Hematology Times

James Kochenderfer, MD

Photo courtesy of ASH

ORLANDO, FL—Chimeric antigen receptor (CAR) T cells can have “powerful activity” in patients with multiple myeloma (MM), according to a speaker at the 2015 ASH Annual Meeting.

The CAR T cells in question are directed against the B-cell maturation antigen (BCMA), a protein expressed by normal and malignant plasma cells.

In a phase 1 study of patients with previously treated MM, CAR-BCMA T cells eliminated plasma cells without causing direct damage to essential organs.

The therapy did produce “substantial” toxicity similar to that observed in previous CAR T-cell trials, but this was reversible, said James N. Kochenderfer, MD, of the National Cancer Institute in Bethesda, Maryland.

Dr Kochenderfer presented these results as a late-breaking abstract at the meeting (LBA-1). He received research funding from bluebird bio, the company developing CAR-BCMA T-cell therapy along with Celgene and Baylor College of Medicine.

The researchers enrolled 12 patients on this study. The patients had received at least 3 prior lines of therapy, had “essentially normal” major organ function, and had clear, uniform expression of BCMA on myeloma cells by flow cytometry or immunohistochemistry.

The patients’ own T cells were genetically modified to express the CAR with a gamma-retroviral vector. The CAR-BCMA incorporates an anti-BCMA

single-chain variable fragment, a CD28 domain, and a CD3-zeta T-cell activation domain. It was previously described in Clinical Cancer Research in 2013.

Before receiving CAR-BCMA T-cell infusions, patients received chemotherapy—cyclophosphamide at 300 mg/m² daily for 3 days and fludarabine at 30 mg/m² daily for 3 days.

Two days later, patients received a single infusion of CAR-BCMA T cells. The doses were escalated based on the number of CAR-positive T cells/kg. The doses were 0.3 x 10⁶, 1 x 10⁶, 3 x 10⁶, and 9 x 10⁶ CAR-positive T cells/kg.

Response and toxicity

“[O]n the lower 2 dose levels, toxicity was minimal—just a couple of fevers,” Dr Kochenderfer noted. “When we got to the higher dose levels, patients started to have more significant toxicity, along with more impressive responses.”

One patient, Patient 10, had a stringent complete response to the highest dose of CAR-BCMA T cells (9 x 10⁶). This response is ongoing and has lasted longer than 12 weeks.

Patient 8, who received a CAR-BCMA T-cell dose of 3 x 10⁶, achieved a very good partial response that lasted 8 weeks. A PET scan showed complete clearance of myeloma in this patient.

Two patients achieved partial responses. One response occurred on the lowest dose of CAR-BCMA T cells (0.3 x 10⁶) and lasted 2 weeks.

The other partial response occurred in Patient 11, who received the highest dose of CAR-BCMA T cells. This response is ongoing and has lasted more than 6 weeks.

The remaining 8 patients had stable disease that lasted anywhere from 2 weeks to 16 weeks.

Best responders

Patient 10, who achieved a stringent complete response, had chemotherapy-resistant IgA MM at baseline. He had received 3 prior lines of therapy and had relapsed with 90% bone marrow plasma cells 3 months after autologous transplant.

“BCMA expression was uniform but dim on his myeloma cells,” Dr Kochenderfer noted.

Within 4 hours of receiving CAR-BCMA T cells, Patient 10 became febrile. He showed other signs of cytokine release syndrome as well, including tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase. But all of these symptoms resolved within 2 weeks.

Patient 10’s absolute neutrophil count was less than 500/µL at the time of CAR-BCMA T-cell infusion and remained less than 500/µL for 40 days after infusion. The patient was platelet-transfusion-dependent for 9 weeks after infusion.

Patient 11, who achieved the ongoing partial response, had received 5 prior lines of therapy. MM made up 80% of his bone marrow cells at baseline.

The patient experienced a rapid decrease in markers of MM after CAR-BCMA T-cell infusion, and his M protein levels continue to decrease.

Patient 11 also experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia, but all of these toxicities have resolved completely.

Dr Kochenderfer noted that patients who had significant responses (Patients 8, 10, and 11) had the highest blood levels of CAR-BCMA T cells. They also had the most severe clinical signs of cytokine release syndrome and much higher serum levels of IL-6 than the other patients.

“We have demonstrated, for the first time, that CAR T cells can have powerful activity against measurable myeloma,” Dr Kochenderfer said in closing. “Anti-BCMA CAR T cells are a promising therapy for multiple myeloma.”

James Kochenderfer, MD

Photo courtesy of ASH

ORLANDO, FL—Chimeric antigen receptor (CAR) T cells can have “powerful activity” in patients with multiple myeloma (MM), according to a speaker at the 2015 ASH Annual Meeting.

The CAR T cells in question are directed against the B-cell maturation antigen (BCMA), a protein expressed by normal and malignant plasma cells.

In a phase 1 study of patients with previously treated MM, CAR-BCMA T cells eliminated plasma cells without causing direct damage to essential organs.

The therapy did produce “substantial” toxicity similar to that observed in previous CAR T-cell trials, but this was reversible, said James N. Kochenderfer, MD, of the National Cancer Institute in Bethesda, Maryland.

Dr Kochenderfer presented these results as a late-breaking abstract at the meeting (LBA-1). He received research funding from bluebird bio, the company developing CAR-BCMA T-cell therapy along with Celgene and Baylor College of Medicine.

The researchers enrolled 12 patients on this study. The patients had received at least 3 prior lines of therapy, had “essentially normal” major organ function, and had clear, uniform expression of BCMA on myeloma cells by flow cytometry or immunohistochemistry.

The patients’ own T cells were genetically modified to express the CAR with a gamma-retroviral vector. The CAR-BCMA incorporates an anti-BCMA

single-chain variable fragment, a CD28 domain, and a CD3-zeta T-cell activation domain. It was previously described in Clinical Cancer Research in 2013.

Before receiving CAR-BCMA T-cell infusions, patients received chemotherapy—cyclophosphamide at 300 mg/m² daily for 3 days and fludarabine at 30 mg/m² daily for 3 days.

Two days later, patients received a single infusion of CAR-BCMA T cells. The doses were escalated based on the number of CAR-positive T cells/kg. The doses were 0.3 x 10⁶, 1 x 10⁶, 3 x 10⁶, and 9 x 10⁶ CAR-positive T cells/kg.

Response and toxicity

“[O]n the lower 2 dose levels, toxicity was minimal—just a couple of fevers,” Dr Kochenderfer noted. “When we got to the higher dose levels, patients started to have more significant toxicity, along with more impressive responses.”

One patient, Patient 10, had a stringent complete response to the highest dose of CAR-BCMA T cells (9 x 10⁶). This response is ongoing and has lasted longer than 12 weeks.

Patient 8, who received a CAR-BCMA T-cell dose of 3 x 10⁶, achieved a very good partial response that lasted 8 weeks. A PET scan showed complete clearance of myeloma in this patient.

Two patients achieved partial responses. One response occurred on the lowest dose of CAR-BCMA T cells (0.3 x 10⁶) and lasted 2 weeks.

The other partial response occurred in Patient 11, who received the highest dose of CAR-BCMA T cells. This response is ongoing and has lasted more than 6 weeks.

The remaining 8 patients had stable disease that lasted anywhere from 2 weeks to 16 weeks.

Best responders

Patient 10, who achieved a stringent complete response, had chemotherapy-resistant IgA MM at baseline. He had received 3 prior lines of therapy and had relapsed with 90% bone marrow plasma cells 3 months after autologous transplant.

“BCMA expression was uniform but dim on his myeloma cells,” Dr Kochenderfer noted.

Within 4 hours of receiving CAR-BCMA T cells, Patient 10 became febrile. He showed other signs of cytokine release syndrome as well, including tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase. But all of these symptoms resolved within 2 weeks.

Patient 10’s absolute neutrophil count was less than 500/µL at the time of CAR-BCMA T-cell infusion and remained less than 500/µL for 40 days after infusion. The patient was platelet-transfusion-dependent for 9 weeks after infusion.

Patient 11, who achieved the ongoing partial response, had received 5 prior lines of therapy. MM made up 80% of his bone marrow cells at baseline.

