ASH 2016

Child with cancer

Photo by Bill Branson

SAN DIEGO—In recent years, pediatric or pediatric-inspired protocols have become the preferred treatment approach for younger adults with acute lymphoblastic leukemia (ALL).

These protocols include higher doses of steroids, vincristine, methotrexate, and L-asparaginase.

However, the upper age limit for this strategy has not been defined.

With the GRAALL-2005 study, investigators set out to determine how old is too old to be treated on pediatric protocols.

Their results suggest 55 is likely the upper age limit for patients with Ph-negative ALL.

The investigators also evaluated a hyper-fractionated (hyper-C) versus standard dose (standard-C) of cyclophosphamide during induction and late intensification.

They found that hyper-C did not provide an event-free survival (EFS) benefit in the overall study population, but patients age 55 and older did appear to benefit from hyper-C.

Françoise Huguet, MD, of the Institut Universitaire du Cancer de Toulouse in Toulouse, France, presented these findings at the 2016 ASH Annual Meeting (abstract 762).

GRAALL investigators had previously evaluated a pediatric-inspired protocol for adult patients in the GRAALL-2003 study, which validated the approach.

Study design

Patients with newly diagnosed, Ph-negative ALL were eligible to enroll if they were 18 to 59 years of age.

Treatment comprised a steroid pre-phase, a 5-drug induction, two 3-block dose-dense consolidation phases, a late intensification, a third consolidation phase, CNS irradiation, and a 2-year maintenance phase.

Patients could proceed to allogeneic transplant in first complete remission (CR) if eligible.

During induction and late intensification, patients received cyclophosphamide at 750 mg/m² on day 1 and were then randomized to hyper-C (300 mg/m²/every 12 hours on days 15 to 17) or standard-C (750 mg/m² on day 15).

The primary endpoint was EFS.

Patient population

Investigators randomized 787 evaluable patients—398 in the standard-C arm and 389 in the hyper-C arm.

Their median age was 36 years, 67% of patients had B-cell precursor ALL, and 33% had T-ALL.

Most had high-risk ALL, 72% of them receiving standard-C and 66% receiving hyper-C.

About a third of the patients in each arm proceeded to allogeneic stem cell transplant in first CR.

Results

The CR rate after induction therapy was 90.2% in the standard-C arm and 93.6% in the hyper-C arm, for an overall CR rate of 92%.

Most patients—87.5% in the standard-C arm and 91.8% in the hyper-C arm—achieved a response in 1 course of therapy.

Sixty percent of patients tested in the standard-C arm and 66% of those tested in the hyper-C arm were minimal residual disease negative at less than 10^-4.

There were 26 (6.5%) deaths in the standard-C arm and 18 (4.6%) in the hyper-C arm.

The 5-year EFS rate was 52% overall, and hyper-C treatment had no impact on EFS (hazard ratio=0.89 [range, 0.7-1.1]; P=0.26).

Impact of age

Investigators conducted a post-hoc subgroup analysis of 5 age groups—18-24 years (n=200), 25-34 (n=172), 35-44 (n=171), 45-54 (n=151), and 55+ (n=93).

Overall, the CR rate tended to decrease with age. The rates were 98.5% (18-24), 95.3% (25-34), 87.7% (35-44), 89.4% (45-54), and 79.6% (55+).

Induction death rates increased from 0.5% in the youngest group to 18.3% in the oldest, but the rate of cumulative incidences of failure at 5 years was similar among all the age groups.

The cumulative incidence of treatment-related mortality, without censoring for transplant, ranged from 7.6% in the youngest group to 39.7% in the oldest.

And the 5-year EFS for the youngest patients was 60%, while, for the oldest, it was 26%.

“Above 50 years, the increase in age became highly significant,” Dr Huguet emphasized. “There were fewer CRs and lower survival.”

Treatment compliance

In terms of treatment compliance and median dose received in the induction course, patients aged 55-59 received significantly less L-asparaginase than those aged 18-54 (P<0.001).

During all 3 consolidation phases, patients aged 55-59 received significantly lower median doses of all medications—cytarabine, methotrexate, cyclophosphamide—than patients aged 18-54.

And in late intensification, patients aged 55-59 received significantly lower median doses of vincristine, prednisone, daunorubicin, and hyper-C than all other patients. The median doses of L-asparaginase and standard-C received were lower in the older patients but not significantly so.

EFS by age and randomization

The 5-year EFS for patients aged 18-54 was 57% with hyper-C, compared with 55% in the standard-C arm (P=0.66).

However, for older patients, there was a significant advantage for those receiving hyper-C. The 5-year EFS was 38% with hyper-C, compared to 12% with standard-C (P=0.007).

Dr Huguet explained that inferior compliance in patients 55 and older “might explain why a benefit associated with early hyper-C reinforcement became apparent in these older patients only.”

Dr Huguet concluded that the results “suggest that 55 years is likely to be the upper age limit to tolerate a pediatric-like therapy for younger adults with Ph-negative ALL.”

She added that patients over 54 might benefit from alternative front-line strategies.

Accordingly, investigators are planning to use new agents, such as blinatumomab or inotuzumab ozogamicin, in the next European Working Group on Adult ALL studies.

Child with cancer

Photo by Bill Branson

SAN DIEGO—In recent years, pediatric or pediatric-inspired protocols have become the preferred treatment approach for younger adults with acute lymphoblastic leukemia (ALL).

These protocols include higher doses of steroids, vincristine, methotrexate, and L-asparaginase.

However, the upper age limit for this strategy has not been defined.

With the GRAALL-2005 study, investigators set out to determine how old is too old to be treated on pediatric protocols.

Their results suggest 55 is likely the upper age limit for patients with Ph-negative ALL.

The investigators also evaluated a hyper-fractionated (hyper-C) versus standard dose (standard-C) of cyclophosphamide during induction and late intensification.

They found that hyper-C did not provide an event-free survival (EFS) benefit in the overall study population, but patients age 55 and older did appear to benefit from hyper-C.

Françoise Huguet, MD, of the Institut Universitaire du Cancer de Toulouse in Toulouse, France, presented these findings at the 2016 ASH Annual Meeting (abstract 762).

GRAALL investigators had previously evaluated a pediatric-inspired protocol for adult patients in the GRAALL-2003 study, which validated the approach.

Study design

Patients with newly diagnosed, Ph-negative ALL were eligible to enroll if they were 18 to 59 years of age.

Treatment comprised a steroid pre-phase, a 5-drug induction, two 3-block dose-dense consolidation phases, a late intensification, a third consolidation phase, CNS irradiation, and a 2-year maintenance phase.

Patients could proceed to allogeneic transplant in first complete remission (CR) if eligible.

During induction and late intensification, patients received cyclophosphamide at 750 mg/m² on day 1 and were then randomized to hyper-C (300 mg/m²/every 12 hours on days 15 to 17) or standard-C (750 mg/m² on day 15).

The primary endpoint was EFS.

Patient population

Investigators randomized 787 evaluable patients—398 in the standard-C arm and 389 in the hyper-C arm.

Their median age was 36 years, 67% of patients had B-cell precursor ALL, and 33% had T-ALL.

Most had high-risk ALL, 72% of them receiving standard-C and 66% receiving hyper-C.

About a third of the patients in each arm proceeded to allogeneic stem cell transplant in first CR.

Results

The CR rate after induction therapy was 90.2% in the standard-C arm and 93.6% in the hyper-C arm, for an overall CR rate of 92%.

Most patients—87.5% in the standard-C arm and 91.8% in the hyper-C arm—achieved a response in 1 course of therapy.

Sixty percent of patients tested in the standard-C arm and 66% of those tested in the hyper-C arm were minimal residual disease negative at less than 10^-4.

There were 26 (6.5%) deaths in the standard-C arm and 18 (4.6%) in the hyper-C arm.

The 5-year EFS rate was 52% overall, and hyper-C treatment had no impact on EFS (hazard ratio=0.89 [range, 0.7-1.1]; P=0.26).

Impact of age

Investigators conducted a post-hoc subgroup analysis of 5 age groups—18-24 years (n=200), 25-34 (n=172), 35-44 (n=171), 45-54 (n=151), and 55+ (n=93).

Overall, the CR rate tended to decrease with age. The rates were 98.5% (18-24), 95.3% (25-34), 87.7% (35-44), 89.4% (45-54), and 79.6% (55+).

Induction death rates increased from 0.5% in the youngest group to 18.3% in the oldest, but the rate of cumulative incidences of failure at 5 years was similar among all the age groups.

The cumulative incidence of treatment-related mortality, without censoring for transplant, ranged from 7.6% in the youngest group to 39.7% in the oldest.

And the 5-year EFS for the youngest patients was 60%, while, for the oldest, it was 26%.

“Above 50 years, the increase in age became highly significant,” Dr Huguet emphasized. “There were fewer CRs and lower survival.”

Treatment compliance

In terms of treatment compliance and median dose received in the induction course, patients aged 55-59 received significantly less L-asparaginase than those aged 18-54 (P<0.001).

During all 3 consolidation phases, patients aged 55-59 received significantly lower median doses of all medications—cytarabine, methotrexate, cyclophosphamide—than patients aged 18-54.

And in late intensification, patients aged 55-59 received significantly lower median doses of vincristine, prednisone, daunorubicin, and hyper-C than all other patients. The median doses of L-asparaginase and standard-C received were lower in the older patients but not significantly so.

EFS by age and randomization

The 5-year EFS for patients aged 18-54 was 57% with hyper-C, compared with 55% in the standard-C arm (P=0.66).

However, for older patients, there was a significant advantage for those receiving hyper-C. The 5-year EFS was 38% with hyper-C, compared to 12% with standard-C (P=0.007).

Dr Huguet explained that inferior compliance in patients 55 and older “might explain why a benefit associated with early hyper-C reinforcement became apparent in these older patients only.”

Dr Huguet concluded that the results “suggest that 55 years is likely to be the upper age limit to tolerate a pediatric-like therapy for younger adults with Ph-negative ALL.”

She added that patients over 54 might benefit from alternative front-line strategies.

Accordingly, investigators are planning to use new agents, such as blinatumomab or inotuzumab ozogamicin, in the next European Working Group on Adult ALL studies.

Child with cancer

Photo by Bill Branson

SAN DIEGO—In recent years, pediatric or pediatric-inspired protocols have become the preferred treatment approach for younger adults with acute lymphoblastic leukemia (ALL).

These protocols include higher doses of steroids, vincristine, methotrexate, and L-asparaginase.

However, the upper age limit for this strategy has not been defined.

With the GRAALL-2005 study, investigators set out to determine how old is too old to be treated on pediatric protocols.

Their results suggest 55 is likely the upper age limit for patients with Ph-negative ALL.

The investigators also evaluated a hyper-fractionated (hyper-C) versus standard dose (standard-C) of cyclophosphamide during induction and late intensification.

They found that hyper-C did not provide an event-free survival (EFS) benefit in the overall study population, but patients age 55 and older did appear to benefit from hyper-C.

Françoise Huguet, MD, of the Institut Universitaire du Cancer de Toulouse in Toulouse, France, presented these findings at the 2016 ASH Annual Meeting (abstract 762).

GRAALL investigators had previously evaluated a pediatric-inspired protocol for adult patients in the GRAALL-2003 study, which validated the approach.

Study design

Patients with newly diagnosed, Ph-negative ALL were eligible to enroll if they were 18 to 59 years of age.

Treatment comprised a steroid pre-phase, a 5-drug induction, two 3-block dose-dense consolidation phases, a late intensification, a third consolidation phase, CNS irradiation, and a 2-year maintenance phase.

Patients could proceed to allogeneic transplant in first complete remission (CR) if eligible.

During induction and late intensification, patients received cyclophosphamide at 750 mg/m² on day 1 and were then randomized to hyper-C (300 mg/m²/every 12 hours on days 15 to 17) or standard-C (750 mg/m² on day 15).

The primary endpoint was EFS.

Patient population

Investigators randomized 787 evaluable patients—398 in the standard-C arm and 389 in the hyper-C arm.

Their median age was 36 years, 67% of patients had B-cell precursor ALL, and 33% had T-ALL.

Most had high-risk ALL, 72% of them receiving standard-C and 66% receiving hyper-C.

About a third of the patients in each arm proceeded to allogeneic stem cell transplant in first CR.

Results

The CR rate after induction therapy was 90.2% in the standard-C arm and 93.6% in the hyper-C arm, for an overall CR rate of 92%.

Most patients—87.5% in the standard-C arm and 91.8% in the hyper-C arm—achieved a response in 1 course of therapy.

Sixty percent of patients tested in the standard-C arm and 66% of those tested in the hyper-C arm were minimal residual disease negative at less than 10^-4.

There were 26 (6.5%) deaths in the standard-C arm and 18 (4.6%) in the hyper-C arm.

The 5-year EFS rate was 52% overall, and hyper-C treatment had no impact on EFS (hazard ratio=0.89 [range, 0.7-1.1]; P=0.26).

Impact of age

Investigators conducted a post-hoc subgroup analysis of 5 age groups—18-24 years (n=200), 25-34 (n=172), 35-44 (n=171), 45-54 (n=151), and 55+ (n=93).

Overall, the CR rate tended to decrease with age. The rates were 98.5% (18-24), 95.3% (25-34), 87.7% (35-44), 89.4% (45-54), and 79.6% (55+).

Induction death rates increased from 0.5% in the youngest group to 18.3% in the oldest, but the rate of cumulative incidences of failure at 5 years was similar among all the age groups.

The cumulative incidence of treatment-related mortality, without censoring for transplant, ranged from 7.6% in the youngest group to 39.7% in the oldest.

And the 5-year EFS for the youngest patients was 60%, while, for the oldest, it was 26%.

“Above 50 years, the increase in age became highly significant,” Dr Huguet emphasized. “There were fewer CRs and lower survival.”

Treatment compliance

In terms of treatment compliance and median dose received in the induction course, patients aged 55-59 received significantly less L-asparaginase than those aged 18-54 (P<0.001).

During all 3 consolidation phases, patients aged 55-59 received significantly lower median doses of all medications—cytarabine, methotrexate, cyclophosphamide—than patients aged 18-54.

And in late intensification, patients aged 55-59 received significantly lower median doses of vincristine, prednisone, daunorubicin, and hyper-C than all other patients. The median doses of L-asparaginase and standard-C received were lower in the older patients but not significantly so.

EFS by age and randomization

The 5-year EFS for patients aged 18-54 was 57% with hyper-C, compared with 55% in the standard-C arm (P=0.66).

However, for older patients, there was a significant advantage for those receiving hyper-C. The 5-year EFS was 38% with hyper-C, compared to 12% with standard-C (P=0.007).

Dr Huguet explained that inferior compliance in patients 55 and older “might explain why a benefit associated with early hyper-C reinforcement became apparent in these older patients only.”

Dr Huguet concluded that the results “suggest that 55 years is likely to be the upper age limit to tolerate a pediatric-like therapy for younger adults with Ph-negative ALL.”

She added that patients over 54 might benefit from alternative front-line strategies.

Accordingly, investigators are planning to use new agents, such as blinatumomab or inotuzumab ozogamicin, in the next European Working Group on Adult ALL studies.

