Hematology Times

Micrograph showing AML

The US Food and Drug Administration (FDA) has placed holds on 3 early stage trials of vadastuximab talirine (SGN-CD33A) in acute myeloid leukemia (AML).

A phase 1/2 trial of vadastuximab talirine monotherapy in pre- and post-allogeneic transplant patients has been placed on full clinical hold.

This means no new subjects can be enrolled on the trial, and there can be no further dosing of subjects who are already enrolled.

Two phase 1 trials of vadastuximab talirine have been placed on partial clinical hold. This means no new subjects can be enrolled, but existing patients may continue treatment with re-consent.

In one of the trials on partial hold, researchers are investigating vadastuximab talirine alone and in combination with hypomethylating agents in AML patients who either relapsed after induction/consolidation or declined treatment with high-dose induction/consolidation.

In the other trial on partial hold, researchers are testing vadastuximab talirine in combination with 7+3 chemotherapy in newly diagnosed AML patients. Results from this trial were presented at the 2016 ASH Annual Meeting.

All 3 clinical holds were initiated to evaluate the potential risk of hepatotoxicity in patients who were treated with vadastuximab talirine and received allogeneic stem cell transplant either before or after treatment.

There have been 6 patients with hepatotoxicity, including several cases of veno-occlusive disease, with 4 fatal events.

Seattle Genetics, Inc., the company developing vadastuximab talirine, said it is working with the FDA to determine whether there is any association between hepatotoxicity and treatment with vadastuximab talirine to identify appropriate protocol amendments for patient safety and to enable continuation of these trials.

No new studies of vadastuximab talirine will be initiated until the clinical holds are lifted.

Seattle Genetics’ other ongoing trials of vadastuximab talirine, including the phase 3 CASCADE trial in older AML patients and phase 1/2 trial in patients with myelodysplastic syndrome (MDS), are proceeding with enrollment.

Overall, more than 300 patients have been treated with vadastuximab talirine in clinical trials across multiple treatment settings.

Vadastuximab talirine is an investigational antibody-drug conjugate (ADC) targeted to CD33, which is expressed on most AML and MDS blast cells. The CD33 engineered cysteine antibody is stably linked to a DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer via site-specific conjugation technology (EC-mAb).

PBD dimers are said to be significantly more potent than systemic chemotherapeutic drugs, and the EC-mAb technology allows uniform drug-loading onto an ADC. The ADC is designed to be stable in the bloodstream and to release its PBD agent upon internalization into CD33-expressing cells.

Micrograph showing AML

The US Food and Drug Administration (FDA) has placed holds on 3 early stage trials of vadastuximab talirine (SGN-CD33A) in acute myeloid leukemia (AML).

A phase 1/2 trial of vadastuximab talirine monotherapy in pre- and post-allogeneic transplant patients has been placed on full clinical hold.

This means no new subjects can be enrolled on the trial, and there can be no further dosing of subjects who are already enrolled.

Two phase 1 trials of vadastuximab talirine have been placed on partial clinical hold. This means no new subjects can be enrolled, but existing patients may continue treatment with re-consent.

In one of the trials on partial hold, researchers are investigating vadastuximab talirine alone and in combination with hypomethylating agents in AML patients who either relapsed after induction/consolidation or declined treatment with high-dose induction/consolidation.

In the other trial on partial hold, researchers are testing vadastuximab talirine in combination with 7+3 chemotherapy in newly diagnosed AML patients. Results from this trial were presented at the 2016 ASH Annual Meeting.

All 3 clinical holds were initiated to evaluate the potential risk of hepatotoxicity in patients who were treated with vadastuximab talirine and received allogeneic stem cell transplant either before or after treatment.

There have been 6 patients with hepatotoxicity, including several cases of veno-occlusive disease, with 4 fatal events.

Seattle Genetics, Inc., the company developing vadastuximab talirine, said it is working with the FDA to determine whether there is any association between hepatotoxicity and treatment with vadastuximab talirine to identify appropriate protocol amendments for patient safety and to enable continuation of these trials.

No new studies of vadastuximab talirine will be initiated until the clinical holds are lifted.

Seattle Genetics’ other ongoing trials of vadastuximab talirine, including the phase 3 CASCADE trial in older AML patients and phase 1/2 trial in patients with myelodysplastic syndrome (MDS), are proceeding with enrollment.

Overall, more than 300 patients have been treated with vadastuximab talirine in clinical trials across multiple treatment settings.

Vadastuximab talirine is an investigational antibody-drug conjugate (ADC) targeted to CD33, which is expressed on most AML and MDS blast cells. The CD33 engineered cysteine antibody is stably linked to a DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer via site-specific conjugation technology (EC-mAb).

PBD dimers are said to be significantly more potent than systemic chemotherapeutic drugs, and the EC-mAb technology allows uniform drug-loading onto an ADC. The ADC is designed to be stable in the bloodstream and to release its PBD agent upon internalization into CD33-expressing cells.

Micrograph showing AML

The US Food and Drug Administration (FDA) has placed holds on 3 early stage trials of vadastuximab talirine (SGN-CD33A) in acute myeloid leukemia (AML).

A phase 1/2 trial of vadastuximab talirine monotherapy in pre- and post-allogeneic transplant patients has been placed on full clinical hold.

This means no new subjects can be enrolled on the trial, and there can be no further dosing of subjects who are already enrolled.

Two phase 1 trials of vadastuximab talirine have been placed on partial clinical hold. This means no new subjects can be enrolled, but existing patients may continue treatment with re-consent.

In one of the trials on partial hold, researchers are investigating vadastuximab talirine alone and in combination with hypomethylating agents in AML patients who either relapsed after induction/consolidation or declined treatment with high-dose induction/consolidation.

In the other trial on partial hold, researchers are testing vadastuximab talirine in combination with 7+3 chemotherapy in newly diagnosed AML patients. Results from this trial were presented at the 2016 ASH Annual Meeting.

All 3 clinical holds were initiated to evaluate the potential risk of hepatotoxicity in patients who were treated with vadastuximab talirine and received allogeneic stem cell transplant either before or after treatment.

There have been 6 patients with hepatotoxicity, including several cases of veno-occlusive disease, with 4 fatal events.

Seattle Genetics, Inc., the company developing vadastuximab talirine, said it is working with the FDA to determine whether there is any association between hepatotoxicity and treatment with vadastuximab talirine to identify appropriate protocol amendments for patient safety and to enable continuation of these trials.

No new studies of vadastuximab talirine will be initiated until the clinical holds are lifted.

Seattle Genetics’ other ongoing trials of vadastuximab talirine, including the phase 3 CASCADE trial in older AML patients and phase 1/2 trial in patients with myelodysplastic syndrome (MDS), are proceeding with enrollment.

Overall, more than 300 patients have been treated with vadastuximab talirine in clinical trials across multiple treatment settings.

Vadastuximab talirine is an investigational antibody-drug conjugate (ADC) targeted to CD33, which is expressed on most AML and MDS blast cells. The CD33 engineered cysteine antibody is stably linked to a DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer via site-specific conjugation technology (EC-mAb).

PBD dimers are said to be significantly more potent than systemic chemotherapeutic drugs, and the EC-mAb technology allows uniform drug-loading onto an ADC. The ADC is designed to be stable in the bloodstream and to release its PBD agent upon internalization into CD33-expressing cells.

Vial of Adynovate

Photo courtesy of Baxalta

The US Food and Drug Administration (FDA) has expanded the approved use of Adynovate, a recombinant pegylated factor VIII (FVIII) product, in patients with hemophilia A.

Adynovate was previously approved as routine prophylaxis and for on-demand treatment of bleeding episodes in patients age 12 and older.

Now, Adynovate is approved for the same indications in patients younger than 12 and for perioperative management in patients of all ages.

Adynovate is built on the full-length Advate molecule, which was approved by the FDA in 2003. Adynovate leverages proprietary pegylation technology designed to extend the amount of FVIII available for use in the body.

The technology was selected because it maintains the integrity of the parent molecule (Advate) while reducing the time at which the body clears Adynovate, resulting in an extended circulating half-life.

Adynovate and Advate are registered trademarks of Baxalta Incorporated, a wholly owned, indirect subsidiary of Shire plc.

For more details on Adynovate, see the full prescribing information.

Trials of Adynovate

The FDA’s approval of Adynovate in children is based on data from a phase 3 trial, which were presented at the World Federation of Hemophilia 2016 World Congress.

The study enrolled previously treated children younger than 12 with no history of FVIII inhibitors. The patients received twice-weekly prophylaxis with Adynovate (50 ± 10 IU/kg) for at least 6 months or 50 exposure days, whichever occurred last.

Sixty-six patients were evaluable. None of them developed inhibitory antibodies, and there were no adverse events related to Adynovate.

The median annualized bleeding rate was 2.0, and 38% of patients did not have any bleeding episodes.

The FDA’s approval of Adynovate for perioperative management was based on interim results of an ongoing phase 3 study in 15 patients with severe hemophilia A undergoing surgical procedures. The interim results were presented at the 2015 ASH Annual Meeting.

The patients underwent 11 major surgical procedures (3 knee replacements, 2 arthroscopic synovectomies, 1 cyst extirpation, 1 port placement, 1 gastric band placement, and 3 multiple tooth extractions including 1 radicular cyst removal) and 4 minor surgeries (1 synoviorthesis, 1 radiosynovectomy, 1 tooth extraction, and 1 dermatological surgery).

Perioperative hemostatic efficacy was rated as “excellent” for most procedures. Excellent hemostatic efficacy was defined as blood loss less than or equal to that expected for the same type of procedure performed in a non-hemophilic patient and requiring blood components for transfusions less than or similar to that expected in the non-hemophilic population.

The median observed intraoperative blood loss (n=10) was 10.0 mL, compared to the predicted average blood loss (n=11) of 50.0 mL for major surgeries.

Vial of Adynovate

Photo courtesy of Baxalta

The US Food and Drug Administration (FDA) has expanded the approved use of Adynovate, a recombinant pegylated factor VIII (FVIII) product, in patients with hemophilia A.

Adynovate was previously approved as routine prophylaxis and for on-demand treatment of bleeding episodes in patients age 12 and older.

Now, Adynovate is approved for the same indications in patients younger than 12 and for perioperative management in patients of all ages.

Adynovate is built on the full-length Advate molecule, which was approved by the FDA in 2003. Adynovate leverages proprietary pegylation technology designed to extend the amount of FVIII available for use in the body.

The technology was selected because it maintains the integrity of the parent molecule (Advate) while reducing the time at which the body clears Adynovate, resulting in an extended circulating half-life.

Adynovate and Advate are registered trademarks of Baxalta Incorporated, a wholly owned, indirect subsidiary of Shire plc.

For more details on Adynovate, see the full prescribing information.

Trials of Adynovate

The FDA’s approval of Adynovate in children is based on data from a phase 3 trial, which were presented at the World Federation of Hemophilia 2016 World Congress.

The study enrolled previously treated children younger than 12 with no history of FVIII inhibitors. The patients received twice-weekly prophylaxis with Adynovate (50 ± 10 IU/kg) for at least 6 months or 50 exposure days, whichever occurred last.

Sixty-six patients were evaluable. None of them developed inhibitory antibodies, and there were no adverse events related to Adynovate.

The median annualized bleeding rate was 2.0, and 38% of patients did not have any bleeding episodes.

The FDA’s approval of Adynovate for perioperative management was based on interim results of an ongoing phase 3 study in 15 patients with severe hemophilia A undergoing surgical procedures. The interim results were presented at the 2015 ASH Annual Meeting.

The patients underwent 11 major surgical procedures (3 knee replacements, 2 arthroscopic synovectomies, 1 cyst extirpation, 1 port placement, 1 gastric band placement, and 3 multiple tooth extractions including 1 radicular cyst removal) and 4 minor surgeries (1 synoviorthesis, 1 radiosynovectomy, 1 tooth extraction, and 1 dermatological surgery).

Perioperative hemostatic efficacy was rated as “excellent” for most procedures. Excellent hemostatic efficacy was defined as blood loss less than or equal to that expected for the same type of procedure performed in a non-hemophilic patient and requiring blood components for transfusions less than or similar to that expected in the non-hemophilic population.

The median observed intraoperative blood loss (n=10) was 10.0 mL, compared to the predicted average blood loss (n=11) of 50.0 mL for major surgeries.

Vial of Adynovate

Photo courtesy of Baxalta

The US Food and Drug Administration (FDA) has expanded the approved use of Adynovate, a recombinant pegylated factor VIII (FVIII) product, in patients with hemophilia A.

Adynovate was previously approved as routine prophylaxis and for on-demand treatment of bleeding episodes in patients age 12 and older.

Now, Adynovate is approved for the same indications in patients younger than 12 and for perioperative management in patients of all ages.

Adynovate is built on the full-length Advate molecule, which was approved by the FDA in 2003. Adynovate leverages proprietary pegylation technology designed to extend the amount of FVIII available for use in the body.

The technology was selected because it maintains the integrity of the parent molecule (Advate) while reducing the time at which the body clears Adynovate, resulting in an extended circulating half-life.

Adynovate and Advate are registered trademarks of Baxalta Incorporated, a wholly owned, indirect subsidiary of Shire plc.

For more details on Adynovate, see the full prescribing information.

Trials of Adynovate

The FDA’s approval of Adynovate in children is based on data from a phase 3 trial, which were presented at the World Federation of Hemophilia 2016 World Congress.

The study enrolled previously treated children younger than 12 with no history of FVIII inhibitors. The patients received twice-weekly prophylaxis with Adynovate (50 ± 10 IU/kg) for at least 6 months or 50 exposure days, whichever occurred last.

