Jen Smith

Photo by Bill Branson

The U.S. Food and Drug Administration (FDA) has approved a second pediatric indication for dasatinib (Sprycel®).

The tyrosine kinase inhibitor is now approved for use in combination with chemotherapy to treat pediatric patients age 1 year and older who have newly diagnosed, Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

Dasatinib is also FDA-approved for use in children age 1 year and older who have chronic phase, Ph+ chronic myeloid leukemia (CML).

In adults, dasatinib is FDA-approved to treat:

• Newly diagnosed, Ph+, chronic phase CML
• Chronic, accelerated, or myeloid/lymphoid blast phase, Ph+ CML with resistance or intolerance to prior therapy including imatinib
• Ph+ ALL with resistance or intolerance to prior therapy.

Trial results

The FDA’s approval of dasatinib in children with Ph+ ALL is based on data from a phase 2 study (CA180-372, NCT01460160).

In this trial, researchers evaluated dasatinib in combination with the AIEOP-BFM ALL 2000 chemotherapy protocol in patients (ages 1 to 17) with newly diagnosed, B-cell precursor, Ph+ ALL.

There were 78 patients evaluated for efficacy in cohort 1. They had a median age of 10.4 years (range, 2.6 to 17.9 years). They received dasatinib at a daily dose of 60 mg/m² for up to 24 months.

Patients with central nervous system 3 disease received cranial irradiation, and patients were assigned to stem cell transplant based on minimal residual disease if they were thought to have a high risk of relapse.

The 3-year event-free survival rate in the 78 patients was 64.1%.

There were 81 patients evaluable for safety who received dasatinib continuously in combination with chemotherapy. Their median duration of treatment was 24 months (range, 2 to 27 months).

The most common adverse events (AEs) in these patients were mucositis (93%), febrile neutropenia (86%), pyrexia (85%), diarrhea (84%), nausea (84%), vomiting (83%), musculoskeletal pain (83%), abdominal pain (78%), cough (78%), headache (77%), rash (68%), fatigue (59%), and constipation (57%).

Eight (10%) patients had AEs leading to treatment discontinuation. These included fungal sepsis, hepatotoxicity in the setting of graft-versus-host disease, thrombocytopenia, cytomegalovirus infection, pneumonia, nausea, enteritis, and drug hypersensitivity.

Three patients (4%) had fatal AEs, all infections.

This trial was sponsored by Bristol-Myers Squibb. Additional data are available in the prescribing information for dasatinib.

Photo by Bill Branson

The U.S. Food and Drug Administration (FDA) has approved a second pediatric indication for dasatinib (Sprycel®).

The tyrosine kinase inhibitor is now approved for use in combination with chemotherapy to treat pediatric patients age 1 year and older who have newly diagnosed, Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

Dasatinib is also FDA-approved for use in children age 1 year and older who have chronic phase, Ph+ chronic myeloid leukemia (CML).

In adults, dasatinib is FDA-approved to treat:

• Newly diagnosed, Ph+, chronic phase CML
• Chronic, accelerated, or myeloid/lymphoid blast phase, Ph+ CML with resistance or intolerance to prior therapy including imatinib
• Ph+ ALL with resistance or intolerance to prior therapy.

Trial results

The FDA’s approval of dasatinib in children with Ph+ ALL is based on data from a phase 2 study (CA180-372, NCT01460160).

In this trial, researchers evaluated dasatinib in combination with the AIEOP-BFM ALL 2000 chemotherapy protocol in patients (ages 1 to 17) with newly diagnosed, B-cell precursor, Ph+ ALL.

There were 78 patients evaluated for efficacy in cohort 1. They had a median age of 10.4 years (range, 2.6 to 17.9 years). They received dasatinib at a daily dose of 60 mg/m² for up to 24 months.

Patients with central nervous system 3 disease received cranial irradiation, and patients were assigned to stem cell transplant based on minimal residual disease if they were thought to have a high risk of relapse.

The 3-year event-free survival rate in the 78 patients was 64.1%.

There were 81 patients evaluable for safety who received dasatinib continuously in combination with chemotherapy. Their median duration of treatment was 24 months (range, 2 to 27 months).

The most common adverse events (AEs) in these patients were mucositis (93%), febrile neutropenia (86%), pyrexia (85%), diarrhea (84%), nausea (84%), vomiting (83%), musculoskeletal pain (83%), abdominal pain (78%), cough (78%), headache (77%), rash (68%), fatigue (59%), and constipation (57%).

Eight (10%) patients had AEs leading to treatment discontinuation. These included fungal sepsis, hepatotoxicity in the setting of graft-versus-host disease, thrombocytopenia, cytomegalovirus infection, pneumonia, nausea, enteritis, and drug hypersensitivity.

Three patients (4%) had fatal AEs, all infections.

This trial was sponsored by Bristol-Myers Squibb. Additional data are available in the prescribing information for dasatinib.

Photo by Bill Branson

The U.S. Food and Drug Administration (FDA) has approved a second pediatric indication for dasatinib (Sprycel®).

The tyrosine kinase inhibitor is now approved for use in combination with chemotherapy to treat pediatric patients age 1 year and older who have newly diagnosed, Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

Dasatinib is also FDA-approved for use in children age 1 year and older who have chronic phase, Ph+ chronic myeloid leukemia (CML).

In adults, dasatinib is FDA-approved to treat:

• Newly diagnosed, Ph+, chronic phase CML
• Chronic, accelerated, or myeloid/lymphoid blast phase, Ph+ CML with resistance or intolerance to prior therapy including imatinib
• Ph+ ALL with resistance or intolerance to prior therapy.

Trial results

The FDA’s approval of dasatinib in children with Ph+ ALL is based on data from a phase 2 study (CA180-372, NCT01460160).

In this trial, researchers evaluated dasatinib in combination with the AIEOP-BFM ALL 2000 chemotherapy protocol in patients (ages 1 to 17) with newly diagnosed, B-cell precursor, Ph+ ALL.

There were 78 patients evaluated for efficacy in cohort 1. They had a median age of 10.4 years (range, 2.6 to 17.9 years). They received dasatinib at a daily dose of 60 mg/m² for up to 24 months.

Patients with central nervous system 3 disease received cranial irradiation, and patients were assigned to stem cell transplant based on minimal residual disease if they were thought to have a high risk of relapse.

The 3-year event-free survival rate in the 78 patients was 64.1%.

There were 81 patients evaluable for safety who received dasatinib continuously in combination with chemotherapy. Their median duration of treatment was 24 months (range, 2 to 27 months).

The most common adverse events (AEs) in these patients were mucositis (93%), febrile neutropenia (86%), pyrexia (85%), diarrhea (84%), nausea (84%), vomiting (83%), musculoskeletal pain (83%), abdominal pain (78%), cough (78%), headache (77%), rash (68%), fatigue (59%), and constipation (57%).

Eight (10%) patients had AEs leading to treatment discontinuation. These included fungal sepsis, hepatotoxicity in the setting of graft-versus-host disease, thrombocytopenia, cytomegalovirus infection, pneumonia, nausea, enteritis, and drug hypersensitivity.

Three patients (4%) had fatal AEs, all infections.

This trial was sponsored by Bristol-Myers Squibb. Additional data are available in the prescribing information for dasatinib.

Photo from Penn Medicine

A group of experts has proposed new consensus definitions and grading systems for cytokine release syndrome (CRS) and neurotoxicity related to immune effector cell therapies.

The group hopes their recommendations will be widely accepted and used in both trials and the clinical setting.

The recommendations were devised by 49 experts at a meeting supported by the American Society for Blood and Marrow Transplantation (ASBMT), compiled by a writing group, and reviewed by stakeholders.

Daniel W. Lee, MD, of the University of Virginia School of Medicine in Charlottesville, and his colleagues described the ASBMT consensus definitions and grading systems in Biology of Blood and Marrow Transplantation.

CRS

The ASBMT consensus definition for CRS is “a supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells.”

To be diagnosed with CRS, a patient must have a fever and may have the following symptoms:

• Hypotension
• Capillary leak (hypoxia)
• End organ dysfunction.

The ASBMT consensus for grading CRS is as follows:

• Grade 1—Patient has a fever, defined as a temperature of 38.0°C or higher
• Grade 2—Patient has a fever, hypotension that doesn’t require vasopressors, and/or hypoxia that requires oxygen delivered by low-flow nasal cannula (≤6 L/min) or blow-by
• Grade 3—Patient has a fever, hypotension requiring one vasopressor (with or without vasopressin), and/or hypoxia (not attributable to any other cause) that requires high-flow nasal cannula (>6 L/min), facemask, non-rebreather mask, or venturi mask
• Grade 4—Patient has a fever, hypotension requiring multiple vasopressors (excluding vasopressin), and/or hypoxia (not attributable to any other cause) requiring positive-pressure ventilation
• Grade 5—Death due to CRS when there is no other “principle factor” leading to death.

Typically, severe CRS can be considered resolved if “fever, oxygen, and pressor requirements have resolved,” Dr. Lee and his coauthors said.

The authors also stressed that neurotoxicity that occurs with or after CRS “does not inform the grade of CRS but is instead captured separately in the neurotoxicity scale.”

Neurotoxicity

Dr. Lee and his coauthors said neurotoxicity in this setting is called “immune effector cell-associated neurotoxicity syndrome (ICANS).”

The ASBMT consensus definition for ICANs is “a disorder characterized by a pathologic process involving the central nervous system following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells.”

Symptoms of ICANS may include:

• Aphasia
• Altered level of consciousness
• Impairment of cognitive skills
• Motor weakness
• Seizures
• Cerebral edema.

The ASBMT consensus for grading ICANS in adults and children age 12 and older is as follows:

• Grade 1—Patient has a score of 7-9 on the 10-point immune effector cell-associated encephalopathy (ICE) assessment and awakens spontaneously
• Grade 2—Patient has a score of 3-6 on the ICE assessment and will awaken to the sound of a voice
• Grade 3—Patient has a score of 0-2 on the ICE assessment, awakens only to tactile stimulus, has any clinical seizure that resolves rapidly or non-convulsive seizures that resolve with intervention, has focal/local edema on neuroimaging
• Grade 4—Patient is unable to perform the ICE assessment, is unarousable or requires “vigorous stimuli” to be aroused, has life-threatening seizure (lasting more than 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between, has deep focal motor weakness, and/or has decerebrate or decorticate posturing, cranial nerve VI palsy, papilledema, Cushing’s triad, or signs of diffuse cerebral edema on neuroimaging
• Grade 5—Death due to ICANS when there is no other “principle factor” leading to death.

Dr. Lee and his coauthors noted that the ICE assessment is not suitable for children younger than 12. For these patients (and older patients with baseline developmental delays), ICANS can be assessed using the Cornell Assessment of Pediatric Delirium (CAPD).

The ASBMT consensus for grading ICANS in children younger than 12 (or older patients with developmental delays) is as follows:

• Grade 1—Patient has a CAPD score lower than 9 and awakens spontaneously
• Grade 2—Patient has a CAPD score lower than 9 and will awaken to the sound of a voice
• Grade 3—Patient has a CAPD score of 9 or higher, awakens only to tactile stimulus, has any clinical seizure that resolves rapidly or non-convulsive seizures that resolve with intervention, and/or has focal/local edema on neuroimaging
• Grade 4—Patient is unable to perform CAPD, is unarousable or requires “vigorous stimuli” to be aroused, has life-threatening seizure (lasting more than 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between, has deep focal motor weakness, and/or has decerebrate or decorticate posturing, cranial nerve VI palsy, papilledema, Cushing’s triad, or signs of diffuse cerebral edema on neuroimaging
• Grade 5—Death due to ICANS when there is no other “principle factor” leading to death.

Dr. Lee and his coauthors reported relationships with a range of companies. 

Photo from Penn Medicine

A group of experts has proposed new consensus definitions and grading systems for cytokine release syndrome (CRS) and neurotoxicity related to immune effector cell therapies.

The group hopes their recommendations will be widely accepted and used in both trials and the clinical setting.

The recommendations were devised by 49 experts at a meeting supported by the American Society for Blood and Marrow Transplantation (ASBMT), compiled by a writing group, and reviewed by stakeholders.

Daniel W. Lee, MD, of the University of Virginia School of Medicine in Charlottesville, and his colleagues described the ASBMT consensus definitions and grading systems in Biology of Blood and Marrow Transplantation.

CRS

The ASBMT consensus definition for CRS is “a supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells.”

To be diagnosed with CRS, a patient must have a fever and may have the following symptoms:

• Hypotension
• Capillary leak (hypoxia)
• End organ dysfunction.

The ASBMT consensus for grading CRS is as follows:

• Grade 1—Patient has a fever, defined as a temperature of 38.0°C or higher
• Grade 2—Patient has a fever, hypotension that doesn’t require vasopressors, and/or hypoxia that requires oxygen delivered by low-flow nasal cannula (≤6 L/min) or blow-by
• Grade 3—Patient has a fever, hypotension requiring one vasopressor (with or without vasopressin), and/or hypoxia (not attributable to any other cause) that requires high-flow nasal cannula (>6 L/min), facemask, non-rebreather mask, or venturi mask
• Grade 4—Patient has a fever, hypotension requiring multiple vasopressors (excluding vasopressin), and/or hypoxia (not attributable to any other cause) requiring positive-pressure ventilation
• Grade 5—Death due to CRS when there is no other “principle factor” leading to death.

Typically, severe CRS can be considered resolved if “fever, oxygen, and pressor requirements have resolved,” Dr. Lee and his coauthors said.

The authors also stressed that neurotoxicity that occurs with or after CRS “does not inform the grade of CRS but is instead captured separately in the neurotoxicity scale.”

Neurotoxicity

Dr. Lee and his coauthors said neurotoxicity in this setting is called “immune effector cell-associated neurotoxicity syndrome (ICANS).”

The ASBMT consensus definition for ICANs is “a disorder characterized by a pathologic process involving the central nervous system following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells.”

Symptoms of ICANS may include:

• Aphasia
• Altered level of consciousness
• Impairment of cognitive skills
• Motor weakness
• Seizures
• Cerebral edema.

The ASBMT consensus for grading ICANS in adults and children age 12 and older is as follows:

• Grade 1—Patient has a score of 7-9 on the 10-point immune effector cell-associated encephalopathy (ICE) assessment and awakens spontaneously
• Grade 2—Patient has a score of 3-6 on the ICE assessment and will awaken to the sound of a voice
• Grade 3—Patient has a score of 0-2 on the ICE assessment, awakens only to tactile stimulus, has any clinical seizure that resolves rapidly or non-convulsive seizures that resolve with intervention, has focal/local edema on neuroimaging
• Grade 4—Patient is unable to perform the ICE assessment, is unarousable or requires “vigorous stimuli” to be aroused, has life-threatening seizure (lasting more than 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between, has deep focal motor weakness, and/or has decerebrate or decorticate posturing, cranial nerve VI palsy, papilledema, Cushing’s triad, or signs of diffuse cerebral edema on neuroimaging
• Grade 5—Death due to ICANS when there is no other “principle factor” leading to death.

Dr. Lee and his coauthors noted that the ICE assessment is not suitable for children younger than 12. For these patients (and older patients with baseline developmental delays), ICANS can be assessed using the Cornell Assessment of Pediatric Delirium (CAPD).

