ASH 2015

Sebastien Maury, MD

Photo courtesy of ASH

ORLANDO, FL—Investigators from the Group for Research on Adult Lymphoblastic Leukemia (GRAALL) recommend integrating rituximab into the treatment of adult patients with acute lymphoblastic leukemia (ALL) based on results of the GRAALL-R 2005 study.

Patients who received rituximab as part of their therapy had a median event-free survival (EFS) at 2 years of 65%, compared to 52% for patients who did not receive rituximab. After censoring for stem cell transplant in first complete remission, the benefit was even greater.

Sébastien Maury, MD, PhD, of Hȏpital Hénri Mondor in Creteil, France, presented the results during the plenary session of the 2015 ASH Annual Meeting as abstract 1.

Dr Maury said GRAALL-R 2005 is the first phase 3, randomized study to evaluate the role of rituximab in the treatment of B-cell precursor (BCP) ALL.

Only one previous study, he said, suggested a potential benefit of adding rituximab compared to historic controls of chemotherapy alone.

He explained that, because the CD20 antigen is expressed at diagnosis in 30% to 40% of patients with BCP-ALL, investigators undertook to evaluate whether adding the anti-CD20 monoclonal antibody rituximab to the ALL treatment regimen could be beneficial for newly diagnosed Ph-negative BCP-ALL patients.

Study design & population

Investigators randomized 105 patients to receive the pediatric-inspired GRAALL protocol plus rituximab and 104 patients to the same regimen without rituximab.

Patients had to have 20% or more CD20-positive leukemic blasts.

Patients in the rituximab arm received 375 mg/m² during induction on days 1 and 7, during salvage reinduction (if needed) on days 1 and 7, during consolidation blocks (6 infusions), during late intensification on days 1 and 7, and during the first year of maintenance (6 infusions), for a total of 16 to 18 infusions.

“In this trial, allogeneic transplantation was offered in first remission to high-risk patients who were those patients with at least one of these baseline or response-related criteria,” Dr Maury said.

Investigators defined high-risk at baseline as having a white blood cell count of 30 x 10⁹/L or higher, CNS involvement, CD10-negative disease, or unfavorable cytogenetics.

And response-related criteria for high-risk disease included poor peripheral blast clearance after the 1-week steroid pre-phase, poor bone marrow blast clearance after the first week of chemotherapy, or no hematologic complete response after the first induction course.

Patient characteristics were well balanced between the arms, with a median age for the entire group of 40.2 years. Rituximab-treated patients had 61% CD20-positive blasts, and the no-rituximab arm had 69%.

More patients in the rituximab arm had a better ECOG performance status, although the difference was not significant. Thirteen percent were assessed as being grade 2 or higher in the rituximab arm, compared with 18% in the no-rituximab arm (P=0.06).

“The proportion of high-risk patients was comparable in both arms,” Dr Maury said, “representing around two-thirds of the study population.”

In the rituximab arm, 70% were considered high-risk, compared with 64% in the no-rituximab arm (P=0.46).

“However, despite this,” he said, “a significantly higher proportion of patients received allo transplant at first remission in the rituximab arm, 34% versus 20%. And since this was not explained by a different proportion of high-risk patients, this was probably due to differences in donor availability.”

Dr Maury noted that compliance to treatment was “quite good.”

Efficacy

The median follow-up was 30 months, and the primary endpoint was EFS.

The EFS rate for rituximab-treated patients at 2 years was 65%, compared with 52% for the non-rituximab patients (hazard ratio=0.66, P=0.038).

EFS was also significantly better with rituximab when patients were censored at allogeneic transplant, with a hazard ratio of 0.59 and a significance of 0.021.

However, there were no significant differences in early complete response rates, minimal residual disease (MRD) after induction, and MRD after consolidation.

“[O]nly 40% of patients could be centrally analyzed [for MRD],” Dr Maury explained, “which may be the reason why we could not detect any impact of rituximab on MRD.”

The cumulative incidence of relapse at 2 years was 18% in the rituximab arm and 32% in the no-rituximab arm (hazard ratio=0.52, P=0.017). And after censoring for stem cell transplant in first complete remission, the hazard ratio was 0.49 in favor of rituximab (P=0.018).

Overall survival (OS) was not significantly different between the arms. Rituximab-treated patients had an OS rate of 71%, compared with 64% in the no-rituximab arm (P=0.095).

“However, this difference became significant when censoring patients at time of allo-transplant,” Dr Maury said.

There was a 12% cumulative incidence of death in first complete remission at 2 years in each arm.

Investigators performed multivariate analysis and found that treatment with rituximab (P=0.020), age (P=0.022), white blood cell count of 30 x 10⁹/L or higher (P=0.005), and CNS involvement all significantly impacted EFS.

When they introduced stem cell transplant in first remission as a covariable, the same factors remained significant. Allogeneic stem cell transplant in first remission did not make a significant difference on EFS (P=0.62).

Safety

One hundred twenty-four patients reported 246 severe adverse events, the most frequent of which was infection—71 in the rituximab arm and 55 in the no-rituximab arm, a difference that was not significant (P=0.16).

Severe allergic events were significantly different between the arms, with 2 severe allergic events reported in the rituximab arm and 14 in the no-rituximab arm (P=0.002). Of these 16 events, all but one were due to asparaginase.

“We believe that this may reflect the protective effect of rituximab that might inhibit B-cell protection of antibodies against asparaginase,” Dr Maury said, although the investigators did not actually measure the antibodies.

Severe lab abnormalities, neurologic and pulmonary events, coagulopathy, cardiologic and gastrointestinal events were not significantly different between the arms.

Dr Maury emphasized that the addition of rituximab to standard intensive chemotherapy is well tolerated, significantly improves EFS, and prolongs OS in patients not receiving allogeneic transplant in first remission.

While the optimal dose schedule of rituximab still remains to be determined, the GRAALL investigators believe that “the addition of rituximab should be the new standard of care for these patients,” Dr Maury declared.

Sebastien Maury, MD

Photo courtesy of ASH

ORLANDO, FL—Investigators from the Group for Research on Adult Lymphoblastic Leukemia (GRAALL) recommend integrating rituximab into the treatment of adult patients with acute lymphoblastic leukemia (ALL) based on results of the GRAALL-R 2005 study.

Patients who received rituximab as part of their therapy had a median event-free survival (EFS) at 2 years of 65%, compared to 52% for patients who did not receive rituximab. After censoring for stem cell transplant in first complete remission, the benefit was even greater.

Sébastien Maury, MD, PhD, of Hȏpital Hénri Mondor in Creteil, France, presented the results during the plenary session of the 2015 ASH Annual Meeting as abstract 1.

Dr Maury said GRAALL-R 2005 is the first phase 3, randomized study to evaluate the role of rituximab in the treatment of B-cell precursor (BCP) ALL.

Only one previous study, he said, suggested a potential benefit of adding rituximab compared to historic controls of chemotherapy alone.

He explained that, because the CD20 antigen is expressed at diagnosis in 30% to 40% of patients with BCP-ALL, investigators undertook to evaluate whether adding the anti-CD20 monoclonal antibody rituximab to the ALL treatment regimen could be beneficial for newly diagnosed Ph-negative BCP-ALL patients.

Study design & population

Investigators randomized 105 patients to receive the pediatric-inspired GRAALL protocol plus rituximab and 104 patients to the same regimen without rituximab.

Patients had to have 20% or more CD20-positive leukemic blasts.

Patients in the rituximab arm received 375 mg/m² during induction on days 1 and 7, during salvage reinduction (if needed) on days 1 and 7, during consolidation blocks (6 infusions), during late intensification on days 1 and 7, and during the first year of maintenance (6 infusions), for a total of 16 to 18 infusions.

“In this trial, allogeneic transplantation was offered in first remission to high-risk patients who were those patients with at least one of these baseline or response-related criteria,” Dr Maury said.

Investigators defined high-risk at baseline as having a white blood cell count of 30 x 10⁹/L or higher, CNS involvement, CD10-negative disease, or unfavorable cytogenetics.

And response-related criteria for high-risk disease included poor peripheral blast clearance after the 1-week steroid pre-phase, poor bone marrow blast clearance after the first week of chemotherapy, or no hematologic complete response after the first induction course.

Patient characteristics were well balanced between the arms, with a median age for the entire group of 40.2 years. Rituximab-treated patients had 61% CD20-positive blasts, and the no-rituximab arm had 69%.

More patients in the rituximab arm had a better ECOG performance status, although the difference was not significant. Thirteen percent were assessed as being grade 2 or higher in the rituximab arm, compared with 18% in the no-rituximab arm (P=0.06).

“The proportion of high-risk patients was comparable in both arms,” Dr Maury said, “representing around two-thirds of the study population.”

In the rituximab arm, 70% were considered high-risk, compared with 64% in the no-rituximab arm (P=0.46).

“However, despite this,” he said, “a significantly higher proportion of patients received allo transplant at first remission in the rituximab arm, 34% versus 20%. And since this was not explained by a different proportion of high-risk patients, this was probably due to differences in donor availability.”

Dr Maury noted that compliance to treatment was “quite good.”

Efficacy

The median follow-up was 30 months, and the primary endpoint was EFS.

The EFS rate for rituximab-treated patients at 2 years was 65%, compared with 52% for the non-rituximab patients (hazard ratio=0.66, P=0.038).

EFS was also significantly better with rituximab when patients were censored at allogeneic transplant, with a hazard ratio of 0.59 and a significance of 0.021.

However, there were no significant differences in early complete response rates, minimal residual disease (MRD) after induction, and MRD after consolidation.

“[O]nly 40% of patients could be centrally analyzed [for MRD],” Dr Maury explained, “which may be the reason why we could not detect any impact of rituximab on MRD.”

The cumulative incidence of relapse at 2 years was 18% in the rituximab arm and 32% in the no-rituximab arm (hazard ratio=0.52, P=0.017). And after censoring for stem cell transplant in first complete remission, the hazard ratio was 0.49 in favor of rituximab (P=0.018).

Overall survival (OS) was not significantly different between the arms. Rituximab-treated patients had an OS rate of 71%, compared with 64% in the no-rituximab arm (P=0.095).

“However, this difference became significant when censoring patients at time of allo-transplant,” Dr Maury said.

There was a 12% cumulative incidence of death in first complete remission at 2 years in each arm.

Investigators performed multivariate analysis and found that treatment with rituximab (P=0.020), age (P=0.022), white blood cell count of 30 x 10⁹/L or higher (P=0.005), and CNS involvement all significantly impacted EFS.

When they introduced stem cell transplant in first remission as a covariable, the same factors remained significant. Allogeneic stem cell transplant in first remission did not make a significant difference on EFS (P=0.62).

Safety

One hundred twenty-four patients reported 246 severe adverse events, the most frequent of which was infection—71 in the rituximab arm and 55 in the no-rituximab arm, a difference that was not significant (P=0.16).

Severe allergic events were significantly different between the arms, with 2 severe allergic events reported in the rituximab arm and 14 in the no-rituximab arm (P=0.002). Of these 16 events, all but one were due to asparaginase.

“We believe that this may reflect the protective effect of rituximab that might inhibit B-cell protection of antibodies against asparaginase,” Dr Maury said, although the investigators did not actually measure the antibodies.

Severe lab abnormalities, neurologic and pulmonary events, coagulopathy, cardiologic and gastrointestinal events were not significantly different between the arms.

Dr Maury emphasized that the addition of rituximab to standard intensive chemotherapy is well tolerated, significantly improves EFS, and prolongs OS in patients not receiving allogeneic transplant in first remission.

While the optimal dose schedule of rituximab still remains to be determined, the GRAALL investigators believe that “the addition of rituximab should be the new standard of care for these patients,” Dr Maury declared.

Sebastien Maury, MD

Photo courtesy of ASH

ORLANDO, FL—Investigators from the Group for Research on Adult Lymphoblastic Leukemia (GRAALL) recommend integrating rituximab into the treatment of adult patients with acute lymphoblastic leukemia (ALL) based on results of the GRAALL-R 2005 study.

Patients who received rituximab as part of their therapy had a median event-free survival (EFS) at 2 years of 65%, compared to 52% for patients who did not receive rituximab. After censoring for stem cell transplant in first complete remission, the benefit was even greater.

Sébastien Maury, MD, PhD, of Hȏpital Hénri Mondor in Creteil, France, presented the results during the plenary session of the 2015 ASH Annual Meeting as abstract 1.

Dr Maury said GRAALL-R 2005 is the first phase 3, randomized study to evaluate the role of rituximab in the treatment of B-cell precursor (BCP) ALL.

Only one previous study, he said, suggested a potential benefit of adding rituximab compared to historic controls of chemotherapy alone.

He explained that, because the CD20 antigen is expressed at diagnosis in 30% to 40% of patients with BCP-ALL, investigators undertook to evaluate whether adding the anti-CD20 monoclonal antibody rituximab to the ALL treatment regimen could be beneficial for newly diagnosed Ph-negative BCP-ALL patients.

Study design & population

Investigators randomized 105 patients to receive the pediatric-inspired GRAALL protocol plus rituximab and 104 patients to the same regimen without rituximab.

Patients had to have 20% or more CD20-positive leukemic blasts.

Patients in the rituximab arm received 375 mg/m² during induction on days 1 and 7, during salvage reinduction (if needed) on days 1 and 7, during consolidation blocks (6 infusions), during late intensification on days 1 and 7, and during the first year of maintenance (6 infusions), for a total of 16 to 18 infusions.

“In this trial, allogeneic transplantation was offered in first remission to high-risk patients who were those patients with at least one of these baseline or response-related criteria,” Dr Maury said.

Investigators defined high-risk at baseline as having a white blood cell count of 30 x 10⁹/L or higher, CNS involvement, CD10-negative disease, or unfavorable cytogenetics.

And response-related criteria for high-risk disease included poor peripheral blast clearance after the 1-week steroid pre-phase, poor bone marrow blast clearance after the first week of chemotherapy, or no hematologic complete response after the first induction course.

Patient characteristics were well balanced between the arms, with a median age for the entire group of 40.2 years. Rituximab-treated patients had 61% CD20-positive blasts, and the no-rituximab arm had 69%.

More patients in the rituximab arm had a better ECOG performance status, although the difference was not significant. Thirteen percent were assessed as being grade 2 or higher in the rituximab arm, compared with 18% in the no-rituximab arm (P=0.06).

“The proportion of high-risk patients was comparable in both arms,” Dr Maury said, “representing around two-thirds of the study population.”

In the rituximab arm, 70% were considered high-risk, compared with 64% in the no-rituximab arm (P=0.46).

“However, despite this,” he said, “a significantly higher proportion of patients received allo transplant at first remission in the rituximab arm, 34% versus 20%. And since this was not explained by a different proportion of high-risk patients, this was probably due to differences in donor availability.”

Dr Maury noted that compliance to treatment was “quite good.”

Efficacy

The median follow-up was 30 months, and the primary endpoint was EFS.

The EFS rate for rituximab-treated patients at 2 years was 65%, compared with 52% for the non-rituximab patients (hazard ratio=0.66, P=0.038).

EFS was also significantly better with rituximab when patients were censored at allogeneic transplant, with a hazard ratio of 0.59 and a significance of 0.021.

However, there were no significant differences in early complete response rates, minimal residual disease (MRD) after induction, and MRD after consolidation.

“[O]nly 40% of patients could be centrally analyzed [for MRD],” Dr Maury explained, “which may be the reason why we could not detect any impact of rituximab on MRD.”

The cumulative incidence of relapse at 2 years was 18% in the rituximab arm and 32% in the no-rituximab arm (hazard ratio=0.52, P=0.017). And after censoring for stem cell transplant in first complete remission, the hazard ratio was 0.49 in favor of rituximab (P=0.018).

Overall survival (OS) was not significantly different between the arms. Rituximab-treated patients had an OS rate of 71%, compared with 64% in the no-rituximab arm (P=0.095).

“However, this difference became significant when censoring patients at time of allo-transplant,” Dr Maury said.

There was a 12% cumulative incidence of death in first complete remission at 2 years in each arm.

Investigators performed multivariate analysis and found that treatment with rituximab (P=0.020), age (P=0.022), white blood cell count of 30 x 10⁹/L or higher (P=0.005), and CNS involvement all significantly impacted EFS.

When they introduced stem cell transplant in first remission as a covariable, the same factors remained significant. Allogeneic stem cell transplant in first remission did not make a significant difference on EFS (P=0.62).

Safety

One hundred twenty-four patients reported 246 severe adverse events, the most frequent of which was infection—71 in the rituximab arm and 55 in the no-rituximab arm, a difference that was not significant (P=0.16).

Severe allergic events were significantly different between the arms, with 2 severe allergic events reported in the rituximab arm and 14 in the no-rituximab arm (P=0.002). Of these 16 events, all but one were due to asparaginase.

“We believe that this may reflect the protective effect of rituximab that might inhibit B-cell protection of antibodies against asparaginase,” Dr Maury said, although the investigators did not actually measure the antibodies.

Severe lab abnormalities, neurologic and pulmonary events, coagulopathy, cardiologic and gastrointestinal events were not significantly different between the arms.

Dr Maury emphasized that the addition of rituximab to standard intensive chemotherapy is well tolerated, significantly improves EFS, and prolongs OS in patients not receiving allogeneic transplant in first remission.

While the optimal dose schedule of rituximab still remains to be determined, the GRAALL investigators believe that “the addition of rituximab should be the new standard of care for these patients,” Dr Maury declared.

Richard Stone, MD

Photo courtesy of ASH

ORLANDO, FL—After almost 10 years, during which time no new drug for acute myeloid leukemia (AML) has been approved, results of the RATIFY trial are available.