Sixty-six patients were evaluable. None of them developed inhibitory antibodies, and there were no adverse events related to Adynovate.

The median annualized bleeding rate was 2.0, and 38% of patients did not have any bleeding episodes.

The FDA’s approval of Adynovate for perioperative management was based on interim results of an ongoing phase 3 study in 15 patients with severe hemophilia A undergoing surgical procedures. The interim results were presented at the 2015 ASH Annual Meeting.

The patients underwent 11 major surgical procedures (3 knee replacements, 2 arthroscopic synovectomies, 1 cyst extirpation, 1 port placement, 1 gastric band placement, and 3 multiple tooth extractions including 1 radicular cyst removal) and 4 minor surgeries (1 synoviorthesis, 1 radiosynovectomy, 1 tooth extraction, and 1 dermatological surgery).

Perioperative hemostatic efficacy was rated as “excellent” for most procedures. Excellent hemostatic efficacy was defined as blood loss less than or equal to that expected for the same type of procedure performed in a non-hemophilic patient and requiring blood components for transfusions less than or similar to that expected in the non-hemophilic population.

The median observed intraoperative blood loss (n=10) was 10.0 mL, compared to the predicted average blood loss (n=11) of 50.0 mL for major surgeries.

Apoptosis

Preclinical research appears to explain why certain tissues in very young children are more sensitive to collateral damage from cancer treatment than tissues in older individuals.

Researchers found evidence to suggest that, early in life, cells in the brain, heart, and kidney are primed for apoptosis.

On the other hand, cells in the healthy adult brain, heart, and kidneys are apoptosis-refractory.

Kristopher A. Sarosiek, PhD, of the Harvard T.H. Chan School of Public Health in Boston, Massachusetts, and his colleagues reported these findings in Cancer Cell.

The researchers used BH3 profiling to measure the relative dominance of pro-survival or pro-death signals inside cells.

A cancer cell in which apoptotic signals are dominant is said to be “highly primed” for self-destruction and therefore easily killed by therapy, while a cell with low priming is more resistant to death or damage.

Dr Sarosiek and his colleagues measured the priming of cells in tissues from adult mice and young mice.

In the adult mice, cells of the hematopoietic lineage from the periphery, thymus, spleen, and bone marrow were the most primed for apoptosis. Cells from the large intestine, small intestine, lungs, and liver were relatively unprimed. And cells in brain, heart, and kidney tissues were far less primed.

However, in embryonic and very young mice, cells in the brain, heart, and kidney were extremely primed for apoptosis.

The researchers found that, in the adult brains, hearts, and kidneys, the molecular machinery needed to perform apoptosis was nearly completely absent.

In contrast, this machinery was abundant in the brains, hearts, and kidneys of young mice. As a result, brain, heart, and kidney cells were much more vulnerable to cell death when exposed to chemotherapy or radiation.

After determining in mouse models that certain cells grew more resistant to treatment toxicity with age, the researchers tested human cells. The team obtained fresh samples of tissue that had been removed from brains of children and adults to prevent intractable epileptic seizures.

As in the mice, the youngest human brain cells were more highly primed with apoptotic machinery and vulnerable to chemotherapy and radiation damage.

The researchers said there was a period of higher heterogeneity in apoptotic priming among patients between 2 and 6 years of age. After that, the brain transitions to full apoptotic resistance.

The team also found that, in young tissues, expression of the apoptotic protein machinery is driven by c-Myc. This transcription factor drives an apoptotically primed state by directly activating transcription of the pro-apoptotic genes Bax, Bim, and Bid.

“[This research] has uncovered some opportunities to selectively block apoptosis in our healthy tissues and prevent toxicity from radiation or chemotherapy while still maintaining sensitivity within cancer cells,” Dr Sarosiek said. “We are actively pursuing the identification of new medicines that can be used exactly for this purpose.”

Apoptosis

Preclinical research appears to explain why certain tissues in very young children are more sensitive to collateral damage from cancer treatment than tissues in older individuals.

Researchers found evidence to suggest that, early in life, cells in the brain, heart, and kidney are primed for apoptosis.

On the other hand, cells in the healthy adult brain, heart, and kidneys are apoptosis-refractory.

Kristopher A. Sarosiek, PhD, of the Harvard T.H. Chan School of Public Health in Boston, Massachusetts, and his colleagues reported these findings in Cancer Cell.

The researchers used BH3 profiling to measure the relative dominance of pro-survival or pro-death signals inside cells.

A cancer cell in which apoptotic signals are dominant is said to be “highly primed” for self-destruction and therefore easily killed by therapy, while a cell with low priming is more resistant to death or damage.

Dr Sarosiek and his colleagues measured the priming of cells in tissues from adult mice and young mice.

In the adult mice, cells of the hematopoietic lineage from the periphery, thymus, spleen, and bone marrow were the most primed for apoptosis. Cells from the large intestine, small intestine, lungs, and liver were relatively unprimed. And cells in brain, heart, and kidney tissues were far less primed.

However, in embryonic and very young mice, cells in the brain, heart, and kidney were extremely primed for apoptosis.

The researchers found that, in the adult brains, hearts, and kidneys, the molecular machinery needed to perform apoptosis was nearly completely absent.

In contrast, this machinery was abundant in the brains, hearts, and kidneys of young mice. As a result, brain, heart, and kidney cells were much more vulnerable to cell death when exposed to chemotherapy or radiation.

After determining in mouse models that certain cells grew more resistant to treatment toxicity with age, the researchers tested human cells. The team obtained fresh samples of tissue that had been removed from brains of children and adults to prevent intractable epileptic seizures.

As in the mice, the youngest human brain cells were more highly primed with apoptotic machinery and vulnerable to chemotherapy and radiation damage.

The researchers said there was a period of higher heterogeneity in apoptotic priming among patients between 2 and 6 years of age. After that, the brain transitions to full apoptotic resistance.

The team also found that, in young tissues, expression of the apoptotic protein machinery is driven by c-Myc. This transcription factor drives an apoptotically primed state by directly activating transcription of the pro-apoptotic genes Bax, Bim, and Bid.

“[This research] has uncovered some opportunities to selectively block apoptosis in our healthy tissues and prevent toxicity from radiation or chemotherapy while still maintaining sensitivity within cancer cells,” Dr Sarosiek said. “We are actively pursuing the identification of new medicines that can be used exactly for this purpose.”

Apoptosis

Preclinical research appears to explain why certain tissues in very young children are more sensitive to collateral damage from cancer treatment than tissues in older individuals.

Researchers found evidence to suggest that, early in life, cells in the brain, heart, and kidney are primed for apoptosis.

On the other hand, cells in the healthy adult brain, heart, and kidneys are apoptosis-refractory.

Kristopher A. Sarosiek, PhD, of the Harvard T.H. Chan School of Public Health in Boston, Massachusetts, and his colleagues reported these findings in Cancer Cell.

The researchers used BH3 profiling to measure the relative dominance of pro-survival or pro-death signals inside cells.

A cancer cell in which apoptotic signals are dominant is said to be “highly primed” for self-destruction and therefore easily killed by therapy, while a cell with low priming is more resistant to death or damage.

Dr Sarosiek and his colleagues measured the priming of cells in tissues from adult mice and young mice.

In the adult mice, cells of the hematopoietic lineage from the periphery, thymus, spleen, and bone marrow were the most primed for apoptosis. Cells from the large intestine, small intestine, lungs, and liver were relatively unprimed. And cells in brain, heart, and kidney tissues were far less primed.

However, in embryonic and very young mice, cells in the brain, heart, and kidney were extremely primed for apoptosis.

The researchers found that, in the adult brains, hearts, and kidneys, the molecular machinery needed to perform apoptosis was nearly completely absent.

In contrast, this machinery was abundant in the brains, hearts, and kidneys of young mice. As a result, brain, heart, and kidney cells were much more vulnerable to cell death when exposed to chemotherapy or radiation.

After determining in mouse models that certain cells grew more resistant to treatment toxicity with age, the researchers tested human cells. The team obtained fresh samples of tissue that had been removed from brains of children and adults to prevent intractable epileptic seizures.

As in the mice, the youngest human brain cells were more highly primed with apoptotic machinery and vulnerable to chemotherapy and radiation damage.

The researchers said there was a period of higher heterogeneity in apoptotic priming among patients between 2 and 6 years of age. After that, the brain transitions to full apoptotic resistance.

The team also found that, in young tissues, expression of the apoptotic protein machinery is driven by c-Myc. This transcription factor drives an apoptotically primed state by directly activating transcription of the pro-apoptotic genes Bax, Bim, and Bid.

“[This research] has uncovered some opportunities to selectively block apoptosis in our healthy tissues and prevent toxicity from radiation or chemotherapy while still maintaining sensitivity within cancer cells,” Dr Sarosiek said. “We are actively pursuing the identification of new medicines that can be used exactly for this purpose.”

Christoph Driessen, MD, PhD

SAN DIEGO—An antiretroviral drug used to treat the human immunodeficiency virus (HIV) may find a role in the treatment of multiple myeloma (MM) patients who are proteasome inhibitor (PI)-refractory.

According to investigators, nelfinavir may sensitize refractory patients so that PI-based treatments become an option for them.

In a phase 2 study of 34 patients, nelfinavir in combination with bortezomib and dexamethasone produced an objective response rate of 65%, which investigators called an “exceptional” response in this heavily pretreated, mostly dual-refractory patient population.

Christoph Driessen, MD, PhD, of Kantonsspital St Gallen in Switzerland, discussed the findings of this study, known as SAKK 39/13, at the 2016 ASH Annual Meeting as abstract 487.

Dr Driessen explained that downregulation of IRE1/XBP1 produces PI resistance, and this downregulation occurs in PI-refractory MM patients.

High expression of IRE1/XBP1 correlates with bortezomib sensitivity, and pharmacologic upregulation of IRE1/XBP1 re-sensitizes myeloma cells to PI treatment.

Nelfinavir, which overcomes PI resistance in vitro, is approved for oral HIV therapy.

“It’s an old drug, it’s a generic drug,” Dr Driessen said, and it’s approved at a dose of 2 x 1250 mg daily.

So the SAKK investigators undertook a phase 1 trial of nelfinavir in MM patients.

In an exploratory extension cohort, they found that 5 of 6 MM patients double-refractory to bortezomib and lenalidomide experienced clinical benefit from nelfinavir at the recommended phase 2 dose (2 x 2500 mg daily) in addition to standard treatment with bortezomib and dexamethasone.

Three patients achieved a partial response (PR) and 3 a minor response (MR).

The investigators’ objective in the phase 2 study was to determine whether the addition of nelfinavir to approved bortezomib-dexamethasone therapy is sufficiently active to merit further investigation in a randomized trial.

Study design

Patients in this prospective, single-arm, multicenter, open-label trial received the following treatment:

• Nelfinavir at 2 x 2500 mg orally on days 1–14
• Bortezomib at 1.3 mg/m² intravenously or subcutaneously on days 1, 4, 8, and 11
• Dexamethasone at 20 mg orally on days 1-2, 4-5, 8-9, and 11-12 of each 21-day cycle.

Trial therapy lasted for a maximum of 6 cycles (18 weeks).

Dr Driessen explained that the trial “was a truly academic trial, without any finances from industry or drug support from industry. So we actually had to get a grant to buy commercial drugs for the study on the commercial drug market, and that limited the duration of treatment in this trial.”

The primary endpoint of the trial was response rate—best response of PR or better by IMWG criteria.

Investigators considered a 30% or higher response rate promising.

Secondary endpoints included adverse events, time to next new anti-myeloma therapy or death, progressive disease under trial treatment, duration of response, progression-free survival, and time to progression.

Patients were eligible to enroll if they had been exposed to or could not tolerate an immunomodulatory drug, were refractory to their most recent PI-containing regimen, had a performance status of 3 or less, had creatinine clearance of 15 mL/minute or greater, had a platelet count of 50,000/μL or more, and had a hemoglobin level of 8.0 g/dL or higher.

Patients were excluded if they had uncontrolled, clinically significant, active concurrent disease, concomitant additional systemic cancer treatment, concomitant radiotherapy, or significant neuropathy of grades 3-4 or grade 2 with pain.

Patient population

Thirty-four patients enrolled on the trial. They were a median age of 67 (range, 42–82), 62% were male, 91% had a performance status of 0 or 1, and 76% had a prior autologous stem cell transplant.

They had a median of 5 prior systemic therapies (range, 2–10), and 38% had poor-risk cytogenetics.

The time from last dose of prior therapy to enrollment on the study was a median of 27 days.

“So [it was] a truly progressive, highly refractory myeloma population,” Dr Driessen emphasized.

All 34 patients were refractory to bortezomib. All patients were also exposed to lenalidomide, and 79% were refractory to it.

Forty-four percent were refractory to pomalidomide, and 6% were refractory to carfilzomib. One patient was refractory to all 4 agents.

“Very few patients were exposed to carfilzomib because it wasn’t available in Switzerland at that time,” Dr Driessen explained.

Efficacy

Patients received a median of 4.5 cycles of therapy (range, 1–6), and the best response of PR or greater was achieved by 22 patients (65%).

Five patients (15%) achieved a very good partial response (VGPR), 17 (50%) PR, 3 (9%) MR, and 4 (12%) stable disease.

Twenty-five patients (74%) achieved a clinical benefit (VGPR+PR+MR).

Ten of the 13 patients (77%) with poor-risk cytogenetics achieved a best response of PR or greater.

Patients had a median of 16 weeks (range, 13–24) time to a new anti-myeloma therapy or death, and 13 patients (38%) had confirmed progressive disease while on trial therapy.