The patient experienced a rapid decrease in markers of MM after CAR-BCMA T-cell infusion, and his M protein levels continue to decrease.

Patient 11 also experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia, but all of these toxicities have resolved completely.

Dr Kochenderfer noted that patients who had significant responses (Patients 8, 10, and 11) had the highest blood levels of CAR-BCMA T cells. They also had the most severe clinical signs of cytokine release syndrome and much higher serum levels of IL-6 than the other patients.

“We have demonstrated, for the first time, that CAR T cells can have powerful activity against measurable myeloma,” Dr Kochenderfer said in closing. “Anti-BCMA CAR T cells are a promising therapy for multiple myeloma.”

James Kochenderfer, MD

Photo courtesy of ASH

ORLANDO, FL—Chimeric antigen receptor (CAR) T cells can have “powerful activity” in patients with multiple myeloma (MM), according to a speaker at the 2015 ASH Annual Meeting.

The CAR T cells in question are directed against the B-cell maturation antigen (BCMA), a protein expressed by normal and malignant plasma cells.

In a phase 1 study of patients with previously treated MM, CAR-BCMA T cells eliminated plasma cells without causing direct damage to essential organs.

The therapy did produce “substantial” toxicity similar to that observed in previous CAR T-cell trials, but this was reversible, said James N. Kochenderfer, MD, of the National Cancer Institute in Bethesda, Maryland.

Dr Kochenderfer presented these results as a late-breaking abstract at the meeting (LBA-1). He received research funding from bluebird bio, the company developing CAR-BCMA T-cell therapy along with Celgene and Baylor College of Medicine.

The researchers enrolled 12 patients on this study. The patients had received at least 3 prior lines of therapy, had “essentially normal” major organ function, and had clear, uniform expression of BCMA on myeloma cells by flow cytometry or immunohistochemistry.

The patients’ own T cells were genetically modified to express the CAR with a gamma-retroviral vector. The CAR-BCMA incorporates an anti-BCMA

single-chain variable fragment, a CD28 domain, and a CD3-zeta T-cell activation domain. It was previously described in Clinical Cancer Research in 2013.

Before receiving CAR-BCMA T-cell infusions, patients received chemotherapy—cyclophosphamide at 300 mg/m² daily for 3 days and fludarabine at 30 mg/m² daily for 3 days.

Two days later, patients received a single infusion of CAR-BCMA T cells. The doses were escalated based on the number of CAR-positive T cells/kg. The doses were 0.3 x 10⁶, 1 x 10⁶, 3 x 10⁶, and 9 x 10⁶ CAR-positive T cells/kg.

Response and toxicity

“[O]n the lower 2 dose levels, toxicity was minimal—just a couple of fevers,” Dr Kochenderfer noted. “When we got to the higher dose levels, patients started to have more significant toxicity, along with more impressive responses.”

One patient, Patient 10, had a stringent complete response to the highest dose of CAR-BCMA T cells (9 x 10⁶). This response is ongoing and has lasted longer than 12 weeks.

Patient 8, who received a CAR-BCMA T-cell dose of 3 x 10⁶, achieved a very good partial response that lasted 8 weeks. A PET scan showed complete clearance of myeloma in this patient.

Two patients achieved partial responses. One response occurred on the lowest dose of CAR-BCMA T cells (0.3 x 10⁶) and lasted 2 weeks.

The other partial response occurred in Patient 11, who received the highest dose of CAR-BCMA T cells. This response is ongoing and has lasted more than 6 weeks.

The remaining 8 patients had stable disease that lasted anywhere from 2 weeks to 16 weeks.

Best responders

Patient 10, who achieved a stringent complete response, had chemotherapy-resistant IgA MM at baseline. He had received 3 prior lines of therapy and had relapsed with 90% bone marrow plasma cells 3 months after autologous transplant.

“BCMA expression was uniform but dim on his myeloma cells,” Dr Kochenderfer noted.

Within 4 hours of receiving CAR-BCMA T cells, Patient 10 became febrile. He showed other signs of cytokine release syndrome as well, including tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase. But all of these symptoms resolved within 2 weeks.

Patient 10’s absolute neutrophil count was less than 500/µL at the time of CAR-BCMA T-cell infusion and remained less than 500/µL for 40 days after infusion. The patient was platelet-transfusion-dependent for 9 weeks after infusion.

Patient 11, who achieved the ongoing partial response, had received 5 prior lines of therapy. MM made up 80% of his bone marrow cells at baseline.

The patient experienced a rapid decrease in markers of MM after CAR-BCMA T-cell infusion, and his M protein levels continue to decrease.

Patient 11 also experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia, but all of these toxicities have resolved completely.

Dr Kochenderfer noted that patients who had significant responses (Patients 8, 10, and 11) had the highest blood levels of CAR-BCMA T cells. They also had the most severe clinical signs of cytokine release syndrome and much higher serum levels of IL-6 than the other patients.

“We have demonstrated, for the first time, that CAR T cells can have powerful activity against measurable myeloma,” Dr Kochenderfer said in closing. “Anti-BCMA CAR T cells are a promising therapy for multiple myeloma.”

AML cells

Image by Lance Liotta

Two genes can stop the development of acute myeloid leukemia (AML), according to research published in the Journal of Experimental Medicine.

The work suggests that Hif-1α and Hif-2α work together to stop the formation of leukemic stem cells, and blocking either Hif-2α or both genes

accelerates AML development.

Investigators said these findings are surprising because previous research suggested that blocking Hif-1α or Hif-2α might stop AML progression.

But their study suggests that therapies designed to block these genes might worsen AML or at least have no impact on the disease.

Conversely, designing new therapies that promote the activity of Hif-1α and Hif-2α could help treat AML or stop relapse after chemotherapy.

“Our discovery that Hif-1α and Hif-2α molecules act together to stop leukemia development is a major milestone in our efforts to combat leukemia,” said study author Kamil R. Kranc, DPhil, of the University of Edinburgh in Scotland.

“We now intend to harness this knowledge to develop curative therapies that eliminate leukemic stem cells, which are the underlying cause of AML.”

AML cells

Image by Lance Liotta

Two genes can stop the development of acute myeloid leukemia (AML), according to research published in the Journal of Experimental Medicine.

The work suggests that Hif-1α and Hif-2α work together to stop the formation of leukemic stem cells, and blocking either Hif-2α or both genes

accelerates AML development.

Investigators said these findings are surprising because previous research suggested that blocking Hif-1α or Hif-2α might stop AML progression.

But their study suggests that therapies designed to block these genes might worsen AML or at least have no impact on the disease.

Conversely, designing new therapies that promote the activity of Hif-1α and Hif-2α could help treat AML or stop relapse after chemotherapy.

“Our discovery that Hif-1α and Hif-2α molecules act together to stop leukemia development is a major milestone in our efforts to combat leukemia,” said study author Kamil R. Kranc, DPhil, of the University of Edinburgh in Scotland.

“We now intend to harness this knowledge to develop curative therapies that eliminate leukemic stem cells, which are the underlying cause of AML.”

AML cells

Image by Lance Liotta

Two genes can stop the development of acute myeloid leukemia (AML), according to research published in the Journal of Experimental Medicine.

The work suggests that Hif-1α and Hif-2α work together to stop the formation of leukemic stem cells, and blocking either Hif-2α or both genes

accelerates AML development.

Investigators said these findings are surprising because previous research suggested that blocking Hif-1α or Hif-2α might stop AML progression.

But their study suggests that therapies designed to block these genes might worsen AML or at least have no impact on the disease.

Conversely, designing new therapies that promote the activity of Hif-1α and Hif-2α could help treat AML or stop relapse after chemotherapy.

“Our discovery that Hif-1α and Hif-2α molecules act together to stop leukemia development is a major milestone in our efforts to combat leukemia,” said study author Kamil R. Kranc, DPhil, of the University of Edinburgh in Scotland.

“We now intend to harness this knowledge to develop curative therapies that eliminate leukemic stem cells, which are the underlying cause of AML.”

Genome sequencing

Photo courtesy of NIGMS

Researchers say they have identified substantial differences in the procedures and quality of cancer genome sequencing between sequencing centers.

And this led to dramatic discrepancies in the number and types of somatic mutations detected when using the same cancer genome sequences for analysis.