In this trial, investigators evaluated midostaurin in combination with chemotherapy for younger patients with FLT3-mutated AML.

Patients who received midostaurin in their regimen instead of placebo experienced significantly longer overall survival (OS) and event-free survival (EFS).

“The primary endpoint of the trial was overall survival—which was very important—uncensored for transplant,” said Richard Stone, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

“This is very much a ‘real-world’ trial. We just took patients from the start and saw how they did until the end.”

Dr Stone presented results from the trial during the plenary session of the 2015 ASH Annual Meeting (abstract 6*).

Midostaurin (PKC412), developed as a VEGF and protein kinase C inhibitor, is a known FLT3 inhibitor that specifically inhibits the growth of leukemic cell lines.

As a multi-kinase inhibitor, its potency against FLT3 may be limited, but it is active against both ITD and TKD mutations. Because AML is polyclonal at diagnosis, a multi-targeted inhibitor may have an advantage in newly diagnosed AML.

As a single agent, Dr Stone explained, midostaurin produced few remissions in advanced, mutant AML. But when combined with chemotherapy in a phase 1B study in newly diagnosed patients, it produced encouraging results.

So members of the Alliance for Clinical Trials in Oncology, formerly CALGB, and many other cooperative groups around the world—the AMLSG, CETLAM, ECOG, EORTC, GIMEMA, NCIC, OSHO, PETHEMA, SAL, and SWOG—conducted a phase 3, randomized, double-blind trial of induction and consolidation with or without midostaurin in patients younger than 60 with newly diagnosed FLT3-mutated AML.

The primary endpoint was OS, and secondary endpoints were OS censored and uncensored at the time of transplant, complete remission (CR) rates, EFS, disease-free survival (DFS), and adverse events.

Mark Levis, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland, who introduced the plenary presentation, suggested that OS may not be the best primary endpoint for an AML trial, given the long time it takes to complete a trial like this.

He pointed out that, “while we waited for RATIFY to accrue and mature, our approach to the disease changed.” Allogeneic transplant is now often the favored consolidation.

Eligibility criteria

Patients aged 18 to 60 with normal end-organ function and documented AML were eligible to enroll. Patients could not have had acute promyelocytic leukemia.

Their FLT3 mutation had to be centrally determined prior to enrollment by 1 of 9 academic labs around the world, and results had to be obtainable within 48 hours of sample collection.

Patients could receive up to 5 days of hydroxyurea prior to the start of treatment while awaiting the results of the mutation analysis.

Trial design

Investigators randomized patients to induction of daunorubicin and cytarabine with either midostaurin or placebo.

Daunorubicin was administered at 60 mg/m² by intravenous push on days 1-3, cytarabine at 200 mg/m² per day on days 1-7, and midostaurin at 50 mg orally twice a day on days 8-21.

A second cycle of induction was given based on day 21 bone marrow biopsy.

When patients achieved CR, they went on to consolidation with high-dose cytarabine (3 g/m² over 3 hours every 12 hours on days 1, 3, and 5) and either midostaurin at the same induction dose or placebo.

After up to 4 doses of consolidation, patients went on to maintenance therapy for 12 months. This consisted of placebo or midostaurin at the same dose twice daily on days 1-28.

Patient population

The investigators screened 3279 patients younger than 60 years with newly diagnosed AML and found 27% (n=887) to be FLT3-positive.

They randomized 717 patients—81% of the FLT3-positive patients—to either the midostaurin arm (n=360) or the placebo arm (n=357). These 717 patients were evaluable for the intent-to-treat analysis.

The median age was 47.1 (range, 19.0–59.8) in the midostaurin arm and 48.6 (range, 18.0–60.9) in the placebo arm. There were significantly more males in the midostaurin arm (48.1%) than in the placebo arm (40.6%, P=0.045).

And the arms were almost identical for FLT3 stratification. In the midostaurin group, 22.5% had FLT3 TKD (no ITD), 47.5% had an ITD allelic ratio (+/- FLT3 TKD) less than 0.7, and 30.0% had a ratio of 0.7 or more.

In the placebo arm, 22.7% had FLT3 TKD, and 47.6% and 29.7% had ITD allelic ratios less than and greater than 0.7, respectively.

Safety

Rash/desquamation was the only significant difference in grade 3-4 non-hematologic events between the arms, with 13% in the midostaurin arm and 8% in the placebo arm (P=0.02).

Other grade 3-4 non-hematologic events occurring in 10% of patients or more included, in the midostaurin and placebo arms, respectively: febrile neutropenia (81%, 82%), infection (40%, 38%), diarrhea (15%, 16%), hypokalemia (13%, 17%), pain (13%, 13%), other infection (12%, 12%), ALT/SGPT (12%, 9%), and fatigue (9%, 11%).

There were 18 deaths (5%) in the midostaurin arm and 19 (5.3%) in the placebo arm during induction and consolidation treatment.

Efficacy

OS was superior for patients randomized to midostaurin. The median survival was 74.7 months (range, 31.7-not estimable) in the midostaurin arm and 25.6 months (range,18.6-42.9) in the placebo arm (P=0.0076).

Overall, there were 357 deaths, 171 and 186 in the midostaurin and placebo arms, respectively.

The 5-year survival rate was 50.9% for midostaurin and 43.9% for placebo.

EFS was also superior for patients randomized to midostaurin (P=0.0032), at a median of 8.0 months for midostaurin and 3.6 months for placebo. The 5-year EFS was 27.5% for midostaurin and 19.3% for placebo.

The CR rates by day 60 were not significantly different between the arms, at 59% and 53% for midostaurin and placebo, respectively. And the median time to CR was the same in each group, at 35 days.

The survival benefit, both overall and event-free, was consistent regardless of whether the patients were FLT3-ITD high, low, or FLT3-TKD.

The OS and EFS benefits were also consistent in censored and uncensored analyses, despite the high stem cell transplant rate. Four hundred eight patients (57%) received a transplant, 212 in the midostaurin arm and 196 in the placebo arm.

“The trial was positive whether you censored the patients at transplant or you kept following them for the whole time,” Dr Stone said.

He concluded that this type of international collaborative AML study based on genotype at diagnosis is feasible to do. But it took “a lot of collaboration, a lot of cooperation, a lot of persistence, because the trial took a long time to conceive of, conduct, and analyze.”

*Data in the presentation differ from the abstract.

Richard Stone, MD

Photo courtesy of ASH

ORLANDO, FL—After almost 10 years, during which time no new drug for acute myeloid leukemia (AML) has been approved, results of the RATIFY trial are available.

In this trial, investigators evaluated midostaurin in combination with chemotherapy for younger patients with FLT3-mutated AML.

Patients who received midostaurin in their regimen instead of placebo experienced significantly longer overall survival (OS) and event-free survival (EFS).

“The primary endpoint of the trial was overall survival—which was very important—uncensored for transplant,” said Richard Stone, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

“This is very much a ‘real-world’ trial. We just took patients from the start and saw how they did until the end.”

Dr Stone presented results from the trial during the plenary session of the 2015 ASH Annual Meeting (abstract 6*).

Midostaurin (PKC412), developed as a VEGF and protein kinase C inhibitor, is a known FLT3 inhibitor that specifically inhibits the growth of leukemic cell lines.

As a multi-kinase inhibitor, its potency against FLT3 may be limited, but it is active against both ITD and TKD mutations. Because AML is polyclonal at diagnosis, a multi-targeted inhibitor may have an advantage in newly diagnosed AML.

As a single agent, Dr Stone explained, midostaurin produced few remissions in advanced, mutant AML. But when combined with chemotherapy in a phase 1B study in newly diagnosed patients, it produced encouraging results.

So members of the Alliance for Clinical Trials in Oncology, formerly CALGB, and many other cooperative groups around the world—the AMLSG, CETLAM, ECOG, EORTC, GIMEMA, NCIC, OSHO, PETHEMA, SAL, and SWOG—conducted a phase 3, randomized, double-blind trial of induction and consolidation with or without midostaurin in patients younger than 60 with newly diagnosed FLT3-mutated AML.

The primary endpoint was OS, and secondary endpoints were OS censored and uncensored at the time of transplant, complete remission (CR) rates, EFS, disease-free survival (DFS), and adverse events.

Mark Levis, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland, who introduced the plenary presentation, suggested that OS may not be the best primary endpoint for an AML trial, given the long time it takes to complete a trial like this.

He pointed out that, “while we waited for RATIFY to accrue and mature, our approach to the disease changed.” Allogeneic transplant is now often the favored consolidation.

Eligibility criteria

Patients aged 18 to 60 with normal end-organ function and documented AML were eligible to enroll. Patients could not have had acute promyelocytic leukemia.

Their FLT3 mutation had to be centrally determined prior to enrollment by 1 of 9 academic labs around the world, and results had to be obtainable within 48 hours of sample collection.

Patients could receive up to 5 days of hydroxyurea prior to the start of treatment while awaiting the results of the mutation analysis.

Trial design

Investigators randomized patients to induction of daunorubicin and cytarabine with either midostaurin or placebo.

Daunorubicin was administered at 60 mg/m² by intravenous push on days 1-3, cytarabine at 200 mg/m² per day on days 1-7, and midostaurin at 50 mg orally twice a day on days 8-21.

A second cycle of induction was given based on day 21 bone marrow biopsy.

When patients achieved CR, they went on to consolidation with high-dose cytarabine (3 g/m² over 3 hours every 12 hours on days 1, 3, and 5) and either midostaurin at the same induction dose or placebo.

After up to 4 doses of consolidation, patients went on to maintenance therapy for 12 months. This consisted of placebo or midostaurin at the same dose twice daily on days 1-28.

Patient population

The investigators screened 3279 patients younger than 60 years with newly diagnosed AML and found 27% (n=887) to be FLT3-positive.

They randomized 717 patients—81% of the FLT3-positive patients—to either the midostaurin arm (n=360) or the placebo arm (n=357). These 717 patients were evaluable for the intent-to-treat analysis.

The median age was 47.1 (range, 19.0–59.8) in the midostaurin arm and 48.6 (range, 18.0–60.9) in the placebo arm. There were significantly more males in the midostaurin arm (48.1%) than in the placebo arm (40.6%, P=0.045).

And the arms were almost identical for FLT3 stratification. In the midostaurin group, 22.5% had FLT3 TKD (no ITD), 47.5% had an ITD allelic ratio (+/- FLT3 TKD) less than 0.7, and 30.0% had a ratio of 0.7 or more.

In the placebo arm, 22.7% had FLT3 TKD, and 47.6% and 29.7% had ITD allelic ratios less than and greater than 0.7, respectively.

Safety

Rash/desquamation was the only significant difference in grade 3-4 non-hematologic events between the arms, with 13% in the midostaurin arm and 8% in the placebo arm (P=0.02).

Other grade 3-4 non-hematologic events occurring in 10% of patients or more included, in the midostaurin and placebo arms, respectively: febrile neutropenia (81%, 82%), infection (40%, 38%), diarrhea (15%, 16%), hypokalemia (13%, 17%), pain (13%, 13%), other infection (12%, 12%), ALT/SGPT (12%, 9%), and fatigue (9%, 11%).

There were 18 deaths (5%) in the midostaurin arm and 19 (5.3%) in the placebo arm during induction and consolidation treatment.

Efficacy

OS was superior for patients randomized to midostaurin. The median survival was 74.7 months (range, 31.7-not estimable) in the midostaurin arm and 25.6 months (range,18.6-42.9) in the placebo arm (P=0.0076).

Overall, there were 357 deaths, 171 and 186 in the midostaurin and placebo arms, respectively.

The 5-year survival rate was 50.9% for midostaurin and 43.9% for placebo.

EFS was also superior for patients randomized to midostaurin (P=0.0032), at a median of 8.0 months for midostaurin and 3.6 months for placebo. The 5-year EFS was 27.5% for midostaurin and 19.3% for placebo.

The CR rates by day 60 were not significantly different between the arms, at 59% and 53% for midostaurin and placebo, respectively. And the median time to CR was the same in each group, at 35 days.

The survival benefit, both overall and event-free, was consistent regardless of whether the patients were FLT3-ITD high, low, or FLT3-TKD.

The OS and EFS benefits were also consistent in censored and uncensored analyses, despite the high stem cell transplant rate. Four hundred eight patients (57%) received a transplant, 212 in the midostaurin arm and 196 in the placebo arm.

“The trial was positive whether you censored the patients at transplant or you kept following them for the whole time,” Dr Stone said.

He concluded that this type of international collaborative AML study based on genotype at diagnosis is feasible to do. But it took “a lot of collaboration, a lot of cooperation, a lot of persistence, because the trial took a long time to conceive of, conduct, and analyze.”

*Data in the presentation differ from the abstract.

Richard Stone, MD

Photo courtesy of ASH

ORLANDO, FL—After almost 10 years, during which time no new drug for acute myeloid leukemia (AML) has been approved, results of the RATIFY trial are available.

In this trial, investigators evaluated midostaurin in combination with chemotherapy for younger patients with FLT3-mutated AML.

Patients who received midostaurin in their regimen instead of placebo experienced significantly longer overall survival (OS) and event-free survival (EFS).

“The primary endpoint of the trial was overall survival—which was very important—uncensored for transplant,” said Richard Stone, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

“This is very much a ‘real-world’ trial. We just took patients from the start and saw how they did until the end.”

Dr Stone presented results from the trial during the plenary session of the 2015 ASH Annual Meeting (abstract 6*).

Midostaurin (PKC412), developed as a VEGF and protein kinase C inhibitor, is a known FLT3 inhibitor that specifically inhibits the growth of leukemic cell lines.

As a multi-kinase inhibitor, its potency against FLT3 may be limited, but it is active against both ITD and TKD mutations. Because AML is polyclonal at diagnosis, a multi-targeted inhibitor may have an advantage in newly diagnosed AML.

As a single agent, Dr Stone explained, midostaurin produced few remissions in advanced, mutant AML. But when combined with chemotherapy in a phase 1B study in newly diagnosed patients, it produced encouraging results.

So members of the Alliance for Clinical Trials in Oncology, formerly CALGB, and many other cooperative groups around the world—the AMLSG, CETLAM, ECOG, EORTC, GIMEMA, NCIC, OSHO, PETHEMA, SAL, and SWOG—conducted a phase 3, randomized, double-blind trial of induction and consolidation with or without midostaurin in patients younger than 60 with newly diagnosed FLT3-mutated AML.

The primary endpoint was OS, and secondary endpoints were OS censored and uncensored at the time of transplant, complete remission (CR) rates, EFS, disease-free survival (DFS), and adverse events.

Mark Levis, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland, who introduced the plenary presentation, suggested that OS may not be the best primary endpoint for an AML trial, given the long time it takes to complete a trial like this.

He pointed out that, “while we waited for RATIFY to accrue and mature, our approach to the disease changed.” Allogeneic transplant is now often the favored consolidation.

Eligibility criteria

Patients aged 18 to 60 with normal end-organ function and documented AML were eligible to enroll. Patients could not have had acute promyelocytic leukemia.

Their FLT3 mutation had to be centrally determined prior to enrollment by 1 of 9 academic labs around the world, and results had to be obtainable within 48 hours of sample collection.

Patients could receive up to 5 days of hydroxyurea prior to the start of treatment while awaiting the results of the mutation analysis.

Trial design

Investigators randomized patients to induction of daunorubicin and cytarabine with either midostaurin or placebo.

Daunorubicin was administered at 60 mg/m² by intravenous push on days 1-3, cytarabine at 200 mg/m² per day on days 1-7, and midostaurin at 50 mg orally twice a day on days 8-21.

A second cycle of induction was given based on day 21 bone marrow biopsy.

When patients achieved CR, they went on to consolidation with high-dose cytarabine (3 g/m² over 3 hours every 12 hours on days 1, 3, and 5) and either midostaurin at the same induction dose or placebo.

After up to 4 doses of consolidation, patients went on to maintenance therapy for 12 months. This consisted of placebo or midostaurin at the same dose twice daily on days 1-28.

Patient population

The investigators screened 3279 patients younger than 60 years with newly diagnosed AML and found 27% (n=887) to be FLT3-positive.

They randomized 717 patients—81% of the FLT3-positive patients—to either the midostaurin arm (n=360) or the placebo arm (n=357). These 717 patients were evaluable for the intent-to-treat analysis.

The median age was 47.1 (range, 19.0–59.8) in the midostaurin arm and 48.6 (range, 18.0–60.9) in the placebo arm. There were significantly more males in the midostaurin arm (48.1%) than in the placebo arm (40.6%, P=0.045).

And the arms were almost identical for FLT3 stratification. In the midostaurin group, 22.5% had FLT3 TKD (no ITD), 47.5% had an ITD allelic ratio (+/- FLT3 TKD) less than 0.7, and 30.0% had a ratio of 0.7 or more.

In the placebo arm, 22.7% had FLT3 TKD, and 47.6% and 29.7% had ITD allelic ratios less than and greater than 0.7, respectively.

Safety

Rash/desquamation was the only significant difference in grade 3-4 non-hematologic events between the arms, with 13% in the midostaurin arm and 8% in the placebo arm (P=0.02).

Other grade 3-4 non-hematologic events occurring in 10% of patients or more included, in the midostaurin and placebo arms, respectively: febrile neutropenia (81%, 82%), infection (40%, 38%), diarrhea (15%, 16%), hypokalemia (13%, 17%), pain (13%, 13%), other infection (12%, 12%), ALT/SGPT (12%, 9%), and fatigue (9%, 11%).

There were 18 deaths (5%) in the midostaurin arm and 19 (5.3%) in the placebo arm during induction and consolidation treatment.