In 32 patients, all but 4 had a decrease from baseline in serum M protein or serum free light chain concentration.

Efficacy by prior therapy

Twenty-two of 34 patients (65%) refractory to bortezomib had a best response of PR or greater.

For patients refractory to bortezomib and lenalidomide, 70% achieved a best response of PR or greater.

For patients refractory to bortezomib, lenalidomide, and pomalidomide, 60% achieved a best response of PR or greater.

And for patients who were refractory to bortezomib, lenalidomide, and carfilzomib, 50% achieved a best response of PR or greater.

Adverse events

“The hematologic toxicity was essentially what you would expect from this heavily pretreated population,” Dr Driessen said.

“We did, however, experience 4 deaths on the trial therapy from infectious complications of sepsis and neutropenia, and we don’t know whether this is a true signal or whether this is due to the low numbers. We did not mandate antibiotic prophylaxis on the trial.”

Grade 3 or higher adverse events (AEs) occurring in 2 or more patients were anemia (n=10), febrile neutropenia (n=4, including 1 grade 5), thrombocytopenia (n=15), lung infection (n=8), sepsis (n=3, all grade 5), fatigue (n=5), peripheral sensory neuropathy (n=3), hypertension (n=6), increased creatinine (n=4), hyperglycemia (n=6) hypokalemia (n=3), and hyponatremia (n=5).

Dr Driessen indicated that with a future generic version of bortezomib, nelfinavir plus bortezomib and dexamethasone “has the potential to become a fully generic, affordable, active therapy option for PI-refractory patients.”

The investigators believe the results of their study call for further development of nelfinavir as a sensitizing drug for PI-based treatments and as a promising new agent for MM therapy.

Christoph Driessen, MD, PhD

SAN DIEGO—An antiretroviral drug used to treat the human immunodeficiency virus (HIV) may find a role in the treatment of multiple myeloma (MM) patients who are proteasome inhibitor (PI)-refractory.

According to investigators, nelfinavir may sensitize refractory patients so that PI-based treatments become an option for them.

In a phase 2 study of 34 patients, nelfinavir in combination with bortezomib and dexamethasone produced an objective response rate of 65%, which investigators called an “exceptional” response in this heavily pretreated, mostly dual-refractory patient population.

Christoph Driessen, MD, PhD, of Kantonsspital St Gallen in Switzerland, discussed the findings of this study, known as SAKK 39/13, at the 2016 ASH Annual Meeting as abstract 487.

Dr Driessen explained that downregulation of IRE1/XBP1 produces PI resistance, and this downregulation occurs in PI-refractory MM patients.

High expression of IRE1/XBP1 correlates with bortezomib sensitivity, and pharmacologic upregulation of IRE1/XBP1 re-sensitizes myeloma cells to PI treatment.

Nelfinavir, which overcomes PI resistance in vitro, is approved for oral HIV therapy.

“It’s an old drug, it’s a generic drug,” Dr Driessen said, and it’s approved at a dose of 2 x 1250 mg daily.

So the SAKK investigators undertook a phase 1 trial of nelfinavir in MM patients.

In an exploratory extension cohort, they found that 5 of 6 MM patients double-refractory to bortezomib and lenalidomide experienced clinical benefit from nelfinavir at the recommended phase 2 dose (2 x 2500 mg daily) in addition to standard treatment with bortezomib and dexamethasone.

Three patients achieved a partial response (PR) and 3 a minor response (MR).

The investigators’ objective in the phase 2 study was to determine whether the addition of nelfinavir to approved bortezomib-dexamethasone therapy is sufficiently active to merit further investigation in a randomized trial.

Study design

Patients in this prospective, single-arm, multicenter, open-label trial received the following treatment:

• Nelfinavir at 2 x 2500 mg orally on days 1–14
• Bortezomib at 1.3 mg/m² intravenously or subcutaneously on days 1, 4, 8, and 11
• Dexamethasone at 20 mg orally on days 1-2, 4-5, 8-9, and 11-12 of each 21-day cycle.

Trial therapy lasted for a maximum of 6 cycles (18 weeks).

Dr Driessen explained that the trial “was a truly academic trial, without any finances from industry or drug support from industry. So we actually had to get a grant to buy commercial drugs for the study on the commercial drug market, and that limited the duration of treatment in this trial.”

The primary endpoint of the trial was response rate—best response of PR or better by IMWG criteria.

Investigators considered a 30% or higher response rate promising.

Secondary endpoints included adverse events, time to next new anti-myeloma therapy or death, progressive disease under trial treatment, duration of response, progression-free survival, and time to progression.

Patients were eligible to enroll if they had been exposed to or could not tolerate an immunomodulatory drug, were refractory to their most recent PI-containing regimen, had a performance status of 3 or less, had creatinine clearance of 15 mL/minute or greater, had a platelet count of 50,000/μL or more, and had a hemoglobin level of 8.0 g/dL or higher.

Patients were excluded if they had uncontrolled, clinically significant, active concurrent disease, concomitant additional systemic cancer treatment, concomitant radiotherapy, or significant neuropathy of grades 3-4 or grade 2 with pain.

Patient population

Thirty-four patients enrolled on the trial. They were a median age of 67 (range, 42–82), 62% were male, 91% had a performance status of 0 or 1, and 76% had a prior autologous stem cell transplant.

They had a median of 5 prior systemic therapies (range, 2–10), and 38% had poor-risk cytogenetics.

The time from last dose of prior therapy to enrollment on the study was a median of 27 days.

“So [it was] a truly progressive, highly refractory myeloma population,” Dr Driessen emphasized.

All 34 patients were refractory to bortezomib. All patients were also exposed to lenalidomide, and 79% were refractory to it.

Forty-four percent were refractory to pomalidomide, and 6% were refractory to carfilzomib. One patient was refractory to all 4 agents.

“Very few patients were exposed to carfilzomib because it wasn’t available in Switzerland at that time,” Dr Driessen explained.

Efficacy

Patients received a median of 4.5 cycles of therapy (range, 1–6), and the best response of PR or greater was achieved by 22 patients (65%).

Five patients (15%) achieved a very good partial response (VGPR), 17 (50%) PR, 3 (9%) MR, and 4 (12%) stable disease.

Twenty-five patients (74%) achieved a clinical benefit (VGPR+PR+MR).

Ten of the 13 patients (77%) with poor-risk cytogenetics achieved a best response of PR or greater.

Patients had a median of 16 weeks (range, 13–24) time to a new anti-myeloma therapy or death, and 13 patients (38%) had confirmed progressive disease while on trial therapy.

In 32 patients, all but 4 had a decrease from baseline in serum M protein or serum free light chain concentration.

Efficacy by prior therapy

Twenty-two of 34 patients (65%) refractory to bortezomib had a best response of PR or greater.

For patients refractory to bortezomib and lenalidomide, 70% achieved a best response of PR or greater.

For patients refractory to bortezomib, lenalidomide, and pomalidomide, 60% achieved a best response of PR or greater.

And for patients who were refractory to bortezomib, lenalidomide, and carfilzomib, 50% achieved a best response of PR or greater.

Adverse events

“The hematologic toxicity was essentially what you would expect from this heavily pretreated population,” Dr Driessen said.

“We did, however, experience 4 deaths on the trial therapy from infectious complications of sepsis and neutropenia, and we don’t know whether this is a true signal or whether this is due to the low numbers. We did not mandate antibiotic prophylaxis on the trial.”

Grade 3 or higher adverse events (AEs) occurring in 2 or more patients were anemia (n=10), febrile neutropenia (n=4, including 1 grade 5), thrombocytopenia (n=15), lung infection (n=8), sepsis (n=3, all grade 5), fatigue (n=5), peripheral sensory neuropathy (n=3), hypertension (n=6), increased creatinine (n=4), hyperglycemia (n=6) hypokalemia (n=3), and hyponatremia (n=5).

Dr Driessen indicated that with a future generic version of bortezomib, nelfinavir plus bortezomib and dexamethasone “has the potential to become a fully generic, affordable, active therapy option for PI-refractory patients.”

The investigators believe the results of their study call for further development of nelfinavir as a sensitizing drug for PI-based treatments and as a promising new agent for MM therapy.

Christoph Driessen, MD, PhD

SAN DIEGO—An antiretroviral drug used to treat the human immunodeficiency virus (HIV) may find a role in the treatment of multiple myeloma (MM) patients who are proteasome inhibitor (PI)-refractory.

According to investigators, nelfinavir may sensitize refractory patients so that PI-based treatments become an option for them.

In a phase 2 study of 34 patients, nelfinavir in combination with bortezomib and dexamethasone produced an objective response rate of 65%, which investigators called an “exceptional” response in this heavily pretreated, mostly dual-refractory patient population.

Christoph Driessen, MD, PhD, of Kantonsspital St Gallen in Switzerland, discussed the findings of this study, known as SAKK 39/13, at the 2016 ASH Annual Meeting as abstract 487.

Dr Driessen explained that downregulation of IRE1/XBP1 produces PI resistance, and this downregulation occurs in PI-refractory MM patients.

High expression of IRE1/XBP1 correlates with bortezomib sensitivity, and pharmacologic upregulation of IRE1/XBP1 re-sensitizes myeloma cells to PI treatment.

Nelfinavir, which overcomes PI resistance in vitro, is approved for oral HIV therapy.

“It’s an old drug, it’s a generic drug,” Dr Driessen said, and it’s approved at a dose of 2 x 1250 mg daily.

So the SAKK investigators undertook a phase 1 trial of nelfinavir in MM patients.

In an exploratory extension cohort, they found that 5 of 6 MM patients double-refractory to bortezomib and lenalidomide experienced clinical benefit from nelfinavir at the recommended phase 2 dose (2 x 2500 mg daily) in addition to standard treatment with bortezomib and dexamethasone.

Three patients achieved a partial response (PR) and 3 a minor response (MR).

The investigators’ objective in the phase 2 study was to determine whether the addition of nelfinavir to approved bortezomib-dexamethasone therapy is sufficiently active to merit further investigation in a randomized trial.

Study design

Patients in this prospective, single-arm, multicenter, open-label trial received the following treatment:

• Nelfinavir at 2 x 2500 mg orally on days 1–14
• Bortezomib at 1.3 mg/m² intravenously or subcutaneously on days 1, 4, 8, and 11
• Dexamethasone at 20 mg orally on days 1-2, 4-5, 8-9, and 11-12 of each 21-day cycle.

Trial therapy lasted for a maximum of 6 cycles (18 weeks).

Dr Driessen explained that the trial “was a truly academic trial, without any finances from industry or drug support from industry. So we actually had to get a grant to buy commercial drugs for the study on the commercial drug market, and that limited the duration of treatment in this trial.”

The primary endpoint of the trial was response rate—best response of PR or better by IMWG criteria.

Investigators considered a 30% or higher response rate promising.

Secondary endpoints included adverse events, time to next new anti-myeloma therapy or death, progressive disease under trial treatment, duration of response, progression-free survival, and time to progression.

Patients were eligible to enroll if they had been exposed to or could not tolerate an immunomodulatory drug, were refractory to their most recent PI-containing regimen, had a performance status of 3 or less, had creatinine clearance of 15 mL/minute or greater, had a platelet count of 50,000/μL or more, and had a hemoglobin level of 8.0 g/dL or higher.

Patients were excluded if they had uncontrolled, clinically significant, active concurrent disease, concomitant additional systemic cancer treatment, concomitant radiotherapy, or significant neuropathy of grades 3-4 or grade 2 with pain.

Patient population

Thirty-four patients enrolled on the trial. They were a median age of 67 (range, 42–82), 62% were male, 91% had a performance status of 0 or 1, and 76% had a prior autologous stem cell transplant.

They had a median of 5 prior systemic therapies (range, 2–10), and 38% had poor-risk cytogenetics.

The time from last dose of prior therapy to enrollment on the study was a median of 27 days.

“So [it was] a truly progressive, highly refractory myeloma population,” Dr Driessen emphasized.

All 34 patients were refractory to bortezomib. All patients were also exposed to lenalidomide, and 79% were refractory to it.

Forty-four percent were refractory to pomalidomide, and 6% were refractory to carfilzomib. One patient was refractory to all 4 agents.

“Very few patients were exposed to carfilzomib because it wasn’t available in Switzerland at that time,” Dr Driessen explained.

Efficacy

Patients received a median of 4.5 cycles of therapy (range, 1–6), and the best response of PR or greater was achieved by 22 patients (65%).

Five patients (15%) achieved a very good partial response (VGPR), 17 (50%) PR, 3 (9%) MR, and 4 (12%) stable disease.

Twenty-five patients (74%) achieved a clinical benefit (VGPR+PR+MR).

Ten of the 13 patients (77%) with poor-risk cytogenetics achieved a best response of PR or greater.

Patients had a median of 16 weeks (range, 13–24) time to a new anti-myeloma therapy or death, and 13 patients (38%) had confirmed progressive disease while on trial therapy.

In 32 patients, all but 4 had a decrease from baseline in serum M protein or serum free light chain concentration.

Efficacy by prior therapy

Twenty-two of 34 patients (65%) refractory to bortezomib had a best response of PR or greater.

For patients refractory to bortezomib and lenalidomide, 70% achieved a best response of PR or greater.

For patients refractory to bortezomib, lenalidomide, and pomalidomide, 60% achieved a best response of PR or greater.

And for patients who were refractory to bortezomib, lenalidomide, and carfilzomib, 50% achieved a best response of PR or greater.

Adverse events

“The hematologic toxicity was essentially what you would expect from this heavily pretreated population,” Dr Driessen said.

