothesis correct, the MAGiC study was a success in one respect.

“Intravenous magnesium does not shorten length of stay, lessen opioid use, or improve quality of life in children hospitalized for sickle cell pain crises,” he said. “[However,] a collaboration between pediatric emergency department medicine physicians and pediatric hematologists allowed for successful enrollment in an acute intervention trial with a median time to first study drug of 7.5 hours.”

SAN FRANCISCO—Administering brentuximab vedotin immediately after autologous stem cell transplant can improve progression-free survival (PFS) in patients with Hodgkin lymphoma (HL), results of the phase 3 AETHERA trial suggest.

The overall survival (OS) data for this study are not yet mature, but the significant improvement in PFS will likely translate to improved OS in a few years’ time, according to Craig Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr Moskowitz presented results from the AETHERA trial at the 2014 ASH Annual Meeting as abstract 673. The trial was funded by Seattle Genetics, Inc., and Takeda Pharmaceutical Company Limited, the companies developing brentuximab.

The trial included HL patients with at least one risk factor for progression. Eligible patients must have had a history of refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-transplant relapse.

Researchers enrolled 329 patients, and they were randomized to receive brentuximab or placebo every 3 weeks for up to about a year. Baseline characteristics were similar between the 2 arms.

Dr Moskowitz pointed out that 43% of patients in the brentuximab arm and 48% in the placebo arm had required 2 or more prior salvage therapies, and 60% and 59%, respectively, had primary refractory HL.

Patients in both arms received a median of 15 treatment cycles, with an average of 12 cycles on the brentuximab arm and 11 cycles on the placebo arm.

“Patients who progressed in the placebo arm could be unblinded and subsequently receive brentuximab on a companion study,” Dr Moskowitz noted. “So technically, this was a cross-over design, making overall survival at 24 months quite unlikely.”

Efficacy/survival results

About half of patients in each arm completed treatment—47% in the brentuximab arm and 49% in the placebo arm. The reasons for discontinuation included disease progression (15% and 42%, respectively), adverse events (33% and 6%, respectively), and patient decision (5% and 2%, respectively).

Still, the trial achieved its primary endpoint, demonstrating a significant increase in PFS, according to an independent review facility (IRF).

The median PFS per the IRF was 43 months for patients in the brentuximab arm and 24 months in the placebo arm (hazard ratio=0.57, P=0.001). The 2-year PFS rates per the IRF were 63% and 51%, respectively.

The 2-year PFS rate according to investigators was 65% in the brentuximab arm and 45% in the placebo arm. The median PFS per investigators has not yet been reached for brentuximab but was 16 months for placebo.

The PFS benefit was consistent across all pre-specified subgroups, Dr Moskowitz noted, including primary refractory patients, patients who relapsed within 12 months of frontline therapy, and patients who relapsed after 12 months with extranodal disease.

Patients who experienced disease progression received a variety of subsequent therapies.

In the brentuximab arm, 16% of patients receiving subsequent therapy were treated with brentuximab after relapse. In the placebo arm, 85% of patients receiving subsequent therapy were treated with single-agent brentuximab.

Twenty-eight percent of patients in the placebo arm and 25% in the brentuximab arm received stem cell transplant as subsequent therapy, the majority of which were allogeneic transplants. Dr Moskowitz said a second transplant could have improved survival in these patients, but whether it actually did is unclear.

He noted that the OS data are immature, but there is currently no significant difference in OS between the treatment arms (hazard ratio=1.15; P=0.62).

“The median follow-up right now is 24 months,” he said. “So one will have to wait for a survival advantage or disadvantage, but from my point of view, a PFS of 65% at 2 years will translate to an overall survival difference. We’re just going to have to wait a few more years.”

Dr Moskowitz said another analysis of OS is planned in 2016.

Safety data

The most common adverse events in the brentuximab arm were peripheral sensory neuropathy (56%), neutropenia (35%), upper respiratory tract infection (26%), fatigue (24%), and peripheral motor neuropathy (23%).

The most common adverse events in the placebo arm were upper respiratory tract infection (23%), fatigue (18%), peripheral sensory neuropathy (16%), cough (16%), and neutropenia (12%).

Eighty-five percent of patients with peripheral neuropathy in the brentuximab arm had a resolution or improvement in symptoms, with a median time to improvement of 23.4 weeks.

Grade 3 or higher adverse events in the brentuximab arm included neutropenia, peripheral sensory neuropathy, peripheral motor neuropathy, nausea, fatigue, and diarrhea.

Grade 3 or higher adverse events in the placebo arm included neutropenia, fatigue, peripheral motor neuropathy, diarrhea, and peripheral sensory neuropathy. No Grade 4 peripheral neuropathy events occurred.

One death occurred within 30 days of brentuximab treatment. The patient died from treatment-related acute respiratory distress syndrome (ARDS) associated with pneumonitis.

Another death occurred on the brentuximab arm at day 40 from ARDS following an episode of treatment-related acute pancreatitis, which had resolved at the time of death.

Nevertheless, Dr Moskowitz characterized brentuximab consolidation as “very well-tolerated” in this patient population.

He concluded, “For patients with a remission duration of less than a year, patients with primary refractory Hodgkin lymphoma, and patients with Hodgkin lymphoma with extranodal involvement, I do believe this will become standard treatment.”

SAN FRANCISCO—Administering brentuximab vedotin immediately after autologous stem cell transplant can improve progression-free survival (PFS) in patients with Hodgkin lymphoma (HL), results of the phase 3 AETHERA trial suggest.

The overall survival (OS) data for this study are not yet mature, but the significant improvement in PFS will likely translate to improved OS in a few years’ time, according to Craig Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr Moskowitz presented results from the AETHERA trial at the 2014 ASH Annual Meeting as abstract 673. The trial was funded by Seattle Genetics, Inc., and Takeda Pharmaceutical Company Limited, the companies developing brentuximab.