Efficacy

OS was superior for patients randomized to midostaurin. The median survival was 74.7 months (range, 31.7-not estimable) in the midostaurin arm and 25.6 months (range,18.6-42.9) in the placebo arm (P=0.0076).

Overall, there were 357 deaths, 171 and 186 in the midostaurin and placebo arms, respectively.

The 5-year survival rate was 50.9% for midostaurin and 43.9% for placebo.

EFS was also superior for patients randomized to midostaurin (P=0.0032), at a median of 8.0 months for midostaurin and 3.6 months for placebo. The 5-year EFS was 27.5% for midostaurin and 19.3% for placebo.

The CR rates by day 60 were not significantly different between the arms, at 59% and 53% for midostaurin and placebo, respectively. And the median time to CR was the same in each group, at 35 days.

The survival benefit, both overall and event-free, was consistent regardless of whether the patients were FLT3-ITD high, low, or FLT3-TKD.

The OS and EFS benefits were also consistent in censored and uncensored analyses, despite the high stem cell transplant rate. Four hundred eight patients (57%) received a transplant, 212 in the midostaurin arm and 196 in the placebo arm.

“The trial was positive whether you censored the patients at transplant or you kept following them for the whole time,” Dr Stone said.

He concluded that this type of international collaborative AML study based on genotype at diagnosis is feasible to do. But it took “a lot of collaboration, a lot of cooperation, a lot of persistence, because the trial took a long time to conceive of, conduct, and analyze.”

*Data in the presentation differ from the abstract.

Rivaroxaban

ORLANDO, FL—“Real-world” data appear to confirm phase 3 results with rivaroxaban in patients who have deep vein thrombosis (DVT), with or without concomitant pulmonary embolism (PE).

Results of the phase 4 XALIA study suggest that, in clinical practice, the rates of major bleeding and recurrent venous thromboembolism (VTE) in patients taking rivaroxaban are generally consistent with results of the phase 3 EINSTEIN-DVT study.

Investigators noted, however, that methodological and other differences between the studies limit the ability to directly compare results of XALIA and EINSTEIN-DVT.

Alexander G. G. Turpie, MD, of McMaster University and Hamilton Health Sciences in Hamilton, Ontario, Canada, and his colleagues reported data from the XALIA study at the 2015 ASH Annual Meeting (abstract 894) and in The Lancet Haematology.

The study was sponsored by Janssen and Bayer HealthCare.

“The real-world insights from XALIA confirm the positive benefit-risk profile of rivaroxaban for the treatment of deep vein thrombosis that was observed in the phase 3 EINSTEIN-DVT study, signaling that the medicine is performing as expected in patients that physicians typically see in everyday clinical practice,” Dr Turpie said.

Study design

For the XALIA study, investigators compared once-daily rivaroxaban to standard anticoagulation in patients with DVT, with or without concomitant PE. Standard anticoagulation was considered initial treatment with heparin, low-molecular-weight heparin, or fondaparinux, typically overlapping with and followed by warfarin.

The study enrolled 5142 patients age 18 and older. Patients were enrolled between June 2012 and March 2014 and followed for at least 12 months.

A total of 4768 patients were included in the primary analysis—2619 in the rivaroxaban group and 2149 in the standard anticoagulation group.

But the investigators also completed a propensity-score analysis to address differences in baseline characteristics and help correct for any selection bias. There were 4515 patients in this analysis—2505 in the rivaroxaban group and 2010 in the standard anticoagulation group.

The primary outcomes were major bleeding, recurrent VTE, and all-cause mortality.

Results

In the propensity score-adjusted population, major bleeding occurred in 0.8% of patients receiving rivaroxaban and 2.1% of those receiving standard anticoagulation (hazard ratio[HR]=0.77, P=0.44).

There were no fatal bleeding events in the rivaroxaban group and 2 fatal bleeding events in the standard anticoagulation group.

In EINSTEIN-DVT, major bleeding occurred in 0.8% of patients taking rivaroxaban, and there was 1 fatal bleeding event.

In XALIA (propensity score-adjusted population), VTE recurred in 1.4% of patients receiving rivaroxaban and 2.3% of those receiving standard anticoagulation (HR=0.91, P=0.72).

In EINSTEIN-DVT, VTE recurred in 2.1% of patients taking rivaroxaban.

In XALIA (propensity score-adjusted population), the rate of all-cause mortality was 0.4% in patients taking rivaroxaban and 3.4% in those receiving standard anticoagulation (HR=0.51, P=0.07).

In EINSTEIN-DVT, the rate of all-cause mortality was 2.2% in patients taking rivaroxaban.

Rivaroxaban

ORLANDO, FL—“Real-world” data appear to confirm phase 3 results with rivaroxaban in patients who have deep vein thrombosis (DVT), with or without concomitant pulmonary embolism (PE).

Results of the phase 4 XALIA study suggest that, in clinical practice, the rates of major bleeding and recurrent venous thromboembolism (VTE) in patients taking rivaroxaban are generally consistent with results of the phase 3 EINSTEIN-DVT study.

Investigators noted, however, that methodological and other differences between the studies limit the ability to directly compare results of XALIA and EINSTEIN-DVT.

Alexander G. G. Turpie, MD, of McMaster University and Hamilton Health Sciences in Hamilton, Ontario, Canada, and his colleagues reported data from the XALIA study at the 2015 ASH Annual Meeting (abstract 894) and in The Lancet Haematology.

The study was sponsored by Janssen and Bayer HealthCare.

“The real-world insights from XALIA confirm the positive benefit-risk profile of rivaroxaban for the treatment of deep vein thrombosis that was observed in the phase 3 EINSTEIN-DVT study, signaling that the medicine is performing as expected in patients that physicians typically see in everyday clinical practice,” Dr Turpie said.

Study design

For the XALIA study, investigators compared once-daily rivaroxaban to standard anticoagulation in patients with DVT, with or without concomitant PE. Standard anticoagulation was considered initial treatment with heparin, low-molecular-weight heparin, or fondaparinux, typically overlapping with and followed by warfarin.

The study enrolled 5142 patients age 18 and older. Patients were enrolled between June 2012 and March 2014 and followed for at least 12 months.

A total of 4768 patients were included in the primary analysis—2619 in the rivaroxaban group and 2149 in the standard anticoagulation group.

But the investigators also completed a propensity-score analysis to address differences in baseline characteristics and help correct for any selection bias. There were 4515 patients in this analysis—2505 in the rivaroxaban group and 2010 in the standard anticoagulation group.

The primary outcomes were major bleeding, recurrent VTE, and all-cause mortality.

Results

In the propensity score-adjusted population, major bleeding occurred in 0.8% of patients receiving rivaroxaban and 2.1% of those receiving standard anticoagulation (hazard ratio[HR]=0.77, P=0.44).

There were no fatal bleeding events in the rivaroxaban group and 2 fatal bleeding events in the standard anticoagulation group.

In EINSTEIN-DVT, major bleeding occurred in 0.8% of patients taking rivaroxaban, and there was 1 fatal bleeding event.

In XALIA (propensity score-adjusted population), VTE recurred in 1.4% of patients receiving rivaroxaban and 2.3% of those receiving standard anticoagulation (HR=0.91, P=0.72).

In EINSTEIN-DVT, VTE recurred in 2.1% of patients taking rivaroxaban.

In XALIA (propensity score-adjusted population), the rate of all-cause mortality was 0.4% in patients taking rivaroxaban and 3.4% in those receiving standard anticoagulation (HR=0.51, P=0.07).

In EINSTEIN-DVT, the rate of all-cause mortality was 2.2% in patients taking rivaroxaban.

Rivaroxaban

ORLANDO, FL—“Real-world” data appear to confirm phase 3 results with rivaroxaban in patients who have deep vein thrombosis (DVT), with or without concomitant pulmonary embolism (PE).

Results of the phase 4 XALIA study suggest that, in clinical practice, the rates of major bleeding and recurrent venous thromboembolism (VTE) in patients taking rivaroxaban are generally consistent with results of the phase 3 EINSTEIN-DVT study.

Investigators noted, however, that methodological and other differences between the studies limit the ability to directly compare results of XALIA and EINSTEIN-DVT.

Alexander G. G. Turpie, MD, of McMaster University and Hamilton Health Sciences in Hamilton, Ontario, Canada, and his colleagues reported data from the XALIA study at the 2015 ASH Annual Meeting (abstract 894) and in The Lancet Haematology.

The study was sponsored by Janssen and Bayer HealthCare.

“The real-world insights from XALIA confirm the positive benefit-risk profile of rivaroxaban for the treatment of deep vein thrombosis that was observed in the phase 3 EINSTEIN-DVT study, signaling that the medicine is performing as expected in patients that physicians typically see in everyday clinical practice,” Dr Turpie said.

Study design

For the XALIA study, investigators compared once-daily rivaroxaban to standard anticoagulation in patients with DVT, with or without concomitant PE. Standard anticoagulation was considered initial treatment with heparin, low-molecular-weight heparin, or fondaparinux, typically overlapping with and followed by warfarin.

The study enrolled 5142 patients age 18 and older. Patients were enrolled between June 2012 and March 2014 and followed for at least 12 months.

A total of 4768 patients were included in the primary analysis—2619 in the rivaroxaban group and 2149 in the standard anticoagulation group.

But the investigators also completed a propensity-score analysis to address differences in baseline characteristics and help correct for any selection bias. There were 4515 patients in this analysis—2505 in the rivaroxaban group and 2010 in the standard anticoagulation group.

The primary outcomes were major bleeding, recurrent VTE, and all-cause mortality.

Results

In the propensity score-adjusted population, major bleeding occurred in 0.8% of patients receiving rivaroxaban and 2.1% of those receiving standard anticoagulation (hazard ratio[HR]=0.77, P=0.44).

There were no fatal bleeding events in the rivaroxaban group and 2 fatal bleeding events in the standard anticoagulation group.

In EINSTEIN-DVT, major bleeding occurred in 0.8% of patients taking rivaroxaban, and there was 1 fatal bleeding event.

In XALIA (propensity score-adjusted population), VTE recurred in 1.4% of patients receiving rivaroxaban and 2.3% of those receiving standard anticoagulation (HR=0.91, P=0.72).

In EINSTEIN-DVT, VTE recurred in 2.1% of patients taking rivaroxaban.

In XALIA (propensity score-adjusted population), the rate of all-cause mortality was 0.4% in patients taking rivaroxaban and 3.4% in those receiving standard anticoagulation (HR=0.51, P=0.07).

In EINSTEIN-DVT, the rate of all-cause mortality was 2.2% in patients taking rivaroxaban.

 

 

2015 ASH Annual Meeting

Photo courtesy of ASH

 

ORLANDO, FL—A 3-drug regimen is likely not worth pursuing as a first-line treatment option for follicular lymphoma (FL), according to a presentation at the 2015 ASH Annual Meeting.

In a phase 1 study, combination ibrutinib, rituximab, and lenalidomide did not provide any response benefit over that previously observed with rituximab and lenalidomide.

But the triplet increased toxicity—particularly the incidence of rash—and necessitated dose modifications.

Chaitra S. Ujjani, MD, of Georgetown University Hospital in Washington, DC, presented these results at the meeting as abstract 471.*

“The combination of rituximab and lenalidomide has demonstrated remarkable activity in follicular lymphoma,” Dr Ujjani began.

She noted that, in the CALGB 50401 trial of relapsed FL (Leonard et al. JCO 2015), the combination elicited an overall response rate (ORR) of 76% and a complete response (CR) rate of 39%, and the 2-year time to progression was 52%.

In the CALGB 50803 trial of previously untreated FL (Martin et al. ASCO 2014, 8521), the regimen produced an ORR of 96%, a CR rate of 71%, and a 2-year progression-free survival (PFS) of 89%. In another trial of previously untreated FL (Fowler et al. Lanc Onc 2014), the ORR was 90%, the CR rate was 80%, and the 3-year PFS was 79%.

Ibrutinib has also demonstrated activity in FL, Dr Ujjani pointed out. In a phase 1 study of relapsed FL (Fowler et al. ASH 2012), the drug produced an ORR of 55%, 3 of 11 patients achieved a CR, and the median PFS was 13.4 months.

In a phase 2 study of ibrutinib in relapsed FL (Bartlett et al. ASH 2014, 800), the ORR was 30%, 1 of 40 patients achieved a CR, and the median PFS was 9.9 months.

With this in mind, Dr Ujjani and her colleagues conducted the A051103 trial to determine the activity and tolerability of rituximab, lenalidomide, and ibrutinib in previously untreated patients with FL.

Study design

The study enrolled patients with grade 1-3a FL; stage III, IV, or bulky stage II disease; an ECOG performance status less than 2; and adequate organ function.

They received 4 doses of rituximab at 375 mg/m² on days 1, 8, 15, and 22 of cycle 1 (28 days). They received 4 additional doses (375 mg/m²) on day 1 of cycles 4, 6, 8, and 10.

The patients received lenalidomide according to their assigned dosing cohort on days 1 to 21 for 18 cycles. They received daily ibrutinib according to their assigned dosing cohort until progression or unacceptable toxicity.

The study had a 3+3 dose-escalation design. Dose level (DL) 0 was lenalidomide at 15 mg and ibrutinib at 420 mg, DL1 was lenalidomide at 15 mg and ibrutinib at 560 mg, and DL2 was lenalidomide at 20 mg and ibrutinib at 560 mg.

Patients also received allopurinol at 300 mg daily for tumor lysis prophylaxis and aspirin as thromboprophylaxis while on lenalidomide.

The researchers assessed dose-limiting toxicities (DLTs) weekly during cycle 1. Given the known incidence of rash with lenalidomide, grade 3 rash that resolved to less than grade 2 within 10 days was not included as a DLT.

Once the maximum-tolerated dose was determined, there was a 10-patient expansion cohort.

Patients and treatment

Twenty-two patients were enrolled between June 2013 and May 2015. Their median age was 53.5 years (range, 36-81), and 68% were male.

Seventy-three percent of patients had grade 1/2 disease, and 77% had stage IV disease. By FLIPI, 18% of patients were low-risk, 55% were intermediate-risk, and 27% were high-risk.

Three patients were treated at DL0, 3 at DL1, and 16 at DL2. There were no DLTs reported at any dose level.

However, 11 patients required dose reductions due to toxicity (7 due to rash), and 12 patients ultimately discontinued treatment.

Reasons for discontinuation included progression (n=2), new diagnosis of carcinoma requiring systemic therapy (n=2), patient decision (n=3), and adverse events (n=6), including grade 3 rash (n=2), grade 3 atrial flutter (n=1), grade 3 diarrhea (n=1), hypertension (n=1), and depression (n=1). (One patient discontinued due to rash and progression.)

Adverse events

Dr Ujjani said the hematologic toxicity profile was similar to that observed with rituximab and lenalidomide in the front-line setting. Grade 3/4 hematologic toxicities included neutropenia (18.2%), thrombocytopenia (4.5%), anemia (4.5%), and lymphopenia (4.5%).

The most common non-hematologic toxicities (occurring in more than 20% of patients) were rash, diarrhea, fatigue, infusion-related reactions, nausea, infection, and neoplasms. There were no grade 4 non-hematologic toxicities.

Compared to rituximab and lenalidomide, the triplet was associated with an increase in rash, diarrhea, arthralgia, and neoplasm. There were 2 cutaneous neoplasms and 3 carcinomas.

Rash

“While no protocol-defined DLTs were observed, the regimen was associated with clinically significant rash,” Dr Ujjani noted. “Rash may have been related to individual study drugs or drug-drug interactions.”

Rash occurred in 82% of patients overall, 100% of patients treated at DL0, 67% at DL1, and 81% at DL2. The incidence of grade 1/2 rash was 46% overall, 67% at DL0, 33% at DL1, and 44% at DL2. The incidence of grade 3 rash was 36% overall, 33% at DL0 and DL1, and 38% at DL2.

The incidence of rash was similar whether or not patients received allopurinol. Ten of 11 patients on allopurinol had a rash, and 8 of 11 patients not on allopurinol had a rash.

“The time of [rash] onset was typically during cycle 1 but was seen as late as cycle 5,” Dr Ujjani said. “Grade 1 and 2 rashes resolved spontaneously without dose modification. The incidence of these milder rashes were comparable to our prior reports of rituximab and lenalidomide.”

“Grade 3 rash, however, occurred in 36% of patients, which is significantly higher than [with] rituximab and lenalidomide, [which is] typically 7% to 8%, or single-agent ibrutinib, which is about 3% to 4%.”

Patients with grade 3 rash were managed with supportive care, including acetaminophen, diphenhydramine, and oral corticosteroids.

All but 1 patient (7/8) had dose delays and reductions due to rash. One patient withdrew from the study because of rash, and 1 patient withdrew because of disease progression that occurred during a dose delay for rash.

Response and survival

The ORR was 95% for the entire cohort, 100% at DL0 and DL1 and 94% at DL2. The CR/unconfirmed CR rate was 63% overall, 67% at DL0, 33% at DL1, and 69% at DL2.

The partial response rate was 32% overall, 33% at DL0, 67% at DL1, and 25% at DL2. Five percent of patients had stable disease, all at DL2 (6% of this group).

The median time to first response was 2.3 months (range, 1.9 to 11.1). And the median time to best response was 5.5 months (range, 1.9 to 20.2).

At a median follow-up of 12.3 months, all patients are still alive. The 12-month PFS is 84%.

“Preliminary response data were similar to the prior CALGB/Alliance study of rituximab and lenalidomide,” Dr Ujjani noted. “However, given the increased toxicity and required dose modifications, the additional benefit of a third agent is not apparent, and further investigation of the triplet in this setting seems unwarranted.”

*Data in the abstract differ from data presented at the meeting.