The ASBMT consensus for grading ICANS in children younger than 12 (or older patients with developmental delays) is as follows:

• Grade 1—Patient has a CAPD score lower than 9 and awakens spontaneously
• Grade 2—Patient has a CAPD score lower than 9 and will awaken to the sound of a voice
• Grade 3—Patient has a CAPD score of 9 or higher, awakens only to tactile stimulus, has any clinical seizure that resolves rapidly or non-convulsive seizures that resolve with intervention, and/or has focal/local edema on neuroimaging
• Grade 4—Patient is unable to perform CAPD, is unarousable or requires “vigorous stimuli” to be aroused, has life-threatening seizure (lasting more than 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between, has deep focal motor weakness, and/or has decerebrate or decorticate posturing, cranial nerve VI palsy, papilledema, Cushing’s triad, or signs of diffuse cerebral edema on neuroimaging
• Grade 5—Death due to ICANS when there is no other “principle factor” leading to death.

Dr. Lee and his coauthors reported relationships with a range of companies. 

Photo from Penn Medicine

A group of experts has proposed new consensus definitions and grading systems for cytokine release syndrome (CRS) and neurotoxicity related to immune effector cell therapies.

The group hopes their recommendations will be widely accepted and used in both trials and the clinical setting.

The recommendations were devised by 49 experts at a meeting supported by the American Society for Blood and Marrow Transplantation (ASBMT), compiled by a writing group, and reviewed by stakeholders.

Daniel W. Lee, MD, of the University of Virginia School of Medicine in Charlottesville, and his colleagues described the ASBMT consensus definitions and grading systems in Biology of Blood and Marrow Transplantation.

CRS

The ASBMT consensus definition for CRS is “a supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells.”

To be diagnosed with CRS, a patient must have a fever and may have the following symptoms:

• Hypotension
• Capillary leak (hypoxia)
• End organ dysfunction.

The ASBMT consensus for grading CRS is as follows:

• Grade 1—Patient has a fever, defined as a temperature of 38.0°C or higher
• Grade 2—Patient has a fever, hypotension that doesn’t require vasopressors, and/or hypoxia that requires oxygen delivered by low-flow nasal cannula (≤6 L/min) or blow-by
• Grade 3—Patient has a fever, hypotension requiring one vasopressor (with or without vasopressin), and/or hypoxia (not attributable to any other cause) that requires high-flow nasal cannula (>6 L/min), facemask, non-rebreather mask, or venturi mask
• Grade 4—Patient has a fever, hypotension requiring multiple vasopressors (excluding vasopressin), and/or hypoxia (not attributable to any other cause) requiring positive-pressure ventilation
• Grade 5—Death due to CRS when there is no other “principle factor” leading to death.

Typically, severe CRS can be considered resolved if “fever, oxygen, and pressor requirements have resolved,” Dr. Lee and his coauthors said.

The authors also stressed that neurotoxicity that occurs with or after CRS “does not inform the grade of CRS but is instead captured separately in the neurotoxicity scale.”

Neurotoxicity

Dr. Lee and his coauthors said neurotoxicity in this setting is called “immune effector cell-associated neurotoxicity syndrome (ICANS).”

The ASBMT consensus definition for ICANs is “a disorder characterized by a pathologic process involving the central nervous system following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells.”

Symptoms of ICANS may include:

• Aphasia
• Altered level of consciousness
• Impairment of cognitive skills
• Motor weakness
• Seizures
• Cerebral edema.

The ASBMT consensus for grading ICANS in adults and children age 12 and older is as follows:

• Grade 1—Patient has a score of 7-9 on the 10-point immune effector cell-associated encephalopathy (ICE) assessment and awakens spontaneously
• Grade 2—Patient has a score of 3-6 on the ICE assessment and will awaken to the sound of a voice
• Grade 3—Patient has a score of 0-2 on the ICE assessment, awakens only to tactile stimulus, has any clinical seizure that resolves rapidly or non-convulsive seizures that resolve with intervention, has focal/local edema on neuroimaging
• Grade 4—Patient is unable to perform the ICE assessment, is unarousable or requires “vigorous stimuli” to be aroused, has life-threatening seizure (lasting more than 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between, has deep focal motor weakness, and/or has decerebrate or decorticate posturing, cranial nerve VI palsy, papilledema, Cushing’s triad, or signs of diffuse cerebral edema on neuroimaging
• Grade 5—Death due to ICANS when there is no other “principle factor” leading to death.

Dr. Lee and his coauthors noted that the ICE assessment is not suitable for children younger than 12. For these patients (and older patients with baseline developmental delays), ICANS can be assessed using the Cornell Assessment of Pediatric Delirium (CAPD).

The ASBMT consensus for grading ICANS in children younger than 12 (or older patients with developmental delays) is as follows:

• Grade 1—Patient has a CAPD score lower than 9 and awakens spontaneously
• Grade 2—Patient has a CAPD score lower than 9 and will awaken to the sound of a voice
• Grade 3—Patient has a CAPD score of 9 or higher, awakens only to tactile stimulus, has any clinical seizure that resolves rapidly or non-convulsive seizures that resolve with intervention, and/or has focal/local edema on neuroimaging
• Grade 4—Patient is unable to perform CAPD, is unarousable or requires “vigorous stimuli” to be aroused, has life-threatening seizure (lasting more than 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between, has deep focal motor weakness, and/or has decerebrate or decorticate posturing, cranial nerve VI palsy, papilledema, Cushing’s triad, or signs of diffuse cerebral edema on neuroimaging
• Grade 5—Death due to ICANS when there is no other “principle factor” leading to death.

Dr. Lee and his coauthors reported relationships with a range of companies. 

Photo from UAB Hospital

SAN DIEGO—Luspatercept can produce “clinically meaningful” results in transfusion-dependent adults with β-thalassemia, according to a speaker at the 2018 ASH Annual Meeting.

In the phase 3 BELIEVE trial, β-thalassemia patients were significantly more likely to experience a reduction in transfusion burden if they were treated with luspatercept rather than placebo.

“Luspatercept showed a statistically significant and clinically meaningful . . . reduction in transfusion burden compared with placebo at any 12- or 24-week [period] along this study,” said Maria Domenica Cappellini, MD, of the University of Milan in Italy.

“At this point, we believe [luspatercept] is a potential new treatment for adult patients with β-thalassemia who are requiring regular blood transfusions.”

Dr. Cappellini presented these results at ASH as abstract 163.

The BELIEVE trial (NCT02604433) enrolled 336 patients from 65 sites in 15 countries. All patients had β-thalassemia or hemoglobin E/β‑thalassemia. They required regular transfusions of six to 20 red blood cell (RBC) units in the 24 weeks prior to randomization, and none had a transfusion-free period lasting 35 days or more.

The patients were randomized 2:1 to receive luspatercept—at a starting dose of 1.0 mg/kg with titration up to 1.25 mg/kg—(n=224) or placebo (n=112) subcutaneously every 3 weeks for at least 48 weeks.

All patients continued to receive RBC transfusions and iron chelation therapy as necessary (so they maintained the same baseline hemoglobin level).

The median age was 30 in both treatment arms (range, 18-66). More than half of patients were female—58.9% in the luspatercept arm and 56.3% in the placebo arm.

A similar percentage of patients in both arms had the β0, β0 genotype—30.4% in the luspatercept arm and 31.3% in the placebo arm.

The median hemoglobin level at baseline was 9.31 g/dL in the luspatercept arm and 9.15 g/dL in the placebo arm. The median RBC transfusion burden was 6.12 units/12 weeks and 6.27 units/12 weeks, respectively.

Other baseline characteristics were similar as well.

Efficacy

“[L]uspatercept showed a statistically significant improvement in the primary endpoint,” Dr. Cappellini noted.

The primary endpoint was at least a 33% reduction in transfusion burden—of at least two RBC units—from week 13 to week 24, as compared to the 12-week baseline period.

This endpoint was achieved by 21.4% (n=48) of patients in the luspatercept arm and 4.5% (n=5) in the placebo arm (odds ratio=5.79; P<0.0001).

“Statistical significance was also demonstrated with luspatercept versus placebo for all the key secondary endpoints,” Dr. Cappellini said.

There were more patients in the luspatercept arm than the placebo arm who achieved at least a 33% reduction in transfusion burden from week 37 to 48—19.6% and 3.6%, respectively (P<0.0001).

Similarly, there were more patients in the luspatercept arm than the placebo arm who achieved at least a 50% reduction in transfusion burden from week 13 to 24—7.6% and 1.8%, respectively (P=0.0303)—and from week 37 to 48—10.3% and 0.9%, respectively (P=0.0017).

During any 12-week interval, 70.5% of luspatercept-treated patients and 29.5% of placebo-treated patients achieved at least a 33% reduction in transfusion burden (P<0.0001), and 40.2% and 6.3%, respectively (P<0.0001), achieved at least a 50% reduction in transfusion burden.

During any 24-week interval, 41.1% of luspatercept-treated patients and 2.7% of placebo-treated patients achieved at least a 33% reduction in transfusion burden (P<0.0001), and 16.5% and 0.9%, respectively (P<0.0001), achieved at least a 50% reduction in transfusion burden.

Safety

Ninety-six percent of patients in the luspatercept arm and 92.7% in the placebo arm had at least one treatment-emergent adverse event (TEAE).

Grade 3 or higher TEAEs occurred in 29.1% of patients in the luspatercept arm and 15.6% of those in the placebo arm. Serious TEAEs occurred in 15.2% and 5.5%, respectively.

One patient in the placebo arm had a TEAE-related death (acute cholecystitis), but there were no treatment-related deaths in the luspatercept arm.

TEAEs leading to treatment discontinuation occurred in 5.4% of luspatercept-treated patients and 0.9% of placebo-treated patients.

TEAEs that occurred more frequently in the luspatercept arm than in the placebo arm (respectively) included bone pain (19.7% and 8.3%), arthralgia (19.3% and 11.9%), and dizziness (11.2% and 4.6%).

Grade 3/4 TEAEs (in the luspatercept and placebo arms, respectively) included anemia (3.1% and 0%), increased liver iron concentration (2.7% and 0.9%), hyperuricemia (2.7% and 0%), hypertension (1.8% and 0%), syncope (1.8% and 0%), back pain (1.3% and 0.9%), bone pain (1.3% and 0%), blood uric acid increase (1.3% and 0%), increased aspartate aminotransferase (1.3% and 0%), increased alanine aminotransferase (0.9% and 2.8%), and thromboembolic events (0.9% and 0%).

Dr. Cappellini noted that thromboembolic events occurred in eight luspatercept-treated patients and one placebo-treated patient. In all cases, the patients had multiple risk factors for thrombosis.

This study was sponsored by Celgene Corporation and Acceleron Pharma. Dr. Cappellini reported relationships with Novartis, Celgene, Sanofi-Genzyme, and Vifor.

Photo from UAB Hospital

SAN DIEGO—Luspatercept can produce “clinically meaningful” results in transfusion-dependent adults with β-thalassemia, according to a speaker at the 2018 ASH Annual Meeting.

In the phase 3 BELIEVE trial, β-thalassemia patients were significantly more likely to experience a reduction in transfusion burden if they were treated with luspatercept rather than placebo.

“Luspatercept showed a statistically significant and clinically meaningful . . . reduction in transfusion burden compared with placebo at any 12- or 24-week [period] along this study,” said Maria Domenica Cappellini, MD, of the University of Milan in Italy.

“At this point, we believe [luspatercept] is a potential new treatment for adult patients with β-thalassemia who are requiring regular blood transfusions.”

Dr. Cappellini presented these results at ASH as abstract 163.

The BELIEVE trial (NCT02604433) enrolled 336 patients from 65 sites in 15 countries. All patients had β-thalassemia or hemoglobin E/β‑thalassemia. They required regular transfusions of six to 20 red blood cell (RBC) units in the 24 weeks prior to randomization, and none had a transfusion-free period lasting 35 days or more.

The patients were randomized 2:1 to receive luspatercept—at a starting dose of 1.0 mg/kg with titration up to 1.25 mg/kg—(n=224) or placebo (n=112) subcutaneously every 3 weeks for at least 48 weeks.

All patients continued to receive RBC transfusions and iron chelation therapy as necessary (so they maintained the same baseline hemoglobin level).

The median age was 30 in both treatment arms (range, 18-66). More than half of patients were female—58.9% in the luspatercept arm and 56.3% in the placebo arm.

A similar percentage of patients in both arms had the β0, β0 genotype—30.4% in the luspatercept arm and 31.3% in the placebo arm.

The median hemoglobin level at baseline was 9.31 g/dL in the luspatercept arm and 9.15 g/dL in the placebo arm. The median RBC transfusion burden was 6.12 units/12 weeks and 6.27 units/12 weeks, respectively.

Other baseline characteristics were similar as well.

Efficacy

“[L]uspatercept showed a statistically significant improvement in the primary endpoint,” Dr. Cappellini noted.

The primary endpoint was at least a 33% reduction in transfusion burden—of at least two RBC units—from week 13 to week 24, as compared to the 12-week baseline period.

This endpoint was achieved by 21.4% (n=48) of patients in the luspatercept arm and 4.5% (n=5) in the placebo arm (odds ratio=5.79; P<0.0001).

“Statistical significance was also demonstrated with luspatercept versus placebo for all the key secondary endpoints,” Dr. Cappellini said.

There were more patients in the luspatercept arm than the placebo arm who achieved at least a 33% reduction in transfusion burden from week 37 to 48—19.6% and 3.6%, respectively (P<0.0001).

Similarly, there were more patients in the luspatercept arm than the placebo arm who achieved at least a 50% reduction in transfusion burden from week 13 to 24—7.6% and 1.8%, respectively (P=0.0303)—and from week 37 to 48—10.3% and 0.9%, respectively (P=0.0017).

During any 12-week interval, 70.5% of luspatercept-treated patients and 29.5% of placebo-treated patients achieved at least a 33% reduction in transfusion burden (P<0.0001), and 40.2% and 6.3%, respectively (P<0.0001), achieved at least a 50% reduction in transfusion burden.

During any 24-week interval, 41.1% of luspatercept-treated patients and 2.7% of placebo-treated patients achieved at least a 33% reduction in transfusion burden (P<0.0001), and 16.5% and 0.9%, respectively (P<0.0001), achieved at least a 50% reduction in transfusion burden.

Safety

Ninety-six percent of patients in the luspatercept arm and 92.7% in the placebo arm had at least one treatment-emergent adverse event (TEAE).

Grade 3 or higher TEAEs occurred in 29.1% of patients in the luspatercept arm and 15.6% of those in the placebo arm. Serious TEAEs occurred in 15.2% and 5.5%, respectively.

One patient in the placebo arm had a TEAE-related death (acute cholecystitis), but there were no treatment-related deaths in the luspatercept arm.

TEAEs leading to treatment discontinuation occurred in 5.4% of luspatercept-treated patients and 0.9% of placebo-treated patients.

TEAEs that occurred more frequently in the luspatercept arm than in the placebo arm (respectively) included bone pain (19.7% and 8.3%), arthralgia (19.3% and 11.9%), and dizziness (11.2% and 4.6%).

Grade 3/4 TEAEs (in the luspatercept and placebo arms, respectively) included anemia (3.1% and 0%), increased liver iron concentration (2.7% and 0.9%), hyperuricemia (2.7% and 0%), hypertension (1.8% and 0%), syncope (1.8% and 0%), back pain (1.3% and 0.9%), bone pain (1.3% and 0%), blood uric acid increase (1.3% and 0%), increased aspartate aminotransferase (1.3% and 0%), increased alanine aminotransferase (0.9% and 2.8%), and thromboembolic events (0.9% and 0%).