The group’s study involved 83 researchers from 78 institutions participating in the International Cancer Genomics Consortium (ICGC).

The ICGC is an international effort to establish a comprehensive description of genomic, transcriptomic, and epigenomic changes in 50 different tumor types and/or subtypes that are thought to be of clinical and societal importance across the globe.

The consortium is characterizing more than 25,000 cancer genomes and carrying out 78 projects supported by different national and international funding agencies.

For the current project, which was published in Nature Communications, researchers studied a patient with chronic lymphocytic leukemia and a patient with medulloblastoma.

The team analyzed the entire tumor genome of each patient and compared it to the normal genome of the same patient to decipher the molecular causes for these cancers.

The researchers said they saw “widely varying mutation call rates and low concordance among analysis pipelines.”

So they established a reference mutation dataset to assess analytical procedures. They said this “gold-set” reference database has helped the ICGC community improve procedures for identifying more true somatic mutations in cancer genomes and making fewer false-positive calls.

“The findings of our study have far-reaching implications for cancer genome analysis,” said Ivo Gut, of Centro Nacional de Analisis Genómico in Barcelona, Spain.

“We have found many inconsistencies in both the sequencing of cancer genomes and the data analysis at different sites. We are making our findings available to the scientific and diagnostic community so that they can improve their systems and generate more standardized and consistent results.”

Genome sequencing

Photo courtesy of NIGMS

Researchers say they have identified substantial differences in the procedures and quality of cancer genome sequencing between sequencing centers.

And this led to dramatic discrepancies in the number and types of somatic mutations detected when using the same cancer genome sequences for analysis.

The group’s study involved 83 researchers from 78 institutions participating in the International Cancer Genomics Consortium (ICGC).

The ICGC is an international effort to establish a comprehensive description of genomic, transcriptomic, and epigenomic changes in 50 different tumor types and/or subtypes that are thought to be of clinical and societal importance across the globe.

The consortium is characterizing more than 25,000 cancer genomes and carrying out 78 projects supported by different national and international funding agencies.

For the current project, which was published in Nature Communications, researchers studied a patient with chronic lymphocytic leukemia and a patient with medulloblastoma.

The team analyzed the entire tumor genome of each patient and compared it to the normal genome of the same patient to decipher the molecular causes for these cancers.

The researchers said they saw “widely varying mutation call rates and low concordance among analysis pipelines.”

So they established a reference mutation dataset to assess analytical procedures. They said this “gold-set” reference database has helped the ICGC community improve procedures for identifying more true somatic mutations in cancer genomes and making fewer false-positive calls.

“The findings of our study have far-reaching implications for cancer genome analysis,” said Ivo Gut, of Centro Nacional de Analisis Genómico in Barcelona, Spain.

“We have found many inconsistencies in both the sequencing of cancer genomes and the data analysis at different sites. We are making our findings available to the scientific and diagnostic community so that they can improve their systems and generate more standardized and consistent results.”

Genome sequencing

Photo courtesy of NIGMS

Researchers say they have identified substantial differences in the procedures and quality of cancer genome sequencing between sequencing centers.

And this led to dramatic discrepancies in the number and types of somatic mutations detected when using the same cancer genome sequences for analysis.

The group’s study involved 83 researchers from 78 institutions participating in the International Cancer Genomics Consortium (ICGC).

The ICGC is an international effort to establish a comprehensive description of genomic, transcriptomic, and epigenomic changes in 50 different tumor types and/or subtypes that are thought to be of clinical and societal importance across the globe.

The consortium is characterizing more than 25,000 cancer genomes and carrying out 78 projects supported by different national and international funding agencies.

For the current project, which was published in Nature Communications, researchers studied a patient with chronic lymphocytic leukemia and a patient with medulloblastoma.

The team analyzed the entire tumor genome of each patient and compared it to the normal genome of the same patient to decipher the molecular causes for these cancers.

The researchers said they saw “widely varying mutation call rates and low concordance among analysis pipelines.”

So they established a reference mutation dataset to assess analytical procedures. They said this “gold-set” reference database has helped the ICGC community improve procedures for identifying more true somatic mutations in cancer genomes and making fewer false-positive calls.

“The findings of our study have far-reaching implications for cancer genome analysis,” said Ivo Gut, of Centro Nacional de Analisis Genómico in Barcelona, Spain.

“We have found many inconsistencies in both the sequencing of cancer genomes and the data analysis at different sites. We are making our findings available to the scientific and diagnostic community so that they can improve their systems and generate more standardized and consistent results.”

Russel Ware, MD, PhD

Photo courtesy of ASH

ORLANDO, FL—Hydroxyurea (HU) is noninferior to chronic blood transfusions for reducing the risk of stroke in children with sickle cell disease (SCD), results of the TWiTCH trial suggest.

The trial showed that daily doses of HU lower the transcranial Doppler (TCD) blood velocity in children with SCD to a similar degree as blood transfusions, thereby decreasing the risk of stroke.

Because of these findings, the trial was terminated early, in November of last year.

Last week, results from TWiTCH were presented at the 2015 ASH Annual Meeting (abstract 3*) and published in The Lancet. The study was funded by the National Heart Lung and Blood Institute.

“Stroke . . . is one of the most severe and catastrophic clinical events that occurs in children with sickle cell, with serious motor and cognitive sequelae,” said study investigator and ASH presenter Russell E. Ware, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.

“With the advent of TCD, we now have the ability to identify high-risk children and use chronic transfusion therapy to prevent primary stroke.”

Dr Ware noted that results of the STOP trial showed that chronic transfusion reduced the risk of stroke in high-risk children with SCD, but the transfusions could not be stopped. The STOP 2 trial confirmed this, showing that stopping transfusions led to an increase in TCD blood velocity and stroke risk.

Because transfusions must be continued indefinitely and are associated with morbidity, an alternative stroke prevention strategy is needed, Dr Ware said. He and his colleagues conducted the TWiTCH trial to determine if HU would fit the bill.

Study design

For this phase 3 study, the researchers compared 24 months of transfusions to HU in children with SCD and abnormal TCD velocities. Study enrollment began in September 2011 and ended in April 2013.

All eligible children had received at least 12 months of transfusions prior to enrollment. They were randomized 1:1 to continue receiving transfusions or to receive the maximum-tolerated dose (MTD) of HU.

In the transfusion arm, the goal was to keep hemoglobin S levels below 30%, and iron overload was managed with daily oral chelation.

In the HU arm, the drug was escalated to the MTD, and children continued receiving transfusions until the MTD was achieved. Iron overload was managed with monthly phlebotomy.

The study had a noninferiority design, and the primary endpoint was the 24-month TCD velocity (with a noninferiority margin of 15 cm/sec). TCD velocities were obtained every 12 weeks and reviewed centrally. Local researchers were masked to the results.

Results

In all, 121 children were randomized—61 to transfusions and 60 to HU. Patient characteristics—baseline TCD velocities, age, duration of transfusion, etc.—were well balanced between the treatment arms.

“The average age of the patients was 9 or 10 years old, with about 3 or 4 years of transfusions coming in to the study,” Dr Ware noted.

In the transfusion arm, the children maintained a hemoglobin level of about 9 g/dL and hemoglobin S levels of less than 30%. Most patients received chelation with deferasirox at 26 ±6 mg/kg/day.

In the HU arm, 57 of 60 patients reached the MTD, which was 27 ± 4 mg/kg/day, on average. The median transfusion overlap was 6 months, the average absolute neutrophil count was 3.5 ± 1.6 x 10⁹/L, the average hemoglobin was about 9 g/dL, and fetal hemoglobin rose to about 25%. There were 756 phlebotomy procedures performed in 54 children.

“[In the HU arm,] very quickly after enrollment, the sickle hemoglobin rises, as the transfusions are weaned,” Dr Ware noted.

“Commensurately, the hemoglobin F rises as a protection. The neutrophil count and reticulocyte count drops, and those curves [counts in the HU and transfusion arms] diverge fairly quickly. The serum ferritin [curves] diverged as well.”

Early termination and noninferiority

Interim data analyses were scheduled to take place after one-third of the patients had exited the study and after two-thirds had exited. The first interim analysis demonstrated noninferiority, and the trial was closed early. An analysis was repeated after half of the patients had exited the study, and the trial was terminated.