The trial included HL patients with at least one risk factor for progression. Eligible patients must have had a history of refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-transplant relapse.

Researchers enrolled 329 patients, and they were randomized to receive brentuximab or placebo every 3 weeks for up to about a year. Baseline characteristics were similar between the 2 arms.

Dr Moskowitz pointed out that 43% of patients in the brentuximab arm and 48% in the placebo arm had required 2 or more prior salvage therapies, and 60% and 59%, respectively, had primary refractory HL.

Patients in both arms received a median of 15 treatment cycles, with an average of 12 cycles on the brentuximab arm and 11 cycles on the placebo arm.

“Patients who progressed in the placebo arm could be unblinded and subsequently receive brentuximab on a companion study,” Dr Moskowitz noted. “So technically, this was a cross-over design, making overall survival at 24 months quite unlikely.”

Efficacy/survival results

About half of patients in each arm completed treatment—47% in the brentuximab arm and 49% in the placebo arm. The reasons for discontinuation included disease progression (15% and 42%, respectively), adverse events (33% and 6%, respectively), and patient decision (5% and 2%, respectively).

Still, the trial achieved its primary endpoint, demonstrating a significant increase in PFS, according to an independent review facility (IRF).

The median PFS per the IRF was 43 months for patients in the brentuximab arm and 24 months in the placebo arm (hazard ratio=0.57, P=0.001). The 2-year PFS rates per the IRF were 63% and 51%, respectively.

The 2-year PFS rate according to investigators was 65% in the brentuximab arm and 45% in the placebo arm. The median PFS per investigators has not yet been reached for brentuximab but was 16 months for placebo.

The PFS benefit was consistent across all pre-specified subgroups, Dr Moskowitz noted, including primary refractory patients, patients who relapsed within 12 months of frontline therapy, and patients who relapsed after 12 months with extranodal disease.

Patients who experienced disease progression received a variety of subsequent therapies.

In the brentuximab arm, 16% of patients receiving subsequent therapy were treated with brentuximab after relapse. In the placebo arm, 85% of patients receiving subsequent therapy were treated with single-agent brentuximab.

Twenty-eight percent of patients in the placebo arm and 25% in the brentuximab arm received stem cell transplant as subsequent therapy, the majority of which were allogeneic transplants. Dr Moskowitz said a second transplant could have improved survival in these patients, but whether it actually did is unclear.

He noted that the OS data are immature, but there is currently no significant difference in OS between the treatment arms (hazard ratio=1.15; P=0.62).

“The median follow-up right now is 24 months,” he said. “So one will have to wait for a survival advantage or disadvantage, but from my point of view, a PFS of 65% at 2 years will translate to an overall survival difference. We’re just going to have to wait a few more years.”

Dr Moskowitz said another analysis of OS is planned in 2016.

Safety data

The most common adverse events in the brentuximab arm were peripheral sensory neuropathy (56%), neutropenia (35%), upper respiratory tract infection (26%), fatigue (24%), and peripheral motor neuropathy (23%).

The most common adverse events in the placebo arm were upper respiratory tract infection (23%), fatigue (18%), peripheral sensory neuropathy (16%), cough (16%), and neutropenia (12%).

Eighty-five percent of patients with peripheral neuropathy in the brentuximab arm had a resolution or improvement in symptoms, with a median time to improvement of 23.4 weeks.

Grade 3 or higher adverse events in the brentuximab arm included neutropenia, peripheral sensory neuropathy, peripheral motor neuropathy, nausea, fatigue, and diarrhea.

Grade 3 or higher adverse events in the placebo arm included neutropenia, fatigue, peripheral motor neuropathy, diarrhea, and peripheral sensory neuropathy. No Grade 4 peripheral neuropathy events occurred.

One death occurred within 30 days of brentuximab treatment. The patient died from treatment-related acute respiratory distress syndrome (ARDS) associated with pneumonitis.

Another death occurred on the brentuximab arm at day 40 from ARDS following an episode of treatment-related acute pancreatitis, which had resolved at the time of death.

Nevertheless, Dr Moskowitz characterized brentuximab consolidation as “very well-tolerated” in this patient population.

He concluded, “For patients with a remission duration of less than a year, patients with primary refractory Hodgkin lymphoma, and patients with Hodgkin lymphoma with extranodal involvement, I do believe this will become standard treatment.”

SAN FRANCISCO—Administering brentuximab vedotin immediately after autologous stem cell transplant can improve progression-free survival (PFS) in patients with Hodgkin lymphoma (HL), results of the phase 3 AETHERA trial suggest.

The overall survival (OS) data for this study are not yet mature, but the significant improvement in PFS will likely translate to improved OS in a few years’ time, according to Craig Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr Moskowitz presented results from the AETHERA trial at the 2014 ASH Annual Meeting as abstract 673. The trial was funded by Seattle Genetics, Inc., and Takeda Pharmaceutical Company Limited, the companies developing brentuximab.

The trial included HL patients with at least one risk factor for progression. Eligible patients must have had a history of refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-transplant relapse.

Researchers enrolled 329 patients, and they were randomized to receive brentuximab or placebo every 3 weeks for up to about a year. Baseline characteristics were similar between the 2 arms.

Dr Moskowitz pointed out that 43% of patients in the brentuximab arm and 48% in the placebo arm had required 2 or more prior salvage therapies, and 60% and 59%, respectively, had primary refractory HL.

Patients in both arms received a median of 15 treatment cycles, with an average of 12 cycles on the brentuximab arm and 11 cycles on the placebo arm.

“Patients who progressed in the placebo arm could be unblinded and subsequently receive brentuximab on a companion study,” Dr Moskowitz noted. “So technically, this was a cross-over design, making overall survival at 24 months quite unlikely.”

Efficacy/survival results

About half of patients in each arm completed treatment—47% in the brentuximab arm and 49% in the placebo arm. The reasons for discontinuation included disease progression (15% and 42%, respectively), adverse events (33% and 6%, respectively), and patient decision (5% and 2%, respectively).