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Researchers have found evidence to suggest that mutations in the CCND1 and CCND2 genes may contribute to the development of core-binding factor acute myeloid leukemia (CBF-AML).

The team noted that CBF-AML is defined by the presence of either t(8;21)(q22;q22)/RUNX1-RUNX1T1 or inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFB-MYH11.

However, the fusion genes alone are not capable of causing CBF-AML.

“The hematology community has long sought to determine what other factors in addition to the fusion genes occur in this special type of leukemia,” said Ann-Kathrin Eisfeld, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.

“We are now the first to describe that mutations in CCND1—and among the first to describe that mutations in the sister gene CCND2—are unique features of CBF-AML with t(8;21). In addition, we have collected the first evidence that mutations in CCND2 lead to more aggressive growth of leukemia cell lines.”

Dr Eisfeld and her colleagues reported these findings in a paper published in Leukemia and in a poster presented at the 2016 ASH Annual Meeting (abstract 2740).

A previous study of genetic mutations in CBF-AML revealed the presence of at least 1 mutation in 85% of patients studied. This meant the remaining 15% of patients harbored other, undiscovered mutations.

For the current study, Dr Eisfeld and her colleagues searched CBF-AML samples for the missing mutations that, together with the fusion genes, might contribute to the leukemia in this subgroup of cases.

The team analyzed pretreatment bone marrow and peripheral blood samples from 177 adult CBF-AML patients who received similar treatment through a clinical trial conducted at multiple centers across the US.

Using a targeted, next-generation sequencing approach, the researchers looked for mutations in 84 leukemia- and/or cancer-associated genes. They also performed tests on blood or bone marrow cells to look for chromosomal irregularities.

The team discovered 2 significant mutations in the CCND1 and CCND2 genes, representing the first dual evidence of these recurrent mutations in patients with t(8;21)-positive CBF-AML.

CCND1 and CCND2 mutations were found in 15% (n=10) of patients with t(8;21)-positive CBF-AML. Two patients had mutations in CCND1, and 8 had mutations in CCND2.

The researchers also found a single CCND2 mutation in 1 (0.9%) patient with inv(16)-positive CBF-AML.

In comparison, the incidence of CCND1 and CCND2 mutations was 0.77% (n=11) in a cohort of 1426 patients with non-CBF-AML.

“This is extremely valuable information that was previously unknown,” Dr Eisfeld said, “and it might help us develop targeted therapies more likely to help patients with [CBF-AML] in the near future.”

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Researchers have found evidence to suggest that mutations in the CCND1 and CCND2 genes may contribute to the development of core-binding factor acute myeloid leukemia (CBF-AML).

The team noted that CBF-AML is defined by the presence of either t(8;21)(q22;q22)/RUNX1-RUNX1T1 or inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFB-MYH11.

However, the fusion genes alone are not capable of causing CBF-AML.

“The hematology community has long sought to determine what other factors in addition to the fusion genes occur in this special type of leukemia,” said Ann-Kathrin Eisfeld, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.

“We are now the first to describe that mutations in CCND1—and among the first to describe that mutations in the sister gene CCND2—are unique features of CBF-AML with t(8;21). In addition, we have collected the first evidence that mutations in CCND2 lead to more aggressive growth of leukemia cell lines.”

Dr Eisfeld and her colleagues reported these findings in a paper published in Leukemia and in a poster presented at the 2016 ASH Annual Meeting (abstract 2740).

A previous study of genetic mutations in CBF-AML revealed the presence of at least 1 mutation in 85% of patients studied. This meant the remaining 15% of patients harbored other, undiscovered mutations.

For the current study, Dr Eisfeld and her colleagues searched CBF-AML samples for the missing mutations that, together with the fusion genes, might contribute to the leukemia in this subgroup of cases.

The team analyzed pretreatment bone marrow and peripheral blood samples from 177 adult CBF-AML patients who received similar treatment through a clinical trial conducted at multiple centers across the US.

Using a targeted, next-generation sequencing approach, the researchers looked for mutations in 84 leukemia- and/or cancer-associated genes. They also performed tests on blood or bone marrow cells to look for chromosomal irregularities.

The team discovered 2 significant mutations in the CCND1 and CCND2 genes, representing the first dual evidence of these recurrent mutations in patients with t(8;21)-positive CBF-AML.

CCND1 and CCND2 mutations were found in 15% (n=10) of patients with t(8;21)-positive CBF-AML. Two patients had mutations in CCND1, and 8 had mutations in CCND2.

The researchers also found a single CCND2 mutation in 1 (0.9%) patient with inv(16)-positive CBF-AML.

In comparison, the incidence of CCND1 and CCND2 mutations was 0.77% (n=11) in a cohort of 1426 patients with non-CBF-AML.

“This is extremely valuable information that was previously unknown,” Dr Eisfeld said, “and it might help us develop targeted therapies more likely to help patients with [CBF-AML] in the near future.”

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Researchers have found evidence to suggest that mutations in the CCND1 and CCND2 genes may contribute to the development of core-binding factor acute myeloid leukemia (CBF-AML).

The team noted that CBF-AML is defined by the presence of either t(8;21)(q22;q22)/RUNX1-RUNX1T1 or inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFB-MYH11.

However, the fusion genes alone are not capable of causing CBF-AML.

“The hematology community has long sought to determine what other factors in addition to the fusion genes occur in this special type of leukemia,” said Ann-Kathrin Eisfeld, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.

“We are now the first to describe that mutations in CCND1—and among the first to describe that mutations in the sister gene CCND2—are unique features of CBF-AML with t(8;21). In addition, we have collected the first evidence that mutations in CCND2 lead to more aggressive growth of leukemia cell lines.”

Dr Eisfeld and her colleagues reported these findings in a paper published in Leukemia and in a poster presented at the 2016 ASH Annual Meeting (abstract 2740).

A previous study of genetic mutations in CBF-AML revealed the presence of at least 1 mutation in 85% of patients studied. This meant the remaining 15% of patients harbored other, undiscovered mutations.

For the current study, Dr Eisfeld and her colleagues searched CBF-AML samples for the missing mutations that, together with the fusion genes, might contribute to the leukemia in this subgroup of cases.

The team analyzed pretreatment bone marrow and peripheral blood samples from 177 adult CBF-AML patients who received similar treatment through a clinical trial conducted at multiple centers across the US.

Using a targeted, next-generation sequencing approach, the researchers looked for mutations in 84 leukemia- and/or cancer-associated genes. They also performed tests on blood or bone marrow cells to look for chromosomal irregularities.

The team discovered 2 significant mutations in the CCND1 and CCND2 genes, representing the first dual evidence of these recurrent mutations in patients with t(8;21)-positive CBF-AML.

CCND1 and CCND2 mutations were found in 15% (n=10) of patients with t(8;21)-positive CBF-AML. Two patients had mutations in CCND1, and 8 had mutations in CCND2.

The researchers also found a single CCND2 mutation in 1 (0.9%) patient with inv(16)-positive CBF-AML.

In comparison, the incidence of CCND1 and CCND2 mutations was 0.77% (n=11) in a cohort of 1426 patients with non-CBF-AML.

“This is extremely valuable information that was previously unknown,” Dr Eisfeld said, “and it might help us develop targeted therapies more likely to help patients with [CBF-AML] in the near future.”

SAN DIEGO – Autologous stem cell transplantation outperformed bortezomib-based intensification in fit patients younger than 66 years of age with newly diagnosed multiple myeloma, based on a prespecified interim analysis of 1,192 patients from a randomized phase III trial.

After a median follow-up of 32 months, median progression-free survival (PFS) had not been reached among patients who received high-dose melphalan plus single or double autologous stem cell transplantation, but was 42.5 months among patients who instead received standard-dose bortezomib-melphalan-prednisone (VMP), Michele Cavo, MD, reported at the annual meeting of the American Society of Hematology. Three-year rates of progression free survival were 65% with ASCT and 57% with VMP (hazard ratio, 0.73; 95% confidence interval, 0.61-0.88; P = .001), he reported.

There was a trend toward better outcomes with double ASCT instead of single ASCT, said Dr. Cavo of Bologna (Italy) University. At 3 years, PFS rates were 74% with double ASCT and 62% with single ASCT (HR, 0.7; P = .05).

The effect was stronger among patients with high-risk cytogenetics, for whom 3-year PFS rates were 65% and 41% (HR, 0.49; P = .046). Those patients had median PFS times of 47 months and 27 months, respectively, Dr. Cavo said. In a multivariable analysis, double ASCT also reduced the chances of death or progression by about 35% compared with single ASCT, even after controlling for high-risk cytogenetics, age, and other risk factors for poor prognosis (HR, 0.65; P = .03).

This is the first trial of its type to prospectively compare single and double ASCT with a novel myeloma regimen, according to Dr. Cavo. The data are not yet mature enough to support firm conclusions, but do highlight the role of ASCT in the bortezomib era and the potential for double ASCT to benefit patients with poor prognostic risk factors, particularly high-risk cytogenetics, he said.

The EMN02/HO95 trial enrolled more than 1,500 patients aged 18-65 years with symptomatic, newly diagnosed multiple myeloma. Patients underwent induction therapy with three to four cycles of bortezomib plus cyclophosphamide and dexamethasone (VCD), and then were randomly assigned to either high-dose melphalan (200 mg/m²) plus single or double ASCT, or to four cycles of bortezomib (1.3 mg/m²), melphalan (9 mg/m²), and prednisone (60 mg/m²; VMP). Patients were then re-randomized to receive lenalidomide maintenance alone or after consolidation with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD).

This prespecified analysis was triggered in early November 2016, when 33% of required events occurred. Future analyses will examine the effects of consolidation as well as safety, toxicity, and quality of life, Dr. Cavo noted.

Celgene and Janssen provided funding for the study. Dr. Cavo disclosed ties to Celgene, Janssen, Takeda, Bristol-Myers Squibb, and Amgen.

SAN DIEGO – Autologous stem cell transplantation outperformed bortezomib-based intensification in fit patients younger than 66 years of age with newly diagnosed multiple myeloma, based on a prespecified interim analysis of 1,192 patients from a randomized phase III trial.

After a median follow-up of 32 months, median progression-free survival (PFS) had not been reached among patients who received high-dose melphalan plus single or double autologous stem cell transplantation, but was 42.5 months among patients who instead received standard-dose bortezomib-melphalan-prednisone (VMP), Michele Cavo, MD, reported at the annual meeting of the American Society of Hematology. Three-year rates of progression free survival were 65% with ASCT and 57% with VMP (hazard ratio, 0.73; 95% confidence interval, 0.61-0.88; P = .001), he reported.

There was a trend toward better outcomes with double ASCT instead of single ASCT, said Dr. Cavo of Bologna (Italy) University. At 3 years, PFS rates were 74% with double ASCT and 62% with single ASCT (HR, 0.7; P = .05).

The effect was stronger among patients with high-risk cytogenetics, for whom 3-year PFS rates were 65% and 41% (HR, 0.49; P = .046). Those patients had median PFS times of 47 months and 27 months, respectively, Dr. Cavo said. In a multivariable analysis, double ASCT also reduced the chances of death or progression by about 35% compared with single ASCT, even after controlling for high-risk cytogenetics, age, and other risk factors for poor prognosis (HR, 0.65; P = .03).

This is the first trial of its type to prospectively compare single and double ASCT with a novel myeloma regimen, according to Dr. Cavo. The data are not yet mature enough to support firm conclusions, but do highlight the role of ASCT in the bortezomib era and the potential for double ASCT to benefit patients with poor prognostic risk factors, particularly high-risk cytogenetics, he said.

The EMN02/HO95 trial enrolled more than 1,500 patients aged 18-65 years with symptomatic, newly diagnosed multiple myeloma. Patients underwent induction therapy with three to four cycles of bortezomib plus cyclophosphamide and dexamethasone (VCD), and then were randomly assigned to either high-dose melphalan (200 mg/m²) plus single or double ASCT, or to four cycles of bortezomib (1.3 mg/m²), melphalan (9 mg/m²), and prednisone (60 mg/m²; VMP). Patients were then re-randomized to receive lenalidomide maintenance alone or after consolidation with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD).

This prespecified analysis was triggered in early November 2016, when 33% of required events occurred. Future analyses will examine the effects of consolidation as well as safety, toxicity, and quality of life, Dr. Cavo noted.

Celgene and Janssen provided funding for the study. Dr. Cavo disclosed ties to Celgene, Janssen, Takeda, Bristol-Myers Squibb, and Amgen.

SAN DIEGO – Autologous stem cell transplantation outperformed bortezomib-based intensification in fit patients younger than 66 years of age with newly diagnosed multiple myeloma, based on a prespecified interim analysis of 1,192 patients from a randomized phase III trial.

After a median follow-up of 32 months, median progression-free survival (PFS) had not been reached among patients who received high-dose melphalan plus single or double autologous stem cell transplantation, but was 42.5 months among patients who instead received standard-dose bortezomib-melphalan-prednisone (VMP), Michele Cavo, MD, reported at the annual meeting of the American Society of Hematology. Three-year rates of progression free survival were 65% with ASCT and 57% with VMP (hazard ratio, 0.73; 95% confidence interval, 0.61-0.88; P = .001), he reported.

There was a trend toward better outcomes with double ASCT instead of single ASCT, said Dr. Cavo of Bologna (Italy) University. At 3 years, PFS rates were 74% with double ASCT and 62% with single ASCT (HR, 0.7; P = .05).

The effect was stronger among patients with high-risk cytogenetics, for whom 3-year PFS rates were 65% and 41% (HR, 0.49; P = .046). Those patients had median PFS times of 47 months and 27 months, respectively, Dr. Cavo said. In a multivariable analysis, double ASCT also reduced the chances of death or progression by about 35% compared with single ASCT, even after controlling for high-risk cytogenetics, age, and other risk factors for poor prognosis (HR, 0.65; P = .03).

This is the first trial of its type to prospectively compare single and double ASCT with a novel myeloma regimen, according to Dr. Cavo. The data are not yet mature enough to support firm conclusions, but do highlight the role of ASCT in the bortezomib era and the potential for double ASCT to benefit patients with poor prognostic risk factors, particularly high-risk cytogenetics, he said.

The EMN02/HO95 trial enrolled more than 1,500 patients aged 18-65 years with symptomatic, newly diagnosed multiple myeloma. Patients underwent induction therapy with three to four cycles of bortezomib plus cyclophosphamide and dexamethasone (VCD), and then were randomly assigned to either high-dose melphalan (200 mg/m²) plus single or double ASCT, or to four cycles of bortezomib (1.3 mg/m²), melphalan (9 mg/m²), and prednisone (60 mg/m²; VMP). Patients were then re-randomized to receive lenalidomide maintenance alone or after consolidation with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD).

This prespecified analysis was triggered in early November 2016, when 33% of required events occurred. Future analyses will examine the effects of consolidation as well as safety, toxicity, and quality of life, Dr. Cavo noted.

Celgene and Janssen provided funding for the study. Dr. Cavo disclosed ties to Celgene, Janssen, Takeda, Bristol-Myers Squibb, and Amgen.

