Leukemia, Myelodysplasia, Transplantation

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.

Vials of drug

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved the use of Bendeka, a liquid, low-volume (50 mL), 10-minute infusion formulation of bendamustine hydrochloride.

Bendeka is now approved to treat patients with chronic lymphocytic leukemia (CLL) and patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

The FDA previously granted Bendeka orphan drug designation for CLL and indolent B-cell NHL.

Under a license agreement with Eagle Pharmaceuticals, Inc., Teva Pharmaceutical Industries Ltd. is responsible for all US commercial activities for Bendeka.

Teva said it expects to make Bendeka commercially available to prescribers during the first quarter of 2016. For details on the drug, see the full prescribing information.

Teva also markets bendamustine hydrochloride under the trade name Treanda, which is FDA-approved to treat CLL and NHL and is available in 2 formulations:

• A solution of 45 mg/0.5 mL or 180 mg/2 mL in a single-dose vial
• A 25 mg or 100 mg lyophilized powder in a single-dose vial for reconstitution.
  

Vials of drug

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved the use of Bendeka, a liquid, low-volume (50 mL), 10-minute infusion formulation of bendamustine hydrochloride.

Bendeka is now approved to treat patients with chronic lymphocytic leukemia (CLL) and patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

The FDA previously granted Bendeka orphan drug designation for CLL and indolent B-cell NHL.

Under a license agreement with Eagle Pharmaceuticals, Inc., Teva Pharmaceutical Industries Ltd. is responsible for all US commercial activities for Bendeka.

Teva said it expects to make Bendeka commercially available to prescribers during the first quarter of 2016. For details on the drug, see the full prescribing information.

Teva also markets bendamustine hydrochloride under the trade name Treanda, which is FDA-approved to treat CLL and NHL and is available in 2 formulations:

• A solution of 45 mg/0.5 mL or 180 mg/2 mL in a single-dose vial
• A 25 mg or 100 mg lyophilized powder in a single-dose vial for reconstitution.
  

Vials of drug

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved the use of Bendeka, a liquid, low-volume (50 mL), 10-minute infusion formulation of bendamustine hydrochloride.

Bendeka is now approved to treat patients with chronic lymphocytic leukemia (CLL) and patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

The FDA previously granted Bendeka orphan drug designation for CLL and indolent B-cell NHL.

Under a license agreement with Eagle Pharmaceuticals, Inc., Teva Pharmaceutical Industries Ltd. is responsible for all US commercial activities for Bendeka.

Teva said it expects to make Bendeka commercially available to prescribers during the first quarter of 2016. For details on the drug, see the full prescribing information.

Teva also markets bendamustine hydrochloride under the trade name Treanda, which is FDA-approved to treat CLL and NHL and is available in 2 formulations:

• A solution of 45 mg/0.5 mL or 180 mg/2 mL in a single-dose vial
• A 25 mg or 100 mg lyophilized powder in a single-dose vial for reconstitution.
  

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.

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

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

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

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

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

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

pwendling@frontlinemedcom.com

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

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

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

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

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

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

pwendling@frontlinemedcom.com

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

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

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

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

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

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

pwendling@frontlinemedcom.com

ORLANDO – Idelalisib given as first-line therapy for patients with chronic lymphocytic leukemia carries a high risk of early fulminant hepatotoxicity requiring drug interruption and steroids, investigators reported.

Among 24 patients who received idelalisib (Zydelig) monotherapy in a phase II trial of a combination of idelalisib followed by idelalisib concurrent with ofatumumab (Arzerra) as first-line therapy for chronic lymphocytic leukemia (CLL), 12 patients developed acute hepatotoxicity, marked by rapidly soaring levels of transaminase within about 28 days of starting therapy. An additional four patients developed hepatotoxicity at around 130 days, noted Dr. Benjamin L. Lampson, a clinical fellow in medicine at the Dana-Farber Cancer Institute in Boston.

“Multiple lines of evidence suggest that this early hepatotoxicity is immune mediated. The proportion of regulatory T cells in the peripheral blood decrease on idelalisib therapy, providing a possible explanation for the development of early hepatotoxicity,” he said at the annual meeting of the American Society of Hematology.

The toxicities occur more frequently among younger and less heavily pretreated patients, and are likely due to on-target, immune-mediated effects, he noted.