Still, the trial achieved its primary endpoint, demonstrating a significant increase in PFS, according to an independent review facility (IRF).

The median PFS per the IRF was 43 months for patients in the brentuximab arm and 24 months in the placebo arm (hazard ratio=0.57, P=0.001). The 2-year PFS rates per the IRF were 63% and 51%, respectively.

The 2-year PFS rate according to investigators was 65% in the brentuximab arm and 45% in the placebo arm. The median PFS per investigators has not yet been reached for brentuximab but was 16 months for placebo.

The PFS benefit was consistent across all pre-specified subgroups, Dr Moskowitz noted, including primary refractory patients, patients who relapsed within 12 months of frontline therapy, and patients who relapsed after 12 months with extranodal disease.

Patients who experienced disease progression received a variety of subsequent therapies.

In the brentuximab arm, 16% of patients receiving subsequent therapy were treated with brentuximab after relapse. In the placebo arm, 85% of patients receiving subsequent therapy were treated with single-agent brentuximab.

Twenty-eight percent of patients in the placebo arm and 25% in the brentuximab arm received stem cell transplant as subsequent therapy, the majority of which were allogeneic transplants. Dr Moskowitz said a second transplant could have improved survival in these patients, but whether it actually did is unclear.

He noted that the OS data are immature, but there is currently no significant difference in OS between the treatment arms (hazard ratio=1.15; P=0.62).

“The median follow-up right now is 24 months,” he said. “So one will have to wait for a survival advantage or disadvantage, but from my point of view, a PFS of 65% at 2 years will translate to an overall survival difference. We’re just going to have to wait a few more years.”

Dr Moskowitz said another analysis of OS is planned in 2016.

Safety data

The most common adverse events in the brentuximab arm were peripheral sensory neuropathy (56%), neutropenia (35%), upper respiratory tract infection (26%), fatigue (24%), and peripheral motor neuropathy (23%).

The most common adverse events in the placebo arm were upper respiratory tract infection (23%), fatigue (18%), peripheral sensory neuropathy (16%), cough (16%), and neutropenia (12%).

Eighty-five percent of patients with peripheral neuropathy in the brentuximab arm had a resolution or improvement in symptoms, with a median time to improvement of 23.4 weeks.

Grade 3 or higher adverse events in the brentuximab arm included neutropenia, peripheral sensory neuropathy, peripheral motor neuropathy, nausea, fatigue, and diarrhea.

Grade 3 or higher adverse events in the placebo arm included neutropenia, fatigue, peripheral motor neuropathy, diarrhea, and peripheral sensory neuropathy. No Grade 4 peripheral neuropathy events occurred.

One death occurred within 30 days of brentuximab treatment. The patient died from treatment-related acute respiratory distress syndrome (ARDS) associated with pneumonitis.

Another death occurred on the brentuximab arm at day 40 from ARDS following an episode of treatment-related acute pancreatitis, which had resolved at the time of death.

Nevertheless, Dr Moskowitz characterized brentuximab consolidation as “very well-tolerated” in this patient population.

He concluded, “For patients with a remission duration of less than a year, patients with primary refractory Hodgkin lymphoma, and patients with Hodgkin lymphoma with extranodal involvement, I do believe this will become standard treatment.”

SAN FRANCISCO—Trial results suggest a 3-drug regimen could represent a new standard of care for relapsed multiple myeloma (MM), according to a speaker at the 2014 ASH Annual Meeting.

In the phase 3 ASPIRE trial, patients who received combination carfilzomib, lenalidomide, and dexamethasone (KRd) had superior progression-free survival compared to patients who received only lenalidomide and dexamethasone (Rd).

There was a trend toward improved overall survival with KRd as well.

Patients who received KRd did experience more adverse events (AEs), but fewer patients discontinued treatment due to AEs in the KRd arm than in the Rd arm.

Keith Stewart, MBChB, of the Mayo Clinic in Arizona, presented these results at the meeting as abstract 79. The data were published in The New England Journal of Medicine as well. The trial was sponsored by Onyx Pharmaceuticals, Inc., the company developing carfilzomib.

ASPIRE included 792 patients with relapsed MM who had received 1 to 3 prior treatment regimens. Patients were randomized to treatment with KRd (n=396) or Rd (n=396), and baseline characteristics were similar between the arms.

“There was a slight preponderance of patients over the age of 65 in the Rd arm of the trial,” Dr Stewart noted. “Conversely, there were more patients on the Rd arm of the trial who had lower-risk cytogenetics.”

“Patients were also well-balanced for baseline exposure to prior therapies. Prior therapies included transplant in 55% of patients, bortezomib in two-thirds of patients, and lenalidomide in 20% of patients—again, equal in both arms of the trial.”

All patients received a standard dosing schedule of lenalidomide (25 mg on days 1-21) and low-dose dexamethasone (40 mg on days 1, 8, 15, and 22).

Patients in the KRd arm also received carfilzomib (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). They received a 10-minute infusion of the drug on days 1, 2, 8, 9, 15, and 16. Carfilzomib was not given on days 8 and 9 in cycles 13 to 18 and not administered beyond 18 cycles.

‘Unprecedented’ results

The study’s primary endpoint was progression-free survival. And results showed progression-free survival was significantly longer in the KRd arm than in the Rd arm—26.3 months and 17.6 months, respectively (hazard ratio=0.69; P<0.0001).

“Progression-free survival was significantly improved by 8.7 months with KRd,” Dr Stewart noted. “In a phase 3 clinical trial setting, this is unprecedented.”

“In all prespecified subgroups, the advantage of KRd in progression-free survival was maintained. That includes age, international staging system, and prior exposure to either bortezomib or lenalidomide, or both drugs.”

The secondary endpoints of the trial were overall survival, overall response rate, duration of response, health-related quality of life, and safety.