“We did, however, experience 4 deaths on the trial therapy from infectious complications of sepsis and neutropenia, and we don’t know whether this is a true signal or whether this is due to the low numbers. We did not mandate antibiotic prophylaxis on the trial.”

Grade 3 or higher adverse events (AEs) occurring in 2 or more patients were anemia (n=10), febrile neutropenia (n=4, including 1 grade 5), thrombocytopenia (n=15), lung infection (n=8), sepsis (n=3, all grade 5), fatigue (n=5), peripheral sensory neuropathy (n=3), hypertension (n=6), increased creatinine (n=4), hyperglycemia (n=6) hypokalemia (n=3), and hyponatremia (n=5).

Dr Driessen indicated that with a future generic version of bortezomib, nelfinavir plus bortezomib and dexamethasone “has the potential to become a fully generic, affordable, active therapy option for PI-refractory patients.”

The investigators believe the results of their study call for further development of nelfinavir as a sensitizing drug for PI-based treatments and as a promising new agent for MM therapy.

Thrombus

Image by Andre E.X. Brown

The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for betrixaban, an oral factor Xa inhibitor, for extended-duration prophylaxis of venous thromboembolism (VTE) in acute medically ill patients with risk factors for VTE.

A priority review shortens the FDA review timeline to 6 months from the standard review period of 10 months.

The application for betrixaban has been given a Prescription Drug User Fee Act action date of June 24, 2017.  (Betrixaban also has fast track designation from the FDA.)

Meanwhile, the European Medicines Agency (EMA) is reviewing a marketing authorization application (MAA) for betrixaban for extended-duration prophylaxis of VTE in adults with acute medical illness and risk factors for VTE.

However, the EMA’s Committee for Medicinal Products for Human Use is reviewing the application under a standard 210-day review period.

“With the filing of the betrixaban NDA and the MAA validation, we now look forward to working with the FDA and EMA to bring this drug to market,” said Bill Lis, chief executive officer of Portola Pharmaceuticals, Inc., the company developing betrixaban.

The NDA and MAA for betrixaban are supported by data from Portola’s phase 3 APEX study, which enrolled 7513 patients at more than 450 clinical sites worldwide.

In this study, researchers compared extended-duration anticoagulation with oral betrixaban for 35-42 days to standard-duration enoxaparin for 10±4 days in preventing VTE in high-risk acute medically ill patients.

Patients who received betrixaban had a significantly lower incidence of VTE than those who received enoxaparin, and there was no significant difference in major bleeding between the treatment groups.

Full results from this study were presented at the 62nd Annual International Society on Thrombosis and Haemostasis Scientific and Standardization Committee Meeting and published in NEJM in May 2016.

Thrombus

Image by Andre E.X. Brown

The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for betrixaban, an oral factor Xa inhibitor, for extended-duration prophylaxis of venous thromboembolism (VTE) in acute medically ill patients with risk factors for VTE.

A priority review shortens the FDA review timeline to 6 months from the standard review period of 10 months.

The application for betrixaban has been given a Prescription Drug User Fee Act action date of June 24, 2017.  (Betrixaban also has fast track designation from the FDA.)

Meanwhile, the European Medicines Agency (EMA) is reviewing a marketing authorization application (MAA) for betrixaban for extended-duration prophylaxis of VTE in adults with acute medical illness and risk factors for VTE.

However, the EMA’s Committee for Medicinal Products for Human Use is reviewing the application under a standard 210-day review period.

“With the filing of the betrixaban NDA and the MAA validation, we now look forward to working with the FDA and EMA to bring this drug to market,” said Bill Lis, chief executive officer of Portola Pharmaceuticals, Inc., the company developing betrixaban.

The NDA and MAA for betrixaban are supported by data from Portola’s phase 3 APEX study, which enrolled 7513 patients at more than 450 clinical sites worldwide.

In this study, researchers compared extended-duration anticoagulation with oral betrixaban for 35-42 days to standard-duration enoxaparin for 10±4 days in preventing VTE in high-risk acute medically ill patients.

Patients who received betrixaban had a significantly lower incidence of VTE than those who received enoxaparin, and there was no significant difference in major bleeding between the treatment groups.

Full results from this study were presented at the 62nd Annual International Society on Thrombosis and Haemostasis Scientific and Standardization Committee Meeting and published in NEJM in May 2016.

Thrombus

Image by Andre E.X. Brown

The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for betrixaban, an oral factor Xa inhibitor, for extended-duration prophylaxis of venous thromboembolism (VTE) in acute medically ill patients with risk factors for VTE.

A priority review shortens the FDA review timeline to 6 months from the standard review period of 10 months.

The application for betrixaban has been given a Prescription Drug User Fee Act action date of June 24, 2017.  (Betrixaban also has fast track designation from the FDA.)

Meanwhile, the European Medicines Agency (EMA) is reviewing a marketing authorization application (MAA) for betrixaban for extended-duration prophylaxis of VTE in adults with acute medical illness and risk factors for VTE.

However, the EMA’s Committee for Medicinal Products for Human Use is reviewing the application under a standard 210-day review period.

“With the filing of the betrixaban NDA and the MAA validation, we now look forward to working with the FDA and EMA to bring this drug to market,” said Bill Lis, chief executive officer of Portola Pharmaceuticals, Inc., the company developing betrixaban.

The NDA and MAA for betrixaban are supported by data from Portola’s phase 3 APEX study, which enrolled 7513 patients at more than 450 clinical sites worldwide.

In this study, researchers compared extended-duration anticoagulation with oral betrixaban for 35-42 days to standard-duration enoxaparin for 10±4 days in preventing VTE in high-risk acute medically ill patients.

Patients who received betrixaban had a significantly lower incidence of VTE than those who received enoxaparin, and there was no significant difference in major bleeding between the treatment groups.

Full results from this study were presented at the 62nd Annual International Society on Thrombosis and Haemostasis Scientific and Standardization Committee Meeting and published in NEJM in May 2016.

Micrograph showing CLL

Results of a phase 2 trial suggest a 2-drug combination may be effective in patients with chronic lymphocytic leukemia (CLL), particularly those with high-risk disease.

The combination consists of ublituximab (TG-1101), a glycoengineered anti-CD20 monoclonal antibody, and the oral BTK inhibitor ibrutinib.

Six months after starting treatment, the overall response rate was 88% among all evaluable patients and 95% among those with high-risk CLL.

Researchers said the long-term clinical benefit of the combination will be defined by an ongoing phase 3 trial.

The team reported results from the phase 2 trial in the British Journal of Haematology. The study was sponsored by TG Therapeutics, Inc., the company developing ublituximab.

The trial included 45 patients. Their median age was 71 (range, 39-86), about half were female, and the median ECOG performance score was 1.

Nearly half of patients (47%, n=21) had high-risk CLL. Twelve patients had del 17p, 12 had del 11q, 5 patients had both, and 2 had a TP53 mutation.

The patients had a median of 2 (range, 1-7) prior treatments, including purine analogues (n=22), bendamustine (n=21), idelalisib (n=2), a spleen-tyrosine kinase inhibitor (n=2), and the BTK inhibitor CC-292 (n=1).

Treatment

For this study, patients received ibrutinib at 420 mg once daily and 2 different doses of ublituximab. The study had a dose-confirmation safety run-in period that was followed by an open enrollment into phase 2.

The dose-confirmation safety assessment enrolled 6 patients in each of 2 cohorts. Patients in cohort 1 received ublituximab at 600 mg on days 1, 8, and 15 of cycle 1. If there was ≤1 dose-limiting toxicity (DLT) in this cohort, the dose escalation would proceed to cohort 2.

In cohort 2, patients’ ublituximab dose increased to 900 mg on days 1, 8, and 15 of cycle 1. If ≤ 1 DLT was reported in this cohort, the dose was considered safe for phase 2.

There were no DLTs observed in either cohort. So subsequent patients were enrolled into the open phase 2 part of the study, in which they received ublituximab at 900 mg on days 1, 8, and 15 of cycle 1, as well as on day 1 of cycles 2 to 6.

Patients had response assessments at cycles 3 and 6. After that, they continued on ibrutinib monotherapy off study.

Safety

All 45 patients were evaluable for safety. The most common adverse events (AEs) were infusion-related reactions (IRRs, 53%), diarrhea (40%), fatigue (33%), cough (27%), rash (27%), and nausea (24%).

Grade 3/4 AEs included anemia (11%), neutropenia (11%), IRRs (7%), thrombocytopenia (7%), diarrhea (4%), and arthralgia (2%).

All rash and grade 3/4 diarrhea events were attributed to ibrutinib, and all IRRs were related to ublituximab. Twenty-one patients (47%) had dose interruptions due to IRRs, and 1 patient had a dose reduction to 600 mg.

Four patients had ublituximab-related dose interruptions—2 due to neutropenia and 2 because of elevated aspartate aminotransferase.

Two patients had ibrutinib-related dose reductions (for diarrhea and dizziness). Ten patients had ibrutinib-related dose interruptions—3 due to rash, 2 due to neutropenia, and 1 each because of anemia, thrombocytopenia, nausea, hypercalcemia, and dehydration.

Efficacy

Forty-one patients were evaluable for efficacy. Two patients were lost to follow-up, and 2 discontinued due to AEs. One of the AEs, diarrhea, was considered related to ibrutinib. The other patient discontinued due to pneumonia and pleural effusion, which were not attributed to study treatment.

At 6 months, the overall response rate was 88% among evaluable patients and 95% among high-risk patients. The median time to response was 8 weeks.

Two patients had a complete response, 34 had a partial response, and 3 had stable disease.

Both complete responders and 1 of the partial responders achieved minimal residual disease negativity. All 3 of these patients had high-risk disease.

“[T]he addition of ublituximab to ibrutinib not only produced high response rates but also allowed patients to achieve deeper responses, with complete responses and minimal residual disease negativity seen, which is rare with ibrutinib alone,” said study author Jeff Sharman, MD, of Willamette Valley Cancer Institute in Eugene, Oregon.

“We look forward to exploring how the increased depth of response may affect the sequence of treatments given to patients.”

Micrograph showing CLL

Results of a phase 2 trial suggest a 2-drug combination may be effective in patients with chronic lymphocytic leukemia (CLL), particularly those with high-risk disease.

The combination consists of ublituximab (TG-1101), a glycoengineered anti-CD20 monoclonal antibody, and the oral BTK inhibitor ibrutinib.

Six months after starting treatment, the overall response rate was 88% among all evaluable patients and 95% among those with high-risk CLL.

Researchers said the long-term clinical benefit of the combination will be defined by an ongoing phase 3 trial.

The team reported results from the phase 2 trial in the British Journal of Haematology. The study was sponsored by TG Therapeutics, Inc., the company developing ublituximab.

The trial included 45 patients. Their median age was 71 (range, 39-86), about half were female, and the median ECOG performance score was 1.

Nearly half of patients (47%, n=21) had high-risk CLL. Twelve patients had del 17p, 12 had del 11q, 5 patients had both, and 2 had a TP53 mutation.

The patients had a median of 2 (range, 1-7) prior treatments, including purine analogues (n=22), bendamustine (n=21), idelalisib (n=2), a spleen-tyrosine kinase inhibitor (n=2), and the BTK inhibitor CC-292 (n=1).

Treatment

For this study, patients received ibrutinib at 420 mg once daily and 2 different doses of ublituximab. The study had a dose-confirmation safety run-in period that was followed by an open enrollment into phase 2.

The dose-confirmation safety assessment enrolled 6 patients in each of 2 cohorts. Patients in cohort 1 received ublituximab at 600 mg on days 1, 8, and 15 of cycle 1. If there was ≤1 dose-limiting toxicity (DLT) in this cohort, the dose escalation would proceed to cohort 2.

In cohort 2, patients’ ublituximab dose increased to 900 mg on days 1, 8, and 15 of cycle 1. If ≤ 1 DLT was reported in this cohort, the dose was considered safe for phase 2.

There were no DLTs observed in either cohort. So subsequent patients were enrolled into the open phase 2 part of the study, in which they received ublituximab at 900 mg on days 1, 8, and 15 of cycle 1, as well as on day 1 of cycles 2 to 6.

Patients had response assessments at cycles 3 and 6. After that, they continued on ibrutinib monotherapy off study.

Safety

All 45 patients were evaluable for safety. The most common adverse events (AEs) were infusion-related reactions (IRRs, 53%), diarrhea (40%), fatigue (33%), cough (27%), rash (27%), and nausea (24%).

Grade 3/4 AEs included anemia (11%), neutropenia (11%), IRRs (7%), thrombocytopenia (7%), diarrhea (4%), and arthralgia (2%).

All rash and grade 3/4 diarrhea events were attributed to ibrutinib, and all IRRs were related to ublituximab. Twenty-one patients (47%) had dose interruptions due to IRRs, and 1 patient had a dose reduction to 600 mg.

Four patients had ublituximab-related dose interruptions—2 due to neutropenia and 2 because of elevated aspartate aminotransferase.

Two patients had ibrutinib-related dose reductions (for diarrhea and dizziness). Ten patients had ibrutinib-related dose interruptions—3 due to rash, 2 due to neutropenia, and 1 each because of anemia, thrombocytopenia, nausea, hypercalcemia, and dehydration.

Efficacy

Forty-one patients were evaluable for efficacy. Two patients were lost to follow-up, and 2 discontinued due to AEs. One of the AEs, diarrhea, was considered related to ibrutinib. The other patient discontinued due to pneumonia and pleural effusion, which were not attributed to study treatment.

At 6 months, the overall response rate was 88% among evaluable patients and 95% among high-risk patients. The median time to response was 8 weeks.