Dr. Lampson presented data on the first 24 patients in an ongoing phase II trial. Patients with previously untreated CLL receive idelalisib 150 mg twice daily for 56 days, in an attempt to mobilize neoplastic B cells from the peripheral lymphoid tissues and into the bloodstream.

Following the monotherapy phase, patients are given ofatumumab in an attempt to clear the disease from peripheral blood.

“This dosing strategy is slightly different than what has been previously been used in trials combining these particular drugs. Specifically, previously reported trials have started these agents simultaneously without a lead-in period of monotherapy,” Dr. Lampson explained.

When the lead-in phase is completed, patients receive idelalisib plus ofatumumab infusions once weekly for 8 weeks, followed by once-monthly infusions for 4 months. Patients then continue on idelalisib indefinitely. The primary endpoint is the overall response rate assessed 2 months after the completion of the combination therapy.

For the first 24 patients treated as of Nov. 9, 2015, the median time on therapy was 7.7 months and median follow-up was 14.7 months.

The median patient age was 67.4 years (range 57.6-84.9). CLL genetics showed that 13 patients had unmutated immunoglobulin heavy chain variable region (IgHV) disease, 4 had the 17p deletion and TP53 mutation, 1 had deletion 11q, and 13 had deletion 13q; some patients had more than one mutation.

“What we began to notice after enrolling just a few subjects on the trial was that severe hepatotoxicity was occurring shortly after initiating idelalisib,” Dr. Lampson said.

He presented one case, a 58-year-old man who was in the idelalisib monotherapy phase of the study. He developed grade 3 hepatotoxicity 28 days after starting the drug, despite having a normal liver function test just 1 day earlier. The drug was stopped, but his liver function tests continued to rise, suggesting a self-perpetuating or self-sustaining process.

On day 32, the patient was admitted to the hospital, and on day 33 he was started on steroids, based on the hypothesis that the hepatotoxicity might have been immune mediated. Two days after initiation of steroids, his liver function tests continued to rise, whereupon he was started on mycophenolate mofetil.

“With these two forms of immunosuppression, the [liver function tests] did eventually normalize, although the steroids and mycophenolate had to be tapered over a period of many weeks. And this patient was not the only patient to experience toxicity; in fact, hepatotoxicity was frequent and often severe,” he said.

At the time of maximum incidence, week 4, the percentage of patients with any hepatotoxicity was 46%, with 13% at grade 4, and 21% at grade 3.

“The median time to initial development of hepatotoxicity is 28 days. This suggests that the mechanism of hepatotoxicity is not immediate, but takes time to develop, consistent with an adaptive immune response. Furthermore, hepatotoxicity is typically occurring before the first dose of ofatumumab is occurring at week 8, suggesting idelalisib alone is the cause of the hepatotoxicity,” Dr. Lampson said.

A comparison of data from the ongoing study and from three previous studies – two with idelalisib in relapsed refractory disease, and one as first-line therapy in patients 65 and older – showed that grade 3 or greater hepatotoxicity was lowest in a phase I trial of idelalisib in which patients had received a median of five prior lines of therapy, occurring in only 1.9% of patients. In contrast, in the current study, 52% of patients experienced grade 3 or 4 transaminitis at some point in the trial.

Evidence for the hepatotoxicity being an on-target immune-mediated effect comes from lymphocytic infiltrate on liver biopsy and lymphocytic colitis in idelalisib-treated patients. Additional evidence comes from the fact that the toxicity is both treatable and preventable with steroids, he said.

He cautioned that hepatotoxicity can recur rapidly when the drug is reintroduced.

“In general, our experience has been if idelalisib is resumed while the subject remains on steroids, the drug is more likely to be tolerated and the subject eventually can be tapered off steroids,” he said.

Asked by an audience member whether patients who are receiving idelalisib in the first-line setting should also receive steroids, Dr. Lampson said that they closely monitor patient liver enzymes around 28 days, and if grade 1 transaminitis is detected, patients are automatically started on low-dose steroids.

The study is sponsored by the Dana-Farber Cancer Institute in collaboration with Gilead Sciences and GlaxoSmithKline. Dr. Lampson and colleagues declared no relevant conflicts of interest.

ORLANDO – Idelalisib given as first-line therapy for patients with chronic lymphocytic leukemia carries a high risk of early fulminant hepatotoxicity requiring drug interruption and steroids, investigators reported.