The data for median overall survival are not yet mature based on the prespecified statistical boundary at the interim analysis (P=0.005). However, there was a trend in favor of KRd (hazard ratio, 0.79; P=0.018).

The overall response rate was 87.1% with KRd and 66.7% with Rd (P<0.0001), and the complete response rates were 14.1% and 4.3%, respectively (P<0.001). The median duration of response was 28.6 months and 21.2 months, respectively.

In addition, KRd improved global health-related quality of life compared with Rd over 18 cycles of treatment (P=0.0001).

‘Reassuring’ toxicity data

“In the discussion of adverse events,” Dr Stewart said, “it’s important to note that the median treatment duration was 88 weeks with KRd and 57 weeks with Rd.”

Most patients in each arm experienced at least one AE—96.9% in the KRd arm and 97.2% in the RD arm.

In the KRd arm, 7.7% of patients died while still on treatment or within 30 days of receiving their last dose of treatment, as did 8.5% of patients in the Rd arm. The percentage of deaths attributable to AEs was 6.9% in both arms.

The rates of treatment discontinuation were 69.9% in the KRd arm and 77.9% in the Rd arm. More patients discontinued treatment due to disease progression—39.8% in the KRd arm and 50.1% in the Rd arm—than to AEs—15.3% in the KRd arm and 17.7% in the Rd arm.

The most common grade 3 or higher hematologic treatment-emergent AEs (in the KRd and Rd arms, respectively) were neutropenia (29.6% vs 26.5%), anemia (17.9% vs 17.2%), and thrombocytopenia (16.6% vs 12.3%).

The most common grade 3 or higher nonhematologic treatment-emergent AEs (in the KRd and Rd arms, respectively) were hypokalemia (9.4% vs 4.9%), fatigue (7.7% vs 6.4%), and diarrhea (3.8% vs 4.1%).

Other treatment-emergent AEs of any grade (in the KRd and Rd arms, respectively) included dyspnea (19.4% vs 14.9%), hypertension (14.3% vs 6.9%), acute renal failure (8.4% vs 7.2%), cardiac failure (6.4% vs 4.1%), ischemic heart disease (5.9% vs 4.6%), and peripheral neuropathy (17.1% vs 17.0%).

“The results [are] very reassuring with respect to cardiac and renal events, which were reported at rates consistent with, or even lower than, those reported in prior studies of single-agent carfilzomib or more heavily pretreated patients,” Dr Stewart said.

“Based on the results of this phase 3 trial, I think it’s fair to say that KRd could represent a new standard of care in relapsed multiple myeloma.”

SAN FRANCISCO—Trial results suggest a 3-drug regimen could represent a new standard of care for relapsed multiple myeloma (MM), according to a speaker at the 2014 ASH Annual Meeting.

In the phase 3 ASPIRE trial, patients who received combination carfilzomib, lenalidomide, and dexamethasone (KRd) had superior progression-free survival compared to patients who received only lenalidomide and dexamethasone (Rd).

There was a trend toward improved overall survival with KRd as well.

Patients who received KRd did experience more adverse events (AEs), but fewer patients discontinued treatment due to AEs in the KRd arm than in the Rd arm.

Keith Stewart, MBChB, of the Mayo Clinic in Arizona, presented these results at the meeting as abstract 79. The data were published in The New England Journal of Medicine as well. The trial was sponsored by Onyx Pharmaceuticals, Inc., the company developing carfilzomib.

ASPIRE included 792 patients with relapsed MM who had received 1 to 3 prior treatment regimens. Patients were randomized to treatment with KRd (n=396) or Rd (n=396), and baseline characteristics were similar between the arms.

“There was a slight preponderance of patients over the age of 65 in the Rd arm of the trial,” Dr Stewart noted. “Conversely, there were more patients on the Rd arm of the trial who had lower-risk cytogenetics.”

“Patients were also well-balanced for baseline exposure to prior therapies. Prior therapies included transplant in 55% of patients, bortezomib in two-thirds of patients, and lenalidomide in 20% of patients—again, equal in both arms of the trial.”

All patients received a standard dosing schedule of lenalidomide (25 mg on days 1-21) and low-dose dexamethasone (40 mg on days 1, 8, 15, and 22).

Patients in the KRd arm also received carfilzomib (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). They received a 10-minute infusion of the drug on days 1, 2, 8, 9, 15, and 16. Carfilzomib was not given on days 8 and 9 in cycles 13 to 18 and not administered beyond 18 cycles.

‘Unprecedented’ results

The study’s primary endpoint was progression-free survival. And results showed progression-free survival was significantly longer in the KRd arm than in the Rd arm—26.3 months and 17.6 months, respectively (hazard ratio=0.69; P<0.0001).

“Progression-free survival was significantly improved by 8.7 months with KRd,” Dr Stewart noted. “In a phase 3 clinical trial setting, this is unprecedented.”

“In all prespecified subgroups, the advantage of KRd in progression-free survival was maintained. That includes age, international staging system, and prior exposure to either bortezomib or lenalidomide, or both drugs.”

The secondary endpoints of the trial were overall survival, overall response rate, duration of response, health-related quality of life, and safety.

The data for median overall survival are not yet mature based on the prespecified statistical boundary at the interim analysis (P=0.005). However, there was a trend in favor of KRd (hazard ratio, 0.79; P=0.018).

The overall response rate was 87.1% with KRd and 66.7% with Rd (P<0.0001), and the complete response rates were 14.1% and 4.3%, respectively (P<0.001). The median duration of response was 28.6 months and 21.2 months, respectively.

In addition, KRd improved global health-related quality of life compared with Rd over 18 cycles of treatment (P=0.0001).

‘Reassuring’ toxicity data

“In the discussion of adverse events,” Dr Stewart said, “it’s important to note that the median treatment duration was 88 weeks with KRd and 57 weeks with Rd.”

Most patients in each arm experienced at least one AE—96.9% in the KRd arm and 97.2% in the RD arm.