Two patients had a complete response, 34 had a partial response, and 3 had stable disease.

Both complete responders and 1 of the partial responders achieved minimal residual disease negativity. All 3 of these patients had high-risk disease.

“[T]he addition of ublituximab to ibrutinib not only produced high response rates but also allowed patients to achieve deeper responses, with complete responses and minimal residual disease negativity seen, which is rare with ibrutinib alone,” said study author Jeff Sharman, MD, of Willamette Valley Cancer Institute in Eugene, Oregon.

“We look forward to exploring how the increased depth of response may affect the sequence of treatments given to patients.”

Micrograph showing CLL

Results of a phase 2 trial suggest a 2-drug combination may be effective in patients with chronic lymphocytic leukemia (CLL), particularly those with high-risk disease.

The combination consists of ublituximab (TG-1101), a glycoengineered anti-CD20 monoclonal antibody, and the oral BTK inhibitor ibrutinib.

Six months after starting treatment, the overall response rate was 88% among all evaluable patients and 95% among those with high-risk CLL.

Researchers said the long-term clinical benefit of the combination will be defined by an ongoing phase 3 trial.

The team reported results from the phase 2 trial in the British Journal of Haematology. The study was sponsored by TG Therapeutics, Inc., the company developing ublituximab.

The trial included 45 patients. Their median age was 71 (range, 39-86), about half were female, and the median ECOG performance score was 1.

Nearly half of patients (47%, n=21) had high-risk CLL. Twelve patients had del 17p, 12 had del 11q, 5 patients had both, and 2 had a TP53 mutation.

The patients had a median of 2 (range, 1-7) prior treatments, including purine analogues (n=22), bendamustine (n=21), idelalisib (n=2), a spleen-tyrosine kinase inhibitor (n=2), and the BTK inhibitor CC-292 (n=1).

Treatment

For this study, patients received ibrutinib at 420 mg once daily and 2 different doses of ublituximab. The study had a dose-confirmation safety run-in period that was followed by an open enrollment into phase 2.

The dose-confirmation safety assessment enrolled 6 patients in each of 2 cohorts. Patients in cohort 1 received ublituximab at 600 mg on days 1, 8, and 15 of cycle 1. If there was ≤1 dose-limiting toxicity (DLT) in this cohort, the dose escalation would proceed to cohort 2.

In cohort 2, patients’ ublituximab dose increased to 900 mg on days 1, 8, and 15 of cycle 1. If ≤ 1 DLT was reported in this cohort, the dose was considered safe for phase 2.

There were no DLTs observed in either cohort. So subsequent patients were enrolled into the open phase 2 part of the study, in which they received ublituximab at 900 mg on days 1, 8, and 15 of cycle 1, as well as on day 1 of cycles 2 to 6.

Patients had response assessments at cycles 3 and 6. After that, they continued on ibrutinib monotherapy off study.

Safety

All 45 patients were evaluable for safety. The most common adverse events (AEs) were infusion-related reactions (IRRs, 53%), diarrhea (40%), fatigue (33%), cough (27%), rash (27%), and nausea (24%).

Grade 3/4 AEs included anemia (11%), neutropenia (11%), IRRs (7%), thrombocytopenia (7%), diarrhea (4%), and arthralgia (2%).

All rash and grade 3/4 diarrhea events were attributed to ibrutinib, and all IRRs were related to ublituximab. Twenty-one patients (47%) had dose interruptions due to IRRs, and 1 patient had a dose reduction to 600 mg.

Four patients had ublituximab-related dose interruptions—2 due to neutropenia and 2 because of elevated aspartate aminotransferase.

Two patients had ibrutinib-related dose reductions (for diarrhea and dizziness). Ten patients had ibrutinib-related dose interruptions—3 due to rash, 2 due to neutropenia, and 1 each because of anemia, thrombocytopenia, nausea, hypercalcemia, and dehydration.

Efficacy

Forty-one patients were evaluable for efficacy. Two patients were lost to follow-up, and 2 discontinued due to AEs. One of the AEs, diarrhea, was considered related to ibrutinib. The other patient discontinued due to pneumonia and pleural effusion, which were not attributed to study treatment.

At 6 months, the overall response rate was 88% among evaluable patients and 95% among high-risk patients. The median time to response was 8 weeks.

Two patients had a complete response, 34 had a partial response, and 3 had stable disease.

Both complete responders and 1 of the partial responders achieved minimal residual disease negativity. All 3 of these patients had high-risk disease.

“[T]he addition of ublituximab to ibrutinib not only produced high response rates but also allowed patients to achieve deeper responses, with complete responses and minimal residual disease negativity seen, which is rare with ibrutinib alone,” said study author Jeff Sharman, MD, of Willamette Valley Cancer Institute in Eugene, Oregon.

“We look forward to exploring how the increased depth of response may affect the sequence of treatments given to patients.”

Shaji Kumar, MD

SAN DIEGO—Venetoclax, the oral BCL-2 inhibitor approved by the US Food and Drug Administration to treat chronic lymphocytic leukemia (CLL) patients with 17p deletion, is also showing activity in multiple myeloma (MM) patients, particularly those with t(11;14).

Final results of a phase 1 study showed venetoclax to be safe as monotherapy in relapsed or refractory MM, producing a response rate of 40% in patients with the translocation and 21% overall.

Preliminary results of the study were presented at the 2015 ASH Annual Meeting, and final results were presented at the 2016 ASH Annual Meeting.

“So I think we have a drug that potentially can change the outcome of a lot of patients with myeloma,” Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota, said during the presentation of the findings at ASH (abstract 488*).

“[It] also opens the possibility of being combined with a variety of other therapeutics that we have in this disease today.”

Venetoclax induces cell death in MM cell lines, particularly those positive for t(11;14). The translocation correlates with higher ratios of BCL-2 to MCL-1 and BCL-2 to MCL-2L1 (BCL-X_L) mRNA. BCL-2 and MCL-1 promote survival of MM cells.

Study design and enrollment

The phase 1, open-label, multicenter study was designed to determine the best tolerated dose of venetoclax.

Secondary and exploratory objectives included overall response rate (ORR), time to progression, duration of response, and predictive biomarkers.

Patients had to have previously treated MM with measurable disease, ECOG status of 0 or 1, and adequate organ function.

They were excluded if they had an active infection, a history of significant renal, neurologic, psychiatric, endocrine, immunologic, cardiovascular, or hepatic disease within 6 months of study entry, or a history of other active malignancies within 3 years of study entry.

The study called for a 2-week lead-in period of venetoclax with weekly dose escalation. Four different dose cohorts were evaluated—300 mg, 600 mg, 900 mg, and 1200 mg.

Thirty patients were enrolled during the lead-in period, and 36 additional patients enrolled at the maximum evaluated dose of 1200 mg in the safety expansion cohort, for a total of 66 patients.

Patients were treated on a 21-day cycle with daily venetoclax. They could also receive dexamethasone to continue on the study if they progressed while receiving the monotherapy.

Patient characteristics

Patient characteristics were “similar to what you would see in relapsed/refractory multiple myloma,” Dr Kumar said.

Median age was 63 (range, 31–79), and most (62%) were ISS stage II/III.

“I want to draw your attention to two features here,” Dr Kumar said.

“Thirty patients, or 46% of the patients, had 11;14 translocation, and that reflects the interest in this drug for this particular class of patients.”

Twelve patients (18%) had 17p deletion, 32 (48%) had 13q deletion, and 27 (41%) were hyperdiploid.

“What is most striking in this cohort of patients,” Dr Kumar added, “is the fact that the median number of prior lines of therapy was 5, with some as high as 15 prior lines of therapy.”

Seventy percent were refractory to bortezomib, 77% refractory to lenalidomide, and 61% refractory to both. Fifty-two patients (79%) were refractory to their last prior therapy.

Patient disposition

At the time of data cutoff on August 19, 2016, 11 patients (17%) were still active on the study.

The median time on study was 3.3 months (range, 0.2–27), median time on venetoclax monotherapy was 2.5 months (range, 0.2–25), and median time on venetoclax plus dexamethasone was 1.4 months (range, 1–13). Seventeen patients received the combination after disease progression.

Fifty-five patients (83%) discontinued treatment, 41 (62%) because of disease progression, 5 (8%) because of adverse events, 2 (3%) withdrew consent, 1 (2%) was lost to follow-up, and 6 (9%) for unspecified reasons.

The 5 adverse events leading to withdrawal included renal failure (n=2), worsening pulmonary disorder (n=1), paralyzing sciatica (n=1), and shortness of breath and pain (n=1). 

“Eight patients died on study,” Dr Kumar said, “none thought to be related to the drug.”

Adverse events

The toxicity profile was primarily hematologic and gastrointestinal.

All patients experienced an adverse event of any grade, and 45 (68%) had a grade 3 or 4 event.

“I wanted to highlight that the majority of the gastrointestinal and non-hematologic toxicity we saw were grades 1 and 2,” Dr Kumar pointed out, “and could be managed symptomatically or with dose modifications.”

Grade 3-4 hematologic adverse events included thrombocytopenia (26%), neutropenia (21%), anemia (14%), leukopenia (14%), and lymphopenia (15%).

Grade 3-4 non-hematologic adverse events included nausea (3%), diarrhea (3%), fatigue (5%), back pain (8%), and vomiting (3%).

Serious adverse events occurring in 2% or more of patients included pneumonia (8%), sepsis (5%), pain, pyrexia, cough, and hypotension (3% each).

Two patients had dose-limiting toxicities of abdominal pain and nausea at the 600 mg dose.

No events of tumor lysis syndrome (TLS) were reported.  Dr Kumar explained that this may have been the case because patients thought to be at high risk for TLS were mandated to be in the hospital and observed for early tumor lysis in the initial part of the study.

Response

The ORR was 21% in all patients, including a stringent complete response (sCR) of 3% and a CR of 4%.

“But what was really striking was the response rate that we observed in the 30 patients with translocation 11;14,” Dr Kumar said. “The overall response rate was 40%, with 14% of the patients having complete response or better [stringent CR] and 13% of the patients with very good partial response.”

The 36 patients without t(11;14) had a 6% ORR, 3% sCR, and 3% very good partial response.

“If you look at the response rates based on the type of therapy they were coming off or the drugs they were refractory to, the response rate is very similar across all these patient subgroups, irrespective of what groups of drugs they were refractory to,” he added.

Time to progression for all patients was about 2.5 months. For patients with the translocation, it was about 6.6 months.

“Responses were fairly durable among those who had a response,” Dr Kumar said, “considering these are patients with a median of 5 prior lines of therapy.”

Duration of response for patients with t(11;14) was close to 10 months.

Biomarker analysis

The underlying biology for the response was the BCL-2 to BCL-2L1 ratio, as the investigators had observed in the cell lines.

So they analyzed the BCL-2 gene expression ratio in 24 of the 30 patients with t(11;14).

The investigators used droplet digital PCR performed on CD138-selected bone marrow mononuclear cells collected at baseline.

Nine patients had a high ratio, and their ORR was 88%. Fifteen patients had a low ratio, and their ORR was 20%.

Median time to progression for patients with a high ratio was about 12 months. For those with a low ratio, it was about 9 months.

Median change in M protein for patients with t(11;14) was –53%, compared to +11% in the patients without the translocation.

The investigators recommend additional studies with venetoclax in MM, including those with alternative combination therapies.

Venetoclax is being developed by AbbVie, in partnership with Genentech and Roche. This study was sponsored by AbbVie.

*Data in the abstract differ from the presentation.

Shaji Kumar, MD

SAN DIEGO—Venetoclax, the oral BCL-2 inhibitor approved by the US Food and Drug Administration to treat chronic lymphocytic leukemia (CLL) patients with 17p deletion, is also showing activity in multiple myeloma (MM) patients, particularly those with t(11;14).

Final results of a phase 1 study showed venetoclax to be safe as monotherapy in relapsed or refractory MM, producing a response rate of 40% in patients with the translocation and 21% overall.

Preliminary results of the study were presented at the 2015 ASH Annual Meeting, and final results were presented at the 2016 ASH Annual Meeting.

“So I think we have a drug that potentially can change the outcome of a lot of patients with myeloma,” Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota, said during the presentation of the findings at ASH (abstract 488*).

“[It] also opens the possibility of being combined with a variety of other therapeutics that we have in this disease today.”

Venetoclax induces cell death in MM cell lines, particularly those positive for t(11;14). The translocation correlates with higher ratios of BCL-2 to MCL-1 and BCL-2 to MCL-2L1 (BCL-X_L) mRNA. BCL-2 and MCL-1 promote survival of MM cells.

Study design and enrollment

The phase 1, open-label, multicenter study was designed to determine the best tolerated dose of venetoclax.

Secondary and exploratory objectives included overall response rate (ORR), time to progression, duration of response, and predictive biomarkers.

Patients had to have previously treated MM with measurable disease, ECOG status of 0 or 1, and adequate organ function.

They were excluded if they had an active infection, a history of significant renal, neurologic, psychiatric, endocrine, immunologic, cardiovascular, or hepatic disease within 6 months of study entry, or a history of other active malignancies within 3 years of study entry.

The study called for a 2-week lead-in period of venetoclax with weekly dose escalation. Four different dose cohorts were evaluated—300 mg, 600 mg, 900 mg, and 1200 mg.

Thirty patients were enrolled during the lead-in period, and 36 additional patients enrolled at the maximum evaluated dose of 1200 mg in the safety expansion cohort, for a total of 66 patients.

Patients were treated on a 21-day cycle with daily venetoclax. They could also receive dexamethasone to continue on the study if they progressed while receiving the monotherapy.