Among 24 patients who received idelalisib (Zydelig) monotherapy in a phase II trial of a combination of idelalisib followed by idelalisib concurrent with ofatumumab (Arzerra) as first-line therapy for chronic lymphocytic leukemia (CLL), 12 patients developed acute hepatotoxicity, marked by rapidly soaring levels of transaminase within about 28 days of starting therapy. An additional four patients developed hepatotoxicity at around 130 days, noted Dr. Benjamin L. Lampson, a clinical fellow in medicine at the Dana-Farber Cancer Institute in Boston.

“Multiple lines of evidence suggest that this early hepatotoxicity is immune mediated. The proportion of regulatory T cells in the peripheral blood decrease on idelalisib therapy, providing a possible explanation for the development of early hepatotoxicity,” he said at the annual meeting of the American Society of Hematology.

The toxicities occur more frequently among younger and less heavily pretreated patients, and are likely due to on-target, immune-mediated effects, he noted.

Dr. Lampson presented data on the first 24 patients in an ongoing phase II trial. Patients with previously untreated CLL receive idelalisib 150 mg twice daily for 56 days, in an attempt to mobilize neoplastic B cells from the peripheral lymphoid tissues and into the bloodstream.

Following the monotherapy phase, patients are given ofatumumab in an attempt to clear the disease from peripheral blood.

“This dosing strategy is slightly different than what has been previously been used in trials combining these particular drugs. Specifically, previously reported trials have started these agents simultaneously without a lead-in period of monotherapy,” Dr. Lampson explained.

When the lead-in phase is completed, patients receive idelalisib plus ofatumumab infusions once weekly for 8 weeks, followed by once-monthly infusions for 4 months. Patients then continue on idelalisib indefinitely. The primary endpoint is the overall response rate assessed 2 months after the completion of the combination therapy.

For the first 24 patients treated as of Nov. 9, 2015, the median time on therapy was 7.7 months and median follow-up was 14.7 months.

The median patient age was 67.4 years (range 57.6-84.9). CLL genetics showed that 13 patients had unmutated immunoglobulin heavy chain variable region (IgHV) disease, 4 had the 17p deletion and TP53 mutation, 1 had deletion 11q, and 13 had deletion 13q; some patients had more than one mutation.

“What we began to notice after enrolling just a few subjects on the trial was that severe hepatotoxicity was occurring shortly after initiating idelalisib,” Dr. Lampson said.

He presented one case, a 58-year-old man who was in the idelalisib monotherapy phase of the study. He developed grade 3 hepatotoxicity 28 days after starting the drug, despite having a normal liver function test just 1 day earlier. The drug was stopped, but his liver function tests continued to rise, suggesting a self-perpetuating or self-sustaining process.

On day 32, the patient was admitted to the hospital, and on day 33 he was started on steroids, based on the hypothesis that the hepatotoxicity might have been immune mediated. Two days after initiation of steroids, his liver function tests continued to rise, whereupon he was started on mycophenolate mofetil.

“With these two forms of immunosuppression, the [liver function tests] did eventually normalize, although the steroids and mycophenolate had to be tapered over a period of many weeks. And this patient was not the only patient to experience toxicity; in fact, hepatotoxicity was frequent and often severe,” he said.

At the time of maximum incidence, week 4, the percentage of patients with any hepatotoxicity was 46%, with 13% at grade 4, and 21% at grade 3.

“The median time to initial development of hepatotoxicity is 28 days. This suggests that the mechanism of hepatotoxicity is not immediate, but takes time to develop, consistent with an adaptive immune response. Furthermore, hepatotoxicity is typically occurring before the first dose of ofatumumab is occurring at week 8, suggesting idelalisib alone is the cause of the hepatotoxicity,” Dr. Lampson said.

A comparison of data from the ongoing study and from three previous studies – two with idelalisib in relapsed refractory disease, and one as first-line therapy in patients 65 and older – showed that grade 3 or greater hepatotoxicity was lowest in a phase I trial of idelalisib in which patients had received a median of five prior lines of therapy, occurring in only 1.9% of patients. In contrast, in the current study, 52% of patients experienced grade 3 or 4 transaminitis at some point in the trial.

Evidence for the hepatotoxicity being an on-target immune-mediated effect comes from lymphocytic infiltrate on liver biopsy and lymphocytic colitis in idelalisib-treated patients. Additional evidence comes from the fact that the toxicity is both treatable and preventable with steroids, he said.