At that point, 42 children had completed 24 months of treatment in the transfusion arm, 11 patients had truncated treatment, and 8 had early exits. Forty-one patients had completed 24 months of therapy in the HU arm, 13 had truncated treatment, and 6 had early exits.

The final TCD velocity (mean ± standard error) was 143 ± 1.6 cm/sec in the transfusion arm and 138 ± 1.6 cm/sec in the HU arm. The P value for noninferiority (in the intent-to-treat population) was 8.82 x 10^-16. By post-hoc analysis, the P value for superiority was 0.023.

Secondary endpoints

There were 29 new neurological events during the trial—12 in the transfusion arm and 17 in the HU arm. There were no new strokes, but there were 6 new transient ischemic attacks—3 in each arm.

There were no new cerebral infarcts in either arm. But there was 1 new progressive vasculopathy in the transfusion arm. And 1 child in the transfusion arm was withdrawn from the study for increasing TCD (>240 cm/sec).

Iron overload improved more in the HU arm than the transfusion arm, with a greater average change in both serum ferritin (P<0.001) and liver iron concentration (P=0.001).

Serious adverse events were more common in the HU arm than the transfusion arm—23 events in 9 patients and 10 events in 6 patients, respectively. But none of these events were thought to be related to study treatment or procedures.

The most common serious adverse event in both groups was vaso-occlusive pain—11 events in 5 HU-treated patients and 3 events in 1 transfusion-treated patient.

Dr Ware noted that there were no secondary leukemias associated with HU in this trial, and there is “a cumulative body of evidence” spanning 20 years that suggests the drug is not carcinogenic in this patient population.

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

Russel Ware, MD, PhD

Photo courtesy of ASH

ORLANDO, FL—Hydroxyurea (HU) is noninferior to chronic blood transfusions for reducing the risk of stroke in children with sickle cell disease (SCD), results of the TWiTCH trial suggest.

The trial showed that daily doses of HU lower the transcranial Doppler (TCD) blood velocity in children with SCD to a similar degree as blood transfusions, thereby decreasing the risk of stroke.

Because of these findings, the trial was terminated early, in November of last year.

Last week, results from TWiTCH were presented at the 2015 ASH Annual Meeting (abstract 3*) and published in The Lancet. The study was funded by the National Heart Lung and Blood Institute.

“Stroke . . . is one of the most severe and catastrophic clinical events that occurs in children with sickle cell, with serious motor and cognitive sequelae,” said study investigator and ASH presenter Russell E. Ware, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.

“With the advent of TCD, we now have the ability to identify high-risk children and use chronic transfusion therapy to prevent primary stroke.”

Dr Ware noted that results of the STOP trial showed that chronic transfusion reduced the risk of stroke in high-risk children with SCD, but the transfusions could not be stopped. The STOP 2 trial confirmed this, showing that stopping transfusions led to an increase in TCD blood velocity and stroke risk.

Because transfusions must be continued indefinitely and are associated with morbidity, an alternative stroke prevention strategy is needed, Dr Ware said. He and his colleagues conducted the TWiTCH trial to determine if HU would fit the bill.

Study design

For this phase 3 study, the researchers compared 24 months of transfusions to HU in children with SCD and abnormal TCD velocities. Study enrollment began in September 2011 and ended in April 2013.

All eligible children had received at least 12 months of transfusions prior to enrollment. They were randomized 1:1 to continue receiving transfusions or to receive the maximum-tolerated dose (MTD) of HU.

In the transfusion arm, the goal was to keep hemoglobin S levels below 30%, and iron overload was managed with daily oral chelation.

In the HU arm, the drug was escalated to the MTD, and children continued receiving transfusions until the MTD was achieved. Iron overload was managed with monthly phlebotomy.

The study had a noninferiority design, and the primary endpoint was the 24-month TCD velocity (with a noninferiority margin of 15 cm/sec). TCD velocities were obtained every 12 weeks and reviewed centrally. Local researchers were masked to the results.

Results

In all, 121 children were randomized—61 to transfusions and 60 to HU. Patient characteristics—baseline TCD velocities, age, duration of transfusion, etc.—were well balanced between the treatment arms.

“The average age of the patients was 9 or 10 years old, with about 3 or 4 years of transfusions coming in to the study,” Dr Ware noted.

In the transfusion arm, the children maintained a hemoglobin level of about 9 g/dL and hemoglobin S levels of less than 30%. Most patients received chelation with deferasirox at 26 ±6 mg/kg/day.

In the HU arm, 57 of 60 patients reached the MTD, which was 27 ± 4 mg/kg/day, on average. The median transfusion overlap was 6 months, the average absolute neutrophil count was 3.5 ± 1.6 x 10⁹/L, the average hemoglobin was about 9 g/dL, and fetal hemoglobin rose to about 25%. There were 756 phlebotomy procedures performed in 54 children.

“[In the HU arm,] very quickly after enrollment, the sickle hemoglobin rises, as the transfusions are weaned,” Dr Ware noted.

“Commensurately, the hemoglobin F rises as a protection. The neutrophil count and reticulocyte count drops, and those curves [counts in the HU and transfusion arms] diverge fairly quickly. The serum ferritin [curves] diverged as well.”

Early termination and noninferiority

Interim data analyses were scheduled to take place after one-third of the patients had exited the study and after two-thirds had exited. The first interim analysis demonstrated noninferiority, and the trial was closed early. An analysis was repeated after half of the patients had exited the study, and the trial was terminated.

At that point, 42 children had completed 24 months of treatment in the transfusion arm, 11 patients had truncated treatment, and 8 had early exits. Forty-one patients had completed 24 months of therapy in the HU arm, 13 had truncated treatment, and 6 had early exits.

The final TCD velocity (mean ± standard error) was 143 ± 1.6 cm/sec in the transfusion arm and 138 ± 1.6 cm/sec in the HU arm. The P value for noninferiority (in the intent-to-treat population) was 8.82 x 10^-16. By post-hoc analysis, the P value for superiority was 0.023.

Secondary endpoints

There were 29 new neurological events during the trial—12 in the transfusion arm and 17 in the HU arm. There were no new strokes, but there were 6 new transient ischemic attacks—3 in each arm.

There were no new cerebral infarcts in either arm. But there was 1 new progressive vasculopathy in the transfusion arm. And 1 child in the transfusion arm was withdrawn from the study for increasing TCD (>240 cm/sec).

Iron overload improved more in the HU arm than the transfusion arm, with a greater average change in both serum ferritin (P<0.001) and liver iron concentration (P=0.001).

Serious adverse events were more common in the HU arm than the transfusion arm—23 events in 9 patients and 10 events in 6 patients, respectively. But none of these events were thought to be related to study treatment or procedures.

The most common serious adverse event in both groups was vaso-occlusive pain—11 events in 5 HU-treated patients and 3 events in 1 transfusion-treated patient.

Dr Ware noted that there were no secondary leukemias associated with HU in this trial, and there is “a cumulative body of evidence” spanning 20 years that suggests the drug is not carcinogenic in this patient population.

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

Russel Ware, MD, PhD

Photo courtesy of ASH

ORLANDO, FL—Hydroxyurea (HU) is noninferior to chronic blood transfusions for reducing the risk of stroke in children with sickle cell disease (SCD), results of the TWiTCH trial suggest.

The trial showed that daily doses of HU lower the transcranial Doppler (TCD) blood velocity in children with SCD to a similar degree as blood transfusions, thereby decreasing the risk of stroke.

Because of these findings, the trial was terminated early, in November of last year.

Last week, results from TWiTCH were presented at the 2015 ASH Annual Meeting (abstract 3*) and published in The Lancet. The study was funded by the National Heart Lung and Blood Institute.

“Stroke . . . is one of the most severe and catastrophic clinical events that occurs in children with sickle cell, with serious motor and cognitive sequelae,” said study investigator and ASH presenter Russell E. Ware, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.

“With the advent of TCD, we now have the ability to identify high-risk children and use chronic transfusion therapy to prevent primary stroke.”

Dr Ware noted that results of the STOP trial showed that chronic transfusion reduced the risk of stroke in high-risk children with SCD, but the transfusions could not be stopped. The STOP 2 trial confirmed this, showing that stopping transfusions led to an increase in TCD blood velocity and stroke risk.