SAN DIEGO – Anti-CD19 chimeric antigen receptor (CAR) T cells engineered with a “safety switch” yielded high rates of complete response and an acceptable toxicity profile in chemotherapy-resistant B cell acute lymphoblastic leukemia, according to a multicenter phase I/II trial.

Importantly, high tumor burden did not increase the risk of cytokine release syndrome, said Lung-Ji Chang, PhD, of Shenzhen (China) Genoimmune Medical Institute and the University of Florida in Gainesville. “This reliable, standardized CAR T-cell preparation protocol has now served more than 30 major medical centers in China,” he said at the annual meeting of the American Society of Hematology.

Anti-CD19 CAR T cells have shown dramatic potential for treating B-cell malignancies, but toxicities have been a concern. One potentially serious adverse reaction is cytokine release syndrome, in which patients develop marked rises in blood levels of several types of cytokines. Another problem is that anti-CD19 CAR T cells can trigger loss of CD19 B cells, ultimately leading to humoral deficiencies, Dr. Chang noted. Consequently, researchers have searched for ways to continue controlling the activity of CAR T cells even after infusing them into patients.

As part of that effort, Dr. Chang and his associates developed a standardized protocol for engineering next-generation anti-CD19 CAR T cells based on the established concept of a “safety switch.” After collecting T cells from patients with chemotherapy-resistant ALL, they used a lentiviral vector to transform them into CAR T cells with fusion proteins consisting of a proapoptotic molecule called caspase-9 that is linked to modified human FK506-binding proteins, or FKBP. The addition of iCaspase9-FKBP enables clinicians to induce CAR T cell apoptosis by treating patients with a synthetic dimerizer called AP1903.

Apoptosis occurs about 45 minutes after this drug is given, according to Dr. Chang. This “safety switch” also enables clinicians to eliminate anti-CD19 CAR T cells after tumor cells are eradicated so that patients can recover their humoral immunity. He and his associates further modified these anti-CD19 CAR T cells by introducing four intracellular signaling domains that are associated with T-cell activation, survival, and longevity, he said.

A total of 22 treatment centers helped test this approach in a phase I/II trial of 110 leukemia patients, about half of whom were children with a median age of 9 years. The median age of adults was 37 years, and the oldest patient was 70. Cancer types included Philadelphia chromosome–positive ALL, Philadelphia chromosome–negative ALL, and chronic myeloid leukemia with blast crisis. About a third of patients had bone marrow samples with at least 50% blasts, and a similar proportion had already undergone hematopoietic stem cell transplantation.

Cytokine release syndrome affected 86% of patients with low or no tumor burden, but only 53% of patients with bone marrow blasts exceeding 5%, Dr. Chang reported. He emphasized that patients with high tumor burden were no more likely to develop moderate or severe cytokine release syndrome than were patients with little or no tumor burden (P = .3). Furthermore, among 17 patients with more than 80% bone marrow involvement, only three developed grade 3-4 cytokine release syndrome, while eight developed grade 1 cytokine release syndrome.

A total of 96 patients (87%) had a complete response to this CAR T cell regimen, including 51 children and 45 adults, Dr. Chang reported. Median overall survival was 222 days (range, 23-1,041 days), and 60% of patients lived at least 400 days after treatment. Patients survived a median of 115 days without relapsing (range, 0-455 days), and 55% ultimately relapsed. Age did not appear to predict relapse, he noted.

Kaplan-Meier curves revealed no major differences in rates of overall survival (OS) between adults and children at 400-day data cutoff, Dr. Chang said. However, patients with more than 50% blast cells in their bone marrow had significantly lower rates of survival (P = .02) than did patients with less advanced ALL. A lower T-cell dose predicted lower survival in children (P = .04), but not in adults. Dr. Chang and his colleagues now dose patients of all ages with 106 cells per kilogram, he said.

Survival was significantly more likely when CAR T cell recipients went on to allogeneic hematopoietic stem cell transplantation (P = .0002) than otherwise. Based on the findings, Dr. Chang particularly recommends this approach for highly chemotherapy-resistant disease with a high tumor burden. Among patients who relapsed, repeating CAR T cell therapy led to better survival than administering combination chemotherapy-tyrosine kinase inhibitor therapy (P = .01).

These safety and efficacy results suggest that CAR T cell immunotherapy can benefit patients if they have very high-burden leukemia, Dr. Chang concluded. Patients outcomes remained consistent across centers due to a “highly standardized CAR T cell preparation profile,” he said.

Dr. Chang did not report funding sources. He reported having no relevant conflicts of interest.

SAN DIEGO – Anti-CD19 chimeric antigen receptor (CAR) T cells engineered with a “safety switch” yielded high rates of complete response and an acceptable toxicity profile in chemotherapy-resistant B cell acute lymphoblastic leukemia, according to a multicenter phase I/II trial.

Importantly, high tumor burden did not increase the risk of cytokine release syndrome, said Lung-Ji Chang, PhD, of Shenzhen (China) Genoimmune Medical Institute and the University of Florida in Gainesville. “This reliable, standardized CAR T-cell preparation protocol has now served more than 30 major medical centers in China,” he said at the annual meeting of the American Society of Hematology.

Anti-CD19 CAR T cells have shown dramatic potential for treating B-cell malignancies, but toxicities have been a concern. One potentially serious adverse reaction is cytokine release syndrome, in which patients develop marked rises in blood levels of several types of cytokines. Another problem is that anti-CD19 CAR T cells can trigger loss of CD19 B cells, ultimately leading to humoral deficiencies, Dr. Chang noted. Consequently, researchers have searched for ways to continue controlling the activity of CAR T cells even after infusing them into patients.

As part of that effort, Dr. Chang and his associates developed a standardized protocol for engineering next-generation anti-CD19 CAR T cells based on the established concept of a “safety switch.” After collecting T cells from patients with chemotherapy-resistant ALL, they used a lentiviral vector to transform them into CAR T cells with fusion proteins consisting of a proapoptotic molecule called caspase-9 that is linked to modified human FK506-binding proteins, or FKBP. The addition of iCaspase9-FKBP enables clinicians to induce CAR T cell apoptosis by treating patients with a synthetic dimerizer called AP1903.

Apoptosis occurs about 45 minutes after this drug is given, according to Dr. Chang. This “safety switch” also enables clinicians to eliminate anti-CD19 CAR T cells after tumor cells are eradicated so that patients can recover their humoral immunity. He and his associates further modified these anti-CD19 CAR T cells by introducing four intracellular signaling domains that are associated with T-cell activation, survival, and longevity, he said.

A total of 22 treatment centers helped test this approach in a phase I/II trial of 110 leukemia patients, about half of whom were children with a median age of 9 years. The median age of adults was 37 years, and the oldest patient was 70. Cancer types included Philadelphia chromosome–positive ALL, Philadelphia chromosome–negative ALL, and chronic myeloid leukemia with blast crisis. About a third of patients had bone marrow samples with at least 50% blasts, and a similar proportion had already undergone hematopoietic stem cell transplantation.

Cytokine release syndrome affected 86% of patients with low or no tumor burden, but only 53% of patients with bone marrow blasts exceeding 5%, Dr. Chang reported. He emphasized that patients with high tumor burden were no more likely to develop moderate or severe cytokine release syndrome than were patients with little or no tumor burden (P = .3). Furthermore, among 17 patients with more than 80% bone marrow involvement, only three developed grade 3-4 cytokine release syndrome, while eight developed grade 1 cytokine release syndrome.

A total of 96 patients (87%) had a complete response to this CAR T cell regimen, including 51 children and 45 adults, Dr. Chang reported. Median overall survival was 222 days (range, 23-1,041 days), and 60% of patients lived at least 400 days after treatment. Patients survived a median of 115 days without relapsing (range, 0-455 days), and 55% ultimately relapsed. Age did not appear to predict relapse, he noted.

Kaplan-Meier curves revealed no major differences in rates of overall survival (OS) between adults and children at 400-day data cutoff, Dr. Chang said. However, patients with more than 50% blast cells in their bone marrow had significantly lower rates of survival (P = .02) than did patients with less advanced ALL. A lower T-cell dose predicted lower survival in children (P = .04), but not in adults. Dr. Chang and his colleagues now dose patients of all ages with 106 cells per kilogram, he said.

Survival was significantly more likely when CAR T cell recipients went on to allogeneic hematopoietic stem cell transplantation (P = .0002) than otherwise. Based on the findings, Dr. Chang particularly recommends this approach for highly chemotherapy-resistant disease with a high tumor burden. Among patients who relapsed, repeating CAR T cell therapy led to better survival than administering combination chemotherapy-tyrosine kinase inhibitor therapy (P = .01).

These safety and efficacy results suggest that CAR T cell immunotherapy can benefit patients if they have very high-burden leukemia, Dr. Chang concluded. Patients outcomes remained consistent across centers due to a “highly standardized CAR T cell preparation profile,” he said.

Dr. Chang did not report funding sources. He reported having no relevant conflicts of interest.

SAN DIEGO – Anti-CD19 chimeric antigen receptor (CAR) T cells engineered with a “safety switch” yielded high rates of complete response and an acceptable toxicity profile in chemotherapy-resistant B cell acute lymphoblastic leukemia, according to a multicenter phase I/II trial.

Importantly, high tumor burden did not increase the risk of cytokine release syndrome, said Lung-Ji Chang, PhD, of Shenzhen (China) Genoimmune Medical Institute and the University of Florida in Gainesville. “This reliable, standardized CAR T-cell preparation protocol has now served more than 30 major medical centers in China,” he said at the annual meeting of the American Society of Hematology.

Anti-CD19 CAR T cells have shown dramatic potential for treating B-cell malignancies, but toxicities have been a concern. One potentially serious adverse reaction is cytokine release syndrome, in which patients develop marked rises in blood levels of several types of cytokines. Another problem is that anti-CD19 CAR T cells can trigger loss of CD19 B cells, ultimately leading to humoral deficiencies, Dr. Chang noted. Consequently, researchers have searched for ways to continue controlling the activity of CAR T cells even after infusing them into patients.

As part of that effort, Dr. Chang and his associates developed a standardized protocol for engineering next-generation anti-CD19 CAR T cells based on the established concept of a “safety switch.” After collecting T cells from patients with chemotherapy-resistant ALL, they used a lentiviral vector to transform them into CAR T cells with fusion proteins consisting of a proapoptotic molecule called caspase-9 that is linked to modified human FK506-binding proteins, or FKBP. The addition of iCaspase9-FKBP enables clinicians to induce CAR T cell apoptosis by treating patients with a synthetic dimerizer called AP1903.

Apoptosis occurs about 45 minutes after this drug is given, according to Dr. Chang. This “safety switch” also enables clinicians to eliminate anti-CD19 CAR T cells after tumor cells are eradicated so that patients can recover their humoral immunity. He and his associates further modified these anti-CD19 CAR T cells by introducing four intracellular signaling domains that are associated with T-cell activation, survival, and longevity, he said.

A total of 22 treatment centers helped test this approach in a phase I/II trial of 110 leukemia patients, about half of whom were children with a median age of 9 years. The median age of adults was 37 years, and the oldest patient was 70. Cancer types included Philadelphia chromosome–positive ALL, Philadelphia chromosome–negative ALL, and chronic myeloid leukemia with blast crisis. About a third of patients had bone marrow samples with at least 50% blasts, and a similar proportion had already undergone hematopoietic stem cell transplantation.

Cytokine release syndrome affected 86% of patients with low or no tumor burden, but only 53% of patients with bone marrow blasts exceeding 5%, Dr. Chang reported. He emphasized that patients with high tumor burden were no more likely to develop moderate or severe cytokine release syndrome than were patients with little or no tumor burden (P = .3). Furthermore, among 17 patients with more than 80% bone marrow involvement, only three developed grade 3-4 cytokine release syndrome, while eight developed grade 1 cytokine release syndrome.

A total of 96 patients (87%) had a complete response to this CAR T cell regimen, including 51 children and 45 adults, Dr. Chang reported. Median overall survival was 222 days (range, 23-1,041 days), and 60% of patients lived at least 400 days after treatment. Patients survived a median of 115 days without relapsing (range, 0-455 days), and 55% ultimately relapsed. Age did not appear to predict relapse, he noted.

Kaplan-Meier curves revealed no major differences in rates of overall survival (OS) between adults and children at 400-day data cutoff, Dr. Chang said. However, patients with more than 50% blast cells in their bone marrow had significantly lower rates of survival (P = .02) than did patients with less advanced ALL. A lower T-cell dose predicted lower survival in children (P = .04), but not in adults. Dr. Chang and his colleagues now dose patients of all ages with 106 cells per kilogram, he said.

Survival was significantly more likely when CAR T cell recipients went on to allogeneic hematopoietic stem cell transplantation (P = .0002) than otherwise. Based on the findings, Dr. Chang particularly recommends this approach for highly chemotherapy-resistant disease with a high tumor burden. Among patients who relapsed, repeating CAR T cell therapy led to better survival than administering combination chemotherapy-tyrosine kinase inhibitor therapy (P = .01).

These safety and efficacy results suggest that CAR T cell immunotherapy can benefit patients if they have very high-burden leukemia, Dr. Chang concluded. Patients outcomes remained consistent across centers due to a “highly standardized CAR T cell preparation profile,” he said.

Dr. Chang did not report funding sources. He reported having no relevant conflicts of interest.

Kenneth Ataga, MD

Photo courtesy of ASH

SAN DIEGO—The first-in-class humanized anti-P-selectin antibody SelG1, also known as crizanlizumab, significantly reduced sickle cell pain crises (SCPC) when compared to placebo in the phase 2 SUSTAIN trial.

The higher dose of SelG1 tested reduced the annual rate of SCPC by 45% (P=0.01) and the annual rate of uncomplicated SCPC by 63% (P=0.015).

Acute painful crises are the primary cause for patients with sickle cell disease (SCD) to seek medical attention.

Kenneth I. Ataga, MD, of the University of North Carolina at Chapel Hill, explained that upregulation of P-selectin on endothelial cells and platelets contributes to the cell-cell interaction involved in the pathogenesis of SCPC. SelG1 binds to P-selectin and inhibits its interaction with P-selectin glycoprotein ligand 1.

Dr Ataga presented results from the SUSTAIN study during the plenary session of the 2016 ASH Annual Meeting (abstract 1).

The study was also published in NEJM. The research was sponsored by Selexys Pharmaceuticals Corporation, which was recently acquired by Novartis.

Patient population

A total of 198 patients were randomized, 67 to high-dose SelG1 (5.0 mg/kg), 66 to low-dose SelG1 (2.5 mg/kg), and 65 to placebo.

They received a loading dose in the first 2 weeks of treatment, followed by monthly dosing for a year.

Patients had to have a diagnosis of SCD, including genotypes HbSS, HbSC, HbSb⁰-thalassemia, or HbSB⁺-thalassemia.

They had to have at least 2 but not more than 10 acute sickle-related pain events within 12 months of study entry.

Patients ranged in age from 16 to 57 years, about 70% had HbSS, and 60% were on concomitant hydroxyurea therapy.

Patients not already receiving hydroxyurea were not permitted to start it during the study. And patients could not be on chronic transfusion therapy.