He cautioned that hepatotoxicity can recur rapidly when the drug is reintroduced.

“In general, our experience has been if idelalisib is resumed while the subject remains on steroids, the drug is more likely to be tolerated and the subject eventually can be tapered off steroids,” he said.

Asked by an audience member whether patients who are receiving idelalisib in the first-line setting should also receive steroids, Dr. Lampson said that they closely monitor patient liver enzymes around 28 days, and if grade 1 transaminitis is detected, patients are automatically started on low-dose steroids.

The study is sponsored by the Dana-Farber Cancer Institute in collaboration with Gilead Sciences and GlaxoSmithKline. Dr. Lampson and colleagues declared no relevant conflicts of interest.

ORLANDO – Idelalisib given as first-line therapy for patients with chronic lymphocytic leukemia carries a high risk of early fulminant hepatotoxicity requiring drug interruption and steroids, investigators reported.

Among 24 patients who received idelalisib (Zydelig) monotherapy in a phase II trial of a combination of idelalisib followed by idelalisib concurrent with ofatumumab (Arzerra) as first-line therapy for chronic lymphocytic leukemia (CLL), 12 patients developed acute hepatotoxicity, marked by rapidly soaring levels of transaminase within about 28 days of starting therapy. An additional four patients developed hepatotoxicity at around 130 days, noted Dr. Benjamin L. Lampson, a clinical fellow in medicine at the Dana-Farber Cancer Institute in Boston.

“Multiple lines of evidence suggest that this early hepatotoxicity is immune mediated. The proportion of regulatory T cells in the peripheral blood decrease on idelalisib therapy, providing a possible explanation for the development of early hepatotoxicity,” he said at the annual meeting of the American Society of Hematology.

The toxicities occur more frequently among younger and less heavily pretreated patients, and are likely due to on-target, immune-mediated effects, he noted.

Dr. Lampson presented data on the first 24 patients in an ongoing phase II trial. Patients with previously untreated CLL receive idelalisib 150 mg twice daily for 56 days, in an attempt to mobilize neoplastic B cells from the peripheral lymphoid tissues and into the bloodstream.

Following the monotherapy phase, patients are given ofatumumab in an attempt to clear the disease from peripheral blood.

“This dosing strategy is slightly different than what has been previously been used in trials combining these particular drugs. Specifically, previously reported trials have started these agents simultaneously without a lead-in period of monotherapy,” Dr. Lampson explained.

When the lead-in phase is completed, patients receive idelalisib plus ofatumumab infusions once weekly for 8 weeks, followed by once-monthly infusions for 4 months. Patients then continue on idelalisib indefinitely. The primary endpoint is the overall response rate assessed 2 months after the completion of the combination therapy.

For the first 24 patients treated as of Nov. 9, 2015, the median time on therapy was 7.7 months and median follow-up was 14.7 months.

The median patient age was 67.4 years (range 57.6-84.9). CLL genetics showed that 13 patients had unmutated immunoglobulin heavy chain variable region (IgHV) disease, 4 had the 17p deletion and TP53 mutation, 1 had deletion 11q, and 13 had deletion 13q; some patients had more than one mutation.

“What we began to notice after enrolling just a few subjects on the trial was that severe hepatotoxicity was occurring shortly after initiating idelalisib,” Dr. Lampson said.

He presented one case, a 58-year-old man who was in the idelalisib monotherapy phase of the study. He developed grade 3 hepatotoxicity 28 days after starting the drug, despite having a normal liver function test just 1 day earlier. The drug was stopped, but his liver function tests continued to rise, suggesting a self-perpetuating or self-sustaining process.

On day 32, the patient was admitted to the hospital, and on day 33 he was started on steroids, based on the hypothesis that the hepatotoxicity might have been immune mediated. Two days after initiation of steroids, his liver function tests continued to rise, whereupon he was started on mycophenolate mofetil.

“With these two forms of immunosuppression, the [liver function tests] did eventually normalize, although the steroids and mycophenolate had to be tapered over a period of many weeks. And this patient was not the only patient to experience toxicity; in fact, hepatotoxicity was frequent and often severe,” he said.

At the time of maximum incidence, week 4, the percentage of patients with any hepatotoxicity was 46%, with 13% at grade 4, and 21% at grade 3.