In the KRd arm, 7.7% of patients died while still on treatment or within 30 days of receiving their last dose of treatment, as did 8.5% of patients in the Rd arm. The percentage of deaths attributable to AEs was 6.9% in both arms.

The rates of treatment discontinuation were 69.9% in the KRd arm and 77.9% in the Rd arm. More patients discontinued treatment due to disease progression—39.8% in the KRd arm and 50.1% in the Rd arm—than to AEs—15.3% in the KRd arm and 17.7% in the Rd arm.

The most common grade 3 or higher hematologic treatment-emergent AEs (in the KRd and Rd arms, respectively) were neutropenia (29.6% vs 26.5%), anemia (17.9% vs 17.2%), and thrombocytopenia (16.6% vs 12.3%).

The most common grade 3 or higher nonhematologic treatment-emergent AEs (in the KRd and Rd arms, respectively) were hypokalemia (9.4% vs 4.9%), fatigue (7.7% vs 6.4%), and diarrhea (3.8% vs 4.1%).

Other treatment-emergent AEs of any grade (in the KRd and Rd arms, respectively) included dyspnea (19.4% vs 14.9%), hypertension (14.3% vs 6.9%), acute renal failure (8.4% vs 7.2%), cardiac failure (6.4% vs 4.1%), ischemic heart disease (5.9% vs 4.6%), and peripheral neuropathy (17.1% vs 17.0%).

“The results [are] very reassuring with respect to cardiac and renal events, which were reported at rates consistent with, or even lower than, those reported in prior studies of single-agent carfilzomib or more heavily pretreated patients,” Dr Stewart said.

“Based on the results of this phase 3 trial, I think it’s fair to say that KRd could represent a new standard of care in relapsed multiple myeloma.”

SAN FRANCISCO—Trial results suggest a 3-drug regimen could represent a new standard of care for relapsed multiple myeloma (MM), according to a speaker at the 2014 ASH Annual Meeting.

In the phase 3 ASPIRE trial, patients who received combination carfilzomib, lenalidomide, and dexamethasone (KRd) had superior progression-free survival compared to patients who received only lenalidomide and dexamethasone (Rd).

There was a trend toward improved overall survival with KRd as well.

Patients who received KRd did experience more adverse events (AEs), but fewer patients discontinued treatment due to AEs in the KRd arm than in the Rd arm.

Keith Stewart, MBChB, of the Mayo Clinic in Arizona, presented these results at the meeting as abstract 79. The data were published in The New England Journal of Medicine as well. The trial was sponsored by Onyx Pharmaceuticals, Inc., the company developing carfilzomib.

ASPIRE included 792 patients with relapsed MM who had received 1 to 3 prior treatment regimens. Patients were randomized to treatment with KRd (n=396) or Rd (n=396), and baseline characteristics were similar between the arms.

“There was a slight preponderance of patients over the age of 65 in the Rd arm of the trial,” Dr Stewart noted. “Conversely, there were more patients on the Rd arm of the trial who had lower-risk cytogenetics.”

“Patients were also well-balanced for baseline exposure to prior therapies. Prior therapies included transplant in 55% of patients, bortezomib in two-thirds of patients, and lenalidomide in 20% of patients—again, equal in both arms of the trial.”

All patients received a standard dosing schedule of lenalidomide (25 mg on days 1-21) and low-dose dexamethasone (40 mg on days 1, 8, 15, and 22).

Patients in the KRd arm also received carfilzomib (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). They received a 10-minute infusion of the drug on days 1, 2, 8, 9, 15, and 16. Carfilzomib was not given on days 8 and 9 in cycles 13 to 18 and not administered beyond 18 cycles.

‘Unprecedented’ results

The study’s primary endpoint was progression-free survival. And results showed progression-free survival was significantly longer in the KRd arm than in the Rd arm—26.3 months and 17.6 months, respectively (hazard ratio=0.69; P<0.0001).

“Progression-free survival was significantly improved by 8.7 months with KRd,” Dr Stewart noted. “In a phase 3 clinical trial setting, this is unprecedented.”

“In all prespecified subgroups, the advantage of KRd in progression-free survival was maintained. That includes age, international staging system, and prior exposure to either bortezomib or lenalidomide, or both drugs.”

The secondary endpoints of the trial were overall survival, overall response rate, duration of response, health-related quality of life, and safety.

The data for median overall survival are not yet mature based on the prespecified statistical boundary at the interim analysis (P=0.005). However, there was a trend in favor of KRd (hazard ratio, 0.79; P=0.018).

The overall response rate was 87.1% with KRd and 66.7% with Rd (P<0.0001), and the complete response rates were 14.1% and 4.3%, respectively (P<0.001). The median duration of response was 28.6 months and 21.2 months, respectively.

In addition, KRd improved global health-related quality of life compared with Rd over 18 cycles of treatment (P=0.0001).

‘Reassuring’ toxicity data

“In the discussion of adverse events,” Dr Stewart said, “it’s important to note that the median treatment duration was 88 weeks with KRd and 57 weeks with Rd.”

Most patients in each arm experienced at least one AE—96.9% in the KRd arm and 97.2% in the RD arm.

In the KRd arm, 7.7% of patients died while still on treatment or within 30 days of receiving their last dose of treatment, as did 8.5% of patients in the Rd arm. The percentage of deaths attributable to AEs was 6.9% in both arms.

The rates of treatment discontinuation were 69.9% in the KRd arm and 77.9% in the Rd arm. More patients discontinued treatment due to disease progression—39.8% in the KRd arm and 50.1% in the Rd arm—than to AEs—15.3% in the KRd arm and 17.7% in the Rd arm.

The most common grade 3 or higher hematologic treatment-emergent AEs (in the KRd and Rd arms, respectively) were neutropenia (29.6% vs 26.5%), anemia (17.9% vs 17.2%), and thrombocytopenia (16.6% vs 12.3%).