Patient characteristics

Patient characteristics were “similar to what you would see in relapsed/refractory multiple myloma,” Dr Kumar said.

Median age was 63 (range, 31–79), and most (62%) were ISS stage II/III.

“I want to draw your attention to two features here,” Dr Kumar said.

“Thirty patients, or 46% of the patients, had 11;14 translocation, and that reflects the interest in this drug for this particular class of patients.”

Twelve patients (18%) had 17p deletion, 32 (48%) had 13q deletion, and 27 (41%) were hyperdiploid.

“What is most striking in this cohort of patients,” Dr Kumar added, “is the fact that the median number of prior lines of therapy was 5, with some as high as 15 prior lines of therapy.”

Seventy percent were refractory to bortezomib, 77% refractory to lenalidomide, and 61% refractory to both. Fifty-two patients (79%) were refractory to their last prior therapy.

Patient disposition

At the time of data cutoff on August 19, 2016, 11 patients (17%) were still active on the study.

The median time on study was 3.3 months (range, 0.2–27), median time on venetoclax monotherapy was 2.5 months (range, 0.2–25), and median time on venetoclax plus dexamethasone was 1.4 months (range, 1–13). Seventeen patients received the combination after disease progression.

Fifty-five patients (83%) discontinued treatment, 41 (62%) because of disease progression, 5 (8%) because of adverse events, 2 (3%) withdrew consent, 1 (2%) was lost to follow-up, and 6 (9%) for unspecified reasons.

The 5 adverse events leading to withdrawal included renal failure (n=2), worsening pulmonary disorder (n=1), paralyzing sciatica (n=1), and shortness of breath and pain (n=1). 

“Eight patients died on study,” Dr Kumar said, “none thought to be related to the drug.”

Adverse events

The toxicity profile was primarily hematologic and gastrointestinal.

All patients experienced an adverse event of any grade, and 45 (68%) had a grade 3 or 4 event.

“I wanted to highlight that the majority of the gastrointestinal and non-hematologic toxicity we saw were grades 1 and 2,” Dr Kumar pointed out, “and could be managed symptomatically or with dose modifications.”

Grade 3-4 hematologic adverse events included thrombocytopenia (26%), neutropenia (21%), anemia (14%), leukopenia (14%), and lymphopenia (15%).

Grade 3-4 non-hematologic adverse events included nausea (3%), diarrhea (3%), fatigue (5%), back pain (8%), and vomiting (3%).

Serious adverse events occurring in 2% or more of patients included pneumonia (8%), sepsis (5%), pain, pyrexia, cough, and hypotension (3% each).

Two patients had dose-limiting toxicities of abdominal pain and nausea at the 600 mg dose.

No events of tumor lysis syndrome (TLS) were reported.  Dr Kumar explained that this may have been the case because patients thought to be at high risk for TLS were mandated to be in the hospital and observed for early tumor lysis in the initial part of the study.

Response

The ORR was 21% in all patients, including a stringent complete response (sCR) of 3% and a CR of 4%.

“But what was really striking was the response rate that we observed in the 30 patients with translocation 11;14,” Dr Kumar said. “The overall response rate was 40%, with 14% of the patients having complete response or better [stringent CR] and 13% of the patients with very good partial response.”

The 36 patients without t(11;14) had a 6% ORR, 3% sCR, and 3% very good partial response.

“If you look at the response rates based on the type of therapy they were coming off or the drugs they were refractory to, the response rate is very similar across all these patient subgroups, irrespective of what groups of drugs they were refractory to,” he added.

Time to progression for all patients was about 2.5 months. For patients with the translocation, it was about 6.6 months.

“Responses were fairly durable among those who had a response,” Dr Kumar said, “considering these are patients with a median of 5 prior lines of therapy.”

Duration of response for patients with t(11;14) was close to 10 months.

Biomarker analysis

The underlying biology for the response was the BCL-2 to BCL-2L1 ratio, as the investigators had observed in the cell lines.

So they analyzed the BCL-2 gene expression ratio in 24 of the 30 patients with t(11;14).

The investigators used droplet digital PCR performed on CD138-selected bone marrow mononuclear cells collected at baseline.

Nine patients had a high ratio, and their ORR was 88%. Fifteen patients had a low ratio, and their ORR was 20%.

Median time to progression for patients with a high ratio was about 12 months. For those with a low ratio, it was about 9 months.

Median change in M protein for patients with t(11;14) was –53%, compared to +11% in the patients without the translocation.

The investigators recommend additional studies with venetoclax in MM, including those with alternative combination therapies.

Venetoclax is being developed by AbbVie, in partnership with Genentech and Roche. This study was sponsored by AbbVie.

*Data in the abstract differ from the presentation.

Shaji Kumar, MD

SAN DIEGO—Venetoclax, the oral BCL-2 inhibitor approved by the US Food and Drug Administration to treat chronic lymphocytic leukemia (CLL) patients with 17p deletion, is also showing activity in multiple myeloma (MM) patients, particularly those with t(11;14).

Final results of a phase 1 study showed venetoclax to be safe as monotherapy in relapsed or refractory MM, producing a response rate of 40% in patients with the translocation and 21% overall.

Preliminary results of the study were presented at the 2015 ASH Annual Meeting, and final results were presented at the 2016 ASH Annual Meeting.

“So I think we have a drug that potentially can change the outcome of a lot of patients with myeloma,” Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota, said during the presentation of the findings at ASH (abstract 488*).

“[It] also opens the possibility of being combined with a variety of other therapeutics that we have in this disease today.”

Venetoclax induces cell death in MM cell lines, particularly those positive for t(11;14). The translocation correlates with higher ratios of BCL-2 to MCL-1 and BCL-2 to MCL-2L1 (BCL-X_L) mRNA. BCL-2 and MCL-1 promote survival of MM cells.

Study design and enrollment

The phase 1, open-label, multicenter study was designed to determine the best tolerated dose of venetoclax.

Secondary and exploratory objectives included overall response rate (ORR), time to progression, duration of response, and predictive biomarkers.

Patients had to have previously treated MM with measurable disease, ECOG status of 0 or 1, and adequate organ function.

They were excluded if they had an active infection, a history of significant renal, neurologic, psychiatric, endocrine, immunologic, cardiovascular, or hepatic disease within 6 months of study entry, or a history of other active malignancies within 3 years of study entry.

The study called for a 2-week lead-in period of venetoclax with weekly dose escalation. Four different dose cohorts were evaluated—300 mg, 600 mg, 900 mg, and 1200 mg.

Thirty patients were enrolled during the lead-in period, and 36 additional patients enrolled at the maximum evaluated dose of 1200 mg in the safety expansion cohort, for a total of 66 patients.

Patients were treated on a 21-day cycle with daily venetoclax. They could also receive dexamethasone to continue on the study if they progressed while receiving the monotherapy.

Patient characteristics

Patient characteristics were “similar to what you would see in relapsed/refractory multiple myloma,” Dr Kumar said.

Median age was 63 (range, 31–79), and most (62%) were ISS stage II/III.

“I want to draw your attention to two features here,” Dr Kumar said.

“Thirty patients, or 46% of the patients, had 11;14 translocation, and that reflects the interest in this drug for this particular class of patients.”

Twelve patients (18%) had 17p deletion, 32 (48%) had 13q deletion, and 27 (41%) were hyperdiploid.

“What is most striking in this cohort of patients,” Dr Kumar added, “is the fact that the median number of prior lines of therapy was 5, with some as high as 15 prior lines of therapy.”

Seventy percent were refractory to bortezomib, 77% refractory to lenalidomide, and 61% refractory to both. Fifty-two patients (79%) were refractory to their last prior therapy.

Patient disposition

At the time of data cutoff on August 19, 2016, 11 patients (17%) were still active on the study.

The median time on study was 3.3 months (range, 0.2–27), median time on venetoclax monotherapy was 2.5 months (range, 0.2–25), and median time on venetoclax plus dexamethasone was 1.4 months (range, 1–13). Seventeen patients received the combination after disease progression.

Fifty-five patients (83%) discontinued treatment, 41 (62%) because of disease progression, 5 (8%) because of adverse events, 2 (3%) withdrew consent, 1 (2%) was lost to follow-up, and 6 (9%) for unspecified reasons.

The 5 adverse events leading to withdrawal included renal failure (n=2), worsening pulmonary disorder (n=1), paralyzing sciatica (n=1), and shortness of breath and pain (n=1). 

“Eight patients died on study,” Dr Kumar said, “none thought to be related to the drug.”

Adverse events

The toxicity profile was primarily hematologic and gastrointestinal.

All patients experienced an adverse event of any grade, and 45 (68%) had a grade 3 or 4 event.

“I wanted to highlight that the majority of the gastrointestinal and non-hematologic toxicity we saw were grades 1 and 2,” Dr Kumar pointed out, “and could be managed symptomatically or with dose modifications.”

Grade 3-4 hematologic adverse events included thrombocytopenia (26%), neutropenia (21%), anemia (14%), leukopenia (14%), and lymphopenia (15%).

Grade 3-4 non-hematologic adverse events included nausea (3%), diarrhea (3%), fatigue (5%), back pain (8%), and vomiting (3%).

Serious adverse events occurring in 2% or more of patients included pneumonia (8%), sepsis (5%), pain, pyrexia, cough, and hypotension (3% each).

Two patients had dose-limiting toxicities of abdominal pain and nausea at the 600 mg dose.

No events of tumor lysis syndrome (TLS) were reported.  Dr Kumar explained that this may have been the case because patients thought to be at high risk for TLS were mandated to be in the hospital and observed for early tumor lysis in the initial part of the study.

Response

The ORR was 21% in all patients, including a stringent complete response (sCR) of 3% and a CR of 4%.

“But what was really striking was the response rate that we observed in the 30 patients with translocation 11;14,” Dr Kumar said. “The overall response rate was 40%, with 14% of the patients having complete response or better [stringent CR] and 13% of the patients with very good partial response.”

The 36 patients without t(11;14) had a 6% ORR, 3% sCR, and 3% very good partial response.

“If you look at the response rates based on the type of therapy they were coming off or the drugs they were refractory to, the response rate is very similar across all these patient subgroups, irrespective of what groups of drugs they were refractory to,” he added.

Time to progression for all patients was about 2.5 months. For patients with the translocation, it was about 6.6 months.

“Responses were fairly durable among those who had a response,” Dr Kumar said, “considering these are patients with a median of 5 prior lines of therapy.”

Duration of response for patients with t(11;14) was close to 10 months.

Biomarker analysis

The underlying biology for the response was the BCL-2 to BCL-2L1 ratio, as the investigators had observed in the cell lines.

So they analyzed the BCL-2 gene expression ratio in 24 of the 30 patients with t(11;14).

The investigators used droplet digital PCR performed on CD138-selected bone marrow mononuclear cells collected at baseline.

Nine patients had a high ratio, and their ORR was 88%. Fifteen patients had a low ratio, and their ORR was 20%.

Median time to progression for patients with a high ratio was about 12 months. For those with a low ratio, it was about 9 months.

Median change in M protein for patients with t(11;14) was –53%, compared to +11% in the patients without the translocation.

The investigators recommend additional studies with venetoclax in MM, including those with alternative combination therapies.

Venetoclax is being developed by AbbVie, in partnership with Genentech and Roche. This study was sponsored by AbbVie.

*Data in the abstract differ from the presentation.

Malaria-infected cell bursting

Image by Peter H. Seeberger

Researchers say they have uncovered one potential reason why it has been difficult to generate protective immunity against the early liver stage of malaria infection in regions where the incidence of malaria is high.

Their research, conducted in mice and published in Cell Reports, suggests that exposure to the blood stage of malaria infection inhibits the formation of the protective immune cells (and their antibodies) that can prevent liver-stage infection.

“The blood stage of malaria infection has a very profound impact on the liver stage immune response, and that impact had never been dissected and visualized at this level,” said study author Marion Pepper, PhD, of the University of Washington School of Medicine in Seattle.

“These studies really suggest that you need a vaccine that is protective against both stages of infection to effectively prevent malaria.”

To track how the blood stage of malaria infection overpowers the liver-stage immune response, Dr Pepper and her colleagues infected 2 groups of mice with different forms of malaria parasites.

One group of mice was infected with Plasmodium yoelii wild-type sporozoites, which complete the pre-erythrocytic stage of infection and establish a blood-stage infection.

The other group was infected with a genetically attenuated Plasmodium yoelii parasite that arrests late in liver stage development and does not cause blood-stage infection.

Six days after infection, the researchers found the levels of antibodies were significantly lower in the mice with the blood stage infection than in mice that only had the parasite targeted to the liver.

To understand this discrepancy, the team tracked the differentiation of Plasmodium liver stage-specific B cells. B cells can differentiate into antibody-secreting early effector cells or long-lived memory cells, both of which contribute to protection against malaria.

The researchers discovered that, 14 days after infection, the B cells in the blood-stage-infected mice never went through the necessary changes to make rapidly responsive memory cells.

However, in the mice that received the liver-stage attenuated version of the parasite, the B cells were still able to differentiate and create the necessary antibodies and memory cells for an effective immune response.

“This work really highlights the importance of looking at antigen-specific B cells,” Dr Pepper said. “These data also suggest that if you’re getting a vaccine while you have an ongoing blood-stage infection, there is a chance that the vaccine will not generate good memory cells because the blood stage disrupts all the processes that are involved in making that immunological memory.”

Dr Pepper and her colleagues are now looking into the possibility of treatment to solve this problem.