Dr. Cappellini noted that thromboembolic events occurred in eight luspatercept-treated patients and one placebo-treated patient. In all cases, the patients had multiple risk factors for thrombosis.

This study was sponsored by Celgene Corporation and Acceleron Pharma. Dr. Cappellini reported relationships with Novartis, Celgene, Sanofi-Genzyme, and Vifor.

Photo from UAB Hospital

SAN DIEGO—Luspatercept can produce “clinically meaningful” results in transfusion-dependent adults with β-thalassemia, according to a speaker at the 2018 ASH Annual Meeting.

In the phase 3 BELIEVE trial, β-thalassemia patients were significantly more likely to experience a reduction in transfusion burden if they were treated with luspatercept rather than placebo.

“Luspatercept showed a statistically significant and clinically meaningful . . . reduction in transfusion burden compared with placebo at any 12- or 24-week [period] along this study,” said Maria Domenica Cappellini, MD, of the University of Milan in Italy.

“At this point, we believe [luspatercept] is a potential new treatment for adult patients with β-thalassemia who are requiring regular blood transfusions.”

Dr. Cappellini presented these results at ASH as abstract 163.

The BELIEVE trial (NCT02604433) enrolled 336 patients from 65 sites in 15 countries. All patients had β-thalassemia or hemoglobin E/β‑thalassemia. They required regular transfusions of six to 20 red blood cell (RBC) units in the 24 weeks prior to randomization, and none had a transfusion-free period lasting 35 days or more.

The patients were randomized 2:1 to receive luspatercept—at a starting dose of 1.0 mg/kg with titration up to 1.25 mg/kg—(n=224) or placebo (n=112) subcutaneously every 3 weeks for at least 48 weeks.

All patients continued to receive RBC transfusions and iron chelation therapy as necessary (so they maintained the same baseline hemoglobin level).

The median age was 30 in both treatment arms (range, 18-66). More than half of patients were female—58.9% in the luspatercept arm and 56.3% in the placebo arm.

A similar percentage of patients in both arms had the β0, β0 genotype—30.4% in the luspatercept arm and 31.3% in the placebo arm.

The median hemoglobin level at baseline was 9.31 g/dL in the luspatercept arm and 9.15 g/dL in the placebo arm. The median RBC transfusion burden was 6.12 units/12 weeks and 6.27 units/12 weeks, respectively.

Other baseline characteristics were similar as well.

Efficacy

“[L]uspatercept showed a statistically significant improvement in the primary endpoint,” Dr. Cappellini noted.

The primary endpoint was at least a 33% reduction in transfusion burden—of at least two RBC units—from week 13 to week 24, as compared to the 12-week baseline period.

This endpoint was achieved by 21.4% (n=48) of patients in the luspatercept arm and 4.5% (n=5) in the placebo arm (odds ratio=5.79; P<0.0001).

“Statistical significance was also demonstrated with luspatercept versus placebo for all the key secondary endpoints,” Dr. Cappellini said.

There were more patients in the luspatercept arm than the placebo arm who achieved at least a 33% reduction in transfusion burden from week 37 to 48—19.6% and 3.6%, respectively (P<0.0001).

Similarly, there were more patients in the luspatercept arm than the placebo arm who achieved at least a 50% reduction in transfusion burden from week 13 to 24—7.6% and 1.8%, respectively (P=0.0303)—and from week 37 to 48—10.3% and 0.9%, respectively (P=0.0017).

During any 12-week interval, 70.5% of luspatercept-treated patients and 29.5% of placebo-treated patients achieved at least a 33% reduction in transfusion burden (P<0.0001), and 40.2% and 6.3%, respectively (P<0.0001), achieved at least a 50% reduction in transfusion burden.

During any 24-week interval, 41.1% of luspatercept-treated patients and 2.7% of placebo-treated patients achieved at least a 33% reduction in transfusion burden (P<0.0001), and 16.5% and 0.9%, respectively (P<0.0001), achieved at least a 50% reduction in transfusion burden.

Safety

Ninety-six percent of patients in the luspatercept arm and 92.7% in the placebo arm had at least one treatment-emergent adverse event (TEAE).

Grade 3 or higher TEAEs occurred in 29.1% of patients in the luspatercept arm and 15.6% of those in the placebo arm. Serious TEAEs occurred in 15.2% and 5.5%, respectively.

One patient in the placebo arm had a TEAE-related death (acute cholecystitis), but there were no treatment-related deaths in the luspatercept arm.

TEAEs leading to treatment discontinuation occurred in 5.4% of luspatercept-treated patients and 0.9% of placebo-treated patients.

TEAEs that occurred more frequently in the luspatercept arm than in the placebo arm (respectively) included bone pain (19.7% and 8.3%), arthralgia (19.3% and 11.9%), and dizziness (11.2% and 4.6%).

Grade 3/4 TEAEs (in the luspatercept and placebo arms, respectively) included anemia (3.1% and 0%), increased liver iron concentration (2.7% and 0.9%), hyperuricemia (2.7% and 0%), hypertension (1.8% and 0%), syncope (1.8% and 0%), back pain (1.3% and 0.9%), bone pain (1.3% and 0%), blood uric acid increase (1.3% and 0%), increased aspartate aminotransferase (1.3% and 0%), increased alanine aminotransferase (0.9% and 2.8%), and thromboembolic events (0.9% and 0%).

Dr. Cappellini noted that thromboembolic events occurred in eight luspatercept-treated patients and one placebo-treated patient. In all cases, the patients had multiple risk factors for thrombosis.

This study was sponsored by Celgene Corporation and Acceleron Pharma. Dr. Cappellini reported relationships with Novartis, Celgene, Sanofi-Genzyme, and Vifor.

Photo by Jen Smith

SAN DIEGO—The combination of melflufen and dexamethasone demonstrated activity in patients with multi-resistant multiple myeloma (MM) in a phase 2 trial.

Melflufen-dexamethasone produced an overall response rate of 33% in patients who had quad- or penta-refractory MM.

The combination was considered well tolerated, although 13% of patients discontinued treatment due to adverse events (AEs).

Paul Richardson, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, presented these results, from the HORIZON trial (NCT02963493), at the 2018 ASH Annual Meeting (abstract 600*).

Dr. Richardson reported results with melflufen-dexamethasone in 83 MM patients. They had a median age of 63 (range, 35-86), and 59% were male. Their median time since diagnosis was 6.5 years (range, 0.7-25) at baseline.

The patients had received a median of 5 prior lines of therapy (range, 2-13). All patients were refractory to pomalidomide or daratumumab, and 60% were refractory to both drugs. Eighty percent of patients were refractory to a monoclonal antibody, and 55% were refractory to an alkylator.

Eighty-six percent of patients were refractory to both a proteasome inhibitor and an immunomodulatory drug. Sixty percent of patients were refractory to a proteasome inhibitor, an immunomodulatory drug, and anti-CD38 therapy.

Ninety-three percent of patients were refractory to their last line of therapy. Sixty-nine percent had received a transplant, and 25% had received two transplants.

“[I]f you look at the refractoriness of these patients, 46% had used three or more prior regimens within the last 12 months before entering the trial, and I think that reflects a real challenge in these patients,” Dr. Richardson said.

Results

The patients received melflufen at 40 mg on day 1 of each 28-day cycle and dexamethasone at 40 mg weekly (20 mg for patients age 75 and older). Patients were treated until progression, consent withdrawal, or unacceptable toxicity.

The overall response rate (partial response or better) was 33%, the clinical benefit rate (minimal response or better) was 39%, and 84% of patients had stable disease or better.

Twenty seven patients responded, including one stringent complete response, nine very good partial responses, and 17 partial responses.

Five patients had a minimal response, 37 had stable disease, and 12 progressed. One patient was not evaluable, and one had data pending.

Dr. Richardson noted that melflufen-dexamethasone demonstrated activity regardless of a patient’s underlying refractory status, but serum albumin was a strong predictor of response. Specifically, patients with higher albumin levels were more likely to respond.

“We do not think it’s a mechanism-of-action issue with [melflufen], but we will be evaluating that,” Dr. Richardson said.

He went on to say that the median progression-free survival was 4.0 months overall, 6.4 months among patients with a partial response or better, and 1 month in patients with progressive disease.

Treatment-related grade 3/4 AEs occurred in 75% of patients. This included neutropenia (61%), thrombocytopenia (59%), anemia (25%), febrile neutropenia (6%), leukopenia (5%), lymphopenia (5%), infections and infestations (7%), and pneumonia (2%).

There were no treatment-related deaths. Thirteen percent of patients discontinued treatment due to AEs, most due to thrombocytopenia (8/11).

In closing, Dr. Richardson said toxicity was “generally manageable” with this treatment, which “has promising activity in multi-resistant, relapsed/refractory myeloma.”

He added that, in the phase 3 OCEAN trial (NCT03151811), researchers are comparing melflufen-dexamethasone to pomalidomide-dexamethasone in a less heavily pretreated MM population.

In the phase 1/2 ANCHOR trial (NCT03481556), researchers are testing melflufen-dexamethasone in combination with daratumumab or bortezomib.

Dr. Richardson disclosed relationships with Karyopharm Pharmaceuticals, Bristol-Myers Squibb, Janssen, Amgen, Jazz Pharmaceuticals, Takeda, Celgene, and Oncopeptides AB. The HORIZON trial is supported by Oncopeptides AB in collaboration with Precision Oncology.

*Data in the abstract differ from the presentation.

Photo by Jen Smith

SAN DIEGO—The combination of melflufen and dexamethasone demonstrated activity in patients with multi-resistant multiple myeloma (MM) in a phase 2 trial.

Melflufen-dexamethasone produced an overall response rate of 33% in patients who had quad- or penta-refractory MM.

The combination was considered well tolerated, although 13% of patients discontinued treatment due to adverse events (AEs).

Paul Richardson, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, presented these results, from the HORIZON trial (NCT02963493), at the 2018 ASH Annual Meeting (abstract 600*).

Dr. Richardson reported results with melflufen-dexamethasone in 83 MM patients. They had a median age of 63 (range, 35-86), and 59% were male. Their median time since diagnosis was 6.5 years (range, 0.7-25) at baseline.

The patients had received a median of 5 prior lines of therapy (range, 2-13). All patients were refractory to pomalidomide or daratumumab, and 60% were refractory to both drugs. Eighty percent of patients were refractory to a monoclonal antibody, and 55% were refractory to an alkylator.

Eighty-six percent of patients were refractory to both a proteasome inhibitor and an immunomodulatory drug. Sixty percent of patients were refractory to a proteasome inhibitor, an immunomodulatory drug, and anti-CD38 therapy.

Ninety-three percent of patients were refractory to their last line of therapy. Sixty-nine percent had received a transplant, and 25% had received two transplants.

“[I]f you look at the refractoriness of these patients, 46% had used three or more prior regimens within the last 12 months before entering the trial, and I think that reflects a real challenge in these patients,” Dr. Richardson said.

Results

The patients received melflufen at 40 mg on day 1 of each 28-day cycle and dexamethasone at 40 mg weekly (20 mg for patients age 75 and older). Patients were treated until progression, consent withdrawal, or unacceptable toxicity.

The overall response rate (partial response or better) was 33%, the clinical benefit rate (minimal response or better) was 39%, and 84% of patients had stable disease or better.

Twenty seven patients responded, including one stringent complete response, nine very good partial responses, and 17 partial responses.

Five patients had a minimal response, 37 had stable disease, and 12 progressed. One patient was not evaluable, and one had data pending.

Dr. Richardson noted that melflufen-dexamethasone demonstrated activity regardless of a patient’s underlying refractory status, but serum albumin was a strong predictor of response. Specifically, patients with higher albumin levels were more likely to respond.

“We do not think it’s a mechanism-of-action issue with [melflufen], but we will be evaluating that,” Dr. Richardson said.

He went on to say that the median progression-free survival was 4.0 months overall, 6.4 months among patients with a partial response or better, and 1 month in patients with progressive disease.

Treatment-related grade 3/4 AEs occurred in 75% of patients. This included neutropenia (61%), thrombocytopenia (59%), anemia (25%), febrile neutropenia (6%), leukopenia (5%), lymphopenia (5%), infections and infestations (7%), and pneumonia (2%).

There were no treatment-related deaths. Thirteen percent of patients discontinued treatment due to AEs, most due to thrombocytopenia (8/11).

In closing, Dr. Richardson said toxicity was “generally manageable” with this treatment, which “has promising activity in multi-resistant, relapsed/refractory myeloma.”

He added that, in the phase 3 OCEAN trial (NCT03151811), researchers are comparing melflufen-dexamethasone to pomalidomide-dexamethasone in a less heavily pretreated MM population.

In the phase 1/2 ANCHOR trial (NCT03481556), researchers are testing melflufen-dexamethasone in combination with daratumumab or bortezomib.

Dr. Richardson disclosed relationships with Karyopharm Pharmaceuticals, Bristol-Myers Squibb, Janssen, Amgen, Jazz Pharmaceuticals, Takeda, Celgene, and Oncopeptides AB. The HORIZON trial is supported by Oncopeptides AB in collaboration with Precision Oncology.

*Data in the abstract differ from the presentation.

Photo by Jen Smith

SAN DIEGO—The combination of melflufen and dexamethasone demonstrated activity in patients with multi-resistant multiple myeloma (MM) in a phase 2 trial.

Melflufen-dexamethasone produced an overall response rate of 33% in patients who had quad- or penta-refractory MM.

The combination was considered well tolerated, although 13% of patients discontinued treatment due to adverse events (AEs).

Paul Richardson, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, presented these results, from the HORIZON trial (NCT02963493), at the 2018 ASH Annual Meeting (abstract 600*).

Dr. Richardson reported results with melflufen-dexamethasone in 83 MM patients. They had a median age of 63 (range, 35-86), and 59% were male. Their median time since diagnosis was 6.5 years (range, 0.7-25) at baseline.

The patients had received a median of 5 prior lines of therapy (range, 2-13). All patients were refractory to pomalidomide or daratumumab, and 60% were refractory to both drugs. Eighty percent of patients were refractory to a monoclonal antibody, and 55% were refractory to an alkylator.

Eighty-six percent of patients were refractory to both a proteasome inhibitor and an immunomodulatory drug. Sixty percent of patients were refractory to a proteasome inhibitor, an immunomodulatory drug, and anti-CD38 therapy.

Ninety-three percent of patients were refractory to their last line of therapy. Sixty-nine percent had received a transplant, and 25% had received two transplants.

“[I]f you look at the refractoriness of these patients, 46% had used three or more prior regimens within the last 12 months before entering the trial, and I think that reflects a real challenge in these patients,” Dr. Richardson said.

Results

The patients received melflufen at 40 mg on day 1 of each 28-day cycle and dexamethasone at 40 mg weekly (20 mg for patients age 75 and older). Patients were treated until progression, consent withdrawal, or unacceptable toxicity.

The overall response rate (partial response or better) was 33%, the clinical benefit rate (minimal response or better) was 39%, and 84% of patients had stable disease or better.

Twenty seven patients responded, including one stringent complete response, nine very good partial responses, and 17 partial responses.

Five patients had a minimal response, 37 had stable disease, and 12 progressed. One patient was not evaluable, and one had data pending.

Dr. Richardson noted that melflufen-dexamethasone demonstrated activity regardless of a patient’s underlying refractory status, but serum albumin was a strong predictor of response. Specifically, patients with higher albumin levels were more likely to respond.

“We do not think it’s a mechanism-of-action issue with [melflufen], but we will be evaluating that,” Dr. Richardson said.