Study endpoints

The primary endpoint was the annual rate of adjudicated SCPC.

“Painful crisis was defined as an active episode of pain, and it was felt to be related to sickle cell disease-specific events and no other medically defined causes,” Dr Ataga explained.

The pain episodes also had to result in a visit to a medical facility and require treatment with parenteral or oral narcotics or parenteral nonsteroidal anti-inflammatory drugs.

The definition of SCPC included not only typical painful episodes but also acute chest syndrome (ACS), hepatic or splenic sequestration, and priapism.

Secondary endpoints included the annual rate of days hospitalized, time to first and second SCPC, the annual rate of uncomplicated pain crises, and the annual rate of ACS, among others.

Efficacy

The median annual rate of SCPC was 1.63 in the high-dose arm, 2.01 in the low-dose arm, and 2.98 in the placebo arm, amounting to a significant 45.3% reduction with the higher dose of SelG1 compared to placebo. The low dose resulted in a reduction of 32.6% compared to placebo, but this was not significant.

Twenty-four patients in the high-dose arm had an SCPC rate of 0, compared with 12 in the low-dose arm and 11 on placebo.

SCD genotype or concomitant hydroxyurea use did not impact these results.

Patients in the high-dose arm had a median annual rate of 4 hospitalization days, compared with 6.87 in both the low-dose and placebo groups. The difference was not significant, although the reduction in the high-dose arm was 41.8%.

The median annual rate of uncomplicated SCPC was 1.08 in the high-dose arm, 2.00 in the low-dose arm, and 2.91 in the placebo arm. Uncomplicated SCPC excluded ACS, splenic or hepatic sequestration, and priapism.

The reduction in the high-dose arm compared to placebo was significant, at 62.9% (P=0.015).

“The rate of ACS was pretty rare,” Dr Ataga said, “so the median rate across the various groups was 0.”

And time to the first SCPC was 4.1 months (P=0.001) in the high-dose group, 2.2 months (P=0.136) in the low-dose group, and 1.4 months in the placebo group.

“The curves separated pretty early,” Dr Ataga noted, “and were maintained throughout the course of the treatment phase, suggesting that the beneficial effect of SelG1 manifested pretty early following initiation of treatment.”

The time to second event was also significant in the high-dose arm compared to placebo, at 10.3 months and 5.1 months, respectively (P=0.022).

Safety

One or more adverse events occurred in over 85% of patients in each group.

Adverse events that occurred in at least 10% of SelG1-treated patients and amounted to at least double the number in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.

Five patients died while on study, but none of these deaths were related to the study drug.

Despite the adverse events, Dr Ataga said the drug was, overall, well-tolerated among the patients who received treatment.

Kenneth Ataga, MD

Photo courtesy of ASH

SAN DIEGO—The first-in-class humanized anti-P-selectin antibody SelG1, also known as crizanlizumab, significantly reduced sickle cell pain crises (SCPC) when compared to placebo in the phase 2 SUSTAIN trial.

The higher dose of SelG1 tested reduced the annual rate of SCPC by 45% (P=0.01) and the annual rate of uncomplicated SCPC by 63% (P=0.015).

Acute painful crises are the primary cause for patients with sickle cell disease (SCD) to seek medical attention.

Kenneth I. Ataga, MD, of the University of North Carolina at Chapel Hill, explained that upregulation of P-selectin on endothelial cells and platelets contributes to the cell-cell interaction involved in the pathogenesis of SCPC. SelG1 binds to P-selectin and inhibits its interaction with P-selectin glycoprotein ligand 1.

Dr Ataga presented results from the SUSTAIN study during the plenary session of the 2016 ASH Annual Meeting (abstract 1).

The study was also published in NEJM. The research was sponsored by Selexys Pharmaceuticals Corporation, which was recently acquired by Novartis.

Patient population

A total of 198 patients were randomized, 67 to high-dose SelG1 (5.0 mg/kg), 66 to low-dose SelG1 (2.5 mg/kg), and 65 to placebo.

They received a loading dose in the first 2 weeks of treatment, followed by monthly dosing for a year.

Patients had to have a diagnosis of SCD, including genotypes HbSS, HbSC, HbSb⁰-thalassemia, or HbSB⁺-thalassemia.

They had to have at least 2 but not more than 10 acute sickle-related pain events within 12 months of study entry.

Patients ranged in age from 16 to 57 years, about 70% had HbSS, and 60% were on concomitant hydroxyurea therapy.

Patients not already receiving hydroxyurea were not permitted to start it during the study. And patients could not be on chronic transfusion therapy.

Study endpoints

The primary endpoint was the annual rate of adjudicated SCPC.

“Painful crisis was defined as an active episode of pain, and it was felt to be related to sickle cell disease-specific events and no other medically defined causes,” Dr Ataga explained.

The pain episodes also had to result in a visit to a medical facility and require treatment with parenteral or oral narcotics or parenteral nonsteroidal anti-inflammatory drugs.

The definition of SCPC included not only typical painful episodes but also acute chest syndrome (ACS), hepatic or splenic sequestration, and priapism.

Secondary endpoints included the annual rate of days hospitalized, time to first and second SCPC, the annual rate of uncomplicated pain crises, and the annual rate of ACS, among others.

Efficacy

The median annual rate of SCPC was 1.63 in the high-dose arm, 2.01 in the low-dose arm, and 2.98 in the placebo arm, amounting to a significant 45.3% reduction with the higher dose of SelG1 compared to placebo. The low dose resulted in a reduction of 32.6% compared to placebo, but this was not significant.

Twenty-four patients in the high-dose arm had an SCPC rate of 0, compared with 12 in the low-dose arm and 11 on placebo.

SCD genotype or concomitant hydroxyurea use did not impact these results.

Patients in the high-dose arm had a median annual rate of 4 hospitalization days, compared with 6.87 in both the low-dose and placebo groups. The difference was not significant, although the reduction in the high-dose arm was 41.8%.

The median annual rate of uncomplicated SCPC was 1.08 in the high-dose arm, 2.00 in the low-dose arm, and 2.91 in the placebo arm. Uncomplicated SCPC excluded ACS, splenic or hepatic sequestration, and priapism.

The reduction in the high-dose arm compared to placebo was significant, at 62.9% (P=0.015).

“The rate of ACS was pretty rare,” Dr Ataga said, “so the median rate across the various groups was 0.”

And time to the first SCPC was 4.1 months (P=0.001) in the high-dose group, 2.2 months (P=0.136) in the low-dose group, and 1.4 months in the placebo group.

“The curves separated pretty early,” Dr Ataga noted, “and were maintained throughout the course of the treatment phase, suggesting that the beneficial effect of SelG1 manifested pretty early following initiation of treatment.”

The time to second event was also significant in the high-dose arm compared to placebo, at 10.3 months and 5.1 months, respectively (P=0.022).

Safety

One or more adverse events occurred in over 85% of patients in each group.

Adverse events that occurred in at least 10% of SelG1-treated patients and amounted to at least double the number in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.

Five patients died while on study, but none of these deaths were related to the study drug.

Despite the adverse events, Dr Ataga said the drug was, overall, well-tolerated among the patients who received treatment.

Kenneth Ataga, MD

Photo courtesy of ASH

SAN DIEGO—The first-in-class humanized anti-P-selectin antibody SelG1, also known as crizanlizumab, significantly reduced sickle cell pain crises (SCPC) when compared to placebo in the phase 2 SUSTAIN trial.

The higher dose of SelG1 tested reduced the annual rate of SCPC by 45% (P=0.01) and the annual rate of uncomplicated SCPC by 63% (P=0.015).

Acute painful crises are the primary cause for patients with sickle cell disease (SCD) to seek medical attention.

Kenneth I. Ataga, MD, of the University of North Carolina at Chapel Hill, explained that upregulation of P-selectin on endothelial cells and platelets contributes to the cell-cell interaction involved in the pathogenesis of SCPC. SelG1 binds to P-selectin and inhibits its interaction with P-selectin glycoprotein ligand 1.

Dr Ataga presented results from the SUSTAIN study during the plenary session of the 2016 ASH Annual Meeting (abstract 1).

The study was also published in NEJM. The research was sponsored by Selexys Pharmaceuticals Corporation, which was recently acquired by Novartis.

Patient population

A total of 198 patients were randomized, 67 to high-dose SelG1 (5.0 mg/kg), 66 to low-dose SelG1 (2.5 mg/kg), and 65 to placebo.

They received a loading dose in the first 2 weeks of treatment, followed by monthly dosing for a year.

Patients had to have a diagnosis of SCD, including genotypes HbSS, HbSC, HbSb⁰-thalassemia, or HbSB⁺-thalassemia.

They had to have at least 2 but not more than 10 acute sickle-related pain events within 12 months of study entry.

Patients ranged in age from 16 to 57 years, about 70% had HbSS, and 60% were on concomitant hydroxyurea therapy.

Patients not already receiving hydroxyurea were not permitted to start it during the study. And patients could not be on chronic transfusion therapy.

Study endpoints

The primary endpoint was the annual rate of adjudicated SCPC.

“Painful crisis was defined as an active episode of pain, and it was felt to be related to sickle cell disease-specific events and no other medically defined causes,” Dr Ataga explained.

The pain episodes also had to result in a visit to a medical facility and require treatment with parenteral or oral narcotics or parenteral nonsteroidal anti-inflammatory drugs.

The definition of SCPC included not only typical painful episodes but also acute chest syndrome (ACS), hepatic or splenic sequestration, and priapism.

Secondary endpoints included the annual rate of days hospitalized, time to first and second SCPC, the annual rate of uncomplicated pain crises, and the annual rate of ACS, among others.

Efficacy

The median annual rate of SCPC was 1.63 in the high-dose arm, 2.01 in the low-dose arm, and 2.98 in the placebo arm, amounting to a significant 45.3% reduction with the higher dose of SelG1 compared to placebo. The low dose resulted in a reduction of 32.6% compared to placebo, but this was not significant.

Twenty-four patients in the high-dose arm had an SCPC rate of 0, compared with 12 in the low-dose arm and 11 on placebo.

SCD genotype or concomitant hydroxyurea use did not impact these results.

Patients in the high-dose arm had a median annual rate of 4 hospitalization days, compared with 6.87 in both the low-dose and placebo groups. The difference was not significant, although the reduction in the high-dose arm was 41.8%.

The median annual rate of uncomplicated SCPC was 1.08 in the high-dose arm, 2.00 in the low-dose arm, and 2.91 in the placebo arm. Uncomplicated SCPC excluded ACS, splenic or hepatic sequestration, and priapism.

The reduction in the high-dose arm compared to placebo was significant, at 62.9% (P=0.015).

“The rate of ACS was pretty rare,” Dr Ataga said, “so the median rate across the various groups was 0.”

And time to the first SCPC was 4.1 months (P=0.001) in the high-dose group, 2.2 months (P=0.136) in the low-dose group, and 1.4 months in the placebo group.

“The curves separated pretty early,” Dr Ataga noted, “and were maintained throughout the course of the treatment phase, suggesting that the beneficial effect of SelG1 manifested pretty early following initiation of treatment.”

The time to second event was also significant in the high-dose arm compared to placebo, at 10.3 months and 5.1 months, respectively (P=0.022).

Safety

One or more adverse events occurred in over 85% of patients in each group.

Adverse events that occurred in at least 10% of SelG1-treated patients and amounted to at least double the number in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.

Five patients died while on study, but none of these deaths were related to the study drug.

Despite the adverse events, Dr Ataga said the drug was, overall, well-tolerated among the patients who received treatment.

Andy Futreal, PhD

Photo courtesy of

MD Anderson Cancer Center

SAN DIEGO―Clonal hematopoiesis could be used as a predictive marker to identify cancer patients at risk of developing therapy-related myeloid neoplasms (t-MNs), according to researchers.

The team conducted a case-control study, which showed that patients who developed t-MNs—acute myeloid leukemia and myelodysplastic syndromes—were significantly more likely than patients without t-MNs to have clonal hematopoiesis at the time of primary cancer diagnosis.

“Based on these findings, we believe pre-leukemic mutations may function as a new biomarker that would predict t-MN development,” said Andy Futreal, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Futreal and his colleagues reported these findings in The Lancet Oncology.

Co-author Koichi Takashi, MD, also of MD Anderson, presented the findings at the 2016 ASH Annual Meeting (abstract 38).

Initial cohort

The researchers analyzed data on patients treated at MD Anderson from 1997 to 2015.

The 14 cases the team identified had been treated for a primary cancer and later developed t-MNs. The 54 age-matched control subjects had been treated for lymphoma, received combination chemotherapy, and did not develop t-MNs after at least 5 years of follow-up.

For both cases and controls, the researchers performed gene sequencing on pre-treatment peripheral blood samples. For cases, the researchers also performed targeted gene sequencing on bone marrow samples taken at t-MN diagnosis.

“We found that prevalence of pre-leukemic mutations was significantly higher in patients who developed t-MNs versus those who did not,” Dr Futreal said.

Clonal hematopoiesis was present in 71% of cases (n=10) and 31% of controls (n=17).

“We found genetic mutations that are present in t-MNs leukemia samples actually could be found in blood samples obtained at the time of their original cancer diagnosis,” Dr Takashi noted.

Overall, the cumulative incidence of t-MNs at 5 years was significantly higher in patients with clonal hematopoiesis than in those without it—30% and 7%, respectively (P=0.016).

Validation cohort

The researchers also assessed clonal hematopoiesis in an external cohort of 74 patients with lymphoma who were treated in a trial of front-line chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without melatonin.

In this cohort, 7% (n=5) of patients developed t-MNs. Eighty percent of these patients (n=4) had clonal hematopoiesis.

Of the 69 patients who did not develop t-MNs, 16% (n=11) had clonal hematopoiesis.

The cumulative incidence of t-MNs at 10 years was significantly higher in patients with clonal hematopoiesis than in those without it—29% and 0%, respectively (P=0.0009).

Multivariate analysis suggested clonal hematopoiesis significantly increased the risk of t-MNs, with a hazard ratio of 13.7 (P=0.013).

“[W]e believe the data suggest potential approaches of screening for clonal hematopoiesis in cancer patients that may identify patients at risk of developing t-MNs, although further studies are needed,” Dr Takashi concluded.

Andy Futreal, PhD

Photo courtesy of

MD Anderson Cancer Center

SAN DIEGO―Clonal hematopoiesis could be used as a predictive marker to identify cancer patients at risk of developing therapy-related myeloid neoplasms (t-MNs), according to researchers.

The team conducted a case-control study, which showed that patients who developed t-MNs—acute myeloid leukemia and myelodysplastic syndromes—were significantly more likely than patients without t-MNs to have clonal hematopoiesis at the time of primary cancer diagnosis.

“Based on these findings, we believe pre-leukemic mutations may function as a new biomarker that would predict t-MN development,” said Andy Futreal, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Futreal and his colleagues reported these findings in The Lancet Oncology.

Co-author Koichi Takashi, MD, also of MD Anderson, presented the findings at the 2016 ASH Annual Meeting (abstract 38).