“The median time to initial development of hepatotoxicity is 28 days. This suggests that the mechanism of hepatotoxicity is not immediate, but takes time to develop, consistent with an adaptive immune response. Furthermore, hepatotoxicity is typically occurring before the first dose of ofatumumab is occurring at week 8, suggesting idelalisib alone is the cause of the hepatotoxicity,” Dr. Lampson said.

A comparison of data from the ongoing study and from three previous studies – two with idelalisib in relapsed refractory disease, and one as first-line therapy in patients 65 and older – showed that grade 3 or greater hepatotoxicity was lowest in a phase I trial of idelalisib in which patients had received a median of five prior lines of therapy, occurring in only 1.9% of patients. In contrast, in the current study, 52% of patients experienced grade 3 or 4 transaminitis at some point in the trial.

Evidence for the hepatotoxicity being an on-target immune-mediated effect comes from lymphocytic infiltrate on liver biopsy and lymphocytic colitis in idelalisib-treated patients. Additional evidence comes from the fact that the toxicity is both treatable and preventable with steroids, he said.

He cautioned that hepatotoxicity can recur rapidly when the drug is reintroduced.

“In general, our experience has been if idelalisib is resumed while the subject remains on steroids, the drug is more likely to be tolerated and the subject eventually can be tapered off steroids,” he said.

Asked by an audience member whether patients who are receiving idelalisib in the first-line setting should also receive steroids, Dr. Lampson said that they closely monitor patient liver enzymes around 28 days, and if grade 1 transaminitis is detected, patients are automatically started on low-dose steroids.

The study is sponsored by the Dana-Farber Cancer Institute in collaboration with Gilead Sciences and GlaxoSmithKline. Dr. Lampson and colleagues declared no relevant conflicts of interest.

Wendy Landier, PhD, CRNP

Photo courtesy of ASH

ORLANDO, FL—A study comparing subjective versus objective reporting of treatment compliance in patients with acute lymphoblastic leukemia (ALL) has shown that about a fourth of patients over-report how compliant they are with taking 6-mercaptopurine (6MP) as part of their maintenance therapy.

An earlier analysis of the Children’s Oncology Group (COG) AALL03N1 compliance study showed that adherence rates of less than 95% were associated with a 3.7-fold increased risk of relapse.

And about 40% of patients were non-adherent. Yet patients indicate they are taking their medication when questioned.

“We ask our patients if they are taking their meds,” said Wendy Landier, PhD, “and they tell us they are.”

“Even in this cohort who were being closely monitored and knew that they were being closely monitored electronically and were asked to self-report, we found over-reporting.”

Dr Landier, of the University of Alabama at Birmingham, reported these findings comparing self-reported adherence with electronic monitoring of 6MP intake at the 2015 ASH Annual Meeting (abstract 82).

The investigators collected data over 6 months from 416 ALL patients who were 21 years at diagnosis or younger and were receiving 6MP as part of their maintenance therapy.

Investigators measured subjective self-reporting by a patient questionnaire, which included patient demographic information in addition to the number of days the patient took 6MP over the past month.

For the objective medication event-monitoring system (MEMS), patients received a 6MP bottle that was fitted with a TrackCap^TM. The cap had a microprocessor chip that recorded the date and time of each bottle opening.

Investigators downloaded the data at the end of the study. They then compared the MEMS with the self-reported data.

The investigators classified perfect reporters as those whose self-report corresponded to their MEMS.

They classified over-reporters as those whose self-report was greater than their MEMS data for 5 days or more and 50% of the months.

The rest they classified as others.

Patients were a median age of 6.0 years, and 277 (66.6%) were male. Parents completed the survey for patients younger than 12.

Two hundred forty-two patients (60.9%) had fathers whose education was less than some college, 159 (38.4%) had NCI high-risk disease, and 168 (40.4%) were non-adherent to 6MP as determined by earlier analysis of the COG AALL03N1 study.

Thirty-six percent were non-Hispanic white, 37% were Hispanic, 14% Asian, and 13% African American.

The investigators monitored the patients’ 6MP intake for a total of 1344 patient-months at 87 COG sites.

And the correlation between subjective and objective reporting was moderate, Dr Landier said, with the correlation ranging from 0.36 to 0.58.

Twelve percent of the patients were perfect reporters, with no difference between the reporting methods.