He went on to say that the median progression-free survival was 4.0 months overall, 6.4 months among patients with a partial response or better, and 1 month in patients with progressive disease.

Treatment-related grade 3/4 AEs occurred in 75% of patients. This included neutropenia (61%), thrombocytopenia (59%), anemia (25%), febrile neutropenia (6%), leukopenia (5%), lymphopenia (5%), infections and infestations (7%), and pneumonia (2%).

There were no treatment-related deaths. Thirteen percent of patients discontinued treatment due to AEs, most due to thrombocytopenia (8/11).

In closing, Dr. Richardson said toxicity was “generally manageable” with this treatment, which “has promising activity in multi-resistant, relapsed/refractory myeloma.”

He added that, in the phase 3 OCEAN trial (NCT03151811), researchers are comparing melflufen-dexamethasone to pomalidomide-dexamethasone in a less heavily pretreated MM population.

In the phase 1/2 ANCHOR trial (NCT03481556), researchers are testing melflufen-dexamethasone in combination with daratumumab or bortezomib.

Dr. Richardson disclosed relationships with Karyopharm Pharmaceuticals, Bristol-Myers Squibb, Janssen, Amgen, Jazz Pharmaceuticals, Takeda, Celgene, and Oncopeptides AB. The HORIZON trial is supported by Oncopeptides AB in collaboration with Precision Oncology.

*Data in the abstract differ from the presentation.

© ASH/Rodney White 2018

SAN DIEGO—A phase 1 study suggests lymphodepletion can improve the efficacy of CD30-directed chimeric antigen receptor (CAR) T-cell therapy in patients with Hodgkin lymphoma (HL).

Researchers observed improved responses in HL patients treated with fludarabine and cyclophosphamide prior to CD30.CAR T-cell therapy.

This lymphodepleting regimen was also associated with increased toxicity, compared to no lymphodepletion. However, researchers consider the regimen safe.

Carlos A. Ramos, MD, of Baylor College of Medicine in Houston, Texas, presented these results at the 2018 ASH Annual Meeting (abstract 680*).

Without lymphodepletion

Dr. Ramos first discussed a previous phase 1 trial (NCT01316146), which was published in The Journal of Clinical Investigation in 2017.

In this trial, he and his colleagues had tested CD30.CAR T-cell therapy in patients with relapsed/refractory, CD30+ HL or T-cell non-Hodgkin lymphoma. None of these patients underwent lymphodepletion.

There were no dose-limiting toxicities in this trial—including no neurotoxicity or cytokine release syndrome—but responses were “limited,” according to Dr. Ramos.

Three patients achieved a complete response (CR), three had stable disease, and three progressed.

“Although we saw no significant toxicities and some good clinical responses . . ., the bottom line is that the responses were still quite limited, with several patients having, at most, stable disease or progressive disease,” Dr. Ramos said.

With lymphodepletion

Results from the previous trial prompted Dr. Ramos and his colleagues to conduct the RELY-30 trial (NCT02917083) and investigate whether lymphodepletion would improve responses to CD30.CAR T-cell therapy.

Thus far, 11 patients have been treated on this trial. All had relapsed, CD30+ HL at baseline. Six patients are male, and their median age at baseline was 30 (range, 17-69).

The patients had a median of 5 prior treatments (range, 2-9). This included PD-1 inhibitors (n=10), brentuximab vedotin (n=8), and transplant (n=6).

All patients received lymphodepletion with cyclophosphamide at 500 mg/m² and fludarabine at 30 mg/m² daily for 3 days. They then received CD30.CAR T-cell therapy at 2×10⁷ cells/m² or 1×10⁸ cells/m².

Dr. Ramos noted that CD30.CAR T-cell expansion was dose-dependent and increased by lymphodepleting chemotherapy.

“The peak expansion is much higher [with lymphodepletion], probably in the order of two to three logs higher than what we see without lymphodepleting chemotherapy,” he said. “So chemotherapy makes a difference.”

Increased CD30.CAR T-cell expansion was associated with improved response. Of the nine evaluable patients, six achieved a CR, and three progressed.

Four complete responders were still in CR at last follow-up, one of them for more than a year. However, two complete responders ultimately progressed.

In addition to improved responses, the researchers observed increased toxicity in this trial. Dr. Ramos said some of these toxicities are “probably attributable” to the lymphodepleting chemotherapy.

Toxicities included grade 1 cytokine release syndrome (no tocilizumab required), maculopapular rash, transient cytopenias, nausea, vomiting, and alopecia.

Dr. Ramos said these results suggest adoptive transfer of CD30.CAR T cells is “safe, even with chemotherapy.”

He noted that the duration of response with this treatment is unknown, but trial enrollment and follow-up are ongoing.

RELY-30 was sponsored by Baylor College of Medicine. Dr. Ramos reported relationships with Novartis, Celgene, Bluebird Bio, and Tessa Therapeutics.

*Data in the abstract differ from the presentation.

© ASH/Rodney White 2018

SAN DIEGO—A phase 1 study suggests lymphodepletion can improve the efficacy of CD30-directed chimeric antigen receptor (CAR) T-cell therapy in patients with Hodgkin lymphoma (HL).

Researchers observed improved responses in HL patients treated with fludarabine and cyclophosphamide prior to CD30.CAR T-cell therapy.

This lymphodepleting regimen was also associated with increased toxicity, compared to no lymphodepletion. However, researchers consider the regimen safe.

Carlos A. Ramos, MD, of Baylor College of Medicine in Houston, Texas, presented these results at the 2018 ASH Annual Meeting (abstract 680*).

Without lymphodepletion

Dr. Ramos first discussed a previous phase 1 trial (NCT01316146), which was published in The Journal of Clinical Investigation in 2017.

In this trial, he and his colleagues had tested CD30.CAR T-cell therapy in patients with relapsed/refractory, CD30+ HL or T-cell non-Hodgkin lymphoma. None of these patients underwent lymphodepletion.

There were no dose-limiting toxicities in this trial—including no neurotoxicity or cytokine release syndrome—but responses were “limited,” according to Dr. Ramos.

Three patients achieved a complete response (CR), three had stable disease, and three progressed.

“Although we saw no significant toxicities and some good clinical responses . . ., the bottom line is that the responses were still quite limited, with several patients having, at most, stable disease or progressive disease,” Dr. Ramos said.

With lymphodepletion

Results from the previous trial prompted Dr. Ramos and his colleagues to conduct the RELY-30 trial (NCT02917083) and investigate whether lymphodepletion would improve responses to CD30.CAR T-cell therapy.

Thus far, 11 patients have been treated on this trial. All had relapsed, CD30+ HL at baseline. Six patients are male, and their median age at baseline was 30 (range, 17-69).

The patients had a median of 5 prior treatments (range, 2-9). This included PD-1 inhibitors (n=10), brentuximab vedotin (n=8), and transplant (n=6).

All patients received lymphodepletion with cyclophosphamide at 500 mg/m² and fludarabine at 30 mg/m² daily for 3 days. They then received CD30.CAR T-cell therapy at 2×10⁷ cells/m² or 1×10⁸ cells/m².

Dr. Ramos noted that CD30.CAR T-cell expansion was dose-dependent and increased by lymphodepleting chemotherapy.

“The peak expansion is much higher [with lymphodepletion], probably in the order of two to three logs higher than what we see without lymphodepleting chemotherapy,” he said. “So chemotherapy makes a difference.”

Increased CD30.CAR T-cell expansion was associated with improved response. Of the nine evaluable patients, six achieved a CR, and three progressed.

Four complete responders were still in CR at last follow-up, one of them for more than a year. However, two complete responders ultimately progressed.

In addition to improved responses, the researchers observed increased toxicity in this trial. Dr. Ramos said some of these toxicities are “probably attributable” to the lymphodepleting chemotherapy.

Toxicities included grade 1 cytokine release syndrome (no tocilizumab required), maculopapular rash, transient cytopenias, nausea, vomiting, and alopecia.

Dr. Ramos said these results suggest adoptive transfer of CD30.CAR T cells is “safe, even with chemotherapy.”

He noted that the duration of response with this treatment is unknown, but trial enrollment and follow-up are ongoing.

RELY-30 was sponsored by Baylor College of Medicine. Dr. Ramos reported relationships with Novartis, Celgene, Bluebird Bio, and Tessa Therapeutics.

*Data in the abstract differ from the presentation.

© ASH/Rodney White 2018

SAN DIEGO—A phase 1 study suggests lymphodepletion can improve the efficacy of CD30-directed chimeric antigen receptor (CAR) T-cell therapy in patients with Hodgkin lymphoma (HL).

Researchers observed improved responses in HL patients treated with fludarabine and cyclophosphamide prior to CD30.CAR T-cell therapy.

This lymphodepleting regimen was also associated with increased toxicity, compared to no lymphodepletion. However, researchers consider the regimen safe.

Carlos A. Ramos, MD, of Baylor College of Medicine in Houston, Texas, presented these results at the 2018 ASH Annual Meeting (abstract 680*).

Without lymphodepletion

Dr. Ramos first discussed a previous phase 1 trial (NCT01316146), which was published in The Journal of Clinical Investigation in 2017.

In this trial, he and his colleagues had tested CD30.CAR T-cell therapy in patients with relapsed/refractory, CD30+ HL or T-cell non-Hodgkin lymphoma. None of these patients underwent lymphodepletion.

There were no dose-limiting toxicities in this trial—including no neurotoxicity or cytokine release syndrome—but responses were “limited,” according to Dr. Ramos.

Three patients achieved a complete response (CR), three had stable disease, and three progressed.

“Although we saw no significant toxicities and some good clinical responses . . ., the bottom line is that the responses were still quite limited, with several patients having, at most, stable disease or progressive disease,” Dr. Ramos said.

With lymphodepletion

Results from the previous trial prompted Dr. Ramos and his colleagues to conduct the RELY-30 trial (NCT02917083) and investigate whether lymphodepletion would improve responses to CD30.CAR T-cell therapy.

Thus far, 11 patients have been treated on this trial. All had relapsed, CD30+ HL at baseline. Six patients are male, and their median age at baseline was 30 (range, 17-69).

The patients had a median of 5 prior treatments (range, 2-9). This included PD-1 inhibitors (n=10), brentuximab vedotin (n=8), and transplant (n=6).

All patients received lymphodepletion with cyclophosphamide at 500 mg/m² and fludarabine at 30 mg/m² daily for 3 days. They then received CD30.CAR T-cell therapy at 2×10⁷ cells/m² or 1×10⁸ cells/m².

Dr. Ramos noted that CD30.CAR T-cell expansion was dose-dependent and increased by lymphodepleting chemotherapy.

“The peak expansion is much higher [with lymphodepletion], probably in the order of two to three logs higher than what we see without lymphodepleting chemotherapy,” he said. “So chemotherapy makes a difference.”

Increased CD30.CAR T-cell expansion was associated with improved response. Of the nine evaluable patients, six achieved a CR, and three progressed.

Four complete responders were still in CR at last follow-up, one of them for more than a year. However, two complete responders ultimately progressed.

In addition to improved responses, the researchers observed increased toxicity in this trial. Dr. Ramos said some of these toxicities are “probably attributable” to the lymphodepleting chemotherapy.

Toxicities included grade 1 cytokine release syndrome (no tocilizumab required), maculopapular rash, transient cytopenias, nausea, vomiting, and alopecia.

Dr. Ramos said these results suggest adoptive transfer of CD30.CAR T cells is “safe, even with chemotherapy.”

He noted that the duration of response with this treatment is unknown, but trial enrollment and follow-up are ongoing.

RELY-30 was sponsored by Baylor College of Medicine. Dr. Ramos reported relationships with Novartis, Celgene, Bluebird Bio, and Tessa Therapeutics.

*Data in the abstract differ from the presentation.

Photo courtesy of ASH

SAN DIEGO—Fludarabine is “very important” for lymphodepletion prior to CD30-directed chimeric antigen receptor (CAR) T-cell therapy, according to a presentation at the 2018 ASH Annual Meeting.

A phase 1/2 study showed that bendamustine alone was not sufficient as lymphodepletion.

However, adding fludarabine to bendamustine could enhance responses to CD30.CAR T-cell therapy and improve progression-free survival (PFS) in patients with Hodgkin or non-Hodgkin lymphoma.

Natalie S. Grover, MD, of the University of North Carolina in Chapel Hill, presented these results as abstract 681.*

This trial (NCT02690545) included patients with relapsed/refractory, CD30+ Hodgkin lymphoma or T-cell non-Hodgkin lymphoma.

Twenty-four adult patients have been treated thus far. Twenty-two had classical Hodgkin lymphoma, one had Sézary syndrome, and one had enteropathy-associated T-cell lymphoma.

The patients’ median age at baseline was 34.5 years (range, 23-69), and they had received a median of 7.5 prior lines of therapy (range, 3-17).

Prior treatments included brentuximab vedotin (n=23), checkpoint inhibitors (n=16), autologous transplant (n=17), and allogeneic transplant (n=7).

In this trial, patients could receive bridging therapy while their T cells were being processed. They then underwent lymphodepletion and received CAR T-cell therapy at one of two doses.

Bendamustine alone

Eight patients received lymphodepletion with 2 days of bendamustine at 90 mg/m². Three of these patients received CD30.CAR T-cell therapy at 1×10⁸ cells/m², and all three progressed.

Of the five patients who received CAR T-cell therapy at a dose of 2×10⁸ cells/m², one progressed, one had stable disease, and three had a complete response (CR).

However, all three complete responders were in CR prior to lymphodepletion as a result of bridging therapy.

“Responses were more modest than what we were hoping for with lymphodepletion,” Dr. Grover noted. “We looked at the cytokine levels in patients getting bendamustine lymphodepletion and saw that bendamustine wasn’t supporting an ideal cytokine milieu. IL-7 and IL-15 are important for T-cell expansion, and these levels were not increased in patients post-bendamustine.”

When the researchers added fludarabine to the lymphodepleting regimen, they observed an increase in T-cell expansion.

Bendamustine plus fludarabine

Sixteen patients received bendamustine plus fludarabine prior to CAR T-cell therapy. The regimen consisted of 3 days of bendamustine at 70 mg/m² and fludarabine at 30 mg/m².

All 16 patients received CAR T cells at 2×10⁸ cells/m², which was the recommended phase 2 dose.

“Responses were more impressive in the bendamustine-fludarabine cohort,” Dr. Grover noted.

Twelve of the 16 patients achieved a CR, although two patients were already in CR prior to lymphodepletion.

Two patients had a partial response, one had stable disease, and one progressed.

PFS and toxicity

Dr. Grover and her colleagues also assessed PFS. At a median follow-up of 100 days, the median PFS was 164 days for the entire cohort, excluding patients who were in CR prior to lymphodepletion.

The median PFS was 396 days for the bendamustine-fludarabine cohort and 55 days for patients in the bendamustine-alone cohort (P=0.001).

There was no neurotoxicity in this trial.

Three patients developed cytokine release syndrome (CRS). Two patients had grade 1 CRS that resolved spontaneously, and one patient had grade 2 CRS, which responded to tocilizumab. Two of the patients with CRS had T-cell lymphoma. The Sézary patient had grade 2 CRS.

Eight patients had a mild rash, one of whom had a rash at baseline.

“CAR T cells against CD30 preceded by lymphodepletion with bendamustine and fludarabine have promising efficacy and a good safety profile in treating patients with relapsed/refractory, CD30+ lymphomas,” Dr. Grover said in closing.

“Fludarabine is very important in enhancing cytokines for improved growth and persistence of CAR T cells.”