Because transfusions must be continued indefinitely and are associated with morbidity, an alternative stroke prevention strategy is needed, Dr Ware said. He and his colleagues conducted the TWiTCH trial to determine if HU would fit the bill.

Study design

For this phase 3 study, the researchers compared 24 months of transfusions to HU in children with SCD and abnormal TCD velocities. Study enrollment began in September 2011 and ended in April 2013.

All eligible children had received at least 12 months of transfusions prior to enrollment. They were randomized 1:1 to continue receiving transfusions or to receive the maximum-tolerated dose (MTD) of HU.

In the transfusion arm, the goal was to keep hemoglobin S levels below 30%, and iron overload was managed with daily oral chelation.

In the HU arm, the drug was escalated to the MTD, and children continued receiving transfusions until the MTD was achieved. Iron overload was managed with monthly phlebotomy.

The study had a noninferiority design, and the primary endpoint was the 24-month TCD velocity (with a noninferiority margin of 15 cm/sec). TCD velocities were obtained every 12 weeks and reviewed centrally. Local researchers were masked to the results.

Results

In all, 121 children were randomized—61 to transfusions and 60 to HU. Patient characteristics—baseline TCD velocities, age, duration of transfusion, etc.—were well balanced between the treatment arms.

“The average age of the patients was 9 or 10 years old, with about 3 or 4 years of transfusions coming in to the study,” Dr Ware noted.

In the transfusion arm, the children maintained a hemoglobin level of about 9 g/dL and hemoglobin S levels of less than 30%. Most patients received chelation with deferasirox at 26 ±6 mg/kg/day.

In the HU arm, 57 of 60 patients reached the MTD, which was 27 ± 4 mg/kg/day, on average. The median transfusion overlap was 6 months, the average absolute neutrophil count was 3.5 ± 1.6 x 10⁹/L, the average hemoglobin was about 9 g/dL, and fetal hemoglobin rose to about 25%. There were 756 phlebotomy procedures performed in 54 children.

“[In the HU arm,] very quickly after enrollment, the sickle hemoglobin rises, as the transfusions are weaned,” Dr Ware noted.

“Commensurately, the hemoglobin F rises as a protection. The neutrophil count and reticulocyte count drops, and those curves [counts in the HU and transfusion arms] diverge fairly quickly. The serum ferritin [curves] diverged as well.”

Early termination and noninferiority

Interim data analyses were scheduled to take place after one-third of the patients had exited the study and after two-thirds had exited. The first interim analysis demonstrated noninferiority, and the trial was closed early. An analysis was repeated after half of the patients had exited the study, and the trial was terminated.

At that point, 42 children had completed 24 months of treatment in the transfusion arm, 11 patients had truncated treatment, and 8 had early exits. Forty-one patients had completed 24 months of therapy in the HU arm, 13 had truncated treatment, and 6 had early exits.

The final TCD velocity (mean ± standard error) was 143 ± 1.6 cm/sec in the transfusion arm and 138 ± 1.6 cm/sec in the HU arm. The P value for noninferiority (in the intent-to-treat population) was 8.82 x 10^-16. By post-hoc analysis, the P value for superiority was 0.023.

Secondary endpoints

There were 29 new neurological events during the trial—12 in the transfusion arm and 17 in the HU arm. There were no new strokes, but there were 6 new transient ischemic attacks—3 in each arm.

There were no new cerebral infarcts in either arm. But there was 1 new progressive vasculopathy in the transfusion arm. And 1 child in the transfusion arm was withdrawn from the study for increasing TCD (>240 cm/sec).

Iron overload improved more in the HU arm than the transfusion arm, with a greater average change in both serum ferritin (P<0.001) and liver iron concentration (P=0.001).

Serious adverse events were more common in the HU arm than the transfusion arm—23 events in 9 patients and 10 events in 6 patients, respectively. But none of these events were thought to be related to study treatment or procedures.

The most common serious adverse event in both groups was vaso-occlusive pain—11 events in 5 HU-treated patients and 3 events in 1 transfusion-treated patient.

Dr Ware noted that there were no secondary leukemias associated with HU in this trial, and there is “a cumulative body of evidence” spanning 20 years that suggests the drug is not carcinogenic in this patient population.

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

Team performing surgery

Photo by Piotr Bodzek

New research suggests that individualized feedback is more effective than group instructions for helping general surgery residents prevent venous thromboembolism (VTE) in their patients.

The single-center study showed that regular, one-on-one feedback and written report cards helped ensure the use of correct VTE prophylaxis more effectively than the usual group lectures that newly minted surgeons receive as part of their training.

These results were published in Annals of Surgery.

The study, conducted between July 2013 and March 2014, involved 49 general surgery residents in their first through fifth year of training at Johns Hopkins Hospital in Baltimore, Maryland.

For the first 3 months, residents received no personalized feedback. For the following 3 months, they received an electronic score card via email detailing their individual performance, including how many times they prescribed the appropriate VTE prophylaxis, how many times they failed to do so, and how they fared compared with others.

For the next 3 months, all residents continued to receive monthly scores, but subpar performers—those who failed to prescribe appropriate treatment to every single patient they cared for—also received one-on-one coaching from a senior resident.

In the span of 6 months, this approach decreased—from 3 to 0—the number of preventable complications among surgery patients (complications occurring in patients who didn’t receive appropriate VTE prophylaxis).

In the 3-month period prior to deploying the personalized feedback strategy, 7 out of 865 surgical patients developed complications. Three of the 7 cases were subsequently identified as preventable. In comparison, there were no such preventable complications after residents received individualized feedback.

As a result of the feedback, the number of patients getting appropriate treatment increased from 89% to 96%.

The number of residents who performed at 100% (prescribing the correct treatment to every patient all the time) went up from 22 (45%) to 38 (78%). Most of the prescription failures—19 out of 28 such cases—were clustered in a group of 4 residents.

“Our results show that personalized, concrete feedback can be a form of forced introspection that improves self-awareness and decision-making on clotting prophylaxis,” said Elliott Haut, MD, PhD, of the Johns Hopkins University School of Medicine.

Beyond that, Dr Haut and his colleagues believe these results illustrate the notion that simple interventions can be harnessed to foster learning and improve performance among any frontline clinician.

“Speaking more broadly, why stop with residents? Why stop with anticlotting prophylaxis?” Dr Haut asked. “If our findings are borne out by larger studies, this approach could be harnessed to improve training and outcomes for anyone who touches a patient, from nurses to physicians to physical therapists.”

Team performing surgery

Photo by Piotr Bodzek

New research suggests that individualized feedback is more effective than group instructions for helping general surgery residents prevent venous thromboembolism (VTE) in their patients.

The single-center study showed that regular, one-on-one feedback and written report cards helped ensure the use of correct VTE prophylaxis more effectively than the usual group lectures that newly minted surgeons receive as part of their training.

These results were published in Annals of Surgery.

The study, conducted between July 2013 and March 2014, involved 49 general surgery residents in their first through fifth year of training at Johns Hopkins Hospital in Baltimore, Maryland.

For the first 3 months, residents received no personalized feedback. For the following 3 months, they received an electronic score card via email detailing their individual performance, including how many times they prescribed the appropriate VTE prophylaxis, how many times they failed to do so, and how they fared compared with others.

For the next 3 months, all residents continued to receive monthly scores, but subpar performers—those who failed to prescribe appropriate treatment to every single patient they cared for—also received one-on-one coaching from a senior resident.

In the span of 6 months, this approach decreased—from 3 to 0—the number of preventable complications among surgery patients (complications occurring in patients who didn’t receive appropriate VTE prophylaxis).

In the 3-month period prior to deploying the personalized feedback strategy, 7 out of 865 surgical patients developed complications. Three of the 7 cases were subsequently identified as preventable. In comparison, there were no such preventable complications after residents received individualized feedback.

As a result of the feedback, the number of patients getting appropriate treatment increased from 89% to 96%.

The number of residents who performed at 100% (prescribing the correct treatment to every patient all the time) went up from 22 (45%) to 38 (78%). Most of the prescription failures—19 out of 28 such cases—were clustered in a group of 4 residents.