Initial cohort

The researchers analyzed data on patients treated at MD Anderson from 1997 to 2015.

The 14 cases the team identified had been treated for a primary cancer and later developed t-MNs. The 54 age-matched control subjects had been treated for lymphoma, received combination chemotherapy, and did not develop t-MNs after at least 5 years of follow-up.

For both cases and controls, the researchers performed gene sequencing on pre-treatment peripheral blood samples. For cases, the researchers also performed targeted gene sequencing on bone marrow samples taken at t-MN diagnosis.

“We found that prevalence of pre-leukemic mutations was significantly higher in patients who developed t-MNs versus those who did not,” Dr Futreal said.

Clonal hematopoiesis was present in 71% of cases (n=10) and 31% of controls (n=17).

“We found genetic mutations that are present in t-MNs leukemia samples actually could be found in blood samples obtained at the time of their original cancer diagnosis,” Dr Takashi noted.

Overall, the cumulative incidence of t-MNs at 5 years was significantly higher in patients with clonal hematopoiesis than in those without it—30% and 7%, respectively (P=0.016).

Validation cohort

The researchers also assessed clonal hematopoiesis in an external cohort of 74 patients with lymphoma who were treated in a trial of front-line chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without melatonin.

In this cohort, 7% (n=5) of patients developed t-MNs. Eighty percent of these patients (n=4) had clonal hematopoiesis.

Of the 69 patients who did not develop t-MNs, 16% (n=11) had clonal hematopoiesis.

The cumulative incidence of t-MNs at 10 years was significantly higher in patients with clonal hematopoiesis than in those without it—29% and 0%, respectively (P=0.0009).

Multivariate analysis suggested clonal hematopoiesis significantly increased the risk of t-MNs, with a hazard ratio of 13.7 (P=0.013).

“[W]e believe the data suggest potential approaches of screening for clonal hematopoiesis in cancer patients that may identify patients at risk of developing t-MNs, although further studies are needed,” Dr Takashi concluded.

Andy Futreal, PhD

Photo courtesy of

MD Anderson Cancer Center

SAN DIEGO―Clonal hematopoiesis could be used as a predictive marker to identify cancer patients at risk of developing therapy-related myeloid neoplasms (t-MNs), according to researchers.

The team conducted a case-control study, which showed that patients who developed t-MNs—acute myeloid leukemia and myelodysplastic syndromes—were significantly more likely than patients without t-MNs to have clonal hematopoiesis at the time of primary cancer diagnosis.

“Based on these findings, we believe pre-leukemic mutations may function as a new biomarker that would predict t-MN development,” said Andy Futreal, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Futreal and his colleagues reported these findings in The Lancet Oncology.

Co-author Koichi Takashi, MD, also of MD Anderson, presented the findings at the 2016 ASH Annual Meeting (abstract 38).

Initial cohort

The researchers analyzed data on patients treated at MD Anderson from 1997 to 2015.

The 14 cases the team identified had been treated for a primary cancer and later developed t-MNs. The 54 age-matched control subjects had been treated for lymphoma, received combination chemotherapy, and did not develop t-MNs after at least 5 years of follow-up.

For both cases and controls, the researchers performed gene sequencing on pre-treatment peripheral blood samples. For cases, the researchers also performed targeted gene sequencing on bone marrow samples taken at t-MN diagnosis.

“We found that prevalence of pre-leukemic mutations was significantly higher in patients who developed t-MNs versus those who did not,” Dr Futreal said.

Clonal hematopoiesis was present in 71% of cases (n=10) and 31% of controls (n=17).

“We found genetic mutations that are present in t-MNs leukemia samples actually could be found in blood samples obtained at the time of their original cancer diagnosis,” Dr Takashi noted.

Overall, the cumulative incidence of t-MNs at 5 years was significantly higher in patients with clonal hematopoiesis than in those without it—30% and 7%, respectively (P=0.016).

Validation cohort

The researchers also assessed clonal hematopoiesis in an external cohort of 74 patients with lymphoma who were treated in a trial of front-line chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without melatonin.

In this cohort, 7% (n=5) of patients developed t-MNs. Eighty percent of these patients (n=4) had clonal hematopoiesis.

Of the 69 patients who did not develop t-MNs, 16% (n=11) had clonal hematopoiesis.

The cumulative incidence of t-MNs at 10 years was significantly higher in patients with clonal hematopoiesis than in those without it—29% and 0%, respectively (P=0.0009).

Multivariate analysis suggested clonal hematopoiesis significantly increased the risk of t-MNs, with a hazard ratio of 13.7 (P=0.013).

“[W]e believe the data suggest potential approaches of screening for clonal hematopoiesis in cancer patients that may identify patients at risk of developing t-MNs, although further studies are needed,” Dr Takashi concluded.

Blood for transfusion

Photo from UAB Hospital

SAN DIEGO—Results of the phase 3 TRIST study support the use of a restrictive red blood cell (RBC) transfusion strategy in patients undergoing hematopoietic stem cell transplant (HSCT) to treat hematologic disorders.

The study suggests a restrictive strategy—in which patients receive 2 RBC units if their hemoglobin level is below 70 g/L—is non-inferior to a liberal strategy—in which patients receive 2 units if their hemoglobin level is below 90 g/L.

Clinical outcomes and health-related quality of life (HRQOL) were similar with both strategies.

Therefore, a restrictive strategy should be considered the standard of care in patients undergoing HSCT, according to study investigator Jason Tay, MD, of the University of Calgary/Tom Baker Cancer Center in Alberta, Canada.

Dr Tay presented results of the TRIST study at the 2016 ASH Annual Meeting (abstract 1032*).

He noted that recent AABB guidelines recommend using a restrictive RBC transfusion strategy in most circumstances. However, these recommendations do not apply to patients treated for hematologic or oncologic diseases who are at risk of bleeding, as there is a lack of randomized trials in such patients.

So Dr Tay and his colleagues decided to conduct a randomized, controlled trial comparing 2 RBC transfusion strategies in patients undergoing HSCT to treat hematologic disorders.

The study enrolled 300 patients who underwent HSCT between March 28, 2011, and February 3, 2016, at 4 Canadian centers.

The patients were randomized to 1 of 2 transfusion strategies from day 0 to day 100 post-HSCT:

• Restrictive strategy (n=149)—patients received 2 RBC units if their hemoglobin levels were below 70 g/L, to target a hemoglobin level of 70-90 g/L
• Liberal strategy (n=150)—patients received 2 RBC units if their hemoglobin levels were below 90 g/L, to target a hemoglobin level of 90-110 g/L.

The median age was 57.47 (range, 48.94-62.66) in the restrictive group and 56.04 (range, 48.27-62.24) in the liberal group. Most patients were male—65.10% and 62.67%, respectively.

Patients had acute leukemia (25.50% and 24.00%, respectively), chronic leukemia (6.71% and 6.00%), myeloproliferative disorders (2.68% and 2.00%), lymphoma (30.87% and 33.33%), myeloma (24.16% and 28.00%), and other disorders (10.07% and 6.67%, respectively).

About half of patients in each transfusion group received an autologous HSCT (49.66% and 50.00%, respectively), and about half received an allogeneic HSCT (50.34% and 50.00%, respectively).

Transfusion use

The total number of RBC units transfused was 407 in the restrictive group and 753 in the liberal group. The median number of RBC units transfused per patient was 2 (range, 0-2) and 4 (range, 2-6), respectively. The mean number was 2.73 and 5.02, respectively (P=0.0004).

The total number of RBC transfusion episodes was 234 in the restrictive group and 407 in the liberal group. The median number per patient was 1 (range, 0-2) and 2 (range, 1-3), respectively, and the mean was 1.57 and 2.70, respectively (P=0.002).

The median storage duration of the RBC units transfused was 17 days (range, 13-23) in the restrictive group and 20 days (range, 15-25) in the liberal group. The mean was 18.46 and 19.95, respectively (P=0.0003).

The between-group difference in the overall mean pre-transfusion hemoglobin per patient over the study period was 13.71 g/L.

The median number of platelet units transfused was 2 (range, 1-3) in the

restrictive group and 3 (range, 1-4) in the liberal group. The mean was 3.84 and 3.61, respectively (P=0.6930).

The median number of platelet transfusion episodes was 2 for both groups (range, 1-3 and

1-4, respectively). The mean was 3.84 in the restrictive group and 3.61 in the liberal group (P=0.77).

Adherence

In both groups, there were cases of non-adherence to the trigger hemoglobin value.

There were 49 non-adherent patients (32.89%) in the restrictive group—35 in whom an RBC transfusion occurred above the assigned trigger and 14 in whom a transfusion did not occur when the assigned trigger was reached.

There were 83 non-adherent patients (55.3%) in the liberal group—11 in whom an RBC transfusion occurred above the assigned trigger and 72 in whom a transfusion did not occur when the assigned trigger was reached.

Sixty-nine patients (46.31%) in the restrictive group and 21 (14%) in the liberal group never received an RBC transfusion.

Outcomes

The study’s primary endpoint was HRQOL, as measured by the FACT-BMT scale.

The total FACT-BMT score at day 100 was 116.3 (range, 98-129.2) in the restrictive group and 109.2 (range, 92.1-125.2) in the liberal group (P<0.0001 for non-inferiority).

Non-inferiority in HRQOL was shown for all other time points assessed as well—day 7 (P<0.001), day 14 (P<0.0001), day 28 (P<0.0001), and day 60 (P<0.0001). Total FACT-BMT scores at all time points were higher for patients in the restrictive group than the liberal one.

The study’s secondary endpoints included clinical outcomes and FACT-Anemia scores at several time points.

There was no significant difference in clinical outcomes between the restrictive and liberal transfusion groups.

There were 2 cases of transplant-related mortality in the restrictive group and 4 in the liberal group (P=0.42). And there were 4 cases of sinusoidal obstruction syndrome in both groups (P=0.98).

The median Bearman toxicity score at day 28 was 2 in both groups (range, 1-3 and 1-4, respectively). The mean was 2.5 in the restrictive group and 2.8 in the liberal group (P=0.33).

There was no significant between-group difference in WHO bleeding score at day 14 (P=0.13), day 28 (P=0.81), or day 100 (P=0.28).

There was no significant difference between the transfusion groups in the length of hospital stay for patients who received autologous HSCT (P=0.95) or allogeneic HSCT (P=0.23) or in the number of hospital readmissions for patients who received autologous HSCT (P=0.29) or allogeneic HSCT (P=0.81).

The total FACT-Anemia score was significantly higher in the restrictive transfusion group at day 7 (P=0.03) and day 60 (P=0.03) post-HSCT.

However, there was no significant between-group difference in FACT-Anemia score at 14 days (P=0.07), 28 days (P=0.51), or 100 days (P=0.14).

Dr Tay said these results suggest a restrictive RBC transfusion strategy is non-inferior to a liberal one in patients undergoing HSCT to treat a hematologic disorder.

“Moreover, a restrictive strategy is safe and results in less blood transfusions,” he said. “We’d like to suggest that a strategy of 70 g/L can be considered the standard of care in patients undergoing a stem cell transplantation.”

*Information presented at the meeting differs from the abstract.

Blood for transfusion

Photo from UAB Hospital

SAN DIEGO—Results of the phase 3 TRIST study support the use of a restrictive red blood cell (RBC) transfusion strategy in patients undergoing hematopoietic stem cell transplant (HSCT) to treat hematologic disorders.

The study suggests a restrictive strategy—in which patients receive 2 RBC units if their hemoglobin level is below 70 g/L—is non-inferior to a liberal strategy—in which patients receive 2 units if their hemoglobin level is below 90 g/L.

Clinical outcomes and health-related quality of life (HRQOL) were similar with both strategies.

Therefore, a restrictive strategy should be considered the standard of care in patients undergoing HSCT, according to study investigator Jason Tay, MD, of the University of Calgary/Tom Baker Cancer Center in Alberta, Canada.

Dr Tay presented results of the TRIST study at the 2016 ASH Annual Meeting (abstract 1032*).

He noted that recent AABB guidelines recommend using a restrictive RBC transfusion strategy in most circumstances. However, these recommendations do not apply to patients treated for hematologic or oncologic diseases who are at risk of bleeding, as there is a lack of randomized trials in such patients.

So Dr Tay and his colleagues decided to conduct a randomized, controlled trial comparing 2 RBC transfusion strategies in patients undergoing HSCT to treat hematologic disorders.

The study enrolled 300 patients who underwent HSCT between March 28, 2011, and February 3, 2016, at 4 Canadian centers.

The patients were randomized to 1 of 2 transfusion strategies from day 0 to day 100 post-HSCT:

• Restrictive strategy (n=149)—patients received 2 RBC units if their hemoglobin levels were below 70 g/L, to target a hemoglobin level of 70-90 g/L
• Liberal strategy (n=150)—patients received 2 RBC units if their hemoglobin levels were below 90 g/L, to target a hemoglobin level of 90-110 g/L.

The median age was 57.47 (range, 48.94-62.66) in the restrictive group and 56.04 (range, 48.27-62.24) in the liberal group. Most patients were male—65.10% and 62.67%, respectively.

Patients had acute leukemia (25.50% and 24.00%, respectively), chronic leukemia (6.71% and 6.00%), myeloproliferative disorders (2.68% and 2.00%), lymphoma (30.87% and 33.33%), myeloma (24.16% and 28.00%), and other disorders (10.07% and 6.67%, respectively).

About half of patients in each transfusion group received an autologous HSCT (49.66% and 50.00%, respectively), and about half received an allogeneic HSCT (50.34% and 50.00%, respectively).

Transfusion use

The total number of RBC units transfused was 407 in the restrictive group and 753 in the liberal group. The median number of RBC units transfused per patient was 2 (range, 0-2) and 4 (range, 2-6), respectively. The mean number was 2.73 and 5.02, respectively (P=0.0004).

The total number of RBC transfusion episodes was 234 in the restrictive group and 407 in the liberal group. The median number per patient was 1 (range, 0-2) and 2 (range, 1-3), respectively, and the mean was 1.57 and 2.70, respectively (P=0.002).

The median storage duration of the RBC units transfused was 17 days (range, 13-23) in the restrictive group and 20 days (range, 15-25) in the liberal group. The mean was 18.46 and 19.95, respectively (P=0.0003).

The between-group difference in the overall mean pre-transfusion hemoglobin per patient over the study period was 13.71 g/L.

The median number of platelet units transfused was 2 (range, 1-3) in the

restrictive group and 3 (range, 1-4) in the liberal group. The mean was 3.84 and 3.61, respectively (P=0.6930).

The median number of platelet transfusion episodes was 2 for both groups (range, 1-3 and

1-4, respectively). The mean was 3.84 in the restrictive group and 3.61 in the liberal group (P=0.77).

Adherence

In both groups, there were cases of non-adherence to the trigger hemoglobin value.

There were 49 non-adherent patients (32.89%) in the restrictive group—35 in whom an RBC transfusion occurred above the assigned trigger and 14 in whom a transfusion did not occur when the assigned trigger was reached.

There were 83 non-adherent patients (55.3%) in the liberal group—11 in whom an RBC transfusion occurred above the assigned trigger and 72 in whom a transfusion did not occur when the assigned trigger was reached.