This trial was sponsored by UNC Lineberger Comprehensive Cancer Center. Dr. Grover reported consulting for Seattle Genetics.

*Data in the abstract differ from the presentation.

Photo courtesy of ASH

SAN DIEGO—Fludarabine is “very important” for lymphodepletion prior to CD30-directed chimeric antigen receptor (CAR) T-cell therapy, according to a presentation at the 2018 ASH Annual Meeting.

A phase 1/2 study showed that bendamustine alone was not sufficient as lymphodepletion.

However, adding fludarabine to bendamustine could enhance responses to CD30.CAR T-cell therapy and improve progression-free survival (PFS) in patients with Hodgkin or non-Hodgkin lymphoma.

Natalie S. Grover, MD, of the University of North Carolina in Chapel Hill, presented these results as abstract 681.*

This trial (NCT02690545) included patients with relapsed/refractory, CD30+ Hodgkin lymphoma or T-cell non-Hodgkin lymphoma.

Twenty-four adult patients have been treated thus far. Twenty-two had classical Hodgkin lymphoma, one had Sézary syndrome, and one had enteropathy-associated T-cell lymphoma.

The patients’ median age at baseline was 34.5 years (range, 23-69), and they had received a median of 7.5 prior lines of therapy (range, 3-17).

Prior treatments included brentuximab vedotin (n=23), checkpoint inhibitors (n=16), autologous transplant (n=17), and allogeneic transplant (n=7).

In this trial, patients could receive bridging therapy while their T cells were being processed. They then underwent lymphodepletion and received CAR T-cell therapy at one of two doses.

Bendamustine alone

Eight patients received lymphodepletion with 2 days of bendamustine at 90 mg/m². Three of these patients received CD30.CAR T-cell therapy at 1×10⁸ cells/m², and all three progressed.

Of the five patients who received CAR T-cell therapy at a dose of 2×10⁸ cells/m², one progressed, one had stable disease, and three had a complete response (CR).

However, all three complete responders were in CR prior to lymphodepletion as a result of bridging therapy.

“Responses were more modest than what we were hoping for with lymphodepletion,” Dr. Grover noted. “We looked at the cytokine levels in patients getting bendamustine lymphodepletion and saw that bendamustine wasn’t supporting an ideal cytokine milieu. IL-7 and IL-15 are important for T-cell expansion, and these levels were not increased in patients post-bendamustine.”

When the researchers added fludarabine to the lymphodepleting regimen, they observed an increase in T-cell expansion.

Bendamustine plus fludarabine

Sixteen patients received bendamustine plus fludarabine prior to CAR T-cell therapy. The regimen consisted of 3 days of bendamustine at 70 mg/m² and fludarabine at 30 mg/m².

All 16 patients received CAR T cells at 2×10⁸ cells/m², which was the recommended phase 2 dose.

“Responses were more impressive in the bendamustine-fludarabine cohort,” Dr. Grover noted.

Twelve of the 16 patients achieved a CR, although two patients were already in CR prior to lymphodepletion.

Two patients had a partial response, one had stable disease, and one progressed.

PFS and toxicity

Dr. Grover and her colleagues also assessed PFS. At a median follow-up of 100 days, the median PFS was 164 days for the entire cohort, excluding patients who were in CR prior to lymphodepletion.

The median PFS was 396 days for the bendamustine-fludarabine cohort and 55 days for patients in the bendamustine-alone cohort (P=0.001).

There was no neurotoxicity in this trial.

Three patients developed cytokine release syndrome (CRS). Two patients had grade 1 CRS that resolved spontaneously, and one patient had grade 2 CRS, which responded to tocilizumab. Two of the patients with CRS had T-cell lymphoma. The Sézary patient had grade 2 CRS.

Eight patients had a mild rash, one of whom had a rash at baseline.

“CAR T cells against CD30 preceded by lymphodepletion with bendamustine and fludarabine have promising efficacy and a good safety profile in treating patients with relapsed/refractory, CD30+ lymphomas,” Dr. Grover said in closing.

“Fludarabine is very important in enhancing cytokines for improved growth and persistence of CAR T cells.”

This trial was sponsored by UNC Lineberger Comprehensive Cancer Center. Dr. Grover reported consulting for Seattle Genetics.

*Data in the abstract differ from the presentation.

Photo courtesy of ASH

SAN DIEGO—Fludarabine is “very important” for lymphodepletion prior to CD30-directed chimeric antigen receptor (CAR) T-cell therapy, according to a presentation at the 2018 ASH Annual Meeting.

A phase 1/2 study showed that bendamustine alone was not sufficient as lymphodepletion.

However, adding fludarabine to bendamustine could enhance responses to CD30.CAR T-cell therapy and improve progression-free survival (PFS) in patients with Hodgkin or non-Hodgkin lymphoma.

Natalie S. Grover, MD, of the University of North Carolina in Chapel Hill, presented these results as abstract 681.*

This trial (NCT02690545) included patients with relapsed/refractory, CD30+ Hodgkin lymphoma or T-cell non-Hodgkin lymphoma.

Twenty-four adult patients have been treated thus far. Twenty-two had classical Hodgkin lymphoma, one had Sézary syndrome, and one had enteropathy-associated T-cell lymphoma.

The patients’ median age at baseline was 34.5 years (range, 23-69), and they had received a median of 7.5 prior lines of therapy (range, 3-17).

Prior treatments included brentuximab vedotin (n=23), checkpoint inhibitors (n=16), autologous transplant (n=17), and allogeneic transplant (n=7).

In this trial, patients could receive bridging therapy while their T cells were being processed. They then underwent lymphodepletion and received CAR T-cell therapy at one of two doses.

Bendamustine alone

Eight patients received lymphodepletion with 2 days of bendamustine at 90 mg/m². Three of these patients received CD30.CAR T-cell therapy at 1×10⁸ cells/m², and all three progressed.

Of the five patients who received CAR T-cell therapy at a dose of 2×10⁸ cells/m², one progressed, one had stable disease, and three had a complete response (CR).

However, all three complete responders were in CR prior to lymphodepletion as a result of bridging therapy.

“Responses were more modest than what we were hoping for with lymphodepletion,” Dr. Grover noted. “We looked at the cytokine levels in patients getting bendamustine lymphodepletion and saw that bendamustine wasn’t supporting an ideal cytokine milieu. IL-7 and IL-15 are important for T-cell expansion, and these levels were not increased in patients post-bendamustine.”

When the researchers added fludarabine to the lymphodepleting regimen, they observed an increase in T-cell expansion.

Bendamustine plus fludarabine

Sixteen patients received bendamustine plus fludarabine prior to CAR T-cell therapy. The regimen consisted of 3 days of bendamustine at 70 mg/m² and fludarabine at 30 mg/m².

All 16 patients received CAR T cells at 2×10⁸ cells/m², which was the recommended phase 2 dose.

“Responses were more impressive in the bendamustine-fludarabine cohort,” Dr. Grover noted.

Twelve of the 16 patients achieved a CR, although two patients were already in CR prior to lymphodepletion.

Two patients had a partial response, one had stable disease, and one progressed.

PFS and toxicity

Dr. Grover and her colleagues also assessed PFS. At a median follow-up of 100 days, the median PFS was 164 days for the entire cohort, excluding patients who were in CR prior to lymphodepletion.

The median PFS was 396 days for the bendamustine-fludarabine cohort and 55 days for patients in the bendamustine-alone cohort (P=0.001).

There was no neurotoxicity in this trial.

Three patients developed cytokine release syndrome (CRS). Two patients had grade 1 CRS that resolved spontaneously, and one patient had grade 2 CRS, which responded to tocilizumab. Two of the patients with CRS had T-cell lymphoma. The Sézary patient had grade 2 CRS.

Eight patients had a mild rash, one of whom had a rash at baseline.

“CAR T cells against CD30 preceded by lymphodepletion with bendamustine and fludarabine have promising efficacy and a good safety profile in treating patients with relapsed/refractory, CD30+ lymphomas,” Dr. Grover said in closing.

“Fludarabine is very important in enhancing cytokines for improved growth and persistence of CAR T cells.”

This trial was sponsored by UNC Lineberger Comprehensive Cancer Center. Dr. Grover reported consulting for Seattle Genetics.

*Data in the abstract differ from the presentation.

Photo courtesy of ASH

SAN DIEGO—Patients who develop metabolic syndrome (MetS) after hematopoietic stem cell transplant (HSCT) have an increased risk of cardiovascular (CV) events and second malignancies, according to research presented at the 2018 ASH Annual Meeting.

Researchers found that HSCT recipients had a higher prevalence of MetS than the general population, and the incidence of MetS increased with age.

In addition, MetS was a predictor of CV events, and these events were associated with second malignancy.

“Our data support metabolic syndrome being an age-related late effect of transplant that is strongly associated with not only cardiovascular events but also the occurrence of second cancers, and this is a novel finding,” said Diana M. Greenfield, RN, PhD, of Sheffield Teaching Hospitals NHS Foundation Trust in Sheffield, United Kingdom.

Dr. Greenfield presented the data at ASH as abstract 251.

She noted that previous studies have reported rates of MetS after HSCT ranging from 31% to 49%. Intensive chemotherapy and radiation have been associated with MetS, and proposed mechanisms of MetS after HSCT include:

• Conditioning regimen-mediated damage to the neuro-hormonal system and vascular endothelium
• Immunological and inflammatory effects of allo-grafting, including graft-vs-host disease (GVHD) and treatment.

“Those with metabolic syndrome in the general population are already known to be twice as likely to develop cardiovascular disease as those without metabolic syndrome,” Dr. Greenfield noted. “The risk of cardiovascular hospitalizations and mortality is 3.6-fold higher in transplant patients vs the general population.”

With all this in mind, she and her colleagues set out to determine the prevalence of MetS and associated complications among HSCT recipients treated at 9 European centers in Belgium, France, Germany, Turkey, and the United Kingdom.

The researchers analyzed 462 patients—375 who had received an allogeneic HSCT and 87 who had undergone autologous HSCT. All patients were at least 18 years of age and at least 2 years post-HSCT.

The median age at transplant was 43 (interquartile range, 32-53), and 57.4% of patients were male.

Patients’ diagnoses included acute leukemia (37.9%), lymphoma (27.3%), myelodysplastic syndromes/myeloproliferative neoplasms (13%), chronic leukemia (12.3%), plasma cell disorders (5%), bone marrow failure (4.1%), solid tumors (0.2%), and inherited disorders (0.2%).

Results

The prevalence of MetS in this population was 30.4%. This is higher than the prevalence in the general population in Europe, which is 25%, according to the World Health Organization.

There was no significant difference in MetS prevalence between allogeneic and autologous HSCT recipients—29% and 35.6%, respectively.

However, there was a significant difference in MetS prevalence by age (P<0.001 with increasing age).

Among allogeneic HSCT recipients, there was no relationship between MetS prevalence and the presence or degree of acute or chronic GVHD, current use of immunosuppressive therapy, or conditioning intensity.

There was a significantly higher prevalence of CV events in patients with MetS than in patients without the syndrome—22.6% and 10.7%, respectively (P=0.006).

And logistic regression analysis confirmed that MetS is a predictor of CV events (odds ratio [OR]=4.72; 95% confidence interval [CI], 2.11-10.57).

The researchers also found that increasing age influenced the prevalence of MetS (OR=7.3; 95% CI, 3.2-16.8) and CV events (OR=3; 95% CI, 0.8-11.32) for patients older than 50, compared to patients in the 18-29 age group.

And CV events were associated with second malignancy (OR=7.93; 95% CI, 2.91-21.61).

“Early intervention of reversible features of metabolic syndrome with lifestyle and medical management may reduce the risk of cardiovascular events,” Dr. Greenfield said. “Meanwhile, screening and management should be robustly integrated within routine transplant long-term follow-up care.”

She added that the CIBMTR and EBMT guidelines on MetS and CV disease after HSCT should help in that regard.

Dr. Greenfield reported no conflicts of interest. However, her fellow researchers reported relationships with a range of pharmaceutical companies.

Photo courtesy of ASH

SAN DIEGO—Patients who develop metabolic syndrome (MetS) after hematopoietic stem cell transplant (HSCT) have an increased risk of cardiovascular (CV) events and second malignancies, according to research presented at the 2018 ASH Annual Meeting.

Researchers found that HSCT recipients had a higher prevalence of MetS than the general population, and the incidence of MetS increased with age.

In addition, MetS was a predictor of CV events, and these events were associated with second malignancy.

“Our data support metabolic syndrome being an age-related late effect of transplant that is strongly associated with not only cardiovascular events but also the occurrence of second cancers, and this is a novel finding,” said Diana M. Greenfield, RN, PhD, of Sheffield Teaching Hospitals NHS Foundation Trust in Sheffield, United Kingdom.

Dr. Greenfield presented the data at ASH as abstract 251.

She noted that previous studies have reported rates of MetS after HSCT ranging from 31% to 49%. Intensive chemotherapy and radiation have been associated with MetS, and proposed mechanisms of MetS after HSCT include:

• Conditioning regimen-mediated damage to the neuro-hormonal system and vascular endothelium
• Immunological and inflammatory effects of allo-grafting, including graft-vs-host disease (GVHD) and treatment.

“Those with metabolic syndrome in the general population are already known to be twice as likely to develop cardiovascular disease as those without metabolic syndrome,” Dr. Greenfield noted. “The risk of cardiovascular hospitalizations and mortality is 3.6-fold higher in transplant patients vs the general population.”

With all this in mind, she and her colleagues set out to determine the prevalence of MetS and associated complications among HSCT recipients treated at 9 European centers in Belgium, France, Germany, Turkey, and the United Kingdom.

The researchers analyzed 462 patients—375 who had received an allogeneic HSCT and 87 who had undergone autologous HSCT. All patients were at least 18 years of age and at least 2 years post-HSCT.

The median age at transplant was 43 (interquartile range, 32-53), and 57.4% of patients were male.

Patients’ diagnoses included acute leukemia (37.9%), lymphoma (27.3%), myelodysplastic syndromes/myeloproliferative neoplasms (13%), chronic leukemia (12.3%), plasma cell disorders (5%), bone marrow failure (4.1%), solid tumors (0.2%), and inherited disorders (0.2%).

Results

The prevalence of MetS in this population was 30.4%. This is higher than the prevalence in the general population in Europe, which is 25%, according to the World Health Organization.

There was no significant difference in MetS prevalence between allogeneic and autologous HSCT recipients—29% and 35.6%, respectively.

However, there was a significant difference in MetS prevalence by age (P<0.001 with increasing age).

Among allogeneic HSCT recipients, there was no relationship between MetS prevalence and the presence or degree of acute or chronic GVHD, current use of immunosuppressive therapy, or conditioning intensity.

There was a significantly higher prevalence of CV events in patients with MetS than in patients without the syndrome—22.6% and 10.7%, respectively (P=0.006).

And logistic regression analysis confirmed that MetS is a predictor of CV events (odds ratio [OR]=4.72; 95% confidence interval [CI], 2.11-10.57).

The researchers also found that increasing age influenced the prevalence of MetS (OR=7.3; 95% CI, 3.2-16.8) and CV events (OR=3; 95% CI, 0.8-11.32) for patients older than 50, compared to patients in the 18-29 age group.

And CV events were associated with second malignancy (OR=7.93; 95% CI, 2.91-21.61).

“Early intervention of reversible features of metabolic syndrome with lifestyle and medical management may reduce the risk of cardiovascular events,” Dr. Greenfield said. “Meanwhile, screening and management should be robustly integrated within routine transplant long-term follow-up care.”