“Our results show that personalized, concrete feedback can be a form of forced introspection that improves self-awareness and decision-making on clotting prophylaxis,” said Elliott Haut, MD, PhD, of the Johns Hopkins University School of Medicine.

Beyond that, Dr Haut and his colleagues believe these results illustrate the notion that simple interventions can be harnessed to foster learning and improve performance among any frontline clinician.

“Speaking more broadly, why stop with residents? Why stop with anticlotting prophylaxis?” Dr Haut asked. “If our findings are borne out by larger studies, this approach could be harnessed to improve training and outcomes for anyone who touches a patient, from nurses to physicians to physical therapists.”

Team performing surgery

Photo by Piotr Bodzek

New research suggests that individualized feedback is more effective than group instructions for helping general surgery residents prevent venous thromboembolism (VTE) in their patients.

The single-center study showed that regular, one-on-one feedback and written report cards helped ensure the use of correct VTE prophylaxis more effectively than the usual group lectures that newly minted surgeons receive as part of their training.

These results were published in Annals of Surgery.

The study, conducted between July 2013 and March 2014, involved 49 general surgery residents in their first through fifth year of training at Johns Hopkins Hospital in Baltimore, Maryland.

For the first 3 months, residents received no personalized feedback. For the following 3 months, they received an electronic score card via email detailing their individual performance, including how many times they prescribed the appropriate VTE prophylaxis, how many times they failed to do so, and how they fared compared with others.

For the next 3 months, all residents continued to receive monthly scores, but subpar performers—those who failed to prescribe appropriate treatment to every single patient they cared for—also received one-on-one coaching from a senior resident.

In the span of 6 months, this approach decreased—from 3 to 0—the number of preventable complications among surgery patients (complications occurring in patients who didn’t receive appropriate VTE prophylaxis).

In the 3-month period prior to deploying the personalized feedback strategy, 7 out of 865 surgical patients developed complications. Three of the 7 cases were subsequently identified as preventable. In comparison, there were no such preventable complications after residents received individualized feedback.

As a result of the feedback, the number of patients getting appropriate treatment increased from 89% to 96%.

The number of residents who performed at 100% (prescribing the correct treatment to every patient all the time) went up from 22 (45%) to 38 (78%). Most of the prescription failures—19 out of 28 such cases—were clustered in a group of 4 residents.

“Our results show that personalized, concrete feedback can be a form of forced introspection that improves self-awareness and decision-making on clotting prophylaxis,” said Elliott Haut, MD, PhD, of the Johns Hopkins University School of Medicine.

Beyond that, Dr Haut and his colleagues believe these results illustrate the notion that simple interventions can be harnessed to foster learning and improve performance among any frontline clinician.

“Speaking more broadly, why stop with residents? Why stop with anticlotting prophylaxis?” Dr Haut asked. “If our findings are borne out by larger studies, this approach could be harnessed to improve training and outcomes for anyone who touches a patient, from nurses to physicians to physical therapists.”

Attendees meet in Orlando

Photo courtesy of ASH

ORLANDO, FL—Idelalisib, the first-in-class PI3Kδ inhibitor, combined with bendamustine and rituximab (BR) for relapsed/refractory chronic

lymphocytic leukemia (CLL) offers “an important new option over the standard of care,” according to Andrew Zelenetz, MD, a member of the

international research team that conducted the phase 3 study of this combination.

Patients who received idelalisib plus BR experienced a much longer progression-free survival (PFS) than those who received BR alone, 23.1

months versus 11.1 months, respectively.

“And the benefit was seen across risk groups,” Dr Zelenetz said.

He pointed out that the trial was stopped early in October because of the “overwhelming benefit” of idelalisib compared to the conventional therapy arm.

Dr Zelenetz, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the findings at the 2015 ASH Annual Meeting as LBA-5.

Idelalisib had already been approved by the US Food and Drug Administration for the treatment of relapsed/refractory CLL.

“Many people refer to this [idelalisib] as a B-cell receptor drug,” Dr Zelenetz said, “but it is more than that. It is involved in signaling of very key pathways in cell survival and migration.”

The investigators hoped that by combining idelalisib with BR, they would be able to improve PFS and maintain tolerable toxicity. So they conducted Study 115 to find out.

Study 115 design and population

Study 115 was a double-blind, placebo-controlled phase 3 study.

The idelalisib arm consisted of 207 patients randomized to receive bendamustine at 70 mg/m² on days 1 and 2 every 4 weeks for 6 cycles, rituximab at 375 mg/m² during cycle 1 and 500 mg/m² cycles 2 through 6, and idelalisib at 150 mg twice daily until progression.

The BR arm consisted of 209 patients randomized to the same BR regimen plus placebo twice daily until progression.

Investigators stratified patients according to 17p deletion and/or TP52 mutation, IGHV mutation status, and refractory versus relapsed disease.

The primary endpoint was PFS and the secondary endpoints were overall response rate (ORR), nodal response, overall survival (OS), and complete response (CR) rate.

Patients had to have disease progression within less than 36 months from their last therapy, measurable disease, and no history of CLL transformation. They could not have progressed in less than 6 months from their last bendamustine treatment and they could not have had any prior inhibitors of BTK, PI3Kδ, or SYK.

Patient disposition and demographics

One hundred fifteen patients (56%) in the idelalisib arm are still on study, and 52% are on treatment. In the BR arm, 63 patients (30%) are still on study, and 29% are on treatment.

Patient characteristics were well balanced between the arms. Most patients (76%) were male, 58% were younger than 65 years and 42% were 65 or older. About half were Rai stage III/IV and the median number of prior regimens was 2 (range, 1–13).

The most common prior regimens in both arms were fludarabine/cyclophosphamide/rituximab, fludarabine/cyclophosphamide, and chlorambucil. Fifteen percent of patients in the idelalisib arm and 8% in the BR arm had prior BR.

A third of patients in each arm had either 17p deletion or TP53 mutation, and two-thirds had neither. Most patients did not have IGHV mutation—84% in the idelalisib group and 83% in the BR group.

Thirty-one percent of the idelalisib-treated patients and 29% of the placebo patients had refractory disease, and 69% and 71%, respectively, had relapsed disease.

Efficacy

Median PFS, as assessed by independent review committee, “was highly statistically significant,” Dr Zelenetz said,  at 23.1 months for idelalisib and 11.1 for BR (P<0.0001).

In addition, all subgroups analyzed favored idelalisib—refractory or relapsed disease, mutation status, cytogenetics, gender, age, and race.

Patients with neither deletion 17p nor TP53 had a hazard ratio of 0.22 favoring the idelalisib group, and patients with either one or the other of those mutations had a hazard ratio of 0.50 favoring idelalisib.

ORR was 68% and 45% for idelalisib and placebo, respectively, with 5% in the idelalisib arm and none in the placebo arm achieving a CR.

Dr Zelenetz pointed out that the CR rate was low largely due to missing confirmatory biopsies.

Ninety-six percent of patients in the idelalisib arm experienced 50% or more reduction in lymph nodes, compared with 61% in the placebo arm.

Patients in the idelalisib arm also experienced a significant improvement in OS of P=0.008 when stratified and P=0.023 when unstratified. Median OS has not been reached in either arm.

There was no difference in survival benefit in patients with refractory disease.

Safety

All patients in the idelalisib arm and 97% in the BR arm experienced an adverse event (AE), with 93% and 76% grade 3 or higher in the idelalisib and BR arms, respectively.

Serious AEs occurred in 66% of idelalisib-treated patients and 44% of placebo patients.

Fifty-four patients (26%) in the idelalisib arm discontinued the study drug due to AEs, and 22 (11%) required a study drug dose reduction. This was compared with 28 patients (13%) discontinuing and 13 patients requiring dose reductions in the placebo arm.

The most frequent AE occurring in more than 10% of patients was neutropenia. Grade 3 or higher neutropenia occurred in 60% of idelalisib patients and 46% of placebo patients.

Most AEs were higher in the idelalisib arm compared with the BR arm, including grade 3 or higher events, such as febrile neutropenia (20%, 6%), anemia (15%, 12%), thrombocytopenia (13%, 12%), pneumonia (11%, 6%), ALT increase (11%, <1%), pyrexia (7%, 3%), diarrhea (7%, 2%), and rash (3%, 0), among others.