Twenty-four percent over-reported their intake, 1% under-reported their intake, and 64% were other.

The investigators analyzed variables associated with over-reporting and found that age 12 years or older (P=0.02), being Hispanic (P=0.02), Asian (P=0.02), or African American (P<0.001), paternal education less than college (P=0.02), and being classified as 6MP non-adherent (P<0.001) were all significant.

“Over-reporting of 6MP ingestion is common,” Dr Landier said, with 88% of patients or parents over-reporting the number of days 6MP was taken.

“What we’ve learned from this study is that we cannot rely on patients’ self-report in the clinic,” she said. “What we found is that only 12% of our patients are perfect, so to speak, and that the others mainly over-estimate, and I don’t believe intentionally.”

“[W]e need to have a better way of identifying which patients are at risk for over-reporting their intake, whether they’re aware of it or not,” she added.

Wendy Landier, PhD, CRNP

Photo courtesy of ASH

ORLANDO, FL—A study comparing subjective versus objective reporting of treatment compliance in patients with acute lymphoblastic leukemia (ALL) has shown that about a fourth of patients over-report how compliant they are with taking 6-mercaptopurine (6MP) as part of their maintenance therapy.

An earlier analysis of the Children’s Oncology Group (COG) AALL03N1 compliance study showed that adherence rates of less than 95% were associated with a 3.7-fold increased risk of relapse.

And about 40% of patients were non-adherent. Yet patients indicate they are taking their medication when questioned.

“We ask our patients if they are taking their meds,” said Wendy Landier, PhD, “and they tell us they are.”

“Even in this cohort who were being closely monitored and knew that they were being closely monitored electronically and were asked to self-report, we found over-reporting.”

Dr Landier, of the University of Alabama at Birmingham, reported these findings comparing self-reported adherence with electronic monitoring of 6MP intake at the 2015 ASH Annual Meeting (abstract 82).

The investigators collected data over 6 months from 416 ALL patients who were 21 years at diagnosis or younger and were receiving 6MP as part of their maintenance therapy.

Investigators measured subjective self-reporting by a patient questionnaire, which included patient demographic information in addition to the number of days the patient took 6MP over the past month.

For the objective medication event-monitoring system (MEMS), patients received a 6MP bottle that was fitted with a TrackCap^TM. The cap had a microprocessor chip that recorded the date and time of each bottle opening.

Investigators downloaded the data at the end of the study. They then compared the MEMS with the self-reported data.

The investigators classified perfect reporters as those whose self-report corresponded to their MEMS.

They classified over-reporters as those whose self-report was greater than their MEMS data for 5 days or more and 50% of the months.

The rest they classified as others.

Patients were a median age of 6.0 years, and 277 (66.6%) were male. Parents completed the survey for patients younger than 12.

Two hundred forty-two patients (60.9%) had fathers whose education was less than some college, 159 (38.4%) had NCI high-risk disease, and 168 (40.4%) were non-adherent to 6MP as determined by earlier analysis of the COG AALL03N1 study.

Thirty-six percent were non-Hispanic white, 37% were Hispanic, 14% Asian, and 13% African American.

The investigators monitored the patients’ 6MP intake for a total of 1344 patient-months at 87 COG sites.

And the correlation between subjective and objective reporting was moderate, Dr Landier said, with the correlation ranging from 0.36 to 0.58.

Twelve percent of the patients were perfect reporters, with no difference between the reporting methods.

Twenty-four percent over-reported their intake, 1% under-reported their intake, and 64% were other.

The investigators analyzed variables associated with over-reporting and found that age 12 years or older (P=0.02), being Hispanic (P=0.02), Asian (P=0.02), or African American (P<0.001), paternal education less than college (P=0.02), and being classified as 6MP non-adherent (P<0.001) were all significant.

“Over-reporting of 6MP ingestion is common,” Dr Landier said, with 88% of patients or parents over-reporting the number of days 6MP was taken.

“What we’ve learned from this study is that we cannot rely on patients’ self-report in the clinic,” she said. “What we found is that only 12% of our patients are perfect, so to speak, and that the others mainly over-estimate, and I don’t believe intentionally.”

“[W]e need to have a better way of identifying which patients are at risk for over-reporting their intake, whether they’re aware of it or not,” she added.