She added that the CIBMTR and EBMT guidelines on MetS and CV disease after HSCT should help in that regard.

Dr. Greenfield reported no conflicts of interest. However, her fellow researchers reported relationships with a range of pharmaceutical companies.

Photo courtesy of ASH

SAN DIEGO—Patients who develop metabolic syndrome (MetS) after hematopoietic stem cell transplant (HSCT) have an increased risk of cardiovascular (CV) events and second malignancies, according to research presented at the 2018 ASH Annual Meeting.

Researchers found that HSCT recipients had a higher prevalence of MetS than the general population, and the incidence of MetS increased with age.

In addition, MetS was a predictor of CV events, and these events were associated with second malignancy.

“Our data support metabolic syndrome being an age-related late effect of transplant that is strongly associated with not only cardiovascular events but also the occurrence of second cancers, and this is a novel finding,” said Diana M. Greenfield, RN, PhD, of Sheffield Teaching Hospitals NHS Foundation Trust in Sheffield, United Kingdom.

Dr. Greenfield presented the data at ASH as abstract 251.

She noted that previous studies have reported rates of MetS after HSCT ranging from 31% to 49%. Intensive chemotherapy and radiation have been associated with MetS, and proposed mechanisms of MetS after HSCT include:

• Conditioning regimen-mediated damage to the neuro-hormonal system and vascular endothelium
• Immunological and inflammatory effects of allo-grafting, including graft-vs-host disease (GVHD) and treatment.

“Those with metabolic syndrome in the general population are already known to be twice as likely to develop cardiovascular disease as those without metabolic syndrome,” Dr. Greenfield noted. “The risk of cardiovascular hospitalizations and mortality is 3.6-fold higher in transplant patients vs the general population.”

With all this in mind, she and her colleagues set out to determine the prevalence of MetS and associated complications among HSCT recipients treated at 9 European centers in Belgium, France, Germany, Turkey, and the United Kingdom.

The researchers analyzed 462 patients—375 who had received an allogeneic HSCT and 87 who had undergone autologous HSCT. All patients were at least 18 years of age and at least 2 years post-HSCT.

The median age at transplant was 43 (interquartile range, 32-53), and 57.4% of patients were male.

Patients’ diagnoses included acute leukemia (37.9%), lymphoma (27.3%), myelodysplastic syndromes/myeloproliferative neoplasms (13%), chronic leukemia (12.3%), plasma cell disorders (5%), bone marrow failure (4.1%), solid tumors (0.2%), and inherited disorders (0.2%).

Results

The prevalence of MetS in this population was 30.4%. This is higher than the prevalence in the general population in Europe, which is 25%, according to the World Health Organization.

There was no significant difference in MetS prevalence between allogeneic and autologous HSCT recipients—29% and 35.6%, respectively.

However, there was a significant difference in MetS prevalence by age (P<0.001 with increasing age).

Among allogeneic HSCT recipients, there was no relationship between MetS prevalence and the presence or degree of acute or chronic GVHD, current use of immunosuppressive therapy, or conditioning intensity.

There was a significantly higher prevalence of CV events in patients with MetS than in patients without the syndrome—22.6% and 10.7%, respectively (P=0.006).

And logistic regression analysis confirmed that MetS is a predictor of CV events (odds ratio [OR]=4.72; 95% confidence interval [CI], 2.11-10.57).

The researchers also found that increasing age influenced the prevalence of MetS (OR=7.3; 95% CI, 3.2-16.8) and CV events (OR=3; 95% CI, 0.8-11.32) for patients older than 50, compared to patients in the 18-29 age group.

And CV events were associated with second malignancy (OR=7.93; 95% CI, 2.91-21.61).

“Early intervention of reversible features of metabolic syndrome with lifestyle and medical management may reduce the risk of cardiovascular events,” Dr. Greenfield said. “Meanwhile, screening and management should be robustly integrated within routine transplant long-term follow-up care.”

She added that the CIBMTR and EBMT guidelines on MetS and CV disease after HSCT should help in that regard.

Dr. Greenfield reported no conflicts of interest. However, her fellow researchers reported relationships with a range of pharmaceutical companies.

Photo by Jen Smith

SAN DIEGO—The KIT D816V inhibitor avapritinib can improve symptoms of systemic mastocytosis (SM), according to researchers.

Patients treated with avapritinib in a phase 1 trial had an overall response rate (ORR) of 83%, a 41% mean reduction in mastocytosis symptoms from baseline, and a 58% mean reduction in the most bothersome symptom domain.

Most adverse events (AEs) in this trial were grade 1 or 2. However, 66% of patients did have grade 3 or higher treatment-related AEs that necessitated dose reductions.

Jason R. Gotlib, MD, of Stanford University School of Medicine in California, presented these results, from the EXPLORER trial (NCT02561988), at the 2018 ASH Annual Meeting (abstract 351).

Patients and treatment

The trial enrolled 67 patients—90% with advanced SM and 10% with indolent or smoldering SM. The patients’ median age was 62 (range, 34 to 83), and 49% were female.

Patients had received a median of 3 (range, 0 to 3) prior therapies. Sixty percent of patients had received any prior therapy, and 23% had received midostaurin. Thirty-three percent were on steroid therapy at baseline.

Eighty-four percent of patients had the KIT D816V mutation, and 1% had the KIT D816Y mutation. Forty-five percent of patients had mutations in SRSF2, ASXL1, and RUNX1.

In the dose-escalation portion of the trial, patients received avapritinib at 30 mg to 400 mg once daily in continuous 28-day cycles. In the expansion portion of the trial, patients received avapritinib at 200 mg or 300 mg once daily.

Response

There were 29 patients evaluable for response. The ORR was 83% (n=24). The rate of complete response (CR) was 10% (n=3), the rate of CR with partial hematologic recovery (CRh) was 14% (n=4), and the partial response rate was 48% (n=14).

Ten percent (n=3) of patients had clinical improvement, 17% (n=5) had stable disease, and none of the patients progressed.

Among the 10 patients treated at a dose of 200 mg or lower, the ORR was 90% (n=9). The CR rate was 30% (n=3), the rate of CRh was 20% (n=2), and the partial response rate was 30% (n=3). Ten percent (n=1) of patients each had clinical improvement or stable disease.

Dr. Gotlib noted that responses have been durable and deepened over time.

At a median follow-up of 14 months, the median duration of response had not been reached. The 12-month response rate is 76%.

The median time to initial response is 2 months, and the median time to CR/CRh is 9 months.

Safety

Seventy-eight percent of patients (52/67) were still on treatment at last follow-up. Four percent (4/67) discontinued treatment due to related AEs, and 66% (44/67) had grade 3 or higher AEs that prompted dose reductions.

AEs prompting discontinuation included refractory ascites, encephalopathy, and intracranial bleeding. AEs necessitating dose reductions were largely hematologic events.

The most common AEs were periorbital edema (67%), anemia (52%), fatigue (37%), nausea (36%), diarrhea (34%), peripheral edema (34%), thrombocytopenia (31%) vomiting (28%), cognitive effects (28%), and hair color changes (25%).

The most common grade 3/4 AEs were anemia (26%), thrombocytopenia (17%), and neutropenia (10%). There were no treatment-related deaths.

Symptoms

For symptom assessment, patients completed the Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF), a patient-reported outcomes (PRO) tool that included eight symptoms:

• Abdominal pain
• Diarrhea
• Nausea
• Vomiting
• Spots
• Itching
• Flushing
• Fatigue.

Symptoms were scored on a scale of 1 to 10. Results were analyzed as a total symptom score (TSS) combining all eight items, as a gastrointestinal domain (combining nausea, vomiting, diarrhea, and abdominal pain), and as a skin domain (combining itching, flushing, and spots). Analyses were based on 7-day average scores.

Among the 32 evaluable patients, there was a 41% reduction in TSS from baseline (P=0.043). Among the 16 most symptomatic patients, there was a 46% reduction in TSS from baseline (P=0.038).

In all 32 evaluable patients, there was a 58% reduction from baseline in the score for most bothersome symptom domain (gastrointestinal or skin; P=0.0034). In the 16 most symptomatic patients, there was 63% reduction from baseline (P=0.0038).

“This is the first advanced SM-specific PRO to demonstrate significant improvements in total symptom score,” Dr. Gotlib said. “The clinical activity and initial PRO data do support further evaluation of avapritinib in both advanced and indolent disease.”

Dr. Gotlib noted that the PATHFINDER trial (NCT03580655), a study of avapritinib in advanced SM, is now enrolling. And the PIONEER trial (NCT03731260), a study of avapritinib in patients with indolent or smoldering SM, is scheduled to begin at the end of the year.

The EXPLORER trial was sponsored by Blueprint Medicines Corporation. Dr. Gotlib reported relationships with Blueprint Medicines, Celgene, Incyte, Novartis, Deciphera, Gilead, Promedior, and Kartos.

Photo by Jen Smith

SAN DIEGO—The KIT D816V inhibitor avapritinib can improve symptoms of systemic mastocytosis (SM), according to researchers.

Patients treated with avapritinib in a phase 1 trial had an overall response rate (ORR) of 83%, a 41% mean reduction in mastocytosis symptoms from baseline, and a 58% mean reduction in the most bothersome symptom domain.

Most adverse events (AEs) in this trial were grade 1 or 2. However, 66% of patients did have grade 3 or higher treatment-related AEs that necessitated dose reductions.

Jason R. Gotlib, MD, of Stanford University School of Medicine in California, presented these results, from the EXPLORER trial (NCT02561988), at the 2018 ASH Annual Meeting (abstract 351).

Patients and treatment

The trial enrolled 67 patients—90% with advanced SM and 10% with indolent or smoldering SM. The patients’ median age was 62 (range, 34 to 83), and 49% were female.

Patients had received a median of 3 (range, 0 to 3) prior therapies. Sixty percent of patients had received any prior therapy, and 23% had received midostaurin. Thirty-three percent were on steroid therapy at baseline.

Eighty-four percent of patients had the KIT D816V mutation, and 1% had the KIT D816Y mutation. Forty-five percent of patients had mutations in SRSF2, ASXL1, and RUNX1.

In the dose-escalation portion of the trial, patients received avapritinib at 30 mg to 400 mg once daily in continuous 28-day cycles. In the expansion portion of the trial, patients received avapritinib at 200 mg or 300 mg once daily.

Response

There were 29 patients evaluable for response. The ORR was 83% (n=24). The rate of complete response (CR) was 10% (n=3), the rate of CR with partial hematologic recovery (CRh) was 14% (n=4), and the partial response rate was 48% (n=14).

Ten percent (n=3) of patients had clinical improvement, 17% (n=5) had stable disease, and none of the patients progressed.

Among the 10 patients treated at a dose of 200 mg or lower, the ORR was 90% (n=9). The CR rate was 30% (n=3), the rate of CRh was 20% (n=2), and the partial response rate was 30% (n=3). Ten percent (n=1) of patients each had clinical improvement or stable disease.

Dr. Gotlib noted that responses have been durable and deepened over time.

At a median follow-up of 14 months, the median duration of response had not been reached. The 12-month response rate is 76%.

The median time to initial response is 2 months, and the median time to CR/CRh is 9 months.

Safety

Seventy-eight percent of patients (52/67) were still on treatment at last follow-up. Four percent (4/67) discontinued treatment due to related AEs, and 66% (44/67) had grade 3 or higher AEs that prompted dose reductions.

AEs prompting discontinuation included refractory ascites, encephalopathy, and intracranial bleeding. AEs necessitating dose reductions were largely hematologic events.

The most common AEs were periorbital edema (67%), anemia (52%), fatigue (37%), nausea (36%), diarrhea (34%), peripheral edema (34%), thrombocytopenia (31%) vomiting (28%), cognitive effects (28%), and hair color changes (25%).

The most common grade 3/4 AEs were anemia (26%), thrombocytopenia (17%), and neutropenia (10%). There were no treatment-related deaths.

Symptoms

For symptom assessment, patients completed the Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF), a patient-reported outcomes (PRO) tool that included eight symptoms:

• Abdominal pain
• Diarrhea
• Nausea
• Vomiting
• Spots
• Itching
• Flushing
• Fatigue.

Symptoms were scored on a scale of 1 to 10. Results were analyzed as a total symptom score (TSS) combining all eight items, as a gastrointestinal domain (combining nausea, vomiting, diarrhea, and abdominal pain), and as a skin domain (combining itching, flushing, and spots). Analyses were based on 7-day average scores.

Among the 32 evaluable patients, there was a 41% reduction in TSS from baseline (P=0.043). Among the 16 most symptomatic patients, there was a 46% reduction in TSS from baseline (P=0.038).

In all 32 evaluable patients, there was a 58% reduction from baseline in the score for most bothersome symptom domain (gastrointestinal or skin; P=0.0034). In the 16 most symptomatic patients, there was 63% reduction from baseline (P=0.0038).

“This is the first advanced SM-specific PRO to demonstrate significant improvements in total symptom score,” Dr. Gotlib said. “The clinical activity and initial PRO data do support further evaluation of avapritinib in both advanced and indolent disease.”

Dr. Gotlib noted that the PATHFINDER trial (NCT03580655), a study of avapritinib in advanced SM, is now enrolling. And the PIONEER trial (NCT03731260), a study of avapritinib in patients with indolent or smoldering SM, is scheduled to begin at the end of the year.

The EXPLORER trial was sponsored by Blueprint Medicines Corporation. Dr. Gotlib reported relationships with Blueprint Medicines, Celgene, Incyte, Novartis, Deciphera, Gilead, Promedior, and Kartos.

Photo by Jen Smith

SAN DIEGO—The KIT D816V inhibitor avapritinib can improve symptoms of systemic mastocytosis (SM), according to researchers.

Patients treated with avapritinib in a phase 1 trial had an overall response rate (ORR) of 83%, a 41% mean reduction in mastocytosis symptoms from baseline, and a 58% mean reduction in the most bothersome symptom domain.

Most adverse events (AEs) in this trial were grade 1 or 2. However, 66% of patients did have grade 3 or higher treatment-related AEs that necessitated dose reductions.

Jason R. Gotlib, MD, of Stanford University School of Medicine in California, presented these results, from the EXPLORER trial (NCT02561988), at the 2018 ASH Annual Meeting (abstract 351).

Patients and treatment

The trial enrolled 67 patients—90% with advanced SM and 10% with indolent or smoldering SM. The patients’ median age was 62 (range, 34 to 83), and 49% were female.

Patients had received a median of 3 (range, 0 to 3) prior therapies. Sixty percent of patients had received any prior therapy, and 23% had received midostaurin. Thirty-three percent were on steroid therapy at baseline.

Eighty-four percent of patients had the KIT D816V mutation, and 1% had the KIT D816Y mutation. Forty-five percent of patients had mutations in SRSF2, ASXL1, and RUNX1.

In the dose-escalation portion of the trial, patients received avapritinib at 30 mg to 400 mg once daily in continuous 28-day cycles. In the expansion portion of the trial, patients received avapritinib at 200 mg or 300 mg once daily.

Response

There were 29 patients evaluable for response. The ORR was 83% (n=24). The rate of complete response (CR) was 10% (n=3), the rate of CR with partial hematologic recovery (CRh) was 14% (n=4), and the partial response rate was 48% (n=14).

Ten percent (n=3) of patients had clinical improvement, 17% (n=5) had stable disease, and none of the patients progressed.