The most common grade 3 or higher nonhematologic treatment-emergent AEs (in the KRd and Rd arms, respectively) were hypokalemia (9.4% vs 4.9%), fatigue (7.7% vs 6.4%), and diarrhea (3.8% vs 4.1%).

Other treatment-emergent AEs of any grade (in the KRd and Rd arms, respectively) included dyspnea (19.4% vs 14.9%), hypertension (14.3% vs 6.9%), acute renal failure (8.4% vs 7.2%), cardiac failure (6.4% vs 4.1%), ischemic heart disease (5.9% vs 4.6%), and peripheral neuropathy (17.1% vs 17.0%).

“The results [are] very reassuring with respect to cardiac and renal events, which were reported at rates consistent with, or even lower than, those reported in prior studies of single-agent carfilzomib or more heavily pretreated patients,” Dr Stewart said.

“Based on the results of this phase 3 trial, I think it’s fair to say that KRd could represent a new standard of care in relapsed multiple myeloma.”

PHILADELPHIA—Researchers believe a simple screening strategy could reduce the risk of transfusion-related acute lung injury (TRALI) in patients receiving apheresis platelets (APs) by about 60%.

Studying TRALI cases reported to the American Red Cross, the investigators found evidence to support the idea that testing female AP donors who report prior pregnancy and deferring those with human leukocyte antigen (HLA) antibodies could greatly decrease the risk of TRALI.

Anne Eder, MD, of the American Red Cross in Rockville, Maryland, presented this research at the AABB Annual Meeting 2014 (abstract S82-040B).

Dr Eder and her colleagues assessed cases of TRALI and possible TRALI reported to the American Red Cross’s national hemovigilance program. The researchers compared the incidence of TRALI according to the type of blood component transfused as well as the sex of the donor.

TRALI cases due to APs and red blood cells (RBCs) from 2006 to 2013 and male-donor-predominant plasma from 2008 to 2013 were calculated as rates per 10⁶ distributed units.

The blood center distributed 6.6 million AP units (>70% from male donors, excluding platelet additive solution), 9.6 million plasma units (>95% from male donors), and 48.6 million RBC units (54% from male donors).

In all, there were 224 cases of TRALI, 175 among patients who received a single type of blood component within 6 hours. There were 36 TRALI cases among plasma recipients, 92 among RBC recipients, and 41 among AP recipients.

The TRALI risk was about 3-fold greater for AP recipients than for RBC recipients or recipients of male-predominant plasma. The odds ratios (ORs) were 3.2, 1.0, and 0.8, respectively. The OR for all plasma recipients (including group AB female plasma) was 2.0.

The rate of fatalities was higher for AP recipients than RBC recipients, at 0.6 per 10⁶ and 0.2 per 10⁶, respectively (P=0.04).

When the researchers analyzed TRALI cases according to donor, they found a nearly 6-fold predilection for female donors among AP recipients (OR=5.6) and a nearly 5-fold predilection for female donors in RBC recipients (OR=4.5).

The investigators also considered the 41 AP TRALI cases individually to assess how effective a screening program might have been for reducing the risk of TRALI.

In 12 cases, patients had received AP from a male donor. Of the 29 female donors, 26 had reported a prior pregnancy, and 2 had test results suggesting a prior pregnancy.

Of those 28 donors, 3 were negative for HLA antibodies, leaving 25 cases, or 61%, positive for HLA antibodies.

Seventeen of the female donors had HLA class I and II antibodies, including 3 whose donation resulted in a fatality. One had HLA class I only, 2 had HLA class II only, 5 had HLA I or II and a specific human neutrophil antigen (HNA) antibody, and 1 had a specific HNA antibody only.

The researchers evaluated 7 cases in which donors had HLA class I or II antibodies. And they found that all 7 had signal-to-cutoff ratios much higher than any cutoff discussed for screening donors (greater than 100).

“So we predict that a strategy to test female apheresis donors who report prior pregnancy and to defer those with HLA antibodies may reduce the risk of TRALI by about 60% and prevent cases from human neutrophil antibodies as well,” Dr Eder concluded.

PHILADELPHIA—Researchers believe a simple screening strategy could reduce the risk of transfusion-related acute lung injury (TRALI) in patients receiving apheresis platelets (APs) by about 60%.

Studying TRALI cases reported to the American Red Cross, the investigators found evidence to support the idea that testing female AP donors who report prior pregnancy and deferring those with human leukocyte antigen (HLA) antibodies could greatly decrease the risk of TRALI.

Anne Eder, MD, of the American Red Cross in Rockville, Maryland, presented this research at the AABB Annual Meeting 2014 (abstract S82-040B).

Dr Eder and her colleagues assessed cases of TRALI and possible TRALI reported to the American Red Cross’s national hemovigilance program. The researchers compared the incidence of TRALI according to the type of blood component transfused as well as the sex of the donor.

TRALI cases due to APs and red blood cells (RBCs) from 2006 to 2013 and male-donor-predominant plasma from 2008 to 2013 were calculated as rates per 10⁶ distributed units.

The blood center distributed 6.6 million AP units (>70% from male donors, excluding platelet additive solution), 9.6 million plasma units (>95% from male donors), and 48.6 million RBC units (54% from male donors).

In all, there were 224 cases of TRALI, 175 among patients who received a single type of blood component within 6 hours. There were 36 TRALI cases among plasma recipients, 92 among RBC recipients, and 41 among AP recipients.

The TRALI risk was about 3-fold greater for AP recipients than for RBC recipients or recipients of male-predominant plasma. The odds ratios (ORs) were 3.2, 1.0, and 0.8, respectively. The OR for all plasma recipients (including group AB female plasma) was 2.0.

The rate of fatalities was higher for AP recipients than RBC recipients, at 0.6 per 10⁶ and 0.2 per 10⁶, respectively (P=0.04).

When the researchers analyzed TRALI cases according to donor, they found a nearly 6-fold predilection for female donors among AP recipients (OR=5.6) and a nearly 5-fold predilection for female donors in RBC recipients (OR=4.5).