Serious AEs occurring in more than 2% of patients were also higher in the idelalisib arm than the BR arm, and included febrile neutropenia (18%, 5%), pneumonia (14%, 6%), pyrexia (12%, 6%), neutropenia (4%, 1%), sepsis (4%, 1%), anemia (2%, 2%), lower respiratory tract infection (2%, 2%), diarrhea (4%, <1%), and neutropenic sepsis (1%, 3%).

The remainder of the serious AEs—urinary tract infection, bronchitis, septic shock, and squamous cell carcinoma—occurred in 2% or fewer patients in either arm.

Dr Zelenetz pointed out that the safety profile is consistent with previously reported studies.

Gilead Sciences developed idelalisib and funded Study 115.

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

Attendees meet in Orlando

Photo courtesy of ASH

ORLANDO, FL—Idelalisib, the first-in-class PI3Kδ inhibitor, combined with bendamustine and rituximab (BR) for relapsed/refractory chronic

lymphocytic leukemia (CLL) offers “an important new option over the standard of care,” according to Andrew Zelenetz, MD, a member of the

international research team that conducted the phase 3 study of this combination.

Patients who received idelalisib plus BR experienced a much longer progression-free survival (PFS) than those who received BR alone, 23.1

months versus 11.1 months, respectively.

“And the benefit was seen across risk groups,” Dr Zelenetz said.

He pointed out that the trial was stopped early in October because of the “overwhelming benefit” of idelalisib compared to the conventional therapy arm.

Dr Zelenetz, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the findings at the 2015 ASH Annual Meeting as LBA-5.

Idelalisib had already been approved by the US Food and Drug Administration for the treatment of relapsed/refractory CLL.

“Many people refer to this [idelalisib] as a B-cell receptor drug,” Dr Zelenetz said, “but it is more than that. It is involved in signaling of very key pathways in cell survival and migration.”

The investigators hoped that by combining idelalisib with BR, they would be able to improve PFS and maintain tolerable toxicity. So they conducted Study 115 to find out.

Study 115 design and population

Study 115 was a double-blind, placebo-controlled phase 3 study.

The idelalisib arm consisted of 207 patients randomized to receive bendamustine at 70 mg/m² on days 1 and 2 every 4 weeks for 6 cycles, rituximab at 375 mg/m² during cycle 1 and 500 mg/m² cycles 2 through 6, and idelalisib at 150 mg twice daily until progression.

The BR arm consisted of 209 patients randomized to the same BR regimen plus placebo twice daily until progression.

Investigators stratified patients according to 17p deletion and/or TP52 mutation, IGHV mutation status, and refractory versus relapsed disease.

The primary endpoint was PFS and the secondary endpoints were overall response rate (ORR), nodal response, overall survival (OS), and complete response (CR) rate.

Patients had to have disease progression within less than 36 months from their last therapy, measurable disease, and no history of CLL transformation. They could not have progressed in less than 6 months from their last bendamustine treatment and they could not have had any prior inhibitors of BTK, PI3Kδ, or SYK.

Patient disposition and demographics

One hundred fifteen patients (56%) in the idelalisib arm are still on study, and 52% are on treatment. In the BR arm, 63 patients (30%) are still on study, and 29% are on treatment.

Patient characteristics were well balanced between the arms. Most patients (76%) were male, 58% were younger than 65 years and 42% were 65 or older. About half were Rai stage III/IV and the median number of prior regimens was 2 (range, 1–13).

The most common prior regimens in both arms were fludarabine/cyclophosphamide/rituximab, fludarabine/cyclophosphamide, and chlorambucil. Fifteen percent of patients in the idelalisib arm and 8% in the BR arm had prior BR.

A third of patients in each arm had either 17p deletion or TP53 mutation, and two-thirds had neither. Most patients did not have IGHV mutation—84% in the idelalisib group and 83% in the BR group.

Thirty-one percent of the idelalisib-treated patients and 29% of the placebo patients had refractory disease, and 69% and 71%, respectively, had relapsed disease.

Efficacy

Median PFS, as assessed by independent review committee, “was highly statistically significant,” Dr Zelenetz said,  at 23.1 months for idelalisib and 11.1 for BR (P<0.0001).

In addition, all subgroups analyzed favored idelalisib—refractory or relapsed disease, mutation status, cytogenetics, gender, age, and race.

Patients with neither deletion 17p nor TP53 had a hazard ratio of 0.22 favoring the idelalisib group, and patients with either one or the other of those mutations had a hazard ratio of 0.50 favoring idelalisib.

ORR was 68% and 45% for idelalisib and placebo, respectively, with 5% in the idelalisib arm and none in the placebo arm achieving a CR.

Dr Zelenetz pointed out that the CR rate was low largely due to missing confirmatory biopsies.

Ninety-six percent of patients in the idelalisib arm experienced 50% or more reduction in lymph nodes, compared with 61% in the placebo arm.

Patients in the idelalisib arm also experienced a significant improvement in OS of P=0.008 when stratified and P=0.023 when unstratified. Median OS has not been reached in either arm.

There was no difference in survival benefit in patients with refractory disease.

Safety

All patients in the idelalisib arm and 97% in the BR arm experienced an adverse event (AE), with 93% and 76% grade 3 or higher in the idelalisib and BR arms, respectively.

Serious AEs occurred in 66% of idelalisib-treated patients and 44% of placebo patients.

Fifty-four patients (26%) in the idelalisib arm discontinued the study drug due to AEs, and 22 (11%) required a study drug dose reduction. This was compared with 28 patients (13%) discontinuing and 13 patients requiring dose reductions in the placebo arm.

The most frequent AE occurring in more than 10% of patients was neutropenia. Grade 3 or higher neutropenia occurred in 60% of idelalisib patients and 46% of placebo patients.

Most AEs were higher in the idelalisib arm compared with the BR arm, including grade 3 or higher events, such as febrile neutropenia (20%, 6%), anemia (15%, 12%), thrombocytopenia (13%, 12%), pneumonia (11%, 6%), ALT increase (11%, <1%), pyrexia (7%, 3%), diarrhea (7%, 2%), and rash (3%, 0), among others.

Serious AEs occurring in more than 2% of patients were also higher in the idelalisib arm than the BR arm, and included febrile neutropenia (18%, 5%), pneumonia (14%, 6%), pyrexia (12%, 6%), neutropenia (4%, 1%), sepsis (4%, 1%), anemia (2%, 2%), lower respiratory tract infection (2%, 2%), diarrhea (4%, <1%), and neutropenic sepsis (1%, 3%).

The remainder of the serious AEs—urinary tract infection, bronchitis, septic shock, and squamous cell carcinoma—occurred in 2% or fewer patients in either arm.

Dr Zelenetz pointed out that the safety profile is consistent with previously reported studies.

Gilead Sciences developed idelalisib and funded Study 115.

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

Attendees meet in Orlando

Photo courtesy of ASH

ORLANDO, FL—Idelalisib, the first-in-class PI3Kδ inhibitor, combined with bendamustine and rituximab (BR) for relapsed/refractory chronic

lymphocytic leukemia (CLL) offers “an important new option over the standard of care,” according to Andrew Zelenetz, MD, a member of the

international research team that conducted the phase 3 study of this combination.

Patients who received idelalisib plus BR experienced a much longer progression-free survival (PFS) than those who received BR alone, 23.1

months versus 11.1 months, respectively.

“And the benefit was seen across risk groups,” Dr Zelenetz said.

He pointed out that the trial was stopped early in October because of the “overwhelming benefit” of idelalisib compared to the conventional therapy arm.

Dr Zelenetz, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the findings at the 2015 ASH Annual Meeting as LBA-5.

Idelalisib had already been approved by the US Food and Drug Administration for the treatment of relapsed/refractory CLL.

“Many people refer to this [idelalisib] as a B-cell receptor drug,” Dr Zelenetz said, “but it is more than that. It is involved in signaling of very key pathways in cell survival and migration.”

The investigators hoped that by combining idelalisib with BR, they would be able to improve PFS and maintain tolerable toxicity. So they conducted Study 115 to find out.

Study 115 design and population

Study 115 was a double-blind, placebo-controlled phase 3 study.