 

 

2015 ASH Annual Meeting

Photo courtesy of ASH

 

ORLANDO, FL—A 3-drug regimen is likely not worth pursuing as a first-line treatment option for follicular lymphoma (FL), according to a presentation at the 2015 ASH Annual Meeting.

In a phase 1 study, combination ibrutinib, rituximab, and lenalidomide did not provide any response benefit over that previously observed with rituximab and lenalidomide.

But the triplet increased toxicity—particularly the incidence of rash—and necessitated dose modifications.

Chaitra S. Ujjani, MD, of Georgetown University Hospital in Washington, DC, presented these results at the meeting as abstract 471.*

“The combination of rituximab and lenalidomide has demonstrated remarkable activity in follicular lymphoma,” Dr Ujjani began.

She noted that, in the CALGB 50401 trial of relapsed FL (Leonard et al. JCO 2015), the combination elicited an overall response rate (ORR) of 76% and a complete response (CR) rate of 39%, and the 2-year time to progression was 52%.

In the CALGB 50803 trial of previously untreated FL (Martin et al. ASCO 2014, 8521), the regimen produced an ORR of 96%, a CR rate of 71%, and a 2-year progression-free survival (PFS) of 89%. In another trial of previously untreated FL (Fowler et al. Lanc Onc 2014), the ORR was 90%, the CR rate was 80%, and the 3-year PFS was 79%.

Ibrutinib has also demonstrated activity in FL, Dr Ujjani pointed out. In a phase 1 study of relapsed FL (Fowler et al. ASH 2012), the drug produced an ORR of 55%, 3 of 11 patients achieved a CR, and the median PFS was 13.4 months.

In a phase 2 study of ibrutinib in relapsed FL (Bartlett et al. ASH 2014, 800), the ORR was 30%, 1 of 40 patients achieved a CR, and the median PFS was 9.9 months.

With this in mind, Dr Ujjani and her colleagues conducted the A051103 trial to determine the activity and tolerability of rituximab, lenalidomide, and ibrutinib in previously untreated patients with FL.

Study design

The study enrolled patients with grade 1-3a FL; stage III, IV, or bulky stage II disease; an ECOG performance status less than 2; and adequate organ function.

They received 4 doses of rituximab at 375 mg/m² on days 1, 8, 15, and 22 of cycle 1 (28 days). They received 4 additional doses (375 mg/m²) on day 1 of cycles 4, 6, 8, and 10.

The patients received lenalidomide according to their assigned dosing cohort on days 1 to 21 for 18 cycles. They received daily ibrutinib according to their assigned dosing cohort until progression or unacceptable toxicity.

The study had a 3+3 dose-escalation design. Dose level (DL) 0 was lenalidomide at 15 mg and ibrutinib at 420 mg, DL1 was lenalidomide at 15 mg and ibrutinib at 560 mg, and DL2 was lenalidomide at 20 mg and ibrutinib at 560 mg.

Patients also received allopurinol at 300 mg daily for tumor lysis prophylaxis and aspirin as thromboprophylaxis while on lenalidomide.

The researchers assessed dose-limiting toxicities (DLTs) weekly during cycle 1. Given the known incidence of rash with lenalidomide, grade 3 rash that resolved to less than grade 2 within 10 days was not included as a DLT.

Once the maximum-tolerated dose was determined, there was a 10-patient expansion cohort.

Patients and treatment

Twenty-two patients were enrolled between June 2013 and May 2015. Their median age was 53.5 years (range, 36-81), and 68% were male.

Seventy-three percent of patients had grade 1/2 disease, and 77% had stage IV disease. By FLIPI, 18% of patients were low-risk, 55% were intermediate-risk, and 27% were high-risk.

Three patients were treated at DL0, 3 at DL1, and 16 at DL2. There were no DLTs reported at any dose level.

However, 11 patients required dose reductions due to toxicity (7 due to rash), and 12 patients ultimately discontinued treatment.

Reasons for discontinuation included progression (n=2), new diagnosis of carcinoma requiring systemic therapy (n=2), patient decision (n=3), and adverse events (n=6), including grade 3 rash (n=2), grade 3 atrial flutter (n=1), grade 3 diarrhea (n=1), hypertension (n=1), and depression (n=1). (One patient discontinued due to rash and progression.)

Adverse events

Dr Ujjani said the hematologic toxicity profile was similar to that observed with rituximab and lenalidomide in the front-line setting. Grade 3/4 hematologic toxicities included neutropenia (18.2%), thrombocytopenia (4.5%), anemia (4.5%), and lymphopenia (4.5%).

The most common non-hematologic toxicities (occurring in more than 20% of patients) were rash, diarrhea, fatigue, infusion-related reactions, nausea, infection, and neoplasms. There were no grade 4 non-hematologic toxicities.

Compared to rituximab and lenalidomide, the triplet was associated with an increase in rash, diarrhea, arthralgia, and neoplasm. There were 2 cutaneous neoplasms and 3 carcinomas.

Rash

“While no protocol-defined DLTs were observed, the regimen was associated with clinically significant rash,” Dr Ujjani noted. “Rash may have been related to individual study drugs or drug-drug interactions.”

Rash occurred in 82% of patients overall, 100% of patients treated at DL0, 67% at DL1, and 81% at DL2. The incidence of grade 1/2 rash was 46% overall, 67% at DL0, 33% at DL1, and 44% at DL2. The incidence of grade 3 rash was 36% overall, 33% at DL0 and DL1, and 38% at DL2.

The incidence of rash was similar whether or not patients received allopurinol. Ten of 11 patients on allopurinol had a rash, and 8 of 11 patients not on allopurinol had a rash.

“The time of [rash] onset was typically during cycle 1 but was seen as late as cycle 5,” Dr Ujjani said. “Grade 1 and 2 rashes resolved spontaneously without dose modification. The incidence of these milder rashes were comparable to our prior reports of rituximab and lenalidomide.”

“Grade 3 rash, however, occurred in 36% of patients, which is significantly higher than [with] rituximab and lenalidomide, [which is] typically 7% to 8%, or single-agent ibrutinib, which is about 3% to 4%.”

Patients with grade 3 rash were managed with supportive care, including acetaminophen, diphenhydramine, and oral corticosteroids.

All but 1 patient (7/8) had dose delays and reductions due to rash. One patient withdrew from the study because of rash, and 1 patient withdrew because of disease progression that occurred during a dose delay for rash.

Response and survival

The ORR was 95% for the entire cohort, 100% at DL0 and DL1 and 94% at DL2. The CR/unconfirmed CR rate was 63% overall, 67% at DL0, 33% at DL1, and 69% at DL2.

The partial response rate was 32% overall, 33% at DL0, 67% at DL1, and 25% at DL2. Five percent of patients had stable disease, all at DL2 (6% of this group).

The median time to first response was 2.3 months (range, 1.9 to 11.1). And the median time to best response was 5.5 months (range, 1.9 to 20.2).

At a median follow-up of 12.3 months, all patients are still alive. The 12-month PFS is 84%.

“Preliminary response data were similar to the prior CALGB/Alliance study of rituximab and lenalidomide,” Dr Ujjani noted. “However, given the increased toxicity and required dose modifications, the additional benefit of a third agent is not apparent, and further investigation of the triplet in this setting seems unwarranted.”

*Data in the abstract differ from data presented at the meeting.

 

 

2015 ASH Annual Meeting

Photo courtesy of ASH

 

ORLANDO, FL—A 3-drug regimen is likely not worth pursuing as a first-line treatment option for follicular lymphoma (FL), according to a presentation at the 2015 ASH Annual Meeting.

In a phase 1 study, combination ibrutinib, rituximab, and lenalidomide did not provide any response benefit over that previously observed with rituximab and lenalidomide.

But the triplet increased toxicity—particularly the incidence of rash—and necessitated dose modifications.

Chaitra S. Ujjani, MD, of Georgetown University Hospital in Washington, DC, presented these results at the meeting as abstract 471.*

“The combination of rituximab and lenalidomide has demonstrated remarkable activity in follicular lymphoma,” Dr Ujjani began.

She noted that, in the CALGB 50401 trial of relapsed FL (Leonard et al. JCO 2015), the combination elicited an overall response rate (ORR) of 76% and a complete response (CR) rate of 39%, and the 2-year time to progression was 52%.

In the CALGB 50803 trial of previously untreated FL (Martin et al. ASCO 2014, 8521), the regimen produced an ORR of 96%, a CR rate of 71%, and a 2-year progression-free survival (PFS) of 89%. In another trial of previously untreated FL (Fowler et al. Lanc Onc 2014), the ORR was 90%, the CR rate was 80%, and the 3-year PFS was 79%.

Ibrutinib has also demonstrated activity in FL, Dr Ujjani pointed out. In a phase 1 study of relapsed FL (Fowler et al. ASH 2012), the drug produced an ORR of 55%, 3 of 11 patients achieved a CR, and the median PFS was 13.4 months.

In a phase 2 study of ibrutinib in relapsed FL (Bartlett et al. ASH 2014, 800), the ORR was 30%, 1 of 40 patients achieved a CR, and the median PFS was 9.9 months.

With this in mind, Dr Ujjani and her colleagues conducted the A051103 trial to determine the activity and tolerability of rituximab, lenalidomide, and ibrutinib in previously untreated patients with FL.

Study design

The study enrolled patients with grade 1-3a FL; stage III, IV, or bulky stage II disease; an ECOG performance status less than 2; and adequate organ function.

They received 4 doses of rituximab at 375 mg/m² on days 1, 8, 15, and 22 of cycle 1 (28 days). They received 4 additional doses (375 mg/m²) on day 1 of cycles 4, 6, 8, and 10.

The patients received lenalidomide according to their assigned dosing cohort on days 1 to 21 for 18 cycles. They received daily ibrutinib according to their assigned dosing cohort until progression or unacceptable toxicity.

The study had a 3+3 dose-escalation design. Dose level (DL) 0 was lenalidomide at 15 mg and ibrutinib at 420 mg, DL1 was lenalidomide at 15 mg and ibrutinib at 560 mg, and DL2 was lenalidomide at 20 mg and ibrutinib at 560 mg.

Patients also received allopurinol at 300 mg daily for tumor lysis prophylaxis and aspirin as thromboprophylaxis while on lenalidomide.

The researchers assessed dose-limiting toxicities (DLTs) weekly during cycle 1. Given the known incidence of rash with lenalidomide, grade 3 rash that resolved to less than grade 2 within 10 days was not included as a DLT.

Once the maximum-tolerated dose was determined, there was a 10-patient expansion cohort.

Patients and treatment

Twenty-two patients were enrolled between June 2013 and May 2015. Their median age was 53.5 years (range, 36-81), and 68% were male.

Seventy-three percent of patients had grade 1/2 disease, and 77% had stage IV disease. By FLIPI, 18% of patients were low-risk, 55% were intermediate-risk, and 27% were high-risk.

Three patients were treated at DL0, 3 at DL1, and 16 at DL2. There were no DLTs reported at any dose level.

However, 11 patients required dose reductions due to toxicity (7 due to rash), and 12 patients ultimately discontinued treatment.

Reasons for discontinuation included progression (n=2), new diagnosis of carcinoma requiring systemic therapy (n=2), patient decision (n=3), and adverse events (n=6), including grade 3 rash (n=2), grade 3 atrial flutter (n=1), grade 3 diarrhea (n=1), hypertension (n=1), and depression (n=1). (One patient discontinued due to rash and progression.)

Adverse events

Dr Ujjani said the hematologic toxicity profile was similar to that observed with rituximab and lenalidomide in the front-line setting. Grade 3/4 hematologic toxicities included neutropenia (18.2%), thrombocytopenia (4.5%), anemia (4.5%), and lymphopenia (4.5%).

The most common non-hematologic toxicities (occurring in more than 20% of patients) were rash, diarrhea, fatigue, infusion-related reactions, nausea, infection, and neoplasms. There were no grade 4 non-hematologic toxicities.

Compared to rituximab and lenalidomide, the triplet was associated with an increase in rash, diarrhea, arthralgia, and neoplasm. There were 2 cutaneous neoplasms and 3 carcinomas.

Rash

“While no protocol-defined DLTs were observed, the regimen was associated with clinically significant rash,” Dr Ujjani noted. “Rash may have been related to individual study drugs or drug-drug interactions.”

Rash occurred in 82% of patients overall, 100% of patients treated at DL0, 67% at DL1, and 81% at DL2. The incidence of grade 1/2 rash was 46% overall, 67% at DL0, 33% at DL1, and 44% at DL2. The incidence of grade 3 rash was 36% overall, 33% at DL0 and DL1, and 38% at DL2.

The incidence of rash was similar whether or not patients received allopurinol. Ten of 11 patients on allopurinol had a rash, and 8 of 11 patients not on allopurinol had a rash.

“The time of [rash] onset was typically during cycle 1 but was seen as late as cycle 5,” Dr Ujjani said. “Grade 1 and 2 rashes resolved spontaneously without dose modification. The incidence of these milder rashes were comparable to our prior reports of rituximab and lenalidomide.”

“Grade 3 rash, however, occurred in 36% of patients, which is significantly higher than [with] rituximab and lenalidomide, [which is] typically 7% to 8%, or single-agent ibrutinib, which is about 3% to 4%.”

Patients with grade 3 rash were managed with supportive care, including acetaminophen, diphenhydramine, and oral corticosteroids.

All but 1 patient (7/8) had dose delays and reductions due to rash. One patient withdrew from the study because of rash, and 1 patient withdrew because of disease progression that occurred during a dose delay for rash.

Response and survival

The ORR was 95% for the entire cohort, 100% at DL0 and DL1 and 94% at DL2. The CR/unconfirmed CR rate was 63% overall, 67% at DL0, 33% at DL1, and 69% at DL2.

The partial response rate was 32% overall, 33% at DL0, 67% at DL1, and 25% at DL2. Five percent of patients had stable disease, all at DL2 (6% of this group).

The median time to first response was 2.3 months (range, 1.9 to 11.1). And the median time to best response was 5.5 months (range, 1.9 to 20.2).

At a median follow-up of 12.3 months, all patients are still alive. The 12-month PFS is 84%.

“Preliminary response data were similar to the prior CALGB/Alliance study of rituximab and lenalidomide,” Dr Ujjani noted. “However, given the increased toxicity and required dose modifications, the additional benefit of a third agent is not apparent, and further investigation of the triplet in this setting seems unwarranted.”

*Data in the abstract differ from data presented at the meeting.

Attendees at the 2015

ASH Annual Meeting

Photo courtesy of ASH

ORLANDO, FL—A monoclonal antibody (mAb) targeting interferon-gamma (IFNγ) has shown promise for treating hemophagocytic lymphohistiocytosis (HLH), according to a late-breaking abstract presented at the 2015 ASH Annual Meeting.

Results of an ongoing phase 2 study suggest the mAb, NI-0501, may be a feasible treatment option for patients with HLH who have demonstrated an unsatisfactory response to, or cannot tolerate, conventional therapy.

Nine of 13 evaluable patients achieved a “satisfactory response” to NI-0501, and no safety concerns were identified, said Michael Jordan, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.

Dr Jordan presented these results at ASH as LBA-3.* The trial was sponsored by Novimmune.

“Treatment of HLH remains very challenging,” Dr Jordan noted. “Initial therapy is directed at trying to suppress the out-of-control immune response. In children that are at risk for recurrent episodes of HLH, they proceed to hematopoietic cell transplantation and, hopefully, this allows long-term survival.”

“First-line therapy has been defined in international trials and involves etoposide and dexamethasone. This regimen, as you might imagine, in children that present already with cytopenias, is myelosuppressive. It’s also broadly immune-suppressive. And although this does allow long-term survival in these children, there’s plenty of room for improvement in results.”

“[T]here is no standard of care for second-line therapy. Though there are no prospective data, children are increasingly treated with T-cell-depleting agents such as alemtuzumab and ATG, but this produces profound and long-lasting immune suppression. Though survival is not well-defined in these patients, it’s thought to be poor.”

In hopes of finding a new treatment option for HLH, Dr Jordan and his colleagues attempted to determine what drives the disease process. In preclinical studies, they identified IFNγ as a rational target in HLH. Blockade of IFNγ led to improved survival in mouse models.

The researchers also found elevated levels of IFNγ in patients with HLH. These preclinical and clinical data led to the development of NI-0501, a fully human, high affinity, anti-IFNγ mAb that binds to and neutralizes IFNγ.

Patients and treatment

In their phase 2 trial, Dr Jordan and his colleagues assessed NI-0501 in 16 patients—8 males and 8 females. Their median age was 1.2 years (range, 0.2-13). Twelve patients had causative mutations—FHL2 (n=4), FHL3 (n=2), FHL4 (n=1), GS-2 (n=3), XLP-1 (n=1), and XLP-2 (n=1). And 4 patients had central nervous system (CNS) involvement.

Two patients were receiving NI-0501 as first-line treatment, and the rest were receiving the mAb as second-line treatment. Patients had previously received dexamethasone (n=13), methylprednisone (n=2), etoposide (n=13), ATG (n=4), cyclosporine A (n=6), and “other” therapy (n=4).

NI-0501 was given at a starting dose of 1 mg/kg every 3 days, with possible dose increases guided by pharmacokinetic data and/or clinical response in each patient. The mAb was administered with dexamethasone at a dose of 5mg/m² to 10 mg/m², but dexamethasone could be tapered during the treatment course.

The treatment duration ranged from 4 weeks to 8 weeks, and the follow-up period was 4 weeks.

Response and survival

One patient was excluded from the analysis due to a lymphoma diagnosis after enrollment. Two patients are still receiving treatment, and 13 have completed treatment.