The team found that when they treated the second stage of the infection with the anti-malarial drug atovaquone, the B cells were able to create the optimally responsive memory cells.

For now, the researchers hope their work can be used to answer immediate questions about the efficacy of malaria vaccines in regions that are most significantly affected by the disease.

“Malaria has evolved with us throughout human existence and therefore has some potent immune evasion strategies,” Dr Pepper said. “We really tried to tease apart some of the factors that could be driving the loss of protective immunity during natural infection and with current vaccine strategies in areas of high malaria transmission.”

“Our next step is to compare malaria-specific B cells after vaccination or natural infection in humans so we can translate these findings and start to determine how to solve this problem.”

Malaria-infected cell bursting

Image by Peter H. Seeberger

Researchers say they have uncovered one potential reason why it has been difficult to generate protective immunity against the early liver stage of malaria infection in regions where the incidence of malaria is high.

Their research, conducted in mice and published in Cell Reports, suggests that exposure to the blood stage of malaria infection inhibits the formation of the protective immune cells (and their antibodies) that can prevent liver-stage infection.

“The blood stage of malaria infection has a very profound impact on the liver stage immune response, and that impact had never been dissected and visualized at this level,” said study author Marion Pepper, PhD, of the University of Washington School of Medicine in Seattle.

“These studies really suggest that you need a vaccine that is protective against both stages of infection to effectively prevent malaria.”

To track how the blood stage of malaria infection overpowers the liver-stage immune response, Dr Pepper and her colleagues infected 2 groups of mice with different forms of malaria parasites.

One group of mice was infected with Plasmodium yoelii wild-type sporozoites, which complete the pre-erythrocytic stage of infection and establish a blood-stage infection.

The other group was infected with a genetically attenuated Plasmodium yoelii parasite that arrests late in liver stage development and does not cause blood-stage infection.

Six days after infection, the researchers found the levels of antibodies were significantly lower in the mice with the blood stage infection than in mice that only had the parasite targeted to the liver.

To understand this discrepancy, the team tracked the differentiation of Plasmodium liver stage-specific B cells. B cells can differentiate into antibody-secreting early effector cells or long-lived memory cells, both of which contribute to protection against malaria.

The researchers discovered that, 14 days after infection, the B cells in the blood-stage-infected mice never went through the necessary changes to make rapidly responsive memory cells.

However, in the mice that received the liver-stage attenuated version of the parasite, the B cells were still able to differentiate and create the necessary antibodies and memory cells for an effective immune response.

“This work really highlights the importance of looking at antigen-specific B cells,” Dr Pepper said. “These data also suggest that if you’re getting a vaccine while you have an ongoing blood-stage infection, there is a chance that the vaccine will not generate good memory cells because the blood stage disrupts all the processes that are involved in making that immunological memory.”

Dr Pepper and her colleagues are now looking into the possibility of treatment to solve this problem.

The team found that when they treated the second stage of the infection with the anti-malarial drug atovaquone, the B cells were able to create the optimally responsive memory cells.

For now, the researchers hope their work can be used to answer immediate questions about the efficacy of malaria vaccines in regions that are most significantly affected by the disease.

“Malaria has evolved with us throughout human existence and therefore has some potent immune evasion strategies,” Dr Pepper said. “We really tried to tease apart some of the factors that could be driving the loss of protective immunity during natural infection and with current vaccine strategies in areas of high malaria transmission.”

“Our next step is to compare malaria-specific B cells after vaccination or natural infection in humans so we can translate these findings and start to determine how to solve this problem.”

Malaria-infected cell bursting

Image by Peter H. Seeberger

Researchers say they have uncovered one potential reason why it has been difficult to generate protective immunity against the early liver stage of malaria infection in regions where the incidence of malaria is high.

Their research, conducted in mice and published in Cell Reports, suggests that exposure to the blood stage of malaria infection inhibits the formation of the protective immune cells (and their antibodies) that can prevent liver-stage infection.

“The blood stage of malaria infection has a very profound impact on the liver stage immune response, and that impact had never been dissected and visualized at this level,” said study author Marion Pepper, PhD, of the University of Washington School of Medicine in Seattle.

“These studies really suggest that you need a vaccine that is protective against both stages of infection to effectively prevent malaria.”

To track how the blood stage of malaria infection overpowers the liver-stage immune response, Dr Pepper and her colleagues infected 2 groups of mice with different forms of malaria parasites.

One group of mice was infected with Plasmodium yoelii wild-type sporozoites, which complete the pre-erythrocytic stage of infection and establish a blood-stage infection.

The other group was infected with a genetically attenuated Plasmodium yoelii parasite that arrests late in liver stage development and does not cause blood-stage infection.

Six days after infection, the researchers found the levels of antibodies were significantly lower in the mice with the blood stage infection than in mice that only had the parasite targeted to the liver.

To understand this discrepancy, the team tracked the differentiation of Plasmodium liver stage-specific B cells. B cells can differentiate into antibody-secreting early effector cells or long-lived memory cells, both of which contribute to protection against malaria.

The researchers discovered that, 14 days after infection, the B cells in the blood-stage-infected mice never went through the necessary changes to make rapidly responsive memory cells.

However, in the mice that received the liver-stage attenuated version of the parasite, the B cells were still able to differentiate and create the necessary antibodies and memory cells for an effective immune response.

“This work really highlights the importance of looking at antigen-specific B cells,” Dr Pepper said. “These data also suggest that if you’re getting a vaccine while you have an ongoing blood-stage infection, there is a chance that the vaccine will not generate good memory cells because the blood stage disrupts all the processes that are involved in making that immunological memory.”

Dr Pepper and her colleagues are now looking into the possibility of treatment to solve this problem.

The team found that when they treated the second stage of the infection with the anti-malarial drug atovaquone, the B cells were able to create the optimally responsive memory cells.

For now, the researchers hope their work can be used to answer immediate questions about the efficacy of malaria vaccines in regions that are most significantly affected by the disease.

“Malaria has evolved with us throughout human existence and therefore has some potent immune evasion strategies,” Dr Pepper said. “We really tried to tease apart some of the factors that could be driving the loss of protective immunity during natural infection and with current vaccine strategies in areas of high malaria transmission.”

“Our next step is to compare malaria-specific B cells after vaccination or natural infection in humans so we can translate these findings and start to determine how to solve this problem.”

Micrograph showing MCL

Bendamustine hydrochloride (TREAKISYM®) has been approved in Japan as first-line treatment for patients with low-grade B-cell non-Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL).

The drug will now be available for adjunctive use with rituximab in these patients.

Bendamustine hydrochloride is already approved in Japan as monotherapy for relapsed or refractory low-grade B-cell NHL and MCL, as well as chronic lymphocytic leukemia.

Bendamustine hydrochloride is the subject of a licensing agreement concluded between Eisai Co., Ltd and SymBio Pharmaceuticals Limited. Under the licensing agreement, Eisai has been marketing the product since December 2010.

Bendamustine hydrochloride is available at doses of 25 mg and 100 mg for intravenous infusion. The recommended dosage and administration is as follows:

• For low-grade B-cell NHL and MCL

  • As first-line treatment

    When used adjunctively with rituximab, the usual adult dose of bendamustine hydrochloride is 90 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 28-day cycles.

  • For relapsed or refractory disease

    The usual adult dose of bendamustine hydrochloride is 120 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 21-day cycles.

• For chronic lymphocytic leukemia

  • The usual adult dose of bendamustine hydrochloride is 100 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 28-day cycles.

All of the aforementioned doses may be reduced appropriately according to the patient’s condition. 

Micrograph showing MCL

Bendamustine hydrochloride (TREAKISYM®) has been approved in Japan as first-line treatment for patients with low-grade B-cell non-Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL).

The drug will now be available for adjunctive use with rituximab in these patients.

Bendamustine hydrochloride is already approved in Japan as monotherapy for relapsed or refractory low-grade B-cell NHL and MCL, as well as chronic lymphocytic leukemia.

Bendamustine hydrochloride is the subject of a licensing agreement concluded between Eisai Co., Ltd and SymBio Pharmaceuticals Limited. Under the licensing agreement, Eisai has been marketing the product since December 2010.

Bendamustine hydrochloride is available at doses of 25 mg and 100 mg for intravenous infusion. The recommended dosage and administration is as follows:

• For low-grade B-cell NHL and MCL

  • As first-line treatment

    When used adjunctively with rituximab, the usual adult dose of bendamustine hydrochloride is 90 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 28-day cycles.

  • For relapsed or refractory disease

    The usual adult dose of bendamustine hydrochloride is 120 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 21-day cycles.

• For chronic lymphocytic leukemia

  • The usual adult dose of bendamustine hydrochloride is 100 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 28-day cycles.

All of the aforementioned doses may be reduced appropriately according to the patient’s condition. 

Micrograph showing MCL

Bendamustine hydrochloride (TREAKISYM®) has been approved in Japan as first-line treatment for patients with low-grade B-cell non-Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL).

The drug will now be available for adjunctive use with rituximab in these patients.

Bendamustine hydrochloride is already approved in Japan as monotherapy for relapsed or refractory low-grade B-cell NHL and MCL, as well as chronic lymphocytic leukemia.

Bendamustine hydrochloride is the subject of a licensing agreement concluded between Eisai Co., Ltd and SymBio Pharmaceuticals Limited. Under the licensing agreement, Eisai has been marketing the product since December 2010.

Bendamustine hydrochloride is available at doses of 25 mg and 100 mg for intravenous infusion. The recommended dosage and administration is as follows:

• For low-grade B-cell NHL and MCL

  • As first-line treatment

    When used adjunctively with rituximab, the usual adult dose of bendamustine hydrochloride is 90 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 28-day cycles.

  • For relapsed or refractory disease

    The usual adult dose of bendamustine hydrochloride is 120 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 21-day cycles.

• For chronic lymphocytic leukemia

  • The usual adult dose of bendamustine hydrochloride is 100 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 28-day cycles.

All of the aforementioned doses may be reduced appropriately according to the patient’s condition. 

ALL patient

Photo by Bill Branson

SAN DIEGO—Trial results suggest treatment with the chimeric antigen receptor (CAR) T-cell therapy KTE-C19 is feasible for most young patients with high-risk B-cell acute lymphoblastic leukemia (ALL).

Nearly all ALL patients in this trial were able to receive their assigned dose of KTE-C19 after a preparative chemotherapy regimen.

The complete response (CR) rate in these patients was 62%, and the rate of severe cytokine release syndrome (CRS) was low.

Daniel W. Lee III, MD, of the University of Virginia in Charlottesville, presented these results at the 2016 ASH Annual Meeting (abstract 218).

Dr Lee noted that CAR T cells have shown promise in early studies, but morbidity related to high-grade CRS and/or neurotoxicity could limit wide applicability of this treatment in patients with high disease burden. Among those who achieve CR to CD19 CAR T-cell therapy, nearly half of patients relapse in the first year.

At ASH, Dr Lee reported results of a non-randomized clinical trial of KTE-C19, a CD19 CAR T-cell therapy under development by Kite Pharmaceuticals. The company did not sponsor this study, although investigators reported relationships with Kite and other companies. The trial was sponsored by the National Cancer Institute.

The trial included 53 children and young adults with relapsed/refractory ALL (n=51) or diffuse large B-cell lymphoma (n=2). The patients’ median age was 13 (range, 4-30), and most were male (n=41).

Of the ALL patients, 11 had primary refractory disease, 5 had Ph-positive ALL, 3 had Down syndrome, 6 had central nervous system (CNS) disease (2 with CNS3, 4 with CNS2), and 2 had MLL-rearranged ALL. The median ALL disease burden was 27%.

The first 21 patients received a low-dose fludarabine/cyclophosphamide preparative regimen, and the subsequent 32 patients received an alternative intensified preparative regimen in an attempt to mitigate severe CRS risk and improve response.

Possible intensive preparative regimens included higher-dose fludarabine/cyclophosphamide, fludarabine/high-dose cytarabine/G-CSF, and ifosfamide/etoposide.

All 53 patients had peripheral blood cells collected, and 52 were infused with CAR T cells. One patient did not receive an infusion due to progressive fungal pneumonia, and 2 patients received less than their assigned dose.

Therefore, Dr Lee said KTE-C19 was feasible in 94% of patients.

Efficacy

The median follow-up was 18.7 months.

Dr Lee said KTE-C19 “produced robust responses in very high-risk ALL patients.” He noted, however, that the CR rate was lower among patients with high disease burden.

The CR rate among the ALL patients was 62%. Of the 31 patients who achieved a CR, 28 had a minimal residual disease (MRD)-negative remission.

The rate of MRD-negative CR was 100% among the 11 patients with primary refractory ALL, 100% among the 6 patients with CNS disease, 60% among the 5 patients with Ph+ ALL, and 67% among the 3 with Down syndrome. Neither of the 2 patients with MLL-rearranged ALL responded.

“Attempts to increase response rate by modifying the preparative regimen have not yet been successful,” Dr Lee pointed out.

However, he noted superior response and overall survival rates among patients who received a   fludarabine/cyclophosphamide preparative regimen.

“Median overall survival in all enrolled patients is 13.3 months with fludarabine/cyclophosphamide prep versus 5.5 months with other regimens,” he said.

The overall survival rate for the ALL patients was 28%, and the median overall survival was 11.2 months.

For patients who achieved an MRD-negative remission, the leukemia-free survival (LFS) rate was 56%. The median LFS was not reached.

Dr Lee noted that hematopoietic stem cell transplant (HSCT) after KTE-C19 correlated with decreased relapse rates and led to superior LFS.