Among the 10 patients treated at a dose of 200 mg or lower, the ORR was 90% (n=9). The CR rate was 30% (n=3), the rate of CRh was 20% (n=2), and the partial response rate was 30% (n=3). Ten percent (n=1) of patients each had clinical improvement or stable disease.

Dr. Gotlib noted that responses have been durable and deepened over time.

At a median follow-up of 14 months, the median duration of response had not been reached. The 12-month response rate is 76%.

The median time to initial response is 2 months, and the median time to CR/CRh is 9 months.

Safety

Seventy-eight percent of patients (52/67) were still on treatment at last follow-up. Four percent (4/67) discontinued treatment due to related AEs, and 66% (44/67) had grade 3 or higher AEs that prompted dose reductions.

AEs prompting discontinuation included refractory ascites, encephalopathy, and intracranial bleeding. AEs necessitating dose reductions were largely hematologic events.

The most common AEs were periorbital edema (67%), anemia (52%), fatigue (37%), nausea (36%), diarrhea (34%), peripheral edema (34%), thrombocytopenia (31%) vomiting (28%), cognitive effects (28%), and hair color changes (25%).

The most common grade 3/4 AEs were anemia (26%), thrombocytopenia (17%), and neutropenia (10%). There were no treatment-related deaths.

Symptoms

For symptom assessment, patients completed the Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF), a patient-reported outcomes (PRO) tool that included eight symptoms:

• Abdominal pain
• Diarrhea
• Nausea
• Vomiting
• Spots
• Itching
• Flushing
• Fatigue.

Symptoms were scored on a scale of 1 to 10. Results were analyzed as a total symptom score (TSS) combining all eight items, as a gastrointestinal domain (combining nausea, vomiting, diarrhea, and abdominal pain), and as a skin domain (combining itching, flushing, and spots). Analyses were based on 7-day average scores.

Among the 32 evaluable patients, there was a 41% reduction in TSS from baseline (P=0.043). Among the 16 most symptomatic patients, there was a 46% reduction in TSS from baseline (P=0.038).

In all 32 evaluable patients, there was a 58% reduction from baseline in the score for most bothersome symptom domain (gastrointestinal or skin; P=0.0034). In the 16 most symptomatic patients, there was 63% reduction from baseline (P=0.0038).

“This is the first advanced SM-specific PRO to demonstrate significant improvements in total symptom score,” Dr. Gotlib said. “The clinical activity and initial PRO data do support further evaluation of avapritinib in both advanced and indolent disease.”

Dr. Gotlib noted that the PATHFINDER trial (NCT03580655), a study of avapritinib in advanced SM, is now enrolling. And the PIONEER trial (NCT03731260), a study of avapritinib in patients with indolent or smoldering SM, is scheduled to begin at the end of the year.

The EXPLORER trial was sponsored by Blueprint Medicines Corporation. Dr. Gotlib reported relationships with Blueprint Medicines, Celgene, Incyte, Novartis, Deciphera, Gilead, Promedior, and Kartos.

Photo by Jen Smith

SAN DIEGO—An algorithm has proven effective for identifying differentiation syndrome (DS) in patients taking ivosidenib or enasidenib, according to a speaker at the 2018 ASH Annual Meeting.

The U.S. Food and Drug Administration (FDA) recently announced that DS is going unnoticed in some patients with acute myeloid leukemia (AML) who are taking the IDH2 inhibitor enasidenib (Idhifa) or the IDH1 inhibitor ivosidenib (Tibsovo).

Though both drug labels include boxed warnings detailing the risk of DS, the FDA found evidence to suggest that DS is underdiagnosed, which can result in fatalities.

The FDA performed a systematic analysis of DS in AML patients taking either drug to determine if an algorithm could uncover a higher incidence of DS than was previously reported.

Kelly J. Norsworthy, MD, of the FDA, described the results of this analysis at ASH as abstract 288.

The analysis included patients with relapsed/refractory AML treated on a phase 1 study of ivosidenib (NCT02074839, AG120-C-001) and a phase 1/2 study of enasidenib (NCT01915498, AG221-C-001).

There were 179 patients treated with the approved dose of ivosidenib and 214 treated with the approved dose of enasidenib.

The researchers searched for DS events in the first 90 days of therapy. Patients were categorized as having DS if they had at least one investigator-reported DS event (IDH DS or retinoic acid syndrome) or if they had at least two signs or symptoms of DS, according to revised Montesinos criteria, within 7 days.

The signs/symptoms included:

• Dyspnea
• Unexplained fever
• Weight gain
• Unexplained hypotension
• Acute renal failure
• Pulmonary infiltrates or pleuropericardial effusion
• Multiple organ dysfunction.

“We added an event for multiple organ dysfunction since this adverse event could satisfy multiple Montesinos criteria,” Dr. Norsworthy said.

“Although leukocytosis is not a diagnostic criterion for DS, it is frequently seen in association with DS, so we performed an additional query for concomitant leukocytosis,” she added.

The researchers looked for adverse events of leukocytosis, hyperleukocytosis, white blood cell count increase, and leukocyte count greater than 10 Gi/L within 7 days of clinical signs/symptoms.

DS incidence

The algorithm suggested 40% of patients in each treatment group had potential DS—72 of 179 patients treated with ivosidenib and 86 of 214 patients treated with enasidenib.

“We reviewed case narratives and laboratory data from the algorithmically defined cases of DS to adjudicate whether cases were DS or unlikely DS due to an alternative explanation, most commonly due to a clinical course inconsistent with DS or confirmed infection,” Dr. Norsworthy said.

The reviewer-adjudicated incidence of DS was 19% in both groups—34 patients on ivosidenib and 41 patients on enasidenib.

“This contrasts with the DS incidence of 11% to 14% reported by investigators,” Dr. Norsworthy said. “Thus, there was a subset of patients where the syndrome was not recognized by investigators.”

Characteristics of DS

The median time to DS onset in this analysis was 20 days (range, 1 to 78) in the ivosidenib group and 19 days in the enasidenib group (range, 1 to 86).

In both treatment groups, most patients had moderate DS—71% (n=24) in the ivosidenib group and 80% (n=33) in the enasidenib group. Moderate DS was defined as meeting two to three of the aforementioned criteria for DS.

Fewer patients had severe DS (four or more criteria)—24% (n=8) in the ivosidenib group and 12% (n=5) in the enasidenib group.

For the remaining patients, DS severity could not be determined—6% (n=2) in the ivosidenib group and 10% (n=4) in the enasidenib group. These were investigator-reported cases of DS.

Most DS cases in the ivosidenib and enasidenib groups—68% (n=23) and 66% (n=27), respectively— included grade 3 or higher adverse reactions.

Two patients in each group died of DS—6% and 5%, respectively. Only one of these cases was recognized as DS and treated with steroids, Dr. Norsworthy noted.

She also pointed out that most patients with DS had leukocytosis—79% (n=27) in the ivosidenib group and 61% (n=25) in the enasidenib group.

In addition, rates of complete response (CR) and CR with incomplete hematologic recovery (CRh) were numerically lower among patients with DS, although the confidence intervals (CI) overlap.

Among patients on ivosidenib, the CR/CRh rate was 18% (95% CI, 7-35) in those with DS and 36% (95% CI, 28-45) in those without DS.

Among patients on enasidenib, the CR/CRh rate was 18% (95% CI, 7-33) in those with DS and 25% (95% CI, 18-32) in those without DS.

“[F]irm conclusions regarding the impact on response cannot be inferred based on this post-hoc subgroup analysis,” Dr. Norsworthy stressed.

Predicting DS

Dr. Norsworthy noted that baseline patient and disease characteristics were similar between patients with and without DS.

The researchers did see a trend toward higher blasts in the marrow and peripheral blood as well as higher white blood cell counts at baseline among patients with DS.

“However, there did not appear to be a distinct baseline white blood cell count or absolute blast cell count cutoff above which DS was more common,” Dr. Norsworthy said.

She added that the patient numbers are small, so it’s not possible to make firm conclusions about prognostic factors for DS.

In closing, Dr. Norsworthy said the algorithmic approach used here “led to the recognition of additional cases of DS not identified by investigators or review committee determination for patients treated with the IDH inhibitors ivo and ena.”

“Increased recognition of the signs and symptoms of DS through the framework of the Montesinos criteria may lead to early diagnosis and treatment, which may decrease severe complications and mortality. Furthermore, integration of the algorithm into clinical trials of differentiating therapies, in a prospective fashion, may help to systematically monitor the incidence and severity of DS.”

Dr. Norsworthy declared no conflicts of interest.

Photo by Jen Smith

SAN DIEGO—An algorithm has proven effective for identifying differentiation syndrome (DS) in patients taking ivosidenib or enasidenib, according to a speaker at the 2018 ASH Annual Meeting.

The U.S. Food and Drug Administration (FDA) recently announced that DS is going unnoticed in some patients with acute myeloid leukemia (AML) who are taking the IDH2 inhibitor enasidenib (Idhifa) or the IDH1 inhibitor ivosidenib (Tibsovo).

Though both drug labels include boxed warnings detailing the risk of DS, the FDA found evidence to suggest that DS is underdiagnosed, which can result in fatalities.

The FDA performed a systematic analysis of DS in AML patients taking either drug to determine if an algorithm could uncover a higher incidence of DS than was previously reported.

Kelly J. Norsworthy, MD, of the FDA, described the results of this analysis at ASH as abstract 288.

The analysis included patients with relapsed/refractory AML treated on a phase 1 study of ivosidenib (NCT02074839, AG120-C-001) and a phase 1/2 study of enasidenib (NCT01915498, AG221-C-001).

There were 179 patients treated with the approved dose of ivosidenib and 214 treated with the approved dose of enasidenib.

The researchers searched for DS events in the first 90 days of therapy. Patients were categorized as having DS if they had at least one investigator-reported DS event (IDH DS or retinoic acid syndrome) or if they had at least two signs or symptoms of DS, according to revised Montesinos criteria, within 7 days.

The signs/symptoms included:

• Dyspnea
• Unexplained fever
• Weight gain
• Unexplained hypotension
• Acute renal failure
• Pulmonary infiltrates or pleuropericardial effusion
• Multiple organ dysfunction.

“We added an event for multiple organ dysfunction since this adverse event could satisfy multiple Montesinos criteria,” Dr. Norsworthy said.

“Although leukocytosis is not a diagnostic criterion for DS, it is frequently seen in association with DS, so we performed an additional query for concomitant leukocytosis,” she added.

The researchers looked for adverse events of leukocytosis, hyperleukocytosis, white blood cell count increase, and leukocyte count greater than 10 Gi/L within 7 days of clinical signs/symptoms.

DS incidence

The algorithm suggested 40% of patients in each treatment group had potential DS—72 of 179 patients treated with ivosidenib and 86 of 214 patients treated with enasidenib.

“We reviewed case narratives and laboratory data from the algorithmically defined cases of DS to adjudicate whether cases were DS or unlikely DS due to an alternative explanation, most commonly due to a clinical course inconsistent with DS or confirmed infection,” Dr. Norsworthy said.

The reviewer-adjudicated incidence of DS was 19% in both groups—34 patients on ivosidenib and 41 patients on enasidenib.

“This contrasts with the DS incidence of 11% to 14% reported by investigators,” Dr. Norsworthy said. “Thus, there was a subset of patients where the syndrome was not recognized by investigators.”

Characteristics of DS

The median time to DS onset in this analysis was 20 days (range, 1 to 78) in the ivosidenib group and 19 days in the enasidenib group (range, 1 to 86).

In both treatment groups, most patients had moderate DS—71% (n=24) in the ivosidenib group and 80% (n=33) in the enasidenib group. Moderate DS was defined as meeting two to three of the aforementioned criteria for DS.

Fewer patients had severe DS (four or more criteria)—24% (n=8) in the ivosidenib group and 12% (n=5) in the enasidenib group.

For the remaining patients, DS severity could not be determined—6% (n=2) in the ivosidenib group and 10% (n=4) in the enasidenib group. These were investigator-reported cases of DS.

Most DS cases in the ivosidenib and enasidenib groups—68% (n=23) and 66% (n=27), respectively— included grade 3 or higher adverse reactions.

Two patients in each group died of DS—6% and 5%, respectively. Only one of these cases was recognized as DS and treated with steroids, Dr. Norsworthy noted.

She also pointed out that most patients with DS had leukocytosis—79% (n=27) in the ivosidenib group and 61% (n=25) in the enasidenib group.

In addition, rates of complete response (CR) and CR with incomplete hematologic recovery (CRh) were numerically lower among patients with DS, although the confidence intervals (CI) overlap.

Among patients on ivosidenib, the CR/CRh rate was 18% (95% CI, 7-35) in those with DS and 36% (95% CI, 28-45) in those without DS.

Among patients on enasidenib, the CR/CRh rate was 18% (95% CI, 7-33) in those with DS and 25% (95% CI, 18-32) in those without DS.

“[F]irm conclusions regarding the impact on response cannot be inferred based on this post-hoc subgroup analysis,” Dr. Norsworthy stressed.

Predicting DS

Dr. Norsworthy noted that baseline patient and disease characteristics were similar between patients with and without DS.

The researchers did see a trend toward higher blasts in the marrow and peripheral blood as well as higher white blood cell counts at baseline among patients with DS.

“However, there did not appear to be a distinct baseline white blood cell count or absolute blast cell count cutoff above which DS was more common,” Dr. Norsworthy said.

She added that the patient numbers are small, so it’s not possible to make firm conclusions about prognostic factors for DS.

In closing, Dr. Norsworthy said the algorithmic approach used here “led to the recognition of additional cases of DS not identified by investigators or review committee determination for patients treated with the IDH inhibitors ivo and ena.”

“Increased recognition of the signs and symptoms of DS through the framework of the Montesinos criteria may lead to early diagnosis and treatment, which may decrease severe complications and mortality. Furthermore, integration of the algorithm into clinical trials of differentiating therapies, in a prospective fashion, may help to systematically monitor the incidence and severity of DS.”

Dr. Norsworthy declared no conflicts of interest.

Photo by Jen Smith

SAN DIEGO—An algorithm has proven effective for identifying differentiation syndrome (DS) in patients taking ivosidenib or enasidenib, according to a speaker at the 2018 ASH Annual Meeting.

The U.S. Food and Drug Administration (FDA) recently announced that DS is going unnoticed in some patients with acute myeloid leukemia (AML) who are taking the IDH2 inhibitor enasidenib (Idhifa) or the IDH1 inhibitor ivosidenib (Tibsovo).

Though both drug labels include boxed warnings detailing the risk of DS, the FDA found evidence to suggest that DS is underdiagnosed, which can result in fatalities.

The FDA performed a systematic analysis of DS in AML patients taking either drug to determine if an algorithm could uncover a higher incidence of DS than was previously reported.

Kelly J. Norsworthy, MD, of the FDA, described the results of this analysis at ASH as abstract 288.

The analysis included patients with relapsed/refractory AML treated on a phase 1 study of ivosidenib (NCT02074839, AG120-C-001) and a phase 1/2 study of enasidenib (NCT01915498, AG221-C-001).

There were 179 patients treated with the approved dose of ivosidenib and 214 treated with the approved dose of enasidenib.

The researchers searched for DS events in the first 90 days of therapy. Patients were categorized as having DS if they had at least one investigator-reported DS event (IDH DS or retinoic acid syndrome) or if they had at least two signs or symptoms of DS, according to revised Montesinos criteria, within 7 days.

The signs/symptoms included:

• Dyspnea
• Unexplained fever
• Weight gain
• Unexplained hypotension
• Acute renal failure
• Pulmonary infiltrates or pleuropericardial effusion
• Multiple organ dysfunction.