The investigators also considered the 41 AP TRALI cases individually to assess how effective a screening program might have been for reducing the risk of TRALI.

In 12 cases, patients had received AP from a male donor. Of the 29 female donors, 26 had reported a prior pregnancy, and 2 had test results suggesting a prior pregnancy.

Of those 28 donors, 3 were negative for HLA antibodies, leaving 25 cases, or 61%, positive for HLA antibodies.

Seventeen of the female donors had HLA class I and II antibodies, including 3 whose donation resulted in a fatality. One had HLA class I only, 2 had HLA class II only, 5 had HLA I or II and a specific human neutrophil antigen (HNA) antibody, and 1 had a specific HNA antibody only.

The researchers evaluated 7 cases in which donors had HLA class I or II antibodies. And they found that all 7 had signal-to-cutoff ratios much higher than any cutoff discussed for screening donors (greater than 100).

“So we predict that a strategy to test female apheresis donors who report prior pregnancy and to defer those with HLA antibodies may reduce the risk of TRALI by about 60% and prevent cases from human neutrophil antibodies as well,” Dr Eder concluded.

PHILADELPHIA—Researchers believe a simple screening strategy could reduce the risk of transfusion-related acute lung injury (TRALI) in patients receiving apheresis platelets (APs) by about 60%.

Studying TRALI cases reported to the American Red Cross, the investigators found evidence to support the idea that testing female AP donors who report prior pregnancy and deferring those with human leukocyte antigen (HLA) antibodies could greatly decrease the risk of TRALI.

Anne Eder, MD, of the American Red Cross in Rockville, Maryland, presented this research at the AABB Annual Meeting 2014 (abstract S82-040B).

Dr Eder and her colleagues assessed cases of TRALI and possible TRALI reported to the American Red Cross’s national hemovigilance program. The researchers compared the incidence of TRALI according to the type of blood component transfused as well as the sex of the donor.

TRALI cases due to APs and red blood cells (RBCs) from 2006 to 2013 and male-donor-predominant plasma from 2008 to 2013 were calculated as rates per 10⁶ distributed units.

The blood center distributed 6.6 million AP units (>70% from male donors, excluding platelet additive solution), 9.6 million plasma units (>95% from male donors), and 48.6 million RBC units (54% from male donors).

In all, there were 224 cases of TRALI, 175 among patients who received a single type of blood component within 6 hours. There were 36 TRALI cases among plasma recipients, 92 among RBC recipients, and 41 among AP recipients.

The TRALI risk was about 3-fold greater for AP recipients than for RBC recipients or recipients of male-predominant plasma. The odds ratios (ORs) were 3.2, 1.0, and 0.8, respectively. The OR for all plasma recipients (including group AB female plasma) was 2.0.

The rate of fatalities was higher for AP recipients than RBC recipients, at 0.6 per 10⁶ and 0.2 per 10⁶, respectively (P=0.04).

When the researchers analyzed TRALI cases according to donor, they found a nearly 6-fold predilection for female donors among AP recipients (OR=5.6) and a nearly 5-fold predilection for female donors in RBC recipients (OR=4.5).

The investigators also considered the 41 AP TRALI cases individually to assess how effective a screening program might have been for reducing the risk of TRALI.

In 12 cases, patients had received AP from a male donor. Of the 29 female donors, 26 had reported a prior pregnancy, and 2 had test results suggesting a prior pregnancy.

Of those 28 donors, 3 were negative for HLA antibodies, leaving 25 cases, or 61%, positive for HLA antibodies.

Seventeen of the female donors had HLA class I and II antibodies, including 3 whose donation resulted in a fatality. One had HLA class I only, 2 had HLA class II only, 5 had HLA I or II and a specific human neutrophil antigen (HNA) antibody, and 1 had a specific HNA antibody only.

The researchers evaluated 7 cases in which donors had HLA class I or II antibodies. And they found that all 7 had signal-to-cutoff ratios much higher than any cutoff discussed for screening donors (greater than 100).

“So we predict that a strategy to test female apheresis donors who report prior pregnancy and to defer those with HLA antibodies may reduce the risk of TRALI by about 60% and prevent cases from human neutrophil antibodies as well,” Dr Eder concluded.

PHILADELPHIA—Results of a population-based study suggest that elderly adults in the US have seen an increase in the rate of transfusion-associated circulatory overload (TACO) in the last few years.

The risk of TACO increased with advancing age and with increases in the number of units transfused.

TACO rates also appeared to be related to the type of blood components transfused. Patients were more likely to develop TACO if they received red blood cells (RBCs) with plasma and/or platelets.

Mikhail Menis, PharmD, of the Center for Biologics Evaluation and Research at the US Food and Drug Administration in Rockville, Maryland, and his colleagues presented these findings in a poster (SP203) at the AABB Annual Meeting 2014.

The researchers conducted this retrospective, claims-based study to assess TACO occurrence and potential risk factors for the condition among elderly Medicare beneficiaries (aged 65 and older) who were transfused as inpatients from 2011 through 2013.

Among the 6,382,814 inpatient transfusion stays, 4405 included a record of TACO. So the overall rate of TACO was 69.0 per 100,000 stays.

TACO rates (per 100,000) increased significantly over time, from 63.0 in 2011 to 68.0 in 2012 and 77.1 in 2013 (P<0.001).

TACO rates also increased significantly with age—44.5 for patients age 65 to 69, 58.8 for patients age 70 to 74, 66.4 for patients age 75 to 79, 78.7 for patients age 80 to 84, and 91.6 for patients age 85 and older (P<0.001).

Women had a significantly higher rate of TACO than men—76.9 and 58.9, respectively (P<0.001), and whites had a significantly higher rate of TACO than non-whites—73.0 and 49.8, respectively (P<0.001).