Of the 28 patients who achieved MRD-negative CR, 21 went on to HSCT after KTE-C19. The median time to HSCT after CAR T-cell dose was 54 days. (Ten of the 28 patients had HSCT before receiving KTE-C19.)

Nineteen (91%) of the patients who proceeded to HSCT after KTE-C19 did not relapse, compared to 1 (14%) of the patients who did not have a post-CAR T transplant.

The median LFS was 4.9 months among the MRD responders who did not proceed to HSCT and undefined among MRD responders with a transplant after KTE-C19.

The probability of survival was 65% beginning at 18 months among patients who underwent HSCT and 14% beginning at 9.8 months among patients without a post-KTE-C19 transplant.

CD19 escape remains a challenge, Dr Lee said. The risk may be diminished, but not eradicated, with HSCT.

Toxicity

“There was a low rate of CRS, which was successfully managed with a grade-driven algorithm,” Dr Lee noted.

Five patients (10%) had grade 3 CRS, and 2 (4%) had grade 4 CRS.

Other grade 3/4 adverse events that were considered at least possibly related to therapy included fever (38% grade 3), febrile neutropenia (23% grade

3), hypotension (9% grade 3, 4% grade 4), LV systolic dysfunction (9% grade 3), prolonged QTc (2% grade 3), dysphasia (2% grade 3), cardiac arrest (2% grade 4), multi-organ failure (2% grade 3), hypoxia (2% grade 3, 2% grade 4), and pulmonary embolism (2% grade 3).

“There were no severe or permanent neurologic toxicities,” Dr Lee said. “Intensive neuropsychological testing in 13 patients revealed no consistent treatment-related neurocognitive decline, and several patients improved following therapy.”

In all, there were 46 cases of neurotoxicity, including visual hallucination (8 grade 1, 17%), headache (1 grade 3 [2%], 3 grade 2 [6%]), confusion (2 grade 1, 4%),

dysphasia (1 grade 3, 2%), delirium (1 grade 3, 2%), seizure (1 grade 2, 1 grade 1 [2% each]), ataxia (1 grade 2, 2%), tremor (1 grade 2, 2%), dysesthesia (1 grade 2, 2%), and dysarthria (1 grade 1, 2%).

ALL patient

Photo by Bill Branson

SAN DIEGO—Trial results suggest treatment with the chimeric antigen receptor (CAR) T-cell therapy KTE-C19 is feasible for most young patients with high-risk B-cell acute lymphoblastic leukemia (ALL).

Nearly all ALL patients in this trial were able to receive their assigned dose of KTE-C19 after a preparative chemotherapy regimen.

The complete response (CR) rate in these patients was 62%, and the rate of severe cytokine release syndrome (CRS) was low.

Daniel W. Lee III, MD, of the University of Virginia in Charlottesville, presented these results at the 2016 ASH Annual Meeting (abstract 218).

Dr Lee noted that CAR T cells have shown promise in early studies, but morbidity related to high-grade CRS and/or neurotoxicity could limit wide applicability of this treatment in patients with high disease burden. Among those who achieve CR to CD19 CAR T-cell therapy, nearly half of patients relapse in the first year.

At ASH, Dr Lee reported results of a non-randomized clinical trial of KTE-C19, a CD19 CAR T-cell therapy under development by Kite Pharmaceuticals. The company did not sponsor this study, although investigators reported relationships with Kite and other companies. The trial was sponsored by the National Cancer Institute.

The trial included 53 children and young adults with relapsed/refractory ALL (n=51) or diffuse large B-cell lymphoma (n=2). The patients’ median age was 13 (range, 4-30), and most were male (n=41).

Of the ALL patients, 11 had primary refractory disease, 5 had Ph-positive ALL, 3 had Down syndrome, 6 had central nervous system (CNS) disease (2 with CNS3, 4 with CNS2), and 2 had MLL-rearranged ALL. The median ALL disease burden was 27%.

The first 21 patients received a low-dose fludarabine/cyclophosphamide preparative regimen, and the subsequent 32 patients received an alternative intensified preparative regimen in an attempt to mitigate severe CRS risk and improve response.

Possible intensive preparative regimens included higher-dose fludarabine/cyclophosphamide, fludarabine/high-dose cytarabine/G-CSF, and ifosfamide/etoposide.

All 53 patients had peripheral blood cells collected, and 52 were infused with CAR T cells. One patient did not receive an infusion due to progressive fungal pneumonia, and 2 patients received less than their assigned dose.

Therefore, Dr Lee said KTE-C19 was feasible in 94% of patients.

Efficacy

The median follow-up was 18.7 months.

Dr Lee said KTE-C19 “produced robust responses in very high-risk ALL patients.” He noted, however, that the CR rate was lower among patients with high disease burden.

The CR rate among the ALL patients was 62%. Of the 31 patients who achieved a CR, 28 had a minimal residual disease (MRD)-negative remission.

The rate of MRD-negative CR was 100% among the 11 patients with primary refractory ALL, 100% among the 6 patients with CNS disease, 60% among the 5 patients with Ph+ ALL, and 67% among the 3 with Down syndrome. Neither of the 2 patients with MLL-rearranged ALL responded.

“Attempts to increase response rate by modifying the preparative regimen have not yet been successful,” Dr Lee pointed out.

However, he noted superior response and overall survival rates among patients who received a   fludarabine/cyclophosphamide preparative regimen.

“Median overall survival in all enrolled patients is 13.3 months with fludarabine/cyclophosphamide prep versus 5.5 months with other regimens,” he said.

The overall survival rate for the ALL patients was 28%, and the median overall survival was 11.2 months.

For patients who achieved an MRD-negative remission, the leukemia-free survival (LFS) rate was 56%. The median LFS was not reached.

Dr Lee noted that hematopoietic stem cell transplant (HSCT) after KTE-C19 correlated with decreased relapse rates and led to superior LFS.

Of the 28 patients who achieved MRD-negative CR, 21 went on to HSCT after KTE-C19. The median time to HSCT after CAR T-cell dose was 54 days. (Ten of the 28 patients had HSCT before receiving KTE-C19.)

Nineteen (91%) of the patients who proceeded to HSCT after KTE-C19 did not relapse, compared to 1 (14%) of the patients who did not have a post-CAR T transplant.

The median LFS was 4.9 months among the MRD responders who did not proceed to HSCT and undefined among MRD responders with a transplant after KTE-C19.

The probability of survival was 65% beginning at 18 months among patients who underwent HSCT and 14% beginning at 9.8 months among patients without a post-KTE-C19 transplant.

CD19 escape remains a challenge, Dr Lee said. The risk may be diminished, but not eradicated, with HSCT.

Toxicity

“There was a low rate of CRS, which was successfully managed with a grade-driven algorithm,” Dr Lee noted.

Five patients (10%) had grade 3 CRS, and 2 (4%) had grade 4 CRS.

Other grade 3/4 adverse events that were considered at least possibly related to therapy included fever (38% grade 3), febrile neutropenia (23% grade

3), hypotension (9% grade 3, 4% grade 4), LV systolic dysfunction (9% grade 3), prolonged QTc (2% grade 3), dysphasia (2% grade 3), cardiac arrest (2% grade 4), multi-organ failure (2% grade 3), hypoxia (2% grade 3, 2% grade 4), and pulmonary embolism (2% grade 3).

“There were no severe or permanent neurologic toxicities,” Dr Lee said. “Intensive neuropsychological testing in 13 patients revealed no consistent treatment-related neurocognitive decline, and several patients improved following therapy.”

In all, there were 46 cases of neurotoxicity, including visual hallucination (8 grade 1, 17%), headache (1 grade 3 [2%], 3 grade 2 [6%]), confusion (2 grade 1, 4%),

dysphasia (1 grade 3, 2%), delirium (1 grade 3, 2%), seizure (1 grade 2, 1 grade 1 [2% each]), ataxia (1 grade 2, 2%), tremor (1 grade 2, 2%), dysesthesia (1 grade 2, 2%), and dysarthria (1 grade 1, 2%).

ALL patient

Photo by Bill Branson

SAN DIEGO—Trial results suggest treatment with the chimeric antigen receptor (CAR) T-cell therapy KTE-C19 is feasible for most young patients with high-risk B-cell acute lymphoblastic leukemia (ALL).

Nearly all ALL patients in this trial were able to receive their assigned dose of KTE-C19 after a preparative chemotherapy regimen.

The complete response (CR) rate in these patients was 62%, and the rate of severe cytokine release syndrome (CRS) was low.

Daniel W. Lee III, MD, of the University of Virginia in Charlottesville, presented these results at the 2016 ASH Annual Meeting (abstract 218).

Dr Lee noted that CAR T cells have shown promise in early studies, but morbidity related to high-grade CRS and/or neurotoxicity could limit wide applicability of this treatment in patients with high disease burden. Among those who achieve CR to CD19 CAR T-cell therapy, nearly half of patients relapse in the first year.

At ASH, Dr Lee reported results of a non-randomized clinical trial of KTE-C19, a CD19 CAR T-cell therapy under development by Kite Pharmaceuticals. The company did not sponsor this study, although investigators reported relationships with Kite and other companies. The trial was sponsored by the National Cancer Institute.

The trial included 53 children and young adults with relapsed/refractory ALL (n=51) or diffuse large B-cell lymphoma (n=2). The patients’ median age was 13 (range, 4-30), and most were male (n=41).

Of the ALL patients, 11 had primary refractory disease, 5 had Ph-positive ALL, 3 had Down syndrome, 6 had central nervous system (CNS) disease (2 with CNS3, 4 with CNS2), and 2 had MLL-rearranged ALL. The median ALL disease burden was 27%.

The first 21 patients received a low-dose fludarabine/cyclophosphamide preparative regimen, and the subsequent 32 patients received an alternative intensified preparative regimen in an attempt to mitigate severe CRS risk and improve response.

Possible intensive preparative regimens included higher-dose fludarabine/cyclophosphamide, fludarabine/high-dose cytarabine/G-CSF, and ifosfamide/etoposide.

All 53 patients had peripheral blood cells collected, and 52 were infused with CAR T cells. One patient did not receive an infusion due to progressive fungal pneumonia, and 2 patients received less than their assigned dose.

Therefore, Dr Lee said KTE-C19 was feasible in 94% of patients.

Efficacy

The median follow-up was 18.7 months.

Dr Lee said KTE-C19 “produced robust responses in very high-risk ALL patients.” He noted, however, that the CR rate was lower among patients with high disease burden.

The CR rate among the ALL patients was 62%. Of the 31 patients who achieved a CR, 28 had a minimal residual disease (MRD)-negative remission.

The rate of MRD-negative CR was 100% among the 11 patients with primary refractory ALL, 100% among the 6 patients with CNS disease, 60% among the 5 patients with Ph+ ALL, and 67% among the 3 with Down syndrome. Neither of the 2 patients with MLL-rearranged ALL responded.

“Attempts to increase response rate by modifying the preparative regimen have not yet been successful,” Dr Lee pointed out.

However, he noted superior response and overall survival rates among patients who received a   fludarabine/cyclophosphamide preparative regimen.

“Median overall survival in all enrolled patients is 13.3 months with fludarabine/cyclophosphamide prep versus 5.5 months with other regimens,” he said.

The overall survival rate for the ALL patients was 28%, and the median overall survival was 11.2 months.

For patients who achieved an MRD-negative remission, the leukemia-free survival (LFS) rate was 56%. The median LFS was not reached.

Dr Lee noted that hematopoietic stem cell transplant (HSCT) after KTE-C19 correlated with decreased relapse rates and led to superior LFS.

Of the 28 patients who achieved MRD-negative CR, 21 went on to HSCT after KTE-C19. The median time to HSCT after CAR T-cell dose was 54 days. (Ten of the 28 patients had HSCT before receiving KTE-C19.)

Nineteen (91%) of the patients who proceeded to HSCT after KTE-C19 did not relapse, compared to 1 (14%) of the patients who did not have a post-CAR T transplant.

The median LFS was 4.9 months among the MRD responders who did not proceed to HSCT and undefined among MRD responders with a transplant after KTE-C19.

The probability of survival was 65% beginning at 18 months among patients who underwent HSCT and 14% beginning at 9.8 months among patients without a post-KTE-C19 transplant.

CD19 escape remains a challenge, Dr Lee said. The risk may be diminished, but not eradicated, with HSCT.

Toxicity

“There was a low rate of CRS, which was successfully managed with a grade-driven algorithm,” Dr Lee noted.

Five patients (10%) had grade 3 CRS, and 2 (4%) had grade 4 CRS.

Other grade 3/4 adverse events that were considered at least possibly related to therapy included fever (38% grade 3), febrile neutropenia (23% grade

3), hypotension (9% grade 3, 4% grade 4), LV systolic dysfunction (9% grade 3), prolonged QTc (2% grade 3), dysphasia (2% grade 3), cardiac arrest (2% grade 4), multi-organ failure (2% grade 3), hypoxia (2% grade 3, 2% grade 4), and pulmonary embolism (2% grade 3).

“There were no severe or permanent neurologic toxicities,” Dr Lee said. “Intensive neuropsychological testing in 13 patients revealed no consistent treatment-related neurocognitive decline, and several patients improved following therapy.”

In all, there were 46 cases of neurotoxicity, including visual hallucination (8 grade 1, 17%), headache (1 grade 3 [2%], 3 grade 2 [6%]), confusion (2 grade 1, 4%),

dysphasia (1 grade 3, 2%), delirium (1 grade 3, 2%), seizure (1 grade 2, 1 grade 1 [2% each]), ataxia (1 grade 2, 2%), tremor (1 grade 2, 2%), dysesthesia (1 grade 2, 2%), and dysarthria (1 grade 1, 2%).