Sixty-nine patients (46.31%) in the restrictive group and 21 (14%) in the liberal group never received an RBC transfusion.

Outcomes

The study’s primary endpoint was HRQOL, as measured by the FACT-BMT scale.

The total FACT-BMT score at day 100 was 116.3 (range, 98-129.2) in the restrictive group and 109.2 (range, 92.1-125.2) in the liberal group (P<0.0001 for non-inferiority).

Non-inferiority in HRQOL was shown for all other time points assessed as well—day 7 (P<0.001), day 14 (P<0.0001), day 28 (P<0.0001), and day 60 (P<0.0001). Total FACT-BMT scores at all time points were higher for patients in the restrictive group than the liberal one.

The study’s secondary endpoints included clinical outcomes and FACT-Anemia scores at several time points.

There was no significant difference in clinical outcomes between the restrictive and liberal transfusion groups.

There were 2 cases of transplant-related mortality in the restrictive group and 4 in the liberal group (P=0.42). And there were 4 cases of sinusoidal obstruction syndrome in both groups (P=0.98).

The median Bearman toxicity score at day 28 was 2 in both groups (range, 1-3 and 1-4, respectively). The mean was 2.5 in the restrictive group and 2.8 in the liberal group (P=0.33).

There was no significant between-group difference in WHO bleeding score at day 14 (P=0.13), day 28 (P=0.81), or day 100 (P=0.28).

There was no significant difference between the transfusion groups in the length of hospital stay for patients who received autologous HSCT (P=0.95) or allogeneic HSCT (P=0.23) or in the number of hospital readmissions for patients who received autologous HSCT (P=0.29) or allogeneic HSCT (P=0.81).

The total FACT-Anemia score was significantly higher in the restrictive transfusion group at day 7 (P=0.03) and day 60 (P=0.03) post-HSCT.

However, there was no significant between-group difference in FACT-Anemia score at 14 days (P=0.07), 28 days (P=0.51), or 100 days (P=0.14).

Dr Tay said these results suggest a restrictive RBC transfusion strategy is non-inferior to a liberal one in patients undergoing HSCT to treat a hematologic disorder.

“Moreover, a restrictive strategy is safe and results in less blood transfusions,” he said. “We’d like to suggest that a strategy of 70 g/L can be considered the standard of care in patients undergoing a stem cell transplantation.”

*Information presented at the meeting differs from the abstract.

Blood for transfusion

Photo from UAB Hospital

SAN DIEGO—Results of the phase 3 TRIST study support the use of a restrictive red blood cell (RBC) transfusion strategy in patients undergoing hematopoietic stem cell transplant (HSCT) to treat hematologic disorders.

The study suggests a restrictive strategy—in which patients receive 2 RBC units if their hemoglobin level is below 70 g/L—is non-inferior to a liberal strategy—in which patients receive 2 units if their hemoglobin level is below 90 g/L.

Clinical outcomes and health-related quality of life (HRQOL) were similar with both strategies.

Therefore, a restrictive strategy should be considered the standard of care in patients undergoing HSCT, according to study investigator Jason Tay, MD, of the University of Calgary/Tom Baker Cancer Center in Alberta, Canada.

Dr Tay presented results of the TRIST study at the 2016 ASH Annual Meeting (abstract 1032*).

He noted that recent AABB guidelines recommend using a restrictive RBC transfusion strategy in most circumstances. However, these recommendations do not apply to patients treated for hematologic or oncologic diseases who are at risk of bleeding, as there is a lack of randomized trials in such patients.

So Dr Tay and his colleagues decided to conduct a randomized, controlled trial comparing 2 RBC transfusion strategies in patients undergoing HSCT to treat hematologic disorders.

The study enrolled 300 patients who underwent HSCT between March 28, 2011, and February 3, 2016, at 4 Canadian centers.

The patients were randomized to 1 of 2 transfusion strategies from day 0 to day 100 post-HSCT:

• Restrictive strategy (n=149)—patients received 2 RBC units if their hemoglobin levels were below 70 g/L, to target a hemoglobin level of 70-90 g/L
• Liberal strategy (n=150)—patients received 2 RBC units if their hemoglobin levels were below 90 g/L, to target a hemoglobin level of 90-110 g/L.

The median age was 57.47 (range, 48.94-62.66) in the restrictive group and 56.04 (range, 48.27-62.24) in the liberal group. Most patients were male—65.10% and 62.67%, respectively.

Patients had acute leukemia (25.50% and 24.00%, respectively), chronic leukemia (6.71% and 6.00%), myeloproliferative disorders (2.68% and 2.00%), lymphoma (30.87% and 33.33%), myeloma (24.16% and 28.00%), and other disorders (10.07% and 6.67%, respectively).

About half of patients in each transfusion group received an autologous HSCT (49.66% and 50.00%, respectively), and about half received an allogeneic HSCT (50.34% and 50.00%, respectively).

Transfusion use

The total number of RBC units transfused was 407 in the restrictive group and 753 in the liberal group. The median number of RBC units transfused per patient was 2 (range, 0-2) and 4 (range, 2-6), respectively. The mean number was 2.73 and 5.02, respectively (P=0.0004).

The total number of RBC transfusion episodes was 234 in the restrictive group and 407 in the liberal group. The median number per patient was 1 (range, 0-2) and 2 (range, 1-3), respectively, and the mean was 1.57 and 2.70, respectively (P=0.002).

The median storage duration of the RBC units transfused was 17 days (range, 13-23) in the restrictive group and 20 days (range, 15-25) in the liberal group. The mean was 18.46 and 19.95, respectively (P=0.0003).

The between-group difference in the overall mean pre-transfusion hemoglobin per patient over the study period was 13.71 g/L.

The median number of platelet units transfused was 2 (range, 1-3) in the

restrictive group and 3 (range, 1-4) in the liberal group. The mean was 3.84 and 3.61, respectively (P=0.6930).

The median number of platelet transfusion episodes was 2 for both groups (range, 1-3 and

1-4, respectively). The mean was 3.84 in the restrictive group and 3.61 in the liberal group (P=0.77).

Adherence

In both groups, there were cases of non-adherence to the trigger hemoglobin value.

There were 49 non-adherent patients (32.89%) in the restrictive group—35 in whom an RBC transfusion occurred above the assigned trigger and 14 in whom a transfusion did not occur when the assigned trigger was reached.

There were 83 non-adherent patients (55.3%) in the liberal group—11 in whom an RBC transfusion occurred above the assigned trigger and 72 in whom a transfusion did not occur when the assigned trigger was reached.

Sixty-nine patients (46.31%) in the restrictive group and 21 (14%) in the liberal group never received an RBC transfusion.

Outcomes

The study’s primary endpoint was HRQOL, as measured by the FACT-BMT scale.

The total FACT-BMT score at day 100 was 116.3 (range, 98-129.2) in the restrictive group and 109.2 (range, 92.1-125.2) in the liberal group (P<0.0001 for non-inferiority).

Non-inferiority in HRQOL was shown for all other time points assessed as well—day 7 (P<0.001), day 14 (P<0.0001), day 28 (P<0.0001), and day 60 (P<0.0001). Total FACT-BMT scores at all time points were higher for patients in the restrictive group than the liberal one.

The study’s secondary endpoints included clinical outcomes and FACT-Anemia scores at several time points.

There was no significant difference in clinical outcomes between the restrictive and liberal transfusion groups.

There were 2 cases of transplant-related mortality in the restrictive group and 4 in the liberal group (P=0.42). And there were 4 cases of sinusoidal obstruction syndrome in both groups (P=0.98).

The median Bearman toxicity score at day 28 was 2 in both groups (range, 1-3 and 1-4, respectively). The mean was 2.5 in the restrictive group and 2.8 in the liberal group (P=0.33).

There was no significant between-group difference in WHO bleeding score at day 14 (P=0.13), day 28 (P=0.81), or day 100 (P=0.28).

There was no significant difference between the transfusion groups in the length of hospital stay for patients who received autologous HSCT (P=0.95) or allogeneic HSCT (P=0.23) or in the number of hospital readmissions for patients who received autologous HSCT (P=0.29) or allogeneic HSCT (P=0.81).

The total FACT-Anemia score was significantly higher in the restrictive transfusion group at day 7 (P=0.03) and day 60 (P=0.03) post-HSCT.

However, there was no significant between-group difference in FACT-Anemia score at 14 days (P=0.07), 28 days (P=0.51), or 100 days (P=0.14).

Dr Tay said these results suggest a restrictive RBC transfusion strategy is non-inferior to a liberal one in patients undergoing HSCT to treat a hematologic disorder.

“Moreover, a restrictive strategy is safe and results in less blood transfusions,” he said. “We’d like to suggest that a strategy of 70 g/L can be considered the standard of care in patients undergoing a stem cell transplantation.”

*Information presented at the meeting differs from the abstract.

 

Hydroxyurea

Photo by Zak Hubbard

 

SAN DIEGO—Results of the PROUD-PV trial suggest ropeginterferon alfa-2b is safer than hydroxyurea (HU) for patients with polycythemia vera (PV).

In this phase 3 trial, ropeginterferon alfa-2b demonstrated non-inferiority to HU with regard to complete hematologic response (CHR).

Ropeginterferon alfa-2b also had a significantly better overall safety profile.

Unlike the patients who received HU, none of the patients on ropeginterferon alfa-2b developed secondary malignancies.

Heinz Gisslinger, MD, of the Medical University of Vienna in Austria, presented these results at the 2016 ASH Annual Meeting (abstract 475). The PROUD-PV study was sponsored by AOP Orphan Pharmaceuticals AG.

Dr Gisslinger noted that interferons have been successful in treating PV since the 1980s, although toxicities contribute to discontinuation rates of approximately 25%. Still, interferons are the only known drugs with the potential for disease modification by specific targeting of the malignant clone.

Ropeginterferon alfa-2b is a long-acting, mono-pegylated proline interferon with improved pharmacokinetic properties that allow for administration once every 2 weeks.

The goal of PROUD-PV was to determine how this drug stacks up against HU in both treatment-naive and HU-pretreated patients with PV.

“Our results from the first and largest, prospective, controlled trial of an interferon in polycythemia vera confirm previously reported efficacy,” Dr Gisslinger said.

“The observed safety and tolerability profile of ropeginterferon appears to be superior compared to previously reported data of interferon treatment. The unique disease-modification capability of interferon and its potential to improve progression-free survival hold promise for long-term benefit for patients.”

Patients and treatment

PROUD-PV enrolled 254 patients, and they were randomized to receive ropeginterferon alfa-2b (n=127) or HU (n=127). In both arms, 100% of patients were Caucasian, slightly more than half were female, and the median age was 60 (overall range, 21-85).

The median disease duration was 1.9 months in the ropeginterferon alfa-2b arm and 3.6 months in the HU arm. Thirty-seven percent (n=47) of patients in each arm had previously received HU.

The mean hematocrit was about 50% in both arms, the median spleen length was about 13 cm, about 90% of patients had a normal/slightly enlarged spleen, and the mean JAK2V617F burden was slightly more than 40%.

The median plateau dose was 450 µg in the ropeginterferon alfa-2b arm and 1250 mg in the HU arm.

A quarter (25.2%) of patients had dose reductions due to adverse events (AEs) in the ropeginterferon alfa-2b arm, as did 51.2% of patients in the HU arm. The 12-month discontinuation rate was 16.5% in the ropeginterferon alfa-2b arm and 12.6% in the HU arm.

Response

The study’s primary objective was to demonstrate non-inferiority of ropeginterferon alfa-2b compared to HU. For this, the researchers used the 12-month CHR rate. CHR was defined as normalization of red blood cell, white blood cell, and platelet counts (without phlebotomy).

At 12 months, in the intent-to-treat population, the CHR rate was 43.1% in the ropeginterferon alfa-2b arm and 45.6% in the HU arm (P=0.0028). In the per-protocol population, the CHR rate was 44.3% and 46.5%, respectively (P=0.0036).

The researchers therefore concluded that non-inferiority was demonstrated.

The study’s pre-specified primary endpoint was actually a composite of CHR and spleen length normality. However, this was confounded by the fact that the patients’ median spleen length was almost normal at baseline and the observed change was not clinically relevant.

In the intent-to-treat-population, CHR with spleen normality occurred in 21.3% of patients in the ropeginterferon alfa-2b arm and 27.6% of patients in the HU arm (P=0.2233).

Safety

The incidence of AEs was 81.9% in the ropeginterferon alfa-2b arm and 87.4% in the HU arm. The incidence of grade 3 AEs was 16.5% and 20.5%, respectively. And the incidence of treatment-related AEs was 59.6% and 75.6%, respectively (P<0.05).

There was a significantly higher incidence (P<0.01) of the following AEs in the HU arm than the ropeginterferon alfa-2b arm: anemia (24.4% vs 6.3%), leukopenia (21.3% vs 8.7%), thrombocytopenia (28.3% vs 15.0%), and nausea (11.8% vs 2.4%).

There was no significant difference in the incidence of fatigue—13.4% in the HU arm and 12.6% in the ropeginterferon alfa-2b arm.

Patients in the ropeginterferon alfa-2b arm had a significantly higher incidence of gamma-glutamyl transferase increase—14.2% vs 0.8% in the HU arm (P<0.01).

Patients in the ropeginterferon alfa-2b arm also had a higher—but non-significant—incidence of endocrine disorders (3.1% vs 0.8%), psychiatric disorders (1.6% vs 0%), cardiac/vascular disorders (3.1% vs 1.6%), and tissue disorders (1.6% vs 0%).

None of the patients in the ropeginterferon alfa-2b arm developed secondary related malignancies. In the HU arm, however, there were 2 cases of acute leukemia, 2 cases of basal cell carcinoma, and 1 case of malignant melanoma. (This includes data from the ongoing follow-up trial CONTINUATION-PV.)

Drug development

AOP Orphan Pharmaceuticals AG said that, in the coming months, it will submit data from PROUD-PV and the ongoing follow-up trial, CONTINUATION-PV, to obtain European marketing authorization for ropeginterferon alfa-2b.

PharmaEssentia plans to submit the same data to the US Food and Drug Administration.

PharmaEssentia discovered ropeginterferon alfa-2b and has licensed the rights for development and commercialization of the drug in myeloproliferative neoplasms to AOP Orphan Pharmaceuticals AG in Europe, the Commonwealth of Independent States, and Middle Eastern markets.

*Information presented at the meeting differs from the abstract.

 

Hydroxyurea

Photo by Zak Hubbard

 

SAN DIEGO—Results of the PROUD-PV trial suggest ropeginterferon alfa-2b is safer than hydroxyurea (HU) for patients with polycythemia vera (PV).

In this phase 3 trial, ropeginterferon alfa-2b demonstrated non-inferiority to HU with regard to complete hematologic response (CHR).

Ropeginterferon alfa-2b also had a significantly better overall safety profile.

Unlike the patients who received HU, none of the patients on ropeginterferon alfa-2b developed secondary malignancies.

Heinz Gisslinger, MD, of the Medical University of Vienna in Austria, presented these results at the 2016 ASH Annual Meeting (abstract 475). The PROUD-PV study was sponsored by AOP Orphan Pharmaceuticals AG.