In addition, the rate of TACO increased significantly with the number of units transfused. Rates were 30.9 for 1 unit, 63.3 for 2 to 4 units, 103.0 for 5 to 9 units, and 139.8 for more than 9 units (P<0.001).

And TACO rates differed according to the type of blood components transfused. The rate of TACO was 29.2 for patients who received only platelets, 60.8 for those received only plasma, and 73.0 for those who received only RBCs.

The rates were 37.8 for patients who received platelets and plasma; 143.5 for those who received RBCs, plasma, and platelets; 167.9 for those who received RBCs and platelets; and 191.4 for those who received RBCs and plasma.

The researchers noted that this study had its limitations, including potential under-recording or misrecording of transfusion procedures and units, as well as a lack of clinical details to validate TACO diagnoses.

In addition, the rate comparisons were not adjusted for potential confounders, but the researchers are planning to perform adjusted analyses to confirm potential risk factors for TACO in the elderly.

PHILADELPHIA—Results of a population-based study suggest that elderly adults in the US have seen an increase in the rate of transfusion-associated circulatory overload (TACO) in the last few years.

The risk of TACO increased with advancing age and with increases in the number of units transfused.

TACO rates also appeared to be related to the type of blood components transfused. Patients were more likely to develop TACO if they received red blood cells (RBCs) with plasma and/or platelets.

Mikhail Menis, PharmD, of the Center for Biologics Evaluation and Research at the US Food and Drug Administration in Rockville, Maryland, and his colleagues presented these findings in a poster (SP203) at the AABB Annual Meeting 2014.

The researchers conducted this retrospective, claims-based study to assess TACO occurrence and potential risk factors for the condition among elderly Medicare beneficiaries (aged 65 and older) who were transfused as inpatients from 2011 through 2013.

Among the 6,382,814 inpatient transfusion stays, 4405 included a record of TACO. So the overall rate of TACO was 69.0 per 100,000 stays.

TACO rates (per 100,000) increased significantly over time, from 63.0 in 2011 to 68.0 in 2012 and 77.1 in 2013 (P<0.001).

TACO rates also increased significantly with age—44.5 for patients age 65 to 69, 58.8 for patients age 70 to 74, 66.4 for patients age 75 to 79, 78.7 for patients age 80 to 84, and 91.6 for patients age 85 and older (P<0.001).

Women had a significantly higher rate of TACO than men—76.9 and 58.9, respectively (P<0.001), and whites had a significantly higher rate of TACO than non-whites—73.0 and 49.8, respectively (P<0.001).

In addition, the rate of TACO increased significantly with the number of units transfused. Rates were 30.9 for 1 unit, 63.3 for 2 to 4 units, 103.0 for 5 to 9 units, and 139.8 for more than 9 units (P<0.001).

And TACO rates differed according to the type of blood components transfused. The rate of TACO was 29.2 for patients who received only platelets, 60.8 for those received only plasma, and 73.0 for those who received only RBCs.

The rates were 37.8 for patients who received platelets and plasma; 143.5 for those who received RBCs, plasma, and platelets; 167.9 for those who received RBCs and platelets; and 191.4 for those who received RBCs and plasma.

The researchers noted that this study had its limitations, including potential under-recording or misrecording of transfusion procedures and units, as well as a lack of clinical details to validate TACO diagnoses.

In addition, the rate comparisons were not adjusted for potential confounders, but the researchers are planning to perform adjusted analyses to confirm potential risk factors for TACO in the elderly.

PHILADELPHIA—Results of a population-based study suggest that elderly adults in the US have seen an increase in the rate of transfusion-associated circulatory overload (TACO) in the last few years.

The risk of TACO increased with advancing age and with increases in the number of units transfused.

TACO rates also appeared to be related to the type of blood components transfused. Patients were more likely to develop TACO if they received red blood cells (RBCs) with plasma and/or platelets.

Mikhail Menis, PharmD, of the Center for Biologics Evaluation and Research at the US Food and Drug Administration in Rockville, Maryland, and his colleagues presented these findings in a poster (SP203) at the AABB Annual Meeting 2014.

The researchers conducted this retrospective, claims-based study to assess TACO occurrence and potential risk factors for the condition among elderly Medicare beneficiaries (aged 65 and older) who were transfused as inpatients from 2011 through 2013.

Among the 6,382,814 inpatient transfusion stays, 4405 included a record of TACO. So the overall rate of TACO was 69.0 per 100,000 stays.

TACO rates (per 100,000) increased significantly over time, from 63.0 in 2011 to 68.0 in 2012 and 77.1 in 2013 (P<0.001).

TACO rates also increased significantly with age—44.5 for patients age 65 to 69, 58.8 for patients age 70 to 74, 66.4 for patients age 75 to 79, 78.7 for patients age 80 to 84, and 91.6 for patients age 85 and older (P<0.001).

Women had a significantly higher rate of TACO than men—76.9 and 58.9, respectively (P<0.001), and whites had a significantly higher rate of TACO than non-whites—73.0 and 49.8, respectively (P<0.001).

In addition, the rate of TACO increased significantly with the number of units transfused. Rates were 30.9 for 1 unit, 63.3 for 2 to 4 units, 103.0 for 5 to 9 units, and 139.8 for more than 9 units (P<0.001).

And TACO rates differed according to the type of blood components transfused. The rate of TACO was 29.2 for patients who received only platelets, 60.8 for those received only plasma, and 73.0 for those who received only RBCs.

The rates were 37.8 for patients who received platelets and plasma; 143.5 for those who received RBCs, plasma, and platelets; 167.9 for those who received RBCs and platelets; and 191.4 for those who received RBCs and plasma.

The researchers noted that this study had its limitations, including potential under-recording or misrecording of transfusion procedures and units, as well as a lack of clinical details to validate TACO diagnoses.

In addition, the rate comparisons were not adjusted for potential confounders, but the researchers are planning to perform adjusted analyses to confirm potential risk factors for TACO in the elderly.