Wendy Landier, PhD, CRNP

Photo courtesy of ASH

ORLANDO, FL—A study comparing subjective versus objective reporting of treatment compliance in patients with acute lymphoblastic leukemia (ALL) has shown that about a fourth of patients over-report how compliant they are with taking 6-mercaptopurine (6MP) as part of their maintenance therapy.

An earlier analysis of the Children’s Oncology Group (COG) AALL03N1 compliance study showed that adherence rates of less than 95% were associated with a 3.7-fold increased risk of relapse.

And about 40% of patients were non-adherent. Yet patients indicate they are taking their medication when questioned.

“We ask our patients if they are taking their meds,” said Wendy Landier, PhD, “and they tell us they are.”

“Even in this cohort who were being closely monitored and knew that they were being closely monitored electronically and were asked to self-report, we found over-reporting.”

Dr Landier, of the University of Alabama at Birmingham, reported these findings comparing self-reported adherence with electronic monitoring of 6MP intake at the 2015 ASH Annual Meeting (abstract 82).

The investigators collected data over 6 months from 416 ALL patients who were 21 years at diagnosis or younger and were receiving 6MP as part of their maintenance therapy.

Investigators measured subjective self-reporting by a patient questionnaire, which included patient demographic information in addition to the number of days the patient took 6MP over the past month.

For the objective medication event-monitoring system (MEMS), patients received a 6MP bottle that was fitted with a TrackCap^TM. The cap had a microprocessor chip that recorded the date and time of each bottle opening.

Investigators downloaded the data at the end of the study. They then compared the MEMS with the self-reported data.

The investigators classified perfect reporters as those whose self-report corresponded to their MEMS.

They classified over-reporters as those whose self-report was greater than their MEMS data for 5 days or more and 50% of the months.

The rest they classified as others.

Patients were a median age of 6.0 years, and 277 (66.6%) were male. Parents completed the survey for patients younger than 12.

Two hundred forty-two patients (60.9%) had fathers whose education was less than some college, 159 (38.4%) had NCI high-risk disease, and 168 (40.4%) were non-adherent to 6MP as determined by earlier analysis of the COG AALL03N1 study.

Thirty-six percent were non-Hispanic white, 37% were Hispanic, 14% Asian, and 13% African American.

The investigators monitored the patients’ 6MP intake for a total of 1344 patient-months at 87 COG sites.

And the correlation between subjective and objective reporting was moderate, Dr Landier said, with the correlation ranging from 0.36 to 0.58.

Twelve percent of the patients were perfect reporters, with no difference between the reporting methods.

Twenty-four percent over-reported their intake, 1% under-reported their intake, and 64% were other.

The investigators analyzed variables associated with over-reporting and found that age 12 years or older (P=0.02), being Hispanic (P=0.02), Asian (P=0.02), or African American (P<0.001), paternal education less than college (P=0.02), and being classified as 6MP non-adherent (P<0.001) were all significant.

“Over-reporting of 6MP ingestion is common,” Dr Landier said, with 88% of patients or parents over-reporting the number of days 6MP was taken.

“What we’ve learned from this study is that we cannot rely on patients’ self-report in the clinic,” she said. “What we found is that only 12% of our patients are perfect, so to speak, and that the others mainly over-estimate, and I don’t believe intentionally.”

“[W]e need to have a better way of identifying which patients are at risk for over-reporting their intake, whether they’re aware of it or not,” she added.

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

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

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

Patrice Wendling/Frontline Medical News

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

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

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

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

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

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

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

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

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

Study details

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

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

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

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

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

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

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

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

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

pwendling@frontlinemedcom.com

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

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

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

Patrice Wendling/Frontline Medical News

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

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

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

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

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

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

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

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

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

Study details

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

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

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

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

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

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

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

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

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

pwendling@frontlinemedcom.com

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

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

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

Patrice Wendling/Frontline Medical News

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

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

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

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

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

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

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

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

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

Study details

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

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

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

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

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

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

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

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

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

pwendling@frontlinemedcom.com

ORLANDO – The oral multikinase inhibitor midostaurin improved overall survival by 23% when added to standard chemotherapy and given as maintenance therapy for 1 year in newly diagnosed patients with FLT3-mutated acute myeloid leukemia (AML) in the global phase III CALGB 10603/RATIFY trial.

The results struck a chord at the annual meeting of the American Society of Hematology because the benefits of targeted therapy have so far eluded AML patients despite transforming the treatment of other blood cancers. Currently, there are no approved, targeted treatments for AML.