Dr Gisslinger noted that interferons have been successful in treating PV since the 1980s, although toxicities contribute to discontinuation rates of approximately 25%. Still, interferons are the only known drugs with the potential for disease modification by specific targeting of the malignant clone.

Ropeginterferon alfa-2b is a long-acting, mono-pegylated proline interferon with improved pharmacokinetic properties that allow for administration once every 2 weeks.

The goal of PROUD-PV was to determine how this drug stacks up against HU in both treatment-naive and HU-pretreated patients with PV.

“Our results from the first and largest, prospective, controlled trial of an interferon in polycythemia vera confirm previously reported efficacy,” Dr Gisslinger said.

“The observed safety and tolerability profile of ropeginterferon appears to be superior compared to previously reported data of interferon treatment. The unique disease-modification capability of interferon and its potential to improve progression-free survival hold promise for long-term benefit for patients.”

Patients and treatment

PROUD-PV enrolled 254 patients, and they were randomized to receive ropeginterferon alfa-2b (n=127) or HU (n=127). In both arms, 100% of patients were Caucasian, slightly more than half were female, and the median age was 60 (overall range, 21-85).

The median disease duration was 1.9 months in the ropeginterferon alfa-2b arm and 3.6 months in the HU arm. Thirty-seven percent (n=47) of patients in each arm had previously received HU.

The mean hematocrit was about 50% in both arms, the median spleen length was about 13 cm, about 90% of patients had a normal/slightly enlarged spleen, and the mean JAK2V617F burden was slightly more than 40%.

The median plateau dose was 450 µg in the ropeginterferon alfa-2b arm and 1250 mg in the HU arm.

A quarter (25.2%) of patients had dose reductions due to adverse events (AEs) in the ropeginterferon alfa-2b arm, as did 51.2% of patients in the HU arm. The 12-month discontinuation rate was 16.5% in the ropeginterferon alfa-2b arm and 12.6% in the HU arm.

Response

The study’s primary objective was to demonstrate non-inferiority of ropeginterferon alfa-2b compared to HU. For this, the researchers used the 12-month CHR rate. CHR was defined as normalization of red blood cell, white blood cell, and platelet counts (without phlebotomy).

At 12 months, in the intent-to-treat population, the CHR rate was 43.1% in the ropeginterferon alfa-2b arm and 45.6% in the HU arm (P=0.0028). In the per-protocol population, the CHR rate was 44.3% and 46.5%, respectively (P=0.0036).

The researchers therefore concluded that non-inferiority was demonstrated.

The study’s pre-specified primary endpoint was actually a composite of CHR and spleen length normality. However, this was confounded by the fact that the patients’ median spleen length was almost normal at baseline and the observed change was not clinically relevant.

In the intent-to-treat-population, CHR with spleen normality occurred in 21.3% of patients in the ropeginterferon alfa-2b arm and 27.6% of patients in the HU arm (P=0.2233).

Safety

The incidence of AEs was 81.9% in the ropeginterferon alfa-2b arm and 87.4% in the HU arm. The incidence of grade 3 AEs was 16.5% and 20.5%, respectively. And the incidence of treatment-related AEs was 59.6% and 75.6%, respectively (P<0.05).

There was a significantly higher incidence (P<0.01) of the following AEs in the HU arm than the ropeginterferon alfa-2b arm: anemia (24.4% vs 6.3%), leukopenia (21.3% vs 8.7%), thrombocytopenia (28.3% vs 15.0%), and nausea (11.8% vs 2.4%).

There was no significant difference in the incidence of fatigue—13.4% in the HU arm and 12.6% in the ropeginterferon alfa-2b arm.

Patients in the ropeginterferon alfa-2b arm had a significantly higher incidence of gamma-glutamyl transferase increase—14.2% vs 0.8% in the HU arm (P<0.01).

Patients in the ropeginterferon alfa-2b arm also had a higher—but non-significant—incidence of endocrine disorders (3.1% vs 0.8%), psychiatric disorders (1.6% vs 0%), cardiac/vascular disorders (3.1% vs 1.6%), and tissue disorders (1.6% vs 0%).

None of the patients in the ropeginterferon alfa-2b arm developed secondary related malignancies. In the HU arm, however, there were 2 cases of acute leukemia, 2 cases of basal cell carcinoma, and 1 case of malignant melanoma. (This includes data from the ongoing follow-up trial CONTINUATION-PV.)

Drug development

AOP Orphan Pharmaceuticals AG said that, in the coming months, it will submit data from PROUD-PV and the ongoing follow-up trial, CONTINUATION-PV, to obtain European marketing authorization for ropeginterferon alfa-2b.

PharmaEssentia plans to submit the same data to the US Food and Drug Administration.

PharmaEssentia discovered ropeginterferon alfa-2b and has licensed the rights for development and commercialization of the drug in myeloproliferative neoplasms to AOP Orphan Pharmaceuticals AG in Europe, the Commonwealth of Independent States, and Middle Eastern markets.

*Information presented at the meeting differs from the abstract.

 

Hydroxyurea

Photo by Zak Hubbard

 

SAN DIEGO—Results of the PROUD-PV trial suggest ropeginterferon alfa-2b is safer than hydroxyurea (HU) for patients with polycythemia vera (PV).

In this phase 3 trial, ropeginterferon alfa-2b demonstrated non-inferiority to HU with regard to complete hematologic response (CHR).

Ropeginterferon alfa-2b also had a significantly better overall safety profile.

Unlike the patients who received HU, none of the patients on ropeginterferon alfa-2b developed secondary malignancies.

Heinz Gisslinger, MD, of the Medical University of Vienna in Austria, presented these results at the 2016 ASH Annual Meeting (abstract 475). The PROUD-PV study was sponsored by AOP Orphan Pharmaceuticals AG.

Dr Gisslinger noted that interferons have been successful in treating PV since the 1980s, although toxicities contribute to discontinuation rates of approximately 25%. Still, interferons are the only known drugs with the potential for disease modification by specific targeting of the malignant clone.

Ropeginterferon alfa-2b is a long-acting, mono-pegylated proline interferon with improved pharmacokinetic properties that allow for administration once every 2 weeks.

The goal of PROUD-PV was to determine how this drug stacks up against HU in both treatment-naive and HU-pretreated patients with PV.

“Our results from the first and largest, prospective, controlled trial of an interferon in polycythemia vera confirm previously reported efficacy,” Dr Gisslinger said.

“The observed safety and tolerability profile of ropeginterferon appears to be superior compared to previously reported data of interferon treatment. The unique disease-modification capability of interferon and its potential to improve progression-free survival hold promise for long-term benefit for patients.”

Patients and treatment

PROUD-PV enrolled 254 patients, and they were randomized to receive ropeginterferon alfa-2b (n=127) or HU (n=127). In both arms, 100% of patients were Caucasian, slightly more than half were female, and the median age was 60 (overall range, 21-85).

The median disease duration was 1.9 months in the ropeginterferon alfa-2b arm and 3.6 months in the HU arm. Thirty-seven percent (n=47) of patients in each arm had previously received HU.

The mean hematocrit was about 50% in both arms, the median spleen length was about 13 cm, about 90% of patients had a normal/slightly enlarged spleen, and the mean JAK2V617F burden was slightly more than 40%.

The median plateau dose was 450 µg in the ropeginterferon alfa-2b arm and 1250 mg in the HU arm.

A quarter (25.2%) of patients had dose reductions due to adverse events (AEs) in the ropeginterferon alfa-2b arm, as did 51.2% of patients in the HU arm. The 12-month discontinuation rate was 16.5% in the ropeginterferon alfa-2b arm and 12.6% in the HU arm.

Response

The study’s primary objective was to demonstrate non-inferiority of ropeginterferon alfa-2b compared to HU. For this, the researchers used the 12-month CHR rate. CHR was defined as normalization of red blood cell, white blood cell, and platelet counts (without phlebotomy).

At 12 months, in the intent-to-treat population, the CHR rate was 43.1% in the ropeginterferon alfa-2b arm and 45.6% in the HU arm (P=0.0028). In the per-protocol population, the CHR rate was 44.3% and 46.5%, respectively (P=0.0036).

The researchers therefore concluded that non-inferiority was demonstrated.

The study’s pre-specified primary endpoint was actually a composite of CHR and spleen length normality. However, this was confounded by the fact that the patients’ median spleen length was almost normal at baseline and the observed change was not clinically relevant.

In the intent-to-treat-population, CHR with spleen normality occurred in 21.3% of patients in the ropeginterferon alfa-2b arm and 27.6% of patients in the HU arm (P=0.2233).

Safety

The incidence of AEs was 81.9% in the ropeginterferon alfa-2b arm and 87.4% in the HU arm. The incidence of grade 3 AEs was 16.5% and 20.5%, respectively. And the incidence of treatment-related AEs was 59.6% and 75.6%, respectively (P<0.05).

There was a significantly higher incidence (P<0.01) of the following AEs in the HU arm than the ropeginterferon alfa-2b arm: anemia (24.4% vs 6.3%), leukopenia (21.3% vs 8.7%), thrombocytopenia (28.3% vs 15.0%), and nausea (11.8% vs 2.4%).

There was no significant difference in the incidence of fatigue—13.4% in the HU arm and 12.6% in the ropeginterferon alfa-2b arm.

Patients in the ropeginterferon alfa-2b arm had a significantly higher incidence of gamma-glutamyl transferase increase—14.2% vs 0.8% in the HU arm (P<0.01).

Patients in the ropeginterferon alfa-2b arm also had a higher—but non-significant—incidence of endocrine disorders (3.1% vs 0.8%), psychiatric disorders (1.6% vs 0%), cardiac/vascular disorders (3.1% vs 1.6%), and tissue disorders (1.6% vs 0%).

None of the patients in the ropeginterferon alfa-2b arm developed secondary related malignancies. In the HU arm, however, there were 2 cases of acute leukemia, 2 cases of basal cell carcinoma, and 1 case of malignant melanoma. (This includes data from the ongoing follow-up trial CONTINUATION-PV.)

Drug development

AOP Orphan Pharmaceuticals AG said that, in the coming months, it will submit data from PROUD-PV and the ongoing follow-up trial, CONTINUATION-PV, to obtain European marketing authorization for ropeginterferon alfa-2b.

PharmaEssentia plans to submit the same data to the US Food and Drug Administration.

PharmaEssentia discovered ropeginterferon alfa-2b and has licensed the rights for development and commercialization of the drug in myeloproliferative neoplasms to AOP Orphan Pharmaceuticals AG in Europe, the Commonwealth of Independent States, and Middle Eastern markets.

*Information presented at the meeting differs from the abstract.

SAN DIEGO – Maintenance therapy with lenalidomide significantly improved progression-free survival in patients of all ages with myeloma, regardless of their risk or response status at the end of induction, Gareth Morgan, MD, PhD, said during an oral session at the annual meeting of the American Society of Hematology.

“The very important point is that maintenance therapy with lenalidomide worked across a range of different risk groups,” said Dr. Morgan, director of the Myeloma Institute at the University of Arkansas for Medical Sciences in Little Rock. “It worked independent of gender, age, [International Staging System] disease stage, and response at baseline,” he added. ‘It also worked irrespective of genetic risk status, which is contrary to what you hear very frequently. All of the curves are consistent with better outcomes if you continue lenalidomide long-term.”

Amy Karon/Frontline Medical News

SAN DIEGO – Maintenance therapy with lenalidomide significantly improved progression-free survival in patients of all ages with myeloma, regardless of their risk or response status at the end of induction, Gareth Morgan, MD, PhD, said during an oral session at the annual meeting of the American Society of Hematology.

“The very important point is that maintenance therapy with lenalidomide worked across a range of different risk groups,” said Dr. Morgan, director of the Myeloma Institute at the University of Arkansas for Medical Sciences in Little Rock. “It worked independent of gender, age, [International Staging System] disease stage, and response at baseline,” he added. ‘It also worked irrespective of genetic risk status, which is contrary to what you hear very frequently. All of the curves are consistent with better outcomes if you continue lenalidomide long-term.”

Amy Karon/Frontline Medical News

SAN DIEGO – Maintenance therapy with lenalidomide significantly improved progression-free survival in patients of all ages with myeloma, regardless of their risk or response status at the end of induction, Gareth Morgan, MD, PhD, said during an oral session at the annual meeting of the American Society of Hematology.

“The very important point is that maintenance therapy with lenalidomide worked across a range of different risk groups,” said Dr. Morgan, director of the Myeloma Institute at the University of Arkansas for Medical Sciences in Little Rock. “It worked independent of gender, age, [International Staging System] disease stage, and response at baseline,” he added. ‘It also worked irrespective of genetic risk status, which is contrary to what you hear very frequently. All of the curves are consistent with better outcomes if you continue lenalidomide long-term.”

Amy Karon/Frontline Medical News

Attendees at the

2016 ASH Annual Meeting

SAN DIEGO—Ibrutinib, a Bruton’s tyrosine kinase inhibitor approved to treat chronic lymphocytic leukemia and other hematologic diseases, appears to provide relief for patients suffering from chronic graft-versus-host disease (cGVHD) after failing corticosteroid therapy.

At present, no approved therapy exists for these patients. Ibrutinib reduced the severity of cGVHD in preclinical models and has been used successfully in the post-allogeneic transplant setting.

The US Food and Drug Administration granted ibrutinib breakthrough therapy and orphan drug designations as a potential treatment for cGVHD.

David Miklos, MD, of Stanford University in California, explained at the 2016 ASH Annual Meeting that, in cGVHD, healthy B cells have been corrupted to produce self-reactive antibody complexes, and the T cells are killing healthy tissues and cells.

This destructive process involves the Bruton’s tyrosine kinase molecule, which can be inhibited and thereby block some of the downstream cGVHD pathogenesis.

“And to this aim, we went about testing the benefits of ibrutinib in the treatment of steroid-refractory chronic graft-versus-host disease,” Dr Miklos said.

In phase 1 of the study, investigators tested the 420 mg oral once-daily dose. They found no dose-limiting toxicities.

“So this dose was carried forward into the phase 2 study,” Dr Miklos said.

He presented results of the phase 2 study at the meeting as a late-breaking abstract (LBA-3).

Study design

Patients were eligible for the study if they had steroid-dependent or -refractory cGVHD. They had to have 3 or fewer prior treatments, and they could continue other systemic immunosuppression if they were using it.

They had to have erythematous rash on more than 25% of their body surface or a total mouth score of more than 4 as defined by National Institutes of Health (NIH) criteria.

Patients with cGVHD had to have failed frontline therapy.

They were treated with the phase 1 dose until progression of cGVHD or unacceptable toxicity.

The primary endpoint was cGVHD response per NIH 2005 response criteria.

Secondary endpoints included rate of sustained response, change in Lee cGVHD symptom scale, changes in corticosteroid requirement over time, and safety endpoints.

Investigators enrolled 42 patients, the first of whom was dosed in July 2014.

Patient demographics

Patients were a median age of 56 (range, 19–74), and 52% were male.