Among the patients who completed therapy, 4 had an insufficient response. Two of these patients died, and 2 proceeded to allogeneic hematopoietic stem cell transplant (HSCT) after receiving additional agents to control their disease.

Nine patients achieved a favorable response to NI-0501. Seven of these patients proceeded to HSCT, and 2 are awaiting HSCT with their disease well-controlled.

Post-transplant follow-up is still early for most patients, but 2 patients have follow-up greater than 1 year. One child died of graft-vs-host disease around day 45, but the remaining patients who went on to HSCT are still alive.

Characteristics of response

For some patients, response to NI-0501 included a significant improvement in neutrophil count (8/10, P<0.001), platelet count (7/12, P<0.001), and ferritin level (P=0.0025). The median serum ferritin level was 4142 ng/mL at baseline and 1648 ng/mL at the end of treatment.

Both patients who were febrile at the start of treatment experienced rapid normalization of fever. Six of 7 patients with palpable spleen or liver at the start of treatment had an improvement in organomegaly. And 3 of 4 patients had resolution or improvement of CNS involvement.

Overall, there was a significant decrease in glucocorticoid dose. The median dose at baseline was 10.0 mg/m². At the end of treatment, the median dose was 4.0 mg/m² (P=0.023).

“One pharmacodynamic readout that’s useful for understanding IFNγ biology in vivo is CXCL9,” Dr Jordan noted. “This is secreted by mononuclear phagocytes in response to IFNγ. And most patients had a very clear fall in CXCL9 while receiving NI-0501.”

Adverse events and death

No off-target effects of NI-0501 have been observed, and none of the patients have withdrawn from the study for safety reasons.

There have been 14 serious adverse events in 8 patients, but only 1 of these events was considered treatment-related. The patient had necrotizing fasciitis following P aeruginosa skin infection, which resolved. This event was considered treatment-related by an investigator but not by the data monitoring committee or the sponsor.

In all, 3 patients have died, but none of the deaths were related to NI-0501. Two patients died of HLH/multi-organ failure, and 1 died of graft-vs-host disease.

Infections

“[NI-0501 provides] a targeted form of immune suppression, so we can expect that most concerns will be related to infection,” Dr Jordan said. “The effects of IFNγ on immune defense are actually predictable, and they’re predictable because of 2 patient populations.”

“First are the rare patients who are born with IFNγ-receptor deficiency, and second are individuals that develop neutralizing autoantibodies against IFNγ. Both patient populations experience infections with atypical mycobacteria, tuberculosis, Salmonella, and so forth.”

There were 10 infections already present at the start of the study—St epidermidis (n=1), C difficile (n=1), E coli (n=1, gram-positive), cytomegalovirus (n=1), Epstein-Barr virus (n=4), and parvovirus (n=1). All of these infections resolved with treatment.

Fourteen infections arose during the study course—St epidermidis (n=1), C difficile (n=1), P aeruginosa (n=1), K pneumoniae (n=1), E coli (1 gram-positive, 1 gram-negative), adenovirus (n=1), cytomegalovirus (n=2), Epstein-Barr virus (1 reactivation), parvovirus (1 reactivation), parainfluenza T3 (n=1), influenza A (n=1), and Candida (n=1).

Most of these infections resolved. The exceptions were the case of adenovirus, 1 case of cytomegalovirus (although there was improvement), the Epstein-Barr virus reactivation, the parvovirus reactivation (though improved), and the case of influenza A.

The researchers did not know if the parainfluenza T3 infection resolved. The patient’s viral status was not reassessed prior to death.

“So, in conclusion, NI-0501 has shown the potential to improve or resolve clinical and laboratory abnormalities of HLH, including CNS signs and symptoms,” Dr Jordan said. “The response to this agent appears to be independent of the underlying causative mutation. It’s also independent of the presence and type of infectious trigger.”

“NI-0501 was very well-tolerated. No safety concerns have emerged to date, and no infections known to be caused by deficiency of IFNγ have been observed. The neutralization of IFNγ by NI-0501 can offer an innovative and targeted approach to the management of HLH.”

*Data in the abstract differ from data presented at the meeting.

Attendees at the 2015

ASH Annual Meeting

Photo courtesy of ASH

ORLANDO, FL—A monoclonal antibody (mAb) targeting interferon-gamma (IFNγ) has shown promise for treating hemophagocytic lymphohistiocytosis (HLH), according to a late-breaking abstract presented at the 2015 ASH Annual Meeting.

Results of an ongoing phase 2 study suggest the mAb, NI-0501, may be a feasible treatment option for patients with HLH who have demonstrated an unsatisfactory response to, or cannot tolerate, conventional therapy.

Nine of 13 evaluable patients achieved a “satisfactory response” to NI-0501, and no safety concerns were identified, said Michael Jordan, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.

Dr Jordan presented these results at ASH as LBA-3.* The trial was sponsored by Novimmune.

“Treatment of HLH remains very challenging,” Dr Jordan noted. “Initial therapy is directed at trying to suppress the out-of-control immune response. In children that are at risk for recurrent episodes of HLH, they proceed to hematopoietic cell transplantation and, hopefully, this allows long-term survival.”

“First-line therapy has been defined in international trials and involves etoposide and dexamethasone. This regimen, as you might imagine, in children that present already with cytopenias, is myelosuppressive. It’s also broadly immune-suppressive. And although this does allow long-term survival in these children, there’s plenty of room for improvement in results.”

“[T]here is no standard of care for second-line therapy. Though there are no prospective data, children are increasingly treated with T-cell-depleting agents such as alemtuzumab and ATG, but this produces profound and long-lasting immune suppression. Though survival is not well-defined in these patients, it’s thought to be poor.”

In hopes of finding a new treatment option for HLH, Dr Jordan and his colleagues attempted to determine what drives the disease process. In preclinical studies, they identified IFNγ as a rational target in HLH. Blockade of IFNγ led to improved survival in mouse models.

The researchers also found elevated levels of IFNγ in patients with HLH. These preclinical and clinical data led to the development of NI-0501, a fully human, high affinity, anti-IFNγ mAb that binds to and neutralizes IFNγ.

Patients and treatment

In their phase 2 trial, Dr Jordan and his colleagues assessed NI-0501 in 16 patients—8 males and 8 females. Their median age was 1.2 years (range, 0.2-13). Twelve patients had causative mutations—FHL2 (n=4), FHL3 (n=2), FHL4 (n=1), GS-2 (n=3), XLP-1 (n=1), and XLP-2 (n=1). And 4 patients had central nervous system (CNS) involvement.

Two patients were receiving NI-0501 as first-line treatment, and the rest were receiving the mAb as second-line treatment. Patients had previously received dexamethasone (n=13), methylprednisone (n=2), etoposide (n=13), ATG (n=4), cyclosporine A (n=6), and “other” therapy (n=4).

NI-0501 was given at a starting dose of 1 mg/kg every 3 days, with possible dose increases guided by pharmacokinetic data and/or clinical response in each patient. The mAb was administered with dexamethasone at a dose of 5mg/m² to 10 mg/m², but dexamethasone could be tapered during the treatment course.

The treatment duration ranged from 4 weeks to 8 weeks, and the follow-up period was 4 weeks.

Response and survival

One patient was excluded from the analysis due to a lymphoma diagnosis after enrollment. Two patients are still receiving treatment, and 13 have completed treatment.

Among the patients who completed therapy, 4 had an insufficient response. Two of these patients died, and 2 proceeded to allogeneic hematopoietic stem cell transplant (HSCT) after receiving additional agents to control their disease.

Nine patients achieved a favorable response to NI-0501. Seven of these patients proceeded to HSCT, and 2 are awaiting HSCT with their disease well-controlled.

Post-transplant follow-up is still early for most patients, but 2 patients have follow-up greater than 1 year. One child died of graft-vs-host disease around day 45, but the remaining patients who went on to HSCT are still alive.

Characteristics of response

For some patients, response to NI-0501 included a significant improvement in neutrophil count (8/10, P<0.001), platelet count (7/12, P<0.001), and ferritin level (P=0.0025). The median serum ferritin level was 4142 ng/mL at baseline and 1648 ng/mL at the end of treatment.

Both patients who were febrile at the start of treatment experienced rapid normalization of fever. Six of 7 patients with palpable spleen or liver at the start of treatment had an improvement in organomegaly. And 3 of 4 patients had resolution or improvement of CNS involvement.

Overall, there was a significant decrease in glucocorticoid dose. The median dose at baseline was 10.0 mg/m². At the end of treatment, the median dose was 4.0 mg/m² (P=0.023).

“One pharmacodynamic readout that’s useful for understanding IFNγ biology in vivo is CXCL9,” Dr Jordan noted. “This is secreted by mononuclear phagocytes in response to IFNγ. And most patients had a very clear fall in CXCL9 while receiving NI-0501.”

Adverse events and death

No off-target effects of NI-0501 have been observed, and none of the patients have withdrawn from the study for safety reasons.

There have been 14 serious adverse events in 8 patients, but only 1 of these events was considered treatment-related. The patient had necrotizing fasciitis following P aeruginosa skin infection, which resolved. This event was considered treatment-related by an investigator but not by the data monitoring committee or the sponsor.

In all, 3 patients have died, but none of the deaths were related to NI-0501. Two patients died of HLH/multi-organ failure, and 1 died of graft-vs-host disease.

Infections

“[NI-0501 provides] a targeted form of immune suppression, so we can expect that most concerns will be related to infection,” Dr Jordan said. “The effects of IFNγ on immune defense are actually predictable, and they’re predictable because of 2 patient populations.”

“First are the rare patients who are born with IFNγ-receptor deficiency, and second are individuals that develop neutralizing autoantibodies against IFNγ. Both patient populations experience infections with atypical mycobacteria, tuberculosis, Salmonella, and so forth.”

There were 10 infections already present at the start of the study—St epidermidis (n=1), C difficile (n=1), E coli (n=1, gram-positive), cytomegalovirus (n=1), Epstein-Barr virus (n=4), and parvovirus (n=1). All of these infections resolved with treatment.

Fourteen infections arose during the study course—St epidermidis (n=1), C difficile (n=1), P aeruginosa (n=1), K pneumoniae (n=1), E coli (1 gram-positive, 1 gram-negative), adenovirus (n=1), cytomegalovirus (n=2), Epstein-Barr virus (1 reactivation), parvovirus (1 reactivation), parainfluenza T3 (n=1), influenza A (n=1), and Candida (n=1).

Most of these infections resolved. The exceptions were the case of adenovirus, 1 case of cytomegalovirus (although there was improvement), the Epstein-Barr virus reactivation, the parvovirus reactivation (though improved), and the case of influenza A.

The researchers did not know if the parainfluenza T3 infection resolved. The patient’s viral status was not reassessed prior to death.

“So, in conclusion, NI-0501 has shown the potential to improve or resolve clinical and laboratory abnormalities of HLH, including CNS signs and symptoms,” Dr Jordan said. “The response to this agent appears to be independent of the underlying causative mutation. It’s also independent of the presence and type of infectious trigger.”

“NI-0501 was very well-tolerated. No safety concerns have emerged to date, and no infections known to be caused by deficiency of IFNγ have been observed. The neutralization of IFNγ by NI-0501 can offer an innovative and targeted approach to the management of HLH.”

*Data in the abstract differ from data presented at the meeting.

Attendees at the 2015

ASH Annual Meeting

Photo courtesy of ASH

ORLANDO, FL—A monoclonal antibody (mAb) targeting interferon-gamma (IFNγ) has shown promise for treating hemophagocytic lymphohistiocytosis (HLH), according to a late-breaking abstract presented at the 2015 ASH Annual Meeting.

Results of an ongoing phase 2 study suggest the mAb, NI-0501, may be a feasible treatment option for patients with HLH who have demonstrated an unsatisfactory response to, or cannot tolerate, conventional therapy.

Nine of 13 evaluable patients achieved a “satisfactory response” to NI-0501, and no safety concerns were identified, said Michael Jordan, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.

Dr Jordan presented these results at ASH as LBA-3.* The trial was sponsored by Novimmune.

“Treatment of HLH remains very challenging,” Dr Jordan noted. “Initial therapy is directed at trying to suppress the out-of-control immune response. In children that are at risk for recurrent episodes of HLH, they proceed to hematopoietic cell transplantation and, hopefully, this allows long-term survival.”

“First-line therapy has been defined in international trials and involves etoposide and dexamethasone. This regimen, as you might imagine, in children that present already with cytopenias, is myelosuppressive. It’s also broadly immune-suppressive. And although this does allow long-term survival in these children, there’s plenty of room for improvement in results.”

“[T]here is no standard of care for second-line therapy. Though there are no prospective data, children are increasingly treated with T-cell-depleting agents such as alemtuzumab and ATG, but this produces profound and long-lasting immune suppression. Though survival is not well-defined in these patients, it’s thought to be poor.”

In hopes of finding a new treatment option for HLH, Dr Jordan and his colleagues attempted to determine what drives the disease process. In preclinical studies, they identified IFNγ as a rational target in HLH. Blockade of IFNγ led to improved survival in mouse models.

The researchers also found elevated levels of IFNγ in patients with HLH. These preclinical and clinical data led to the development of NI-0501, a fully human, high affinity, anti-IFNγ mAb that binds to and neutralizes IFNγ.

Patients and treatment

In their phase 2 trial, Dr Jordan and his colleagues assessed NI-0501 in 16 patients—8 males and 8 females. Their median age was 1.2 years (range, 0.2-13). Twelve patients had causative mutations—FHL2 (n=4), FHL3 (n=2), FHL4 (n=1), GS-2 (n=3), XLP-1 (n=1), and XLP-2 (n=1). And 4 patients had central nervous system (CNS) involvement.

Two patients were receiving NI-0501 as first-line treatment, and the rest were receiving the mAb as second-line treatment. Patients had previously received dexamethasone (n=13), methylprednisone (n=2), etoposide (n=13), ATG (n=4), cyclosporine A (n=6), and “other” therapy (n=4).

NI-0501 was given at a starting dose of 1 mg/kg every 3 days, with possible dose increases guided by pharmacokinetic data and/or clinical response in each patient. The mAb was administered with dexamethasone at a dose of 5mg/m² to 10 mg/m², but dexamethasone could be tapered during the treatment course.

The treatment duration ranged from 4 weeks to 8 weeks, and the follow-up period was 4 weeks.

Response and survival

One patient was excluded from the analysis due to a lymphoma diagnosis after enrollment. Two patients are still receiving treatment, and 13 have completed treatment.

Among the patients who completed therapy, 4 had an insufficient response. Two of these patients died, and 2 proceeded to allogeneic hematopoietic stem cell transplant (HSCT) after receiving additional agents to control their disease.

Nine patients achieved a favorable response to NI-0501. Seven of these patients proceeded to HSCT, and 2 are awaiting HSCT with their disease well-controlled.

Post-transplant follow-up is still early for most patients, but 2 patients have follow-up greater than 1 year. One child died of graft-vs-host disease around day 45, but the remaining patients who went on to HSCT are still alive.

Characteristics of response

For some patients, response to NI-0501 included a significant improvement in neutrophil count (8/10, P<0.001), platelet count (7/12, P<0.001), and ferritin level (P=0.0025). The median serum ferritin level was 4142 ng/mL at baseline and 1648 ng/mL at the end of treatment.

Both patients who were febrile at the start of treatment experienced rapid normalization of fever. Six of 7 patients with palpable spleen or liver at the start of treatment had an improvement in organomegaly. And 3 of 4 patients had resolution or improvement of CNS involvement.

Overall, there was a significant decrease in glucocorticoid dose. The median dose at baseline was 10.0 mg/m². At the end of treatment, the median dose was 4.0 mg/m² (P=0.023).

“One pharmacodynamic readout that’s useful for understanding IFNγ biology in vivo is CXCL9,” Dr Jordan noted. “This is secreted by mononuclear phagocytes in response to IFNγ. And most patients had a very clear fall in CXCL9 while receiving NI-0501.”

Adverse events and death

No off-target effects of NI-0501 have been observed, and none of the patients have withdrawn from the study for safety reasons.

There have been 14 serious adverse events in 8 patients, but only 1 of these events was considered treatment-related. The patient had necrotizing fasciitis following P aeruginosa skin infection, which resolved. This event was considered treatment-related by an investigator but not by the data monitoring committee or the sponsor.

In all, 3 patients have died, but none of the deaths were related to NI-0501. Two patients died of HLH/multi-organ failure, and 1 died of graft-vs-host disease.

Infections

“[NI-0501 provides] a targeted form of immune suppression, so we can expect that most concerns will be related to infection,” Dr Jordan said. “The effects of IFNγ on immune defense are actually predictable, and they’re predictable because of 2 patient populations.”

“First are the rare patients who are born with IFNγ-receptor deficiency, and second are individuals that develop neutralizing autoantibodies against IFNγ. Both patient populations experience infections with atypical mycobacteria, tuberculosis, Salmonella, and so forth.”

There were 10 infections already present at the start of the study—St epidermidis (n=1), C difficile (n=1), E coli (n=1, gram-positive), cytomegalovirus (n=1), Epstein-Barr virus (n=4), and parvovirus (n=1). All of these infections resolved with treatment.

Fourteen infections arose during the study course—St epidermidis (n=1), C difficile (n=1), P aeruginosa (n=1), K pneumoniae (n=1), E coli (1 gram-positive, 1 gram-negative), adenovirus (n=1), cytomegalovirus (n=2), Epstein-Barr virus (1 reactivation), parvovirus (1 reactivation), parainfluenza T3 (n=1), influenza A (n=1), and Candida (n=1).

Most of these infections resolved. The exceptions were the case of adenovirus, 1 case of cytomegalovirus (although there was improvement), the Epstein-Barr virus reactivation, the parvovirus reactivation (though improved), and the case of influenza A.