“We added an event for multiple organ dysfunction since this adverse event could satisfy multiple Montesinos criteria,” Dr. Norsworthy said.

“Although leukocytosis is not a diagnostic criterion for DS, it is frequently seen in association with DS, so we performed an additional query for concomitant leukocytosis,” she added.

The researchers looked for adverse events of leukocytosis, hyperleukocytosis, white blood cell count increase, and leukocyte count greater than 10 Gi/L within 7 days of clinical signs/symptoms.

DS incidence

The algorithm suggested 40% of patients in each treatment group had potential DS—72 of 179 patients treated with ivosidenib and 86 of 214 patients treated with enasidenib.

“We reviewed case narratives and laboratory data from the algorithmically defined cases of DS to adjudicate whether cases were DS or unlikely DS due to an alternative explanation, most commonly due to a clinical course inconsistent with DS or confirmed infection,” Dr. Norsworthy said.

The reviewer-adjudicated incidence of DS was 19% in both groups—34 patients on ivosidenib and 41 patients on enasidenib.

“This contrasts with the DS incidence of 11% to 14% reported by investigators,” Dr. Norsworthy said. “Thus, there was a subset of patients where the syndrome was not recognized by investigators.”

Characteristics of DS

The median time to DS onset in this analysis was 20 days (range, 1 to 78) in the ivosidenib group and 19 days in the enasidenib group (range, 1 to 86).

In both treatment groups, most patients had moderate DS—71% (n=24) in the ivosidenib group and 80% (n=33) in the enasidenib group. Moderate DS was defined as meeting two to three of the aforementioned criteria for DS.

Fewer patients had severe DS (four or more criteria)—24% (n=8) in the ivosidenib group and 12% (n=5) in the enasidenib group.

For the remaining patients, DS severity could not be determined—6% (n=2) in the ivosidenib group and 10% (n=4) in the enasidenib group. These were investigator-reported cases of DS.

Most DS cases in the ivosidenib and enasidenib groups—68% (n=23) and 66% (n=27), respectively— included grade 3 or higher adverse reactions.

Two patients in each group died of DS—6% and 5%, respectively. Only one of these cases was recognized as DS and treated with steroids, Dr. Norsworthy noted.

She also pointed out that most patients with DS had leukocytosis—79% (n=27) in the ivosidenib group and 61% (n=25) in the enasidenib group.

In addition, rates of complete response (CR) and CR with incomplete hematologic recovery (CRh) were numerically lower among patients with DS, although the confidence intervals (CI) overlap.

Among patients on ivosidenib, the CR/CRh rate was 18% (95% CI, 7-35) in those with DS and 36% (95% CI, 28-45) in those without DS.

Among patients on enasidenib, the CR/CRh rate was 18% (95% CI, 7-33) in those with DS and 25% (95% CI, 18-32) in those without DS.

“[F]irm conclusions regarding the impact on response cannot be inferred based on this post-hoc subgroup analysis,” Dr. Norsworthy stressed.

Predicting DS

Dr. Norsworthy noted that baseline patient and disease characteristics were similar between patients with and without DS.

The researchers did see a trend toward higher blasts in the marrow and peripheral blood as well as higher white blood cell counts at baseline among patients with DS.

“However, there did not appear to be a distinct baseline white blood cell count or absolute blast cell count cutoff above which DS was more common,” Dr. Norsworthy said.

She added that the patient numbers are small, so it’s not possible to make firm conclusions about prognostic factors for DS.

In closing, Dr. Norsworthy said the algorithmic approach used here “led to the recognition of additional cases of DS not identified by investigators or review committee determination for patients treated with the IDH inhibitors ivo and ena.”

“Increased recognition of the signs and symptoms of DS through the framework of the Montesinos criteria may lead to early diagnosis and treatment, which may decrease severe complications and mortality. Furthermore, integration of the algorithm into clinical trials of differentiating therapies, in a prospective fashion, may help to systematically monitor the incidence and severity of DS.”

Dr. Norsworthy declared no conflicts of interest.

Photo by Jen Smith

SAN DIEGO—A three-drug combination produced “deep and durable” responses in patients with relapsed/refractory multiple myeloma (MM), according to a speaker at the 2018 ASH Annual Meeting.

Selinexor, dexamethasone, and daratumumab produced a response rate of 73% when given at the recommended dosing schedule to MM patients who had received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent.

Most responders had a very good partial response (VGPR), but there were no complete responses. At a median follow-up of 7.7 months, the median progression-free survival had not been reached.

The most common grade 3/4 adverse events (AEs) in this trial were hematologic toxicities.

Cristina J. Gasparetto, MD, of Duke University Medical Center in Durham, North Carolina, presented these results, from the phase 1/2 STOMP trial (NCT02343042), as abstract 599.*

Patients

As of November 15, the trial had enrolled 28 MM patients. At baseline, their median age was 68 (range, 44-77). There were 14 males and 14 females. The median time from diagnosis to study treatment was 5.9 years (range, <1 to 12.9 years).

Patients had received a median of 3 (range, 2 to 10) prior treatment regimens.

All 28 patients had received a proteasome inhibitor, and 61% of them (n=17) were refractory to the treatment. All 28 patients had also received an immunomodulatory drug, and 64% of them (n=18) were refractory to it.

Seventy-nine percent (n=22) of patients had undergone an autologous transplant, and 7% (n=2) had received prior daratumumab.

Treatment

Patients were treated in two concurrent cohorts.

One cohort included 25 patients who received selinexor at 100 mg once-weekly (QW), dexamethasone at 40 mg QW, and daratumumab at 16 mg/kg QW.

The other cohort included three patients who received selinexor at 60 mg twice-weekly (BIW), dexamethasone at 20 mg BIW, and daratumumab at 16 mg/kg QW.

The recommended phase 2 dose and schedule was selinexor at 100 mg QW, dexamethasone at 40 mg QW, and daratumumab at 16 mg/kg QW.

Safety

Among patients who received the recommended phase 2 dosing schedule, common treatment-related AEs included:

• Nausea (60%)
• Diarrhea (32%)
• Anorexia (28%)
• Vomiting (24%)
• Dysgeusia (20%)
• Fatigue (48%)
• Hyponatremia (28%)
• Insomnia (24%)
• Blurred vision (24%)
• Thrombocytopenia (64%)
• Anemia (48%)
• Leukopenia (44%)
• Neutropenia (44%)
• Lymphopenia (20%).

“[T]he weekly dose was better tolerated [with] only a couple of patients with grade 3 [gastrointestinal] toxicity,” Dr Gasparetto noted.

The most common grade 3/4 AEs were thrombocytopenia (44%), anemia (28%), leukopenia (28%), and neutropenia (24%). There were no grade 5 AEs.

Efficacy

The median follow-up was 7.7 months, and the median time on study was 5.8 months.

Twenty-six patients were evaluable for response, as two patients withdrew consent prior to follow-up.

The overall response rate was 73% (n=19), which includes seven very good partial responses (VGPRs) and 12 partial responses (PRs). Two patients had a minimal response, four had stable disease, and one progressed.

Among patients with a PR or better, the median time on treatment was 7.3 months. The median time to response was 1 month.

Three VGPRs are ongoing, but four patients who achieved a VGPR progressed.

Six PRs are ongoing, and one patient with a PR progressed. Other reasons for treatment discontinuation among patients with a PR included transplant (n=1), AE (n=1), patient decision (n=2), and hospice (n=1).

One patient with a minimal response progressed, and one discontinued treatment due to an AE.

The median progression-free survival was not reached.

“Selinexor in combination with dara and dexa appears to be highly active, producing deep and durable responses in the relapsed setting,” Dr. Gasparetto said.

She reported relationships with Takeda, Janssen, Celgene, and Bristol-Myers Squibb. The trial is sponsored by Karyopharm Therapeutics.

*Data in the presentation differ from the abstract.

Photo by Jen Smith

SAN DIEGO—A three-drug combination produced “deep and durable” responses in patients with relapsed/refractory multiple myeloma (MM), according to a speaker at the 2018 ASH Annual Meeting.

Selinexor, dexamethasone, and daratumumab produced a response rate of 73% when given at the recommended dosing schedule to MM patients who had received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent.

Most responders had a very good partial response (VGPR), but there were no complete responses. At a median follow-up of 7.7 months, the median progression-free survival had not been reached.

The most common grade 3/4 adverse events (AEs) in this trial were hematologic toxicities.

Cristina J. Gasparetto, MD, of Duke University Medical Center in Durham, North Carolina, presented these results, from the phase 1/2 STOMP trial (NCT02343042), as abstract 599.*

Patients

As of November 15, the trial had enrolled 28 MM patients. At baseline, their median age was 68 (range, 44-77). There were 14 males and 14 females. The median time from diagnosis to study treatment was 5.9 years (range, <1 to 12.9 years).

Patients had received a median of 3 (range, 2 to 10) prior treatment regimens.

All 28 patients had received a proteasome inhibitor, and 61% of them (n=17) were refractory to the treatment. All 28 patients had also received an immunomodulatory drug, and 64% of them (n=18) were refractory to it.

Seventy-nine percent (n=22) of patients had undergone an autologous transplant, and 7% (n=2) had received prior daratumumab.

Treatment

Patients were treated in two concurrent cohorts.

One cohort included 25 patients who received selinexor at 100 mg once-weekly (QW), dexamethasone at 40 mg QW, and daratumumab at 16 mg/kg QW.

The other cohort included three patients who received selinexor at 60 mg twice-weekly (BIW), dexamethasone at 20 mg BIW, and daratumumab at 16 mg/kg QW.

The recommended phase 2 dose and schedule was selinexor at 100 mg QW, dexamethasone at 40 mg QW, and daratumumab at 16 mg/kg QW.

Safety

Among patients who received the recommended phase 2 dosing schedule, common treatment-related AEs included:

• Nausea (60%)
• Diarrhea (32%)
• Anorexia (28%)
• Vomiting (24%)
• Dysgeusia (20%)
• Fatigue (48%)
• Hyponatremia (28%)
• Insomnia (24%)
• Blurred vision (24%)
• Thrombocytopenia (64%)
• Anemia (48%)
• Leukopenia (44%)
• Neutropenia (44%)
• Lymphopenia (20%).

“[T]he weekly dose was better tolerated [with] only a couple of patients with grade 3 [gastrointestinal] toxicity,” Dr Gasparetto noted.

The most common grade 3/4 AEs were thrombocytopenia (44%), anemia (28%), leukopenia (28%), and neutropenia (24%). There were no grade 5 AEs.

Efficacy

The median follow-up was 7.7 months, and the median time on study was 5.8 months.

Twenty-six patients were evaluable for response, as two patients withdrew consent prior to follow-up.

The overall response rate was 73% (n=19), which includes seven very good partial responses (VGPRs) and 12 partial responses (PRs). Two patients had a minimal response, four had stable disease, and one progressed.

Among patients with a PR or better, the median time on treatment was 7.3 months. The median time to response was 1 month.

Three VGPRs are ongoing, but four patients who achieved a VGPR progressed.

Six PRs are ongoing, and one patient with a PR progressed. Other reasons for treatment discontinuation among patients with a PR included transplant (n=1), AE (n=1), patient decision (n=2), and hospice (n=1).

One patient with a minimal response progressed, and one discontinued treatment due to an AE.

The median progression-free survival was not reached.

“Selinexor in combination with dara and dexa appears to be highly active, producing deep and durable responses in the relapsed setting,” Dr. Gasparetto said.

She reported relationships with Takeda, Janssen, Celgene, and Bristol-Myers Squibb. The trial is sponsored by Karyopharm Therapeutics.

*Data in the presentation differ from the abstract.

Photo by Jen Smith

SAN DIEGO—A three-drug combination produced “deep and durable” responses in patients with relapsed/refractory multiple myeloma (MM), according to a speaker at the 2018 ASH Annual Meeting.

Selinexor, dexamethasone, and daratumumab produced a response rate of 73% when given at the recommended dosing schedule to MM patients who had received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent.

Most responders had a very good partial response (VGPR), but there were no complete responses. At a median follow-up of 7.7 months, the median progression-free survival had not been reached.

The most common grade 3/4 adverse events (AEs) in this trial were hematologic toxicities.

Cristina J. Gasparetto, MD, of Duke University Medical Center in Durham, North Carolina, presented these results, from the phase 1/2 STOMP trial (NCT02343042), as abstract 599.*

Patients

As of November 15, the trial had enrolled 28 MM patients. At baseline, their median age was 68 (range, 44-77). There were 14 males and 14 females. The median time from diagnosis to study treatment was 5.9 years (range, <1 to 12.9 years).

Patients had received a median of 3 (range, 2 to 10) prior treatment regimens.

All 28 patients had received a proteasome inhibitor, and 61% of them (n=17) were refractory to the treatment. All 28 patients had also received an immunomodulatory drug, and 64% of them (n=18) were refractory to it.

Seventy-nine percent (n=22) of patients had undergone an autologous transplant, and 7% (n=2) had received prior daratumumab.

Treatment

Patients were treated in two concurrent cohorts.

One cohort included 25 patients who received selinexor at 100 mg once-weekly (QW), dexamethasone at 40 mg QW, and daratumumab at 16 mg/kg QW.

The other cohort included three patients who received selinexor at 60 mg twice-weekly (BIW), dexamethasone at 20 mg BIW, and daratumumab at 16 mg/kg QW.

The recommended phase 2 dose and schedule was selinexor at 100 mg QW, dexamethasone at 40 mg QW, and daratumumab at 16 mg/kg QW.

Safety

Among patients who received the recommended phase 2 dosing schedule, common treatment-related AEs included:

• Nausea (60%)
• Diarrhea (32%)
• Anorexia (28%)
• Vomiting (24%)
• Dysgeusia (20%)
• Fatigue (48%)
• Hyponatremia (28%)
• Insomnia (24%)
• Blurred vision (24%)
• Thrombocytopenia (64%)
• Anemia (48%)
• Leukopenia (44%)
• Neutropenia (44%)
• Lymphopenia (20%).

“[T]he weekly dose was better tolerated [with] only a couple of patients with grade 3 [gastrointestinal] toxicity,” Dr Gasparetto noted.

The most common grade 3/4 AEs were thrombocytopenia (44%), anemia (28%), leukopenia (28%), and neutropenia (24%). There were no grade 5 AEs.

Efficacy

The median follow-up was 7.7 months, and the median time on study was 5.8 months.

Twenty-six patients were evaluable for response, as two patients withdrew consent prior to follow-up.

The overall response rate was 73% (n=19), which includes seven very good partial responses (VGPRs) and 12 partial responses (PRs). Two patients had a minimal response, four had stable disease, and one progressed.

Among patients with a PR or better, the median time on treatment was 7.3 months. The median time to response was 1 month.

Three VGPRs are ongoing, but four patients who achieved a VGPR progressed.

Six PRs are ongoing, and one patient with a PR progressed. Other reasons for treatment discontinuation among patients with a PR included transplant (n=1), AE (n=1), patient decision (n=2), and hospice (n=1).

One patient with a minimal response progressed, and one discontinued treatment due to an AE.

The median progression-free survival was not reached.

“Selinexor in combination with dara and dexa appears to be highly active, producing deep and durable responses in the relapsed setting,” Dr. Gasparetto said.

She reported relationships with Takeda, Janssen, Celgene, and Bristol-Myers Squibb. The trial is sponsored by Karyopharm Therapeutics.

*Data in the presentation differ from the abstract.