The median time from allogeneic transplant to the diagnosis of cGVHD was 7.6 months (range, 1.5–76.0), and the median time from initial cGVHD diagnosis to start of ibrutinib therapy was 13.7 months (range, 1.1–63.2).

Most patients had mouth (86%), skin (81%), or gastrointestinal (33%) cGVHD involvement.

And most patients had received matched (88%), unrelated (60%), nonmyeloablative (57%) peripheral blood stem cell (88%) transplants.

“This was a heavily treated patient population,” Dr Miklos said.

They had received a median of 2 (range, 1–3) prior regimens, with a median prednisone dose at enrollment of 0.3 mg/kg/day.

Prior cGVHD therapies included corticosteroids (100%), tacrolimus (50%), extracorporeal photopheresis (33%), rituximab (26%), mycophenolate mofetil (24%), cyclosporine (19%), sirolimus (17%), and other immunosuppressants (5%).

Results

The overall response rate was 67%, including 9 complete responses and 19 partial responses. Seventy-nine percent responded by the first assessment, and 71% of the 28 responders had a sustained cGVHD response of at least 5 months.

Investigators observed responses across multiple organs. Eighty percent (20/25) of patients with at least 2 involved organs at baseline responded in at least 2 organs, and 56% (5/9) of patients with 3 or more involved organs at baseline responded in at least 3 organs.

“These responses seen across all organs and in multiple organs suggest that the ibrutinib is actually targeting the underlying process of chronic GVHD and not simply masking the symptoms of chronic GVHD,” Dr Miklos noted.

Median corticosteroid use decreased throughout the ibrutinib treatment period. Twenty-six patients (62%) reduced steroid doses to less than 0.15/mg/kg/day while on ibrutinib.

Five responders discontinued all corticosteroid treatment.

Dr Miklos pointed out that baseline steroid dose did not vary between those patients who had responses and those who did not.

And ibrutinib produced clinically meaning improvement in the Lee symptom scale score among patients who responded.

Discontinuation and toxicity

At a median follow-up of 14 months, 12 patients were still on ibrutinib therapy.

“Only 5 patients discontinued for the progression of chronic GVHD,” Dr Miklos noted.

Other reasons for discontinuation included adverse events (AEs, n=14), patient decision (n=6), investigator decision (n=2), recurrence or progression of original malignancy (n=2), and noncompliance with study drug (n=1).

“The AE profile largely reflects what has been seen with ibrutinib use in the patients being treated for malignancies,” Dr Miklos said. “They also reflect adverse events that we see in patients receiving corticosteroids for the treatment of chronic GVHD.”

Treatment-emergent AEs occurring in more than 15% of patients included fatigue, diarrhea, muscle spasms, nausea, bruising, upper respiratory tract infection, pneumonia, pyrexia, headache, and fall.

Serious AEs occurred in 22 patients (52%), including pneumonia (n=6), septic shock (n=2), and pyrexia (n=2).

Two patients died while on study due to multilobular pneumonia and bronchopulmonary aspergillosis.

Exploratory endpoints

Investigators measured plasma levels of various factors following ibrutinib therapy through the first 90 days. Proinflammatory, chemotactic, and fibrotic factors decreased significantly while patients were on ibrutinib.

“This indicates that the cellular inflammation, the immune recruitment, and the fibrosis at the root of chronic GVHD was improving,” Dr Mikos said.

These factors included IFNγ, TNFα, IP-10, and CXCL9—biomarkers associated with cGVHD.

“We believe the efficacy of ibrutinib in this population supports further study in frontline treatment of  chronic GVHD in a randomized, double-blinded study,” Dr Miklos concluded.

The current study was sponsored by Pharmacyclics, Inc.

Attendees at the

2016 ASH Annual Meeting

SAN DIEGO—Ibrutinib, a Bruton’s tyrosine kinase inhibitor approved to treat chronic lymphocytic leukemia and other hematologic diseases, appears to provide relief for patients suffering from chronic graft-versus-host disease (cGVHD) after failing corticosteroid therapy.

At present, no approved therapy exists for these patients. Ibrutinib reduced the severity of cGVHD in preclinical models and has been used successfully in the post-allogeneic transplant setting.

The US Food and Drug Administration granted ibrutinib breakthrough therapy and orphan drug designations as a potential treatment for cGVHD.

David Miklos, MD, of Stanford University in California, explained at the 2016 ASH Annual Meeting that, in cGVHD, healthy B cells have been corrupted to produce self-reactive antibody complexes, and the T cells are killing healthy tissues and cells.

This destructive process involves the Bruton’s tyrosine kinase molecule, which can be inhibited and thereby block some of the downstream cGVHD pathogenesis.

“And to this aim, we went about testing the benefits of ibrutinib in the treatment of steroid-refractory chronic graft-versus-host disease,” Dr Miklos said.

In phase 1 of the study, investigators tested the 420 mg oral once-daily dose. They found no dose-limiting toxicities.

“So this dose was carried forward into the phase 2 study,” Dr Miklos said.

He presented results of the phase 2 study at the meeting as a late-breaking abstract (LBA-3).

Study design

Patients were eligible for the study if they had steroid-dependent or -refractory cGVHD. They had to have 3 or fewer prior treatments, and they could continue other systemic immunosuppression if they were using it.

They had to have erythematous rash on more than 25% of their body surface or a total mouth score of more than 4 as defined by National Institutes of Health (NIH) criteria.

Patients with cGVHD had to have failed frontline therapy.

They were treated with the phase 1 dose until progression of cGVHD or unacceptable toxicity.

The primary endpoint was cGVHD response per NIH 2005 response criteria.

Secondary endpoints included rate of sustained response, change in Lee cGVHD symptom scale, changes in corticosteroid requirement over time, and safety endpoints.

Investigators enrolled 42 patients, the first of whom was dosed in July 2014.

Patient demographics

Patients were a median age of 56 (range, 19–74), and 52% were male.

The median time from allogeneic transplant to the diagnosis of cGVHD was 7.6 months (range, 1.5–76.0), and the median time from initial cGVHD diagnosis to start of ibrutinib therapy was 13.7 months (range, 1.1–63.2).

Most patients had mouth (86%), skin (81%), or gastrointestinal (33%) cGVHD involvement.

And most patients had received matched (88%), unrelated (60%), nonmyeloablative (57%) peripheral blood stem cell (88%) transplants.

“This was a heavily treated patient population,” Dr Miklos said.

They had received a median of 2 (range, 1–3) prior regimens, with a median prednisone dose at enrollment of 0.3 mg/kg/day.

Prior cGVHD therapies included corticosteroids (100%), tacrolimus (50%), extracorporeal photopheresis (33%), rituximab (26%), mycophenolate mofetil (24%), cyclosporine (19%), sirolimus (17%), and other immunosuppressants (5%).

Results

The overall response rate was 67%, including 9 complete responses and 19 partial responses. Seventy-nine percent responded by the first assessment, and 71% of the 28 responders had a sustained cGVHD response of at least 5 months.

Investigators observed responses across multiple organs. Eighty percent (20/25) of patients with at least 2 involved organs at baseline responded in at least 2 organs, and 56% (5/9) of patients with 3 or more involved organs at baseline responded in at least 3 organs.

“These responses seen across all organs and in multiple organs suggest that the ibrutinib is actually targeting the underlying process of chronic GVHD and not simply masking the symptoms of chronic GVHD,” Dr Miklos noted.

Median corticosteroid use decreased throughout the ibrutinib treatment period. Twenty-six patients (62%) reduced steroid doses to less than 0.15/mg/kg/day while on ibrutinib.

Five responders discontinued all corticosteroid treatment.

Dr Miklos pointed out that baseline steroid dose did not vary between those patients who had responses and those who did not.

And ibrutinib produced clinically meaning improvement in the Lee symptom scale score among patients who responded.

Discontinuation and toxicity

At a median follow-up of 14 months, 12 patients were still on ibrutinib therapy.

“Only 5 patients discontinued for the progression of chronic GVHD,” Dr Miklos noted.

Other reasons for discontinuation included adverse events (AEs, n=14), patient decision (n=6), investigator decision (n=2), recurrence or progression of original malignancy (n=2), and noncompliance with study drug (n=1).

“The AE profile largely reflects what has been seen with ibrutinib use in the patients being treated for malignancies,” Dr Miklos said. “They also reflect adverse events that we see in patients receiving corticosteroids for the treatment of chronic GVHD.”

Treatment-emergent AEs occurring in more than 15% of patients included fatigue, diarrhea, muscle spasms, nausea, bruising, upper respiratory tract infection, pneumonia, pyrexia, headache, and fall.

Serious AEs occurred in 22 patients (52%), including pneumonia (n=6), septic shock (n=2), and pyrexia (n=2).

Two patients died while on study due to multilobular pneumonia and bronchopulmonary aspergillosis.

Exploratory endpoints

Investigators measured plasma levels of various factors following ibrutinib therapy through the first 90 days. Proinflammatory, chemotactic, and fibrotic factors decreased significantly while patients were on ibrutinib.

“This indicates that the cellular inflammation, the immune recruitment, and the fibrosis at the root of chronic GVHD was improving,” Dr Mikos said.

These factors included IFNγ, TNFα, IP-10, and CXCL9—biomarkers associated with cGVHD.

“We believe the efficacy of ibrutinib in this population supports further study in frontline treatment of  chronic GVHD in a randomized, double-blinded study,” Dr Miklos concluded.

The current study was sponsored by Pharmacyclics, Inc.

Attendees at the

2016 ASH Annual Meeting

SAN DIEGO—Ibrutinib, a Bruton’s tyrosine kinase inhibitor approved to treat chronic lymphocytic leukemia and other hematologic diseases, appears to provide relief for patients suffering from chronic graft-versus-host disease (cGVHD) after failing corticosteroid therapy.

At present, no approved therapy exists for these patients. Ibrutinib reduced the severity of cGVHD in preclinical models and has been used successfully in the post-allogeneic transplant setting.

The US Food and Drug Administration granted ibrutinib breakthrough therapy and orphan drug designations as a potential treatment for cGVHD.

David Miklos, MD, of Stanford University in California, explained at the 2016 ASH Annual Meeting that, in cGVHD, healthy B cells have been corrupted to produce self-reactive antibody complexes, and the T cells are killing healthy tissues and cells.

This destructive process involves the Bruton’s tyrosine kinase molecule, which can be inhibited and thereby block some of the downstream cGVHD pathogenesis.

“And to this aim, we went about testing the benefits of ibrutinib in the treatment of steroid-refractory chronic graft-versus-host disease,” Dr Miklos said.

In phase 1 of the study, investigators tested the 420 mg oral once-daily dose. They found no dose-limiting toxicities.

“So this dose was carried forward into the phase 2 study,” Dr Miklos said.

He presented results of the phase 2 study at the meeting as a late-breaking abstract (LBA-3).

Study design

Patients were eligible for the study if they had steroid-dependent or -refractory cGVHD. They had to have 3 or fewer prior treatments, and they could continue other systemic immunosuppression if they were using it.

They had to have erythematous rash on more than 25% of their body surface or a total mouth score of more than 4 as defined by National Institutes of Health (NIH) criteria.

Patients with cGVHD had to have failed frontline therapy.

They were treated with the phase 1 dose until progression of cGVHD or unacceptable toxicity.

The primary endpoint was cGVHD response per NIH 2005 response criteria.

Secondary endpoints included rate of sustained response, change in Lee cGVHD symptom scale, changes in corticosteroid requirement over time, and safety endpoints.

Investigators enrolled 42 patients, the first of whom was dosed in July 2014.

Patient demographics

Patients were a median age of 56 (range, 19–74), and 52% were male.

The median time from allogeneic transplant to the diagnosis of cGVHD was 7.6 months (range, 1.5–76.0), and the median time from initial cGVHD diagnosis to start of ibrutinib therapy was 13.7 months (range, 1.1–63.2).

Most patients had mouth (86%), skin (81%), or gastrointestinal (33%) cGVHD involvement.

And most patients had received matched (88%), unrelated (60%), nonmyeloablative (57%) peripheral blood stem cell (88%) transplants.

“This was a heavily treated patient population,” Dr Miklos said.

They had received a median of 2 (range, 1–3) prior regimens, with a median prednisone dose at enrollment of 0.3 mg/kg/day.

Prior cGVHD therapies included corticosteroids (100%), tacrolimus (50%), extracorporeal photopheresis (33%), rituximab (26%), mycophenolate mofetil (24%), cyclosporine (19%), sirolimus (17%), and other immunosuppressants (5%).

Results

The overall response rate was 67%, including 9 complete responses and 19 partial responses. Seventy-nine percent responded by the first assessment, and 71% of the 28 responders had a sustained cGVHD response of at least 5 months.

Investigators observed responses across multiple organs. Eighty percent (20/25) of patients with at least 2 involved organs at baseline responded in at least 2 organs, and 56% (5/9) of patients with 3 or more involved organs at baseline responded in at least 3 organs.

“These responses seen across all organs and in multiple organs suggest that the ibrutinib is actually targeting the underlying process of chronic GVHD and not simply masking the symptoms of chronic GVHD,” Dr Miklos noted.

Median corticosteroid use decreased throughout the ibrutinib treatment period. Twenty-six patients (62%) reduced steroid doses to less than 0.15/mg/kg/day while on ibrutinib.

Five responders discontinued all corticosteroid treatment.

Dr Miklos pointed out that baseline steroid dose did not vary between those patients who had responses and those who did not.

And ibrutinib produced clinically meaning improvement in the Lee symptom scale score among patients who responded.

Discontinuation and toxicity

At a median follow-up of 14 months, 12 patients were still on ibrutinib therapy.

“Only 5 patients discontinued for the progression of chronic GVHD,” Dr Miklos noted.

Other reasons for discontinuation included adverse events (AEs, n=14), patient decision (n=6), investigator decision (n=2), recurrence or progression of original malignancy (n=2), and noncompliance with study drug (n=1).

“The AE profile largely reflects what has been seen with ibrutinib use in the patients being treated for malignancies,” Dr Miklos said. “They also reflect adverse events that we see in patients receiving corticosteroids for the treatment of chronic GVHD.”

Treatment-emergent AEs occurring in more than 15% of patients included fatigue, diarrhea, muscle spasms, nausea, bruising, upper respiratory tract infection, pneumonia, pyrexia, headache, and fall.

Serious AEs occurred in 22 patients (52%), including pneumonia (n=6), septic shock (n=2), and pyrexia (n=2).

Two patients died while on study due to multilobular pneumonia and bronchopulmonary aspergillosis.

Exploratory endpoints

Investigators measured plasma levels of various factors following ibrutinib therapy through the first 90 days. Proinflammatory, chemotactic, and fibrotic factors decreased significantly while patients were on ibrutinib.

“This indicates that the cellular inflammation, the immune recruitment, and the fibrosis at the root of chronic GVHD was improving,” Dr Mikos said.

These factors included IFNγ, TNFα, IP-10, and CXCL9—biomarkers associated with cGVHD.

“We believe the efficacy of ibrutinib in this population supports further study in frontline treatment of  chronic GVHD in a randomized, double-blinded study,” Dr Miklos concluded.

The current study was sponsored by Pharmacyclics, Inc.