The idelalisib arm consisted of 207 patients randomized to receive bendamustine at 70 mg/m² on days 1 and 2 every 4 weeks for 6 cycles, rituximab at 375 mg/m² during cycle 1 and 500 mg/m² cycles 2 through 6, and idelalisib at 150 mg twice daily until progression.

The BR arm consisted of 209 patients randomized to the same BR regimen plus placebo twice daily until progression.

Investigators stratified patients according to 17p deletion and/or TP52 mutation, IGHV mutation status, and refractory versus relapsed disease.

The primary endpoint was PFS and the secondary endpoints were overall response rate (ORR), nodal response, overall survival (OS), and complete response (CR) rate.

Patients had to have disease progression within less than 36 months from their last therapy, measurable disease, and no history of CLL transformation. They could not have progressed in less than 6 months from their last bendamustine treatment and they could not have had any prior inhibitors of BTK, PI3Kδ, or SYK.

Patient disposition and demographics

One hundred fifteen patients (56%) in the idelalisib arm are still on study, and 52% are on treatment. In the BR arm, 63 patients (30%) are still on study, and 29% are on treatment.

Patient characteristics were well balanced between the arms. Most patients (76%) were male, 58% were younger than 65 years and 42% were 65 or older. About half were Rai stage III/IV and the median number of prior regimens was 2 (range, 1–13).

The most common prior regimens in both arms were fludarabine/cyclophosphamide/rituximab, fludarabine/cyclophosphamide, and chlorambucil. Fifteen percent of patients in the idelalisib arm and 8% in the BR arm had prior BR.

A third of patients in each arm had either 17p deletion or TP53 mutation, and two-thirds had neither. Most patients did not have IGHV mutation—84% in the idelalisib group and 83% in the BR group.

Thirty-one percent of the idelalisib-treated patients and 29% of the placebo patients had refractory disease, and 69% and 71%, respectively, had relapsed disease.

Efficacy

Median PFS, as assessed by independent review committee, “was highly statistically significant,” Dr Zelenetz said,  at 23.1 months for idelalisib and 11.1 for BR (P<0.0001).

In addition, all subgroups analyzed favored idelalisib—refractory or relapsed disease, mutation status, cytogenetics, gender, age, and race.

Patients with neither deletion 17p nor TP53 had a hazard ratio of 0.22 favoring the idelalisib group, and patients with either one or the other of those mutations had a hazard ratio of 0.50 favoring idelalisib.

ORR was 68% and 45% for idelalisib and placebo, respectively, with 5% in the idelalisib arm and none in the placebo arm achieving a CR.

Dr Zelenetz pointed out that the CR rate was low largely due to missing confirmatory biopsies.

Ninety-six percent of patients in the idelalisib arm experienced 50% or more reduction in lymph nodes, compared with 61% in the placebo arm.

Patients in the idelalisib arm also experienced a significant improvement in OS of P=0.008 when stratified and P=0.023 when unstratified. Median OS has not been reached in either arm.

There was no difference in survival benefit in patients with refractory disease.

Safety

All patients in the idelalisib arm and 97% in the BR arm experienced an adverse event (AE), with 93% and 76% grade 3 or higher in the idelalisib and BR arms, respectively.

Serious AEs occurred in 66% of idelalisib-treated patients and 44% of placebo patients.

Fifty-four patients (26%) in the idelalisib arm discontinued the study drug due to AEs, and 22 (11%) required a study drug dose reduction. This was compared with 28 patients (13%) discontinuing and 13 patients requiring dose reductions in the placebo arm.

The most frequent AE occurring in more than 10% of patients was neutropenia. Grade 3 or higher neutropenia occurred in 60% of idelalisib patients and 46% of placebo patients.

Most AEs were higher in the idelalisib arm compared with the BR arm, including grade 3 or higher events, such as febrile neutropenia (20%, 6%), anemia (15%, 12%), thrombocytopenia (13%, 12%), pneumonia (11%, 6%), ALT increase (11%, <1%), pyrexia (7%, 3%), diarrhea (7%, 2%), and rash (3%, 0), among others.

Serious AEs occurring in more than 2% of patients were also higher in the idelalisib arm than the BR arm, and included febrile neutropenia (18%, 5%), pneumonia (14%, 6%), pyrexia (12%, 6%), neutropenia (4%, 1%), sepsis (4%, 1%), anemia (2%, 2%), lower respiratory tract infection (2%, 2%), diarrhea (4%, <1%), and neutropenic sepsis (1%, 3%).

The remainder of the serious AEs—urinary tract infection, bronchitis, septic shock, and squamous cell carcinoma—occurred in 2% or fewer patients in either arm.

Dr Zelenetz pointed out that the safety profile is consistent with previously reported studies.

Gilead Sciences developed idelalisib and funded Study 115.

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

Sebastien Maury, MD

Photo courtesy of ASH

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

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

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

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

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

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

Study design & population

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

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

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

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

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

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

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

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

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

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

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

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

Efficacy

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

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

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

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

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

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

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

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

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

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

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

Safety

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

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

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

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

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

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

Sebastien Maury, MD

Photo courtesy of ASH

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

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

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

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

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

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

Study design & population

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

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

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

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

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

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

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

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

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

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

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

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

Efficacy

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

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

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

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

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

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

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

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

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

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

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

Safety

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

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

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

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

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

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

Sebastien Maury, MD

Photo courtesy of ASH

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

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

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

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

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

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

Study design & population

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

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

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

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

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

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

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

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

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

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

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

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

Efficacy

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

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

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

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

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

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

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

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

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

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

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

Safety

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

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

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

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

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

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

Richard Stone, MD

Photo courtesy of ASH

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

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

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

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

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

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

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

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

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

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

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

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

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

Eligibility criteria

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

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

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

Trial design

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

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

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

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

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

Patient population

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

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

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

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

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

Safety

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

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

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

Efficacy

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

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

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

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

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

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

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

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

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

*Data in the presentation differ from the abstract.

Richard Stone, MD

Photo courtesy of ASH

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

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

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

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

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

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

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

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

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

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

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

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

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

Eligibility criteria

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

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

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

Trial design

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

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

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

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

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

Patient population

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

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

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

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

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

Safety

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

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

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

Efficacy

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

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

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

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

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

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

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

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

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

*Data in the presentation differ from the abstract.

Richard Stone, MD

Photo courtesy of ASH

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

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

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

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

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

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

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

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

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

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

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

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

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

Eligibility criteria

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

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

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

Trial design

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

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

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

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

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

Patient population

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

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

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

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

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

Safety

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

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

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

Efficacy

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

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

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

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

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

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

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

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

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

*Data in the presentation differ from the abstract.

Rivaroxaban

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

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

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

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

The study was sponsored by Janssen and Bayer HealthCare.

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

Study design

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

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

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

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

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

Results

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

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

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

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

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

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

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

Rivaroxaban

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

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

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

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

The study was sponsored by Janssen and Bayer HealthCare.

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

Study design

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

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

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

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

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

Results

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

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

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

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

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

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

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

Rivaroxaban

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

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

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

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

The study was sponsored by Janssen and Bayer HealthCare.

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

Study design

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

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

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

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

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

Results

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

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

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

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

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

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

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

 

 

2015 ASH Annual Meeting

Photo courtesy of ASH

 

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

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

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

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

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

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

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

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

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

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

Study design

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

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

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

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

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

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

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

Patients and treatment

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

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

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

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

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

Adverse events

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

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

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

Rash

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

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

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

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

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

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

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

Response and survival

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

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

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

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

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

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

 

 

2015 ASH Annual Meeting

Photo courtesy of ASH

 

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

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

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

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

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

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

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

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

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

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

Study design

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

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

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

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

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

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

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

Patients and treatment

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

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

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

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

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

Adverse events

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

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

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

Rash

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

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

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

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

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

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

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

Response and survival

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

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

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

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

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

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

 

 

2015 ASH Annual Meeting

Photo courtesy of ASH

 

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

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

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

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

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

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

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

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

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

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

Study design

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

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

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

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

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

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

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

Patients and treatment

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

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

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

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

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

Adverse events

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

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

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

Rash

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

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

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

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

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

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

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

Response and survival

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

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

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

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

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

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