The researchers did not know if the parainfluenza T3 infection resolved. The patient’s viral status was not reassessed prior to death.

“So, in conclusion, NI-0501 has shown the potential to improve or resolve clinical and laboratory abnormalities of HLH, including CNS signs and symptoms,” Dr Jordan said. “The response to this agent appears to be independent of the underlying causative mutation. It’s also independent of the presence and type of infectious trigger.”

“NI-0501 was very well-tolerated. No safety concerns have emerged to date, and no infections known to be caused by deficiency of IFNγ have been observed. The neutralization of IFNγ by NI-0501 can offer an innovative and targeted approach to the management of HLH.”

*Data in the abstract differ from data presented at the meeting.

Micrograph showing CLL

ORLANDO, FL—The second-generation BTK inhibitor acalabrutinib (ACP-196) can elicit durable partial responses in patients with chronic lymphocytic leukemia (CLL) while producing minimal side effects, according to researchers.

They said data suggest that, compared to the first-generation BTK inhibitor ibrutinib, acalabrutinib more selectively blocks the BTK pathway.

And it does so without disrupting other molecular pathways that are important for preserving platelet and immune function, thereby avoiding or minimizing certain side effects.

John C. Byrd, MD, of The Ohio State University Comprehensive Cancer Center in Columbus, and his colleagues reported data from an ongoing phase 1/2 trial of acalabrutinib in NEJM and at the 2015 ASH Annual Meeting (abstract 831). The study was sponsored by Acerta Pharma.

The researchers reported on 61 patients with relapsed CLL. They had a median age of 62 (range, 44-84) and a median of 3 prior therapies (range, 1-13).

Most patients had an ECOG performance status of 1 (59%) or 0 (36%). Most had high-risk (67%) or intermediate-risk disease (31%) according to Rai classification. Forty-six percent of patients had lymph nodes ≥ 5 cm in diameter, and 5% had lymph nodes ≥ 10 cm.

Seventy-five percent of patients had unmutated immunoglobulin variable-region heavy-chain gene, 31% had 17p deletion, 29% had 17q deletion, and 81% had β2-microglobulin > 3.5 mg/liter.

Patients enrolled in the phase 1 portion of the study received escalating doses of acalabrutinib, with a maximum dose of 400 mg once daily. Patients involved in the phase 2 portion of the study were treated with a 100 mg dose twice daily.

Adverse events and discontinuation

At a median follow-up of 14.3 months (range, 0.5 to 20), 53 patients are still receiving treatment.

The primary reasons for treatment discontinuation were investigator or patient decision (n=2), active autoimmune hemolytic anemia that required additional therapy (n=1), fatal pneumonia (n=1), CLL progression, and adverse events of diarrhea (n=1), gastritis (n=1), and dyspnea (n=1).

The most common adverse events of all grades (occurring in at least 20% of patients) were headache (43%), diarrhea (39%), increased weight (26%), pyrexia (23%), upper respiratory tract infection (23%), fatigue (21%), peripheral edema (21%), hypertension (20%), and nausea (20%).

Grade 3/4 adverse events included diarrhea (2%), increased weight (2%), pyrexia (3%), fatigue (3%), hypertension (7%), and arthralgia (2%).

Response

The overall response rate among the 60 evaluable patients was 95%. This included partial responses in 85% of patients and partial responses with lymphocytosis in 10%. The rate of stable disease was 5%.

The researchers noted that responses occurred in all dosing cohorts, and the response rate increased over time.

All 18 patients with 17p deletion experienced a partial response (89%) or partial response with lymphocytosis (11%). But 1 of these patients later progressed.

All 4 patients who previously received idelalisib responded to acalabrutinib, with partial responses in 75% and partial responses with lymphocytosis in 25%.

There were no cases of Richter’s transformation.

In all, 1 patient experienced progression at 16 months, and 1 patient died of pneumonia at 13 months.

“This data is very exciting because it illustrates that acalabrutinib is a highly potent and selective oral BTK inhibitor that can be given safely in patients with relapsed CLL,” Dr Byrd said. “What is particularly remarkable is how well patients are tolerating this therapy.”

Clinical trials of acalabrutinib in CLL are ongoing, including a phase 3 head-to-head comparison of ibrutinib and acalabrutinib.

Micrograph showing CLL

ORLANDO, FL—The second-generation BTK inhibitor acalabrutinib (ACP-196) can elicit durable partial responses in patients with chronic lymphocytic leukemia (CLL) while producing minimal side effects, according to researchers.

They said data suggest that, compared to the first-generation BTK inhibitor ibrutinib, acalabrutinib more selectively blocks the BTK pathway.

And it does so without disrupting other molecular pathways that are important for preserving platelet and immune function, thereby avoiding or minimizing certain side effects.

John C. Byrd, MD, of The Ohio State University Comprehensive Cancer Center in Columbus, and his colleagues reported data from an ongoing phase 1/2 trial of acalabrutinib in NEJM and at the 2015 ASH Annual Meeting (abstract 831). The study was sponsored by Acerta Pharma.

The researchers reported on 61 patients with relapsed CLL. They had a median age of 62 (range, 44-84) and a median of 3 prior therapies (range, 1-13).

Most patients had an ECOG performance status of 1 (59%) or 0 (36%). Most had high-risk (67%) or intermediate-risk disease (31%) according to Rai classification. Forty-six percent of patients had lymph nodes ≥ 5 cm in diameter, and 5% had lymph nodes ≥ 10 cm.

Seventy-five percent of patients had unmutated immunoglobulin variable-region heavy-chain gene, 31% had 17p deletion, 29% had 17q deletion, and 81% had β2-microglobulin > 3.5 mg/liter.

Patients enrolled in the phase 1 portion of the study received escalating doses of acalabrutinib, with a maximum dose of 400 mg once daily. Patients involved in the phase 2 portion of the study were treated with a 100 mg dose twice daily.

Adverse events and discontinuation

At a median follow-up of 14.3 months (range, 0.5 to 20), 53 patients are still receiving treatment.

The primary reasons for treatment discontinuation were investigator or patient decision (n=2), active autoimmune hemolytic anemia that required additional therapy (n=1), fatal pneumonia (n=1), CLL progression, and adverse events of diarrhea (n=1), gastritis (n=1), and dyspnea (n=1).

The most common adverse events of all grades (occurring in at least 20% of patients) were headache (43%), diarrhea (39%), increased weight (26%), pyrexia (23%), upper respiratory tract infection (23%), fatigue (21%), peripheral edema (21%), hypertension (20%), and nausea (20%).

Grade 3/4 adverse events included diarrhea (2%), increased weight (2%), pyrexia (3%), fatigue (3%), hypertension (7%), and arthralgia (2%).

Response

The overall response rate among the 60 evaluable patients was 95%. This included partial responses in 85% of patients and partial responses with lymphocytosis in 10%. The rate of stable disease was 5%.

The researchers noted that responses occurred in all dosing cohorts, and the response rate increased over time.

All 18 patients with 17p deletion experienced a partial response (89%) or partial response with lymphocytosis (11%). But 1 of these patients later progressed.

All 4 patients who previously received idelalisib responded to acalabrutinib, with partial responses in 75% and partial responses with lymphocytosis in 25%.

There were no cases of Richter’s transformation.

In all, 1 patient experienced progression at 16 months, and 1 patient died of pneumonia at 13 months.

“This data is very exciting because it illustrates that acalabrutinib is a highly potent and selective oral BTK inhibitor that can be given safely in patients with relapsed CLL,” Dr Byrd said. “What is particularly remarkable is how well patients are tolerating this therapy.”

Clinical trials of acalabrutinib in CLL are ongoing, including a phase 3 head-to-head comparison of ibrutinib and acalabrutinib.

Micrograph showing CLL

ORLANDO, FL—The second-generation BTK inhibitor acalabrutinib (ACP-196) can elicit durable partial responses in patients with chronic lymphocytic leukemia (CLL) while producing minimal side effects, according to researchers.

They said data suggest that, compared to the first-generation BTK inhibitor ibrutinib, acalabrutinib more selectively blocks the BTK pathway.

And it does so without disrupting other molecular pathways that are important for preserving platelet and immune function, thereby avoiding or minimizing certain side effects.

John C. Byrd, MD, of The Ohio State University Comprehensive Cancer Center in Columbus, and his colleagues reported data from an ongoing phase 1/2 trial of acalabrutinib in NEJM and at the 2015 ASH Annual Meeting (abstract 831). The study was sponsored by Acerta Pharma.

The researchers reported on 61 patients with relapsed CLL. They had a median age of 62 (range, 44-84) and a median of 3 prior therapies (range, 1-13).

Most patients had an ECOG performance status of 1 (59%) or 0 (36%). Most had high-risk (67%) or intermediate-risk disease (31%) according to Rai classification. Forty-six percent of patients had lymph nodes ≥ 5 cm in diameter, and 5% had lymph nodes ≥ 10 cm.

Seventy-five percent of patients had unmutated immunoglobulin variable-region heavy-chain gene, 31% had 17p deletion, 29% had 17q deletion, and 81% had β2-microglobulin > 3.5 mg/liter.

Patients enrolled in the phase 1 portion of the study received escalating doses of acalabrutinib, with a maximum dose of 400 mg once daily. Patients involved in the phase 2 portion of the study were treated with a 100 mg dose twice daily.

Adverse events and discontinuation

At a median follow-up of 14.3 months (range, 0.5 to 20), 53 patients are still receiving treatment.

The primary reasons for treatment discontinuation were investigator or patient decision (n=2), active autoimmune hemolytic anemia that required additional therapy (n=1), fatal pneumonia (n=1), CLL progression, and adverse events of diarrhea (n=1), gastritis (n=1), and dyspnea (n=1).

The most common adverse events of all grades (occurring in at least 20% of patients) were headache (43%), diarrhea (39%), increased weight (26%), pyrexia (23%), upper respiratory tract infection (23%), fatigue (21%), peripheral edema (21%), hypertension (20%), and nausea (20%).

Grade 3/4 adverse events included diarrhea (2%), increased weight (2%), pyrexia (3%), fatigue (3%), hypertension (7%), and arthralgia (2%).

Response

The overall response rate among the 60 evaluable patients was 95%. This included partial responses in 85% of patients and partial responses with lymphocytosis in 10%. The rate of stable disease was 5%.

The researchers noted that responses occurred in all dosing cohorts, and the response rate increased over time.

All 18 patients with 17p deletion experienced a partial response (89%) or partial response with lymphocytosis (11%). But 1 of these patients later progressed.

All 4 patients who previously received idelalisib responded to acalabrutinib, with partial responses in 75% and partial responses with lymphocytosis in 25%.

There were no cases of Richter’s transformation.

In all, 1 patient experienced progression at 16 months, and 1 patient died of pneumonia at 13 months.

“This data is very exciting because it illustrates that acalabrutinib is a highly potent and selective oral BTK inhibitor that can be given safely in patients with relapsed CLL,” Dr Byrd said. “What is particularly remarkable is how well patients are tolerating this therapy.”

Clinical trials of acalabrutinib in CLL are ongoing, including a phase 3 head-to-head comparison of ibrutinib and acalabrutinib.

Flora Peyvandi, MD, PhD

Photo courtesy of ASH

ORLANDO, FL—The source of factor VIII (FVIII) replacement therapy affects the risk of inhibitor development in previously untreated patients with severe hemophilia A, according to a prospective, randomized trial.

Results of the SIPPET study indicate that receiving recombinant FVIII is associated with a nearly 2-fold higher risk of developing inhibitory alloantibodies than receiving plasma-derived FVIII.

These results have implications for the choice of therapy for previously untreated patients, as inhibitor development remains a major challenge in the management of hemophilia A, said Flora Peyvandi, MD, PhD, of Angelo Bianchi Bonomi Hemophilia and Thrombosis Center in Milan, Italy.

Dr Peyvandi presented results of the SIPPET study during the plenary session of the 2015 ASH Annual Meeting (abstract 5*).

She noted that 13 previous observational studies indicated an increased risk of inhibitor formation with recombinant FVIII. But 2 consecutive, multicenter, observational trials (CANAL and RODIN) suggested there was no difference in immunogenicity between recombinant and plasma-derived FVIII.

A few meta-analyses showed a higher risk of inhibitors with recombinant FVIII, but the difference between recombinant and plasma-derived FVIII was attenuated after researchers adjusted for confounding factors.

In an attempt to obtain some conclusive results, Dr Peyvandi and her colleagues conducted the SIPPET study. It is the first randomized clinical trial in hemophilia with the goal of comparing the immunogenicity of FVIII product classes—plasma-derived FVIII products with von Willebrand factor and recombinant FVIII products.

Study design

Between 2010 and 2014, the researchers enrolled patients from 42 sites in 14 countries from Africa, the Americas, Asia, and Europe.

The all-male patients were younger than 6 years of age at enrollment. They had severe hemophilia A, negative inhibitor measurement at enrollment, and no or minimal exposure (less than 5 exposure days) to blood products.

The patients were randomized to either a single plasma-derived FVIII product containing von Willebrand factor or a single recombinant FVIII product. The treatment was at the discretion of the local physician.

Patients were treated for 50 exposure days, 3 years, or until inhibitor development.

The primary outcome was any FVIII inhibitor at titers ≥ 0.4 BU/mL. High-titer inhibitors (≥ 5 BU/mL) were a secondary outcome. Transient inhibitors were defined as those that spontaneously disappeared within 6 months.

Patients were assessed every 3 to 5 exposure days in the first 20 exposure days, then every 10 exposure days or every 3 months and every 2 weeks during prophylaxis.

“Every time a clinician had some doubt about the development of inhibitors, this [was] measured and also confirmed at the central lab in Milan,” Dr Peyvandi noted.

Results

In all, 251 patients were analyzed—126 randomized to recombinant FVIII and 125 to plasma-derived FVIII.

Dr Peyvandi pointed out that confounders—such as family history, previous exposure, and surgery—were equally distributed between the treatment arms thanks to the randomization. The same was true for the treatment type—on-demand, standard prophylaxis, etc.

Overall, 76 patients developed inhibitors, for a cumulative incidence of 35.4%. Fifty patients had high-titer inhibitors, for a cumulative incidence of 23.3%.

The cumulative incidence of all inhibitors was 44.5% (n=47) in the recombinant FVIII arm and 26.8% (n=29) in the plasma-derived FVIII arm. The cumulative incidence of high-titer inhibitors was 28.4% (n=30) and 18.6% (n=20), respectively.

More than 73% of all inhibitors were non-transient in both arms.

By univariate Cox regression analysis, recombinant FVIII was associated with an 87% higher incidence of inhibitors than plasma-derived FVIII (hazard ratio [HR]=1.87). And recombinant FVIII was associated with a 69% higher incidence of high-titer inhibitors (HR=1.69).

The researchers also adjusted their analysis for range of potential confounders to see how the randomization worked.

“None of this adjustment made any difference, as you would expect from a randomized study,” Dr Peyvandi said.

She went on to highlight a study published in NEJM in 2013, which suggested that second-generation, full-length FVIII products were associated with an increased risk of inhibitor development when compared to third-generation FVIII products.

Based on this finding, the World Federation of Hemophilia recommended against using second-generation products in previously untreated patients.

So Dr Peyvandi and her colleagues stopped the use of those products during the course of the SIPPET study. And they adjusted their analysis to ensure their observations were not due to any confounding effects of the products.

After excluding second-generation, full-length recombinant FVIII from their analysis, the researchers still observed an increased risk of inhibitor development with recombinant FVIII. The HRs were 1.98 for all inhibitors and 2.59 for high-titer inhibitors.

In closing, Dr Peyvandi said these findings are clinically important because inhibitors are the major therapeutic complication in hemophilia A and can cause a marked increase in morbidity, mortality, and treatment costs.

*Data in the abstract differ from data presented at the meeting.

Flora Peyvandi, MD, PhD

Photo courtesy of ASH

ORLANDO, FL—The source of factor VIII (FVIII) replacement therapy affects the risk of inhibitor development in previously untreated patients with severe hemophilia A, according to a prospective, randomized trial.

Results of the SIPPET study indicate that receiving recombinant FVIII is associated with a nearly 2-fold higher risk of developing inhibitory alloantibodies than receiving plasma-derived FVIII.

These results have implications for the choice of therapy for previously untreated patients, as inhibitor development remains a major challenge in the management of hemophilia A, said Flora Peyvandi, MD, PhD, of Angelo Bianchi Bonomi Hemophilia and Thrombosis Center in Milan, Italy.

Dr Peyvandi presented results of the SIPPET study during the plenary session of the 2015 ASH Annual Meeting (abstract 5*).

She noted that 13 previous observational studies indicated an increased risk of inhibitor formation with recombinant FVIII. But 2 consecutive, multicenter, observational trials (CANAL and RODIN) suggested there was no difference in immunogenicity between recombinant and plasma-derived FVIII.

A few meta-analyses showed a higher risk of inhibitors with recombinant FVIII, but the difference between recombinant and plasma-derived FVIII was attenuated after researchers adjusted for confounding factors.

In an attempt to obtain some conclusive results, Dr Peyvandi and her colleagues conducted the SIPPET study. It is the first randomized clinical trial in hemophilia with the goal of comparing the immunogenicity of FVIII product classes—plasma-derived FVIII products with von Willebrand factor and recombinant FVIII products.

Study design

Between 2010 and 2014, the researchers enrolled patients from 42 sites in 14 countries from Africa, the Americas, Asia, and Europe.

The all-male patients were younger than 6 years of age at enrollment. They had severe hemophilia A, negative inhibitor measurement at enrollment, and no or minimal exposure (less than 5 exposure days) to blood products.