CALGB 10603/RATIFY is the first large, controlled trial to show an overall survival benefit in the roughly 30% of AML patients with a mutation in the FLT3 gene.

“This is exciting because we haven’t had a new treatment in AML for 30 years,” Dr. Robert Hromas of the University of Florida, Gainesville, said while moderating a press conference highlighting the plenary abstract.

The results were a decade in the making after midostaurin failed previously when used in all AML patients rather than the subset with the FLT3 mutation. But the persistence of researchers, the international collaboration, and funding in cancer research paid off, Dr. Hromas said.

Study author Dr. Richard M. Stone, chief of staff at Dana-Farber Cancer Institute in Boston, reviewed the results of CALGB 10603/RATIFY in an interview.

CALGB 10603/RATIFY was sponsored by the Cancer Therapy Evaluation Program. Dr. Stone reported financial relationships with several drug companies including Novartis, which provided the study drug and sponsored the trial outside North America. Dr. Hromas disclosed serving as an uncompensated advisory board member without equity for Cloud Pharmaceuticals.

pwendling@frontlinemedcom.com

ORLANDO – The oral multikinase inhibitor midostaurin improved overall survival by 23% when added to standard chemotherapy and given as maintenance therapy for 1 year in newly diagnosed patients with FLT3-mutated acute myeloid leukemia (AML) in the global phase III CALGB 10603/RATIFY trial.

The results struck a chord at the annual meeting of the American Society of Hematology because the benefits of targeted therapy have so far eluded AML patients despite transforming the treatment of other blood cancers. Currently, there are no approved, targeted treatments for AML.

CALGB 10603/RATIFY is the first large, controlled trial to show an overall survival benefit in the roughly 30% of AML patients with a mutation in the FLT3 gene.

“This is exciting because we haven’t had a new treatment in AML for 30 years,” Dr. Robert Hromas of the University of Florida, Gainesville, said while moderating a press conference highlighting the plenary abstract.

The results were a decade in the making after midostaurin failed previously when used in all AML patients rather than the subset with the FLT3 mutation. But the persistence of researchers, the international collaboration, and funding in cancer research paid off, Dr. Hromas said.

Study author Dr. Richard M. Stone, chief of staff at Dana-Farber Cancer Institute in Boston, reviewed the results of CALGB 10603/RATIFY in an interview.

CALGB 10603/RATIFY was sponsored by the Cancer Therapy Evaluation Program. Dr. Stone reported financial relationships with several drug companies including Novartis, which provided the study drug and sponsored the trial outside North America. Dr. Hromas disclosed serving as an uncompensated advisory board member without equity for Cloud Pharmaceuticals.

pwendling@frontlinemedcom.com

ORLANDO – The oral multikinase inhibitor midostaurin improved overall survival by 23% when added to standard chemotherapy and given as maintenance therapy for 1 year in newly diagnosed patients with FLT3-mutated acute myeloid leukemia (AML) in the global phase III CALGB 10603/RATIFY trial.

The results struck a chord at the annual meeting of the American Society of Hematology because the benefits of targeted therapy have so far eluded AML patients despite transforming the treatment of other blood cancers. Currently, there are no approved, targeted treatments for AML.

CALGB 10603/RATIFY is the first large, controlled trial to show an overall survival benefit in the roughly 30% of AML patients with a mutation in the FLT3 gene.

“This is exciting because we haven’t had a new treatment in AML for 30 years,” Dr. Robert Hromas of the University of Florida, Gainesville, said while moderating a press conference highlighting the plenary abstract.

The results were a decade in the making after midostaurin failed previously when used in all AML patients rather than the subset with the FLT3 mutation. But the persistence of researchers, the international collaboration, and funding in cancer research paid off, Dr. Hromas said.

Study author Dr. Richard M. Stone, chief of staff at Dana-Farber Cancer Institute in Boston, reviewed the results of CALGB 10603/RATIFY in an interview.

CALGB 10603/RATIFY was sponsored by the Cancer Therapy Evaluation Program. Dr. Stone reported financial relationships with several drug companies including Novartis, which provided the study drug and sponsored the trial outside North America. Dr. Hromas disclosed serving as an uncompensated advisory board member without equity for Cloud Pharmaceuticals.

pwendling@frontlinemedcom.com