The patients were randomized to either a single plasma-derived FVIII product containing von Willebrand factor or a single recombinant FVIII product. The treatment was at the discretion of the local physician.

Patients were treated for 50 exposure days, 3 years, or until inhibitor development.

The primary outcome was any FVIII inhibitor at titers ≥ 0.4 BU/mL. High-titer inhibitors (≥ 5 BU/mL) were a secondary outcome. Transient inhibitors were defined as those that spontaneously disappeared within 6 months.

Patients were assessed every 3 to 5 exposure days in the first 20 exposure days, then every 10 exposure days or every 3 months and every 2 weeks during prophylaxis.

“Every time a clinician had some doubt about the development of inhibitors, this [was] measured and also confirmed at the central lab in Milan,” Dr Peyvandi noted.

Results

In all, 251 patients were analyzed—126 randomized to recombinant FVIII and 125 to plasma-derived FVIII.

Dr Peyvandi pointed out that confounders—such as family history, previous exposure, and surgery—were equally distributed between the treatment arms thanks to the randomization. The same was true for the treatment type—on-demand, standard prophylaxis, etc.

Overall, 76 patients developed inhibitors, for a cumulative incidence of 35.4%. Fifty patients had high-titer inhibitors, for a cumulative incidence of 23.3%.

The cumulative incidence of all inhibitors was 44.5% (n=47) in the recombinant FVIII arm and 26.8% (n=29) in the plasma-derived FVIII arm. The cumulative incidence of high-titer inhibitors was 28.4% (n=30) and 18.6% (n=20), respectively.

More than 73% of all inhibitors were non-transient in both arms.

By univariate Cox regression analysis, recombinant FVIII was associated with an 87% higher incidence of inhibitors than plasma-derived FVIII (hazard ratio [HR]=1.87). And recombinant FVIII was associated with a 69% higher incidence of high-titer inhibitors (HR=1.69).

The researchers also adjusted their analysis for range of potential confounders to see how the randomization worked.

“None of this adjustment made any difference, as you would expect from a randomized study,” Dr Peyvandi said.

She went on to highlight a study published in NEJM in 2013, which suggested that second-generation, full-length FVIII products were associated with an increased risk of inhibitor development when compared to third-generation FVIII products.

Based on this finding, the World Federation of Hemophilia recommended against using second-generation products in previously untreated patients.

So Dr Peyvandi and her colleagues stopped the use of those products during the course of the SIPPET study. And they adjusted their analysis to ensure their observations were not due to any confounding effects of the products.

After excluding second-generation, full-length recombinant FVIII from their analysis, the researchers still observed an increased risk of inhibitor development with recombinant FVIII. The HRs were 1.98 for all inhibitors and 2.59 for high-titer inhibitors.

In closing, Dr Peyvandi said these findings are clinically important because inhibitors are the major therapeutic complication in hemophilia A and can cause a marked increase in morbidity, mortality, and treatment costs.

*Data in the abstract differ from data presented at the meeting.

Flora Peyvandi, MD, PhD

Photo courtesy of ASH

ORLANDO, FL—The source of factor VIII (FVIII) replacement therapy affects the risk of inhibitor development in previously untreated patients with severe hemophilia A, according to a prospective, randomized trial.

Results of the SIPPET study indicate that receiving recombinant FVIII is associated with a nearly 2-fold higher risk of developing inhibitory alloantibodies than receiving plasma-derived FVIII.

These results have implications for the choice of therapy for previously untreated patients, as inhibitor development remains a major challenge in the management of hemophilia A, said Flora Peyvandi, MD, PhD, of Angelo Bianchi Bonomi Hemophilia and Thrombosis Center in Milan, Italy.

Dr Peyvandi presented results of the SIPPET study during the plenary session of the 2015 ASH Annual Meeting (abstract 5*).

She noted that 13 previous observational studies indicated an increased risk of inhibitor formation with recombinant FVIII. But 2 consecutive, multicenter, observational trials (CANAL and RODIN) suggested there was no difference in immunogenicity between recombinant and plasma-derived FVIII.

A few meta-analyses showed a higher risk of inhibitors with recombinant FVIII, but the difference between recombinant and plasma-derived FVIII was attenuated after researchers adjusted for confounding factors.

In an attempt to obtain some conclusive results, Dr Peyvandi and her colleagues conducted the SIPPET study. It is the first randomized clinical trial in hemophilia with the goal of comparing the immunogenicity of FVIII product classes—plasma-derived FVIII products with von Willebrand factor and recombinant FVIII products.

Study design

Between 2010 and 2014, the researchers enrolled patients from 42 sites in 14 countries from Africa, the Americas, Asia, and Europe.

The all-male patients were younger than 6 years of age at enrollment. They had severe hemophilia A, negative inhibitor measurement at enrollment, and no or minimal exposure (less than 5 exposure days) to blood products.

The patients were randomized to either a single plasma-derived FVIII product containing von Willebrand factor or a single recombinant FVIII product. The treatment was at the discretion of the local physician.

Patients were treated for 50 exposure days, 3 years, or until inhibitor development.

The primary outcome was any FVIII inhibitor at titers ≥ 0.4 BU/mL. High-titer inhibitors (≥ 5 BU/mL) were a secondary outcome. Transient inhibitors were defined as those that spontaneously disappeared within 6 months.

Patients were assessed every 3 to 5 exposure days in the first 20 exposure days, then every 10 exposure days or every 3 months and every 2 weeks during prophylaxis.

“Every time a clinician had some doubt about the development of inhibitors, this [was] measured and also confirmed at the central lab in Milan,” Dr Peyvandi noted.

Results

In all, 251 patients were analyzed—126 randomized to recombinant FVIII and 125 to plasma-derived FVIII.

Dr Peyvandi pointed out that confounders—such as family history, previous exposure, and surgery—were equally distributed between the treatment arms thanks to the randomization. The same was true for the treatment type—on-demand, standard prophylaxis, etc.

Overall, 76 patients developed inhibitors, for a cumulative incidence of 35.4%. Fifty patients had high-titer inhibitors, for a cumulative incidence of 23.3%.

The cumulative incidence of all inhibitors was 44.5% (n=47) in the recombinant FVIII arm and 26.8% (n=29) in the plasma-derived FVIII arm. The cumulative incidence of high-titer inhibitors was 28.4% (n=30) and 18.6% (n=20), respectively.

More than 73% of all inhibitors were non-transient in both arms.

By univariate Cox regression analysis, recombinant FVIII was associated with an 87% higher incidence of inhibitors than plasma-derived FVIII (hazard ratio [HR]=1.87). And recombinant FVIII was associated with a 69% higher incidence of high-titer inhibitors (HR=1.69).

The researchers also adjusted their analysis for range of potential confounders to see how the randomization worked.

“None of this adjustment made any difference, as you would expect from a randomized study,” Dr Peyvandi said.

She went on to highlight a study published in NEJM in 2013, which suggested that second-generation, full-length FVIII products were associated with an increased risk of inhibitor development when compared to third-generation FVIII products.

Based on this finding, the World Federation of Hemophilia recommended against using second-generation products in previously untreated patients.

So Dr Peyvandi and her colleagues stopped the use of those products during the course of the SIPPET study. And they adjusted their analysis to ensure their observations were not due to any confounding effects of the products.

After excluding second-generation, full-length recombinant FVIII from their analysis, the researchers still observed an increased risk of inhibitor development with recombinant FVIII. The HRs were 1.98 for all inhibitors and 2.59 for high-titer inhibitors.

In closing, Dr Peyvandi said these findings are clinically important because inhibitors are the major therapeutic complication in hemophilia A and can cause a marked increase in morbidity, mortality, and treatment costs.

*Data in the abstract differ from data presented at the meeting.

ORLANDO – Adding the PI3K inhibitor idelalisib to a standard regimen of bendamustine and rituximab significantly reduced the risk of both disease progression and death for patients with relapsed and/or refractory chronic lymphocytic leukemia, results of a phase III randomized trial showed.

At a median follow-up of 12 months, the primary endpoint of median progression-free survival was 23.1 months for patients treated with idelalisib (Zydelig), bendamustine, and rituximab (idel+BR), compared with 11.1 months for bendamustine and rituximab (BR) plus a placebo, reported Dr. Andrew Zelenetz of Memorial Sloan Kettering Cancer Center, New York.

“Median overall survival was not reached in either arm. However, there was a significant improvement in overall survival, with a 45% reduction in the risk of death [with idel+BR],” he said in a late-breaking abstract session at the annual meeting of the American Society of Hematology.

The trial was stopped early after a data review at the first planned interim analysis showed significant superiority for the three-drug combination.

The results were consistent across subgroups, including patients with high-risk features such as deletion 17p and mutated TP53 (del[17p]/TP53), unmutated immunoglobulin heavy chain variable region (IgHV), and treatment-refractory disease.

The rationale behind adding idelalisib, an inhibitor of the phosphatidylinositol-3 kinase (PI3K), is that signaling via the PI3K pathway is hyperactive and can be targeted, Dr. Zelenetz explained.

Study 115 was a phase III trial with accrual from June 2012 through August 2015. Investigators enrolled 416 patients with relapsed /refractory CLL and randomly assigned them to receive BR for six 28-day cycles of bendamustine (70 mg/m² on days 1 and 2 of each cycle) and rituximab (375 mg/m² for cycle 1, and 500 mg/m² for cycles 2 through 6), plus either idelalisib 150 mg b.i.d. or placebo, each administered continuously until disease progression, intolerable toxicity, withdrawal of consent, or death.

The patients were stratified by mutational and disease status (refractory defined as CLL progression less than 6 months from completion of prior therapy, or relapsed CLL progression 6 months or more from completion of prior therapy.

The trial was halted early after the first planned interim analysis, which was conducted after 75% of the total number of 260 planned events of CLL progression or death from any cause had occurred. The data cutoff was June 15, 2015.

The intention-to-treat analysis included 207 patients assigned to idelalisib and 209 assigned to placebo. Three-fourths (76%) of the patients were male.

In all, 46% of patients had Rai stage III/IV disease. The median time since the completion of the last therapy was 16 months.

The proportions of patients with high-risk features included del(17p)/p53 mutation in 32.9%, unmutated IgHV in 83.2%, and treatment-refractory disease in 29.8%.

As noted, the median progression-free survival with idelalisib at a median follow-up of 12 months was 23.1 months vs. 11.1 months for placebo. That translated into a hazard ratio of 0.33 (P less than .0001).

Among patients with neither del(17p) nor TP53 mutations, the HR for progression was 0.22. Among patients with either del(17p) or a TP53 mutation, the HR was 0.50 (95% confidence intervals show statistical significance for both).

Overall response rates were 68% among patients who received idelalisib, and 45% for those who received placebo. There were five complete responses (2%) in the idelalisib group and none in the placebo group.

The idelalisib group also had a higher proportion of patients with a greater than 50% reduction in involved lymph nodes (96% vs. 61%), and had better organomegaly responses (spleen and liver) and hematologic responses (hemoglobin, neutrophils, and platelets).

Grade 3 or greater adverse events occurred in 93% of patients on idelalisib, compared with 76% of those on placebo. The proportion of patients with any serious adverse event was 66% vs. 44%, respectively.

Adverse events leading to drug dose reduction were seen in 11% of idelalisib-treated patients, compared with 6% of placebo controls, and therapy was discontinued in 26% vs. 13%, respectively.

Ten patients in the idelalisib arm and seven in the placebo arm died during the study.

Adverse events that occurred more commonly with idelalisib included neutropenia, pyrexia, diarrhea, febrile neutropenia, pneumonia, rash, and elevated liver enzymes.

Session moderator Dr. David P. Steensma of the Dana-Farber Cancer Institute in Boston asked Dr. Zelenetz how idelalisib plus BR stacked up to ibrutinib (Imbruvica) plus BR in this population.

Dr. Zelenetz noted that patients were excluded from the HELIOS trial of ibrutinib plus BR if they had del(17p). Comparing the subset of patients in Study 115 without del(17p) with patients in the ibrutinib study, “the results are virtually superimposable,” Dr. Zelenetz said, and “the two treatments are really remarkably similar.”

The overall survival benefit was larger in the HELIOS trial, Dr. Zelenetz noted, but that was largely because the trial allowed patients to cross over from placebo to the active drug.

Gilead Sciences funded Study 115. Dr. Zelenetz disclosed receiving research funding from the company and discussing off-label use of idelalisib for relapsed/refractory CLL.

ORLANDO – Adding the PI3K inhibitor idelalisib to a standard regimen of bendamustine and rituximab significantly reduced the risk of both disease progression and death for patients with relapsed and/or refractory chronic lymphocytic leukemia, results of a phase III randomized trial showed.

At a median follow-up of 12 months, the primary endpoint of median progression-free survival was 23.1 months for patients treated with idelalisib (Zydelig), bendamustine, and rituximab (idel+BR), compared with 11.1 months for bendamustine and rituximab (BR) plus a placebo, reported Dr. Andrew Zelenetz of Memorial Sloan Kettering Cancer Center, New York.

“Median overall survival was not reached in either arm. However, there was a significant improvement in overall survival, with a 45% reduction in the risk of death [with idel+BR],” he said in a late-breaking abstract session at the annual meeting of the American Society of Hematology.

The trial was stopped early after a data review at the first planned interim analysis showed significant superiority for the three-drug combination.

The results were consistent across subgroups, including patients with high-risk features such as deletion 17p and mutated TP53 (del[17p]/TP53), unmutated immunoglobulin heavy chain variable region (IgHV), and treatment-refractory disease.

The rationale behind adding idelalisib, an inhibitor of the phosphatidylinositol-3 kinase (PI3K), is that signaling via the PI3K pathway is hyperactive and can be targeted, Dr. Zelenetz explained.

Study 115 was a phase III trial with accrual from June 2012 through August 2015. Investigators enrolled 416 patients with relapsed /refractory CLL and randomly assigned them to receive BR for six 28-day cycles of bendamustine (70 mg/m² on days 1 and 2 of each cycle) and rituximab (375 mg/m² for cycle 1, and 500 mg/m² for cycles 2 through 6), plus either idelalisib 150 mg b.i.d. or placebo, each administered continuously until disease progression, intolerable toxicity, withdrawal of consent, or death.

The patients were stratified by mutational and disease status (refractory defined as CLL progression less than 6 months from completion of prior therapy, or relapsed CLL progression 6 months or more from completion of prior therapy.

The trial was halted early after the first planned interim analysis, which was conducted after 75% of the total number of 260 planned events of CLL progression or death from any cause had occurred. The data cutoff was June 15, 2015.

The intention-to-treat analysis included 207 patients assigned to idelalisib and 209 assigned to placebo. Three-fourths (76%) of the patients were male.

In all, 46% of patients had Rai stage III/IV disease. The median time since the completion of the last therapy was 16 months.

The proportions of patients with high-risk features included del(17p)/p53 mutation in 32.9%, unmutated IgHV in 83.2%, and treatment-refractory disease in 29.8%.

As noted, the median progression-free survival with idelalisib at a median follow-up of 12 months was 23.1 months vs. 11.1 months for placebo. That translated into a hazard ratio of 0.33 (P less than .0001).

Among patients with neither del(17p) nor TP53 mutations, the HR for progression was 0.22. Among patients with either del(17p) or a TP53 mutation, the HR was 0.50 (95% confidence intervals show statistical significance for both).

Overall response rates were 68% among patients who received idelalisib, and 45% for those who received placebo. There were five complete responses (2%) in the idelalisib group and none in the placebo group.

The idelalisib group also had a higher proportion of patients with a greater than 50% reduction in involved lymph nodes (96% vs. 61%), and had better organomegaly responses (spleen and liver) and hematologic responses (hemoglobin, neutrophils, and platelets).

Grade 3 or greater adverse events occurred in 93% of patients on idelalisib, compared with 76% of those on placebo. The proportion of patients with any serious adverse event was 66% vs. 44%, respectively.

Adverse events leading to drug dose reduction were seen in 11% of idelalisib-treated patients, compared with 6% of placebo controls, and therapy was discontinued in 26% vs. 13%, respectively.

Ten patients in the idelalisib arm and seven in the placebo arm died during the study.

Adverse events that occurred more commonly with idelalisib included neutropenia, pyrexia, diarrhea, febrile neutropenia, pneumonia, rash, and elevated liver enzymes.

Session moderator Dr. David P. Steensma of the Dana-Farber Cancer Institute in Boston asked Dr. Zelenetz how idelalisib plus BR stacked up to ibrutinib (Imbruvica) plus BR in this population.

Dr. Zelenetz noted that patients were excluded from the HELIOS trial of ibrutinib plus BR if they had del(17p). Comparing the subset of patients in Study 115 without del(17p) with patients in the ibrutinib study, “the results are virtually superimposable,” Dr. Zelenetz said, and “the two treatments are really remarkably similar.”

The overall survival benefit was larger in the HELIOS trial, Dr. Zelenetz noted, but that was largely because the trial allowed patients to cross over from placebo to the active drug.

Gilead Sciences funded Study 115. Dr. Zelenetz disclosed receiving research funding from the company and discussing off-label use of idelalisib for relapsed/refractory CLL.

ORLANDO – Adding the PI3K inhibitor idelalisib to a standard regimen of bendamustine and rituximab significantly reduced the risk of both disease progression and death for patients with relapsed and/or refractory chronic lymphocytic leukemia, results of a phase III randomized trial showed.

At a median follow-up of 12 months, the primary endpoint of median progression-free survival was 23.1 months for patients treated with idelalisib (Zydelig), bendamustine, and rituximab (idel+BR), compared with 11.1 months for bendamustine and rituximab (BR) plus a placebo, reported Dr. Andrew Zelenetz of Memorial Sloan Kettering Cancer Center, New York.

“Median overall survival was not reached in either arm. However, there was a significant improvement in overall survival, with a 45% reduction in the risk of death [with idel+BR],” he said in a late-breaking abstract session at the annual meeting of the American Society of Hematology.

The trial was stopped early after a data review at the first planned interim analysis showed significant superiority for the three-drug combination.

The results were consistent across subgroups, including patients with high-risk features such as deletion 17p and mutated TP53 (del[17p]/TP53), unmutated immunoglobulin heavy chain variable region (IgHV), and treatment-refractory disease.

The rationale behind adding idelalisib, an inhibitor of the phosphatidylinositol-3 kinase (PI3K), is that signaling via the PI3K pathway is hyperactive and can be targeted, Dr. Zelenetz explained.

Study 115 was a phase III trial with accrual from June 2012 through August 2015. Investigators enrolled 416 patients with relapsed /refractory CLL and randomly assigned them to receive BR for six 28-day cycles of bendamustine (70 mg/m² on days 1 and 2 of each cycle) and rituximab (375 mg/m² for cycle 1, and 500 mg/m² for cycles 2 through 6), plus either idelalisib 150 mg b.i.d. or placebo, each administered continuously until disease progression, intolerable toxicity, withdrawal of consent, or death.

The patients were stratified by mutational and disease status (refractory defined as CLL progression less than 6 months from completion of prior therapy, or relapsed CLL progression 6 months or more from completion of prior therapy.

The trial was halted early after the first planned interim analysis, which was conducted after 75% of the total number of 260 planned events of CLL progression or death from any cause had occurred. The data cutoff was June 15, 2015.

The intention-to-treat analysis included 207 patients assigned to idelalisib and 209 assigned to placebo. Three-fourths (76%) of the patients were male.

In all, 46% of patients had Rai stage III/IV disease. The median time since the completion of the last therapy was 16 months.

The proportions of patients with high-risk features included del(17p)/p53 mutation in 32.9%, unmutated IgHV in 83.2%, and treatment-refractory disease in 29.8%.

As noted, the median progression-free survival with idelalisib at a median follow-up of 12 months was 23.1 months vs. 11.1 months for placebo. That translated into a hazard ratio of 0.33 (P less than .0001).

Among patients with neither del(17p) nor TP53 mutations, the HR for progression was 0.22. Among patients with either del(17p) or a TP53 mutation, the HR was 0.50 (95% confidence intervals show statistical significance for both).

Overall response rates were 68% among patients who received idelalisib, and 45% for those who received placebo. There were five complete responses (2%) in the idelalisib group and none in the placebo group.

The idelalisib group also had a higher proportion of patients with a greater than 50% reduction in involved lymph nodes (96% vs. 61%), and had better organomegaly responses (spleen and liver) and hematologic responses (hemoglobin, neutrophils, and platelets).

Grade 3 or greater adverse events occurred in 93% of patients on idelalisib, compared with 76% of those on placebo. The proportion of patients with any serious adverse event was 66% vs. 44%, respectively.

Adverse events leading to drug dose reduction were seen in 11% of idelalisib-treated patients, compared with 6% of placebo controls, and therapy was discontinued in 26% vs. 13%, respectively.

Ten patients in the idelalisib arm and seven in the placebo arm died during the study.

Adverse events that occurred more commonly with idelalisib included neutropenia, pyrexia, diarrhea, febrile neutropenia, pneumonia, rash, and elevated liver enzymes.

Session moderator Dr. David P. Steensma of the Dana-Farber Cancer Institute in Boston asked Dr. Zelenetz how idelalisib plus BR stacked up to ibrutinib (Imbruvica) plus BR in this population.

Dr. Zelenetz noted that patients were excluded from the HELIOS trial of ibrutinib plus BR if they had del(17p). Comparing the subset of patients in Study 115 without del(17p) with patients in the ibrutinib study, “the results are virtually superimposable,” Dr. Zelenetz said, and “the two treatments are really remarkably similar.”

The overall survival benefit was larger in the HELIOS trial, Dr. Zelenetz noted, but that was largely because the trial allowed patients to cross over from placebo to the active drug.

Gilead Sciences funded Study 115. Dr. Zelenetz disclosed receiving research funding from the company and discussing off-label use of idelalisib for relapsed/refractory CLL.

James N. Kochenderfer, MD

Photo courtesy of ASH

ORLANDO, FL—Allogeneic chimeric antigen receptor (CAR) T cells directed against CD19 can have “significant” activity against resistant B-cell malignancies, even when given without prior chemotherapy, according to a presentation at the 2015 ASH Annual Meeting.

Nine of 20 patients responded to treatment with the CAR T cells, despite having failed prior allogeneic transplant. The best responses were observed in patients with acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL).

“Malignancies that were resistant to allogeneic transplants and standard donor lymphocyte infusions regressed after infusions of allogeneic anti-CD19 CAR T cells,” said James N. Kochenderfer, MD, of the National Cancer Institute in Bethesda, Maryland.

“Allogeneic anti-CD19 CAR T cells seem to be particularly effective against ALL and CLL, suggesting a possible antigenic stimulation that may be more pronounced in these malignancies.”

Adverse events associated with these CAR T cells included severe but reversible cytokine release syndrome, mild aphasia, and muscle damage. There were no cases of acute graft-vs-host disease (GVHD).

Dr Kochenderfer presented these results at ASH as abstract 99.

For this phase 1 study, researchers tested a CAR T-cell therapy that was originally developed by Dr Kochenderfer and his colleagues. The therapy is now known as KTE-C19 and is under development by Kite Pharmaceuticals. However, the company did not sponsor this trial.

The study was open to patients with any CD19+ B-cell malignancy that persisted after allogeneic transplant.

All patients except those with ALL were required to have received at least one standard donor lymphocyte infusion. In addition, patients were only eligible if they had minimal or no GVHD and were not receiving any systemic immunosuppressive drugs.

The trial included 20 patients—5 each with ALL, CLL, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL).

All patients received a single infusion of CAR T cells derived from their original transplant donor. Production of these cells took 8 days. The highest dose of CAR T cells given was 10⁷ cells/kg.

Four of the ALL patients obtained a minimal-residual disease-negative complete response (CR), but 2 of these patients subsequently relapsed. Of the other 2 patients, 1 remains in CR at 18 months of follow-up, and the other went on to receive a second allogeneic transplant. That patient remains in CR today.

Among the CLL patients, 1 achieved a CR, and 1 achieved a partial response (PR). One patient had stable disease (SD), and the other 2 progressed. Both the CR and the PR are ongoing at 36 and 18 months of follow-up, respectively.

One MCL patient achieved a CR, 1 had a PR, and 3 had SD. The CR is ongoing at 31 months. One DLBCL patient achieved a CR, 3 had SD, and 1 progressed.

Dr Kochenderfer noted that response was associated with higher blood CAR T-cell levels. There was a significant difference in CAR T-cell levels between responders and nonresponders (P=0.001).

In addition, the presence of blood B-cell levels before CAR T-cell infusion was associated with higher blood CAR T-cell levels. Patients with normal or high B lymphocytes had higher levels of CAR T cells in their blood (P=0.04).

Patients with high tumor burdens developed severe cytokine-release syndrome with fever, tachycardia, and hypotension. The ALL patients were particularly susceptible to cytokine-release syndrome.

Dr Kochenderfer said neurologic toxicity was rare and mild. There was 1 case of mild aphasia.

There were 2 patients with elevations in CPK, indicating muscle damage. Those patients also reported muscle pain, and 1 patient reported weakness.

“This is one of the first reports, I think, of muscle damage in CAR T-cell patients,” Dr Kochenderfer said.

None of the patients developed acute GVHD after CAR T-cell therapy. One patient had continued worsening of pre-existing chronic GVHD after treatment, and 1 patient developed mild chronic eye GVHD more than a year after CAR T-cell infusion.

Dr Kochenderfer said additional details from this trial will be published in an upcoming issue of the Journal of Clinical Oncology.

James N. Kochenderfer, MD

Photo courtesy of ASH

ORLANDO, FL—Allogeneic chimeric antigen receptor (CAR) T cells directed against CD19 can have “significant” activity against resistant B-cell malignancies, even when given without prior chemotherapy, according to a presentation at the 2015 ASH Annual Meeting.

Nine of 20 patients responded to treatment with the CAR T cells, despite having failed prior allogeneic transplant. The best responses were observed in patients with acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL).

“Malignancies that were resistant to allogeneic transplants and standard donor lymphocyte infusions regressed after infusions of allogeneic anti-CD19 CAR T cells,” said James N. Kochenderfer, MD, of the National Cancer Institute in Bethesda, Maryland.

“Allogeneic anti-CD19 CAR T cells seem to be particularly effective against ALL and CLL, suggesting a possible antigenic stimulation that may be more pronounced in these malignancies.”

Adverse events associated with these CAR T cells included severe but reversible cytokine release syndrome, mild aphasia, and muscle damage. There were no cases of acute graft-vs-host disease (GVHD).

Dr Kochenderfer presented these results at ASH as abstract 99.

For this phase 1 study, researchers tested a CAR T-cell therapy that was originally developed by Dr Kochenderfer and his colleagues. The therapy is now known as KTE-C19 and is under development by Kite Pharmaceuticals. However, the company did not sponsor this trial.

The study was open to patients with any CD19+ B-cell malignancy that persisted after allogeneic transplant.

All patients except those with ALL were required to have received at least one standard donor lymphocyte infusion. In addition, patients were only eligible if they had minimal or no GVHD and were not receiving any systemic immunosuppressive drugs.

The trial included 20 patients—5 each with ALL, CLL, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL).

All patients received a single infusion of CAR T cells derived from their original transplant donor. Production of these cells took 8 days. The highest dose of CAR T cells given was 10⁷ cells/kg.

Four of the ALL patients obtained a minimal-residual disease-negative complete response (CR), but 2 of these patients subsequently relapsed. Of the other 2 patients, 1 remains in CR at 18 months of follow-up, and the other went on to receive a second allogeneic transplant. That patient remains in CR today.

Among the CLL patients, 1 achieved a CR, and 1 achieved a partial response (PR). One patient had stable disease (SD), and the other 2 progressed. Both the CR and the PR are ongoing at 36 and 18 months of follow-up, respectively.

One MCL patient achieved a CR, 1 had a PR, and 3 had SD. The CR is ongoing at 31 months. One DLBCL patient achieved a CR, 3 had SD, and 1 progressed.

Dr Kochenderfer noted that response was associated with higher blood CAR T-cell levels. There was a significant difference in CAR T-cell levels between responders and nonresponders (P=0.001).

In addition, the presence of blood B-cell levels before CAR T-cell infusion was associated with higher blood CAR T-cell levels. Patients with normal or high B lymphocytes had higher levels of CAR T cells in their blood (P=0.04).

Patients with high tumor burdens developed severe cytokine-release syndrome with fever, tachycardia, and hypotension. The ALL patients were particularly susceptible to cytokine-release syndrome.

Dr Kochenderfer said neurologic toxicity was rare and mild. There was 1 case of mild aphasia.

There were 2 patients with elevations in CPK, indicating muscle damage. Those patients also reported muscle pain, and 1 patient reported weakness.

“This is one of the first reports, I think, of muscle damage in CAR T-cell patients,” Dr Kochenderfer said.

None of the patients developed acute GVHD after CAR T-cell therapy. One patient had continued worsening of pre-existing chronic GVHD after treatment, and 1 patient developed mild chronic eye GVHD more than a year after CAR T-cell infusion.

Dr Kochenderfer said additional details from this trial will be published in an upcoming issue of the Journal of Clinical Oncology.

James N. Kochenderfer, MD

Photo courtesy of ASH

ORLANDO, FL—Allogeneic chimeric antigen receptor (CAR) T cells directed against CD19 can have “significant” activity against resistant B-cell malignancies, even when given without prior chemotherapy, according to a presentation at the 2015 ASH Annual Meeting.

Nine of 20 patients responded to treatment with the CAR T cells, despite having failed prior allogeneic transplant. The best responses were observed in patients with acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL).

“Malignancies that were resistant to allogeneic transplants and standard donor lymphocyte infusions regressed after infusions of allogeneic anti-CD19 CAR T cells,” said James N. Kochenderfer, MD, of the National Cancer Institute in Bethesda, Maryland.

“Allogeneic anti-CD19 CAR T cells seem to be particularly effective against ALL and CLL, suggesting a possible antigenic stimulation that may be more pronounced in these malignancies.”

Adverse events associated with these CAR T cells included severe but reversible cytokine release syndrome, mild aphasia, and muscle damage. There were no cases of acute graft-vs-host disease (GVHD).

Dr Kochenderfer presented these results at ASH as abstract 99.

For this phase 1 study, researchers tested a CAR T-cell therapy that was originally developed by Dr Kochenderfer and his colleagues. The therapy is now known as KTE-C19 and is under development by Kite Pharmaceuticals. However, the company did not sponsor this trial.

The study was open to patients with any CD19+ B-cell malignancy that persisted after allogeneic transplant.

All patients except those with ALL were required to have received at least one standard donor lymphocyte infusion. In addition, patients were only eligible if they had minimal or no GVHD and were not receiving any systemic immunosuppressive drugs.

The trial included 20 patients—5 each with ALL, CLL, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL).

All patients received a single infusion of CAR T cells derived from their original transplant donor. Production of these cells took 8 days. The highest dose of CAR T cells given was 10⁷ cells/kg.

Four of the ALL patients obtained a minimal-residual disease-negative complete response (CR), but 2 of these patients subsequently relapsed. Of the other 2 patients, 1 remains in CR at 18 months of follow-up, and the other went on to receive a second allogeneic transplant. That patient remains in CR today.

Among the CLL patients, 1 achieved a CR, and 1 achieved a partial response (PR). One patient had stable disease (SD), and the other 2 progressed. Both the CR and the PR are ongoing at 36 and 18 months of follow-up, respectively.

One MCL patient achieved a CR, 1 had a PR, and 3 had SD. The CR is ongoing at 31 months. One DLBCL patient achieved a CR, 3 had SD, and 1 progressed.

Dr Kochenderfer noted that response was associated with higher blood CAR T-cell levels. There was a significant difference in CAR T-cell levels between responders and nonresponders (P=0.001).

In addition, the presence of blood B-cell levels before CAR T-cell infusion was associated with higher blood CAR T-cell levels. Patients with normal or high B lymphocytes had higher levels of CAR T cells in their blood (P=0.04).

Patients with high tumor burdens developed severe cytokine-release syndrome with fever, tachycardia, and hypotension. The ALL patients were particularly susceptible to cytokine-release syndrome.

Dr Kochenderfer said neurologic toxicity was rare and mild. There was 1 case of mild aphasia.

There were 2 patients with elevations in CPK, indicating muscle damage. Those patients also reported muscle pain, and 1 patient reported weakness.

“This is one of the first reports, I think, of muscle damage in CAR T-cell patients,” Dr Kochenderfer said.

None of the patients developed acute GVHD after CAR T-cell therapy. One patient had continued worsening of pre-existing chronic GVHD after treatment, and 1 patient developed mild chronic eye GVHD more than a year after CAR T-cell infusion.

Dr Kochenderfer said additional details from this trial will be published in an upcoming issue of the Journal of Clinical Oncology.

ORLANDO – Adding eltrombopag to standard immunosuppressive treatment for newly-diagnosed severe aplastic anemia boosted overall response rates from around 65% to over 90%, based on a late-breaker study presented by Dr. Danielle M. Townsley at the annual meeting of the American Society of Hematology.

Dr. Townsley said that starting the combination treatment immediately at diagnosis, rather than waiting to introduce eltrombopag at either 2 weeks or 3 months after initiating standard immunosuppressive therapy, was associated with better outcomes. As a result of the findings, a cohort extension of the trial will continue and is enrolling patients.

In our video interview, Dr. Townsley discusses the top-level results and says that it’s too early to introduce the protocol into practice outside a clinical trial. She urges hematologists to enroll their patients in the ongoing cohort study.

mdales@frontlinemedcom.com

On Twitter @maryjodales

ORLANDO – Adding eltrombopag to standard immunosuppressive treatment for newly-diagnosed severe aplastic anemia boosted overall response rates from around 65% to over 90%, based on a late-breaker study presented by Dr. Danielle M. Townsley at the annual meeting of the American Society of Hematology.

Dr. Townsley said that starting the combination treatment immediately at diagnosis, rather than waiting to introduce eltrombopag at either 2 weeks or 3 months after initiating standard immunosuppressive therapy, was associated with better outcomes. As a result of the findings, a cohort extension of the trial will continue and is enrolling patients.

In our video interview, Dr. Townsley discusses the top-level results and says that it’s too early to introduce the protocol into practice outside a clinical trial. She urges hematologists to enroll their patients in the ongoing cohort study.

mdales@frontlinemedcom.com

On Twitter @maryjodales

ORLANDO – Adding eltrombopag to standard immunosuppressive treatment for newly-diagnosed severe aplastic anemia boosted overall response rates from around 65% to over 90%, based on a late-breaker study presented by Dr. Danielle M. Townsley at the annual meeting of the American Society of Hematology.

Dr. Townsley said that starting the combination treatment immediately at diagnosis, rather than waiting to introduce eltrombopag at either 2 weeks or 3 months after initiating standard immunosuppressive therapy, was associated with better outcomes. As a result of the findings, a cohort extension of the trial will continue and is enrolling patients.

In our video interview, Dr. Townsley discusses the top-level results and says that it’s too early to introduce the protocol into practice outside a clinical trial. She urges hematologists to enroll their patients in the ongoing cohort study.

mdales@frontlinemedcom.com

On Twitter @maryjodales