Aggressive Lymphomas

SAN DIEGO – A second-generation CD19-specific “armored” chimeric antigen receptor (CAR) T-cell construct was associated with high complete remission rates in diffuse large B-cell lymphoma (DLBCL) and indolent non-Hodgkin lymphoma (NHL) in a phase 1 trial.

Neil Osterweil/ MDedge News

The CAR T construct – labeled 1928z-41BBL – also induced “encouraging” complete remission rates in patients with chronic lymphocytic leukemia (CLL) with Richter’s transformation, reported Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC), New York, and his colleagues.

“Interestingly and encouragingly, severe [cytokine release syndrome] was not seen and grade 3 neurotoxicity was observed in less than 10%, with no grade 4 neurotoxicity, so there appears to be a favorable side effect profile,” Dr. Park said at the annual meeting of the American Society of Hematology.

Just as armored cars are designed to protect their valuable contents from people with bad intent, armored CAR T cells are engineered to protect the modified T-cells from a hostile tumor microenvironment and simultaneously recruit non-modified T cells to the target to produce a more robust immune response against malignant cells.

MSKCC investigators had previously shown that in contrast to other CAR T-cell constructs, the 1928z-41BBL configuration, which consists of two signaling domains (CD28 and CD3zeta) and the 4-1BB ligand, hit the sweet spot between tumor-killing function and T-cell persistence (Cancer Cell. 2015 Oct 12;28[4]:415-28).

In the current study, they enrolled 35 adults with relapsed or refractory CD19-positive hematologic malignancies, 29 of whom eventually underwent CAR T-cell infusions. The treated population comprised 14 patients with CLL (4 of whom had Richter’s transformation), 9 with DLBCL, 5 with indolent NHL, and 1 with acute lymphoblastic leukemia.

The patients with CLL had received a median of 5.5 prior lines of therapy, including ibrutinib (Imbruvica) and venetoclax (Venclexta).

There were 15 complete remissions (CR), with CR rates of 78% in DLBCL, 20% in CLL, 67% in CLL with Richter’s transformation, 60% in patients with indolent NHL, as well as CR in the single patient with ALL.

There were eight partial remissions. One patient with CLL had stable disease, and four patients had disease progression (one patient each with DLBCL, CLL, CLL with Richter’s, and indolent NHL).

Dr. Park noted that T cells are being detected in peripheral blood more than 6 months after T-cell infusion.

There were no cases of severe cytokine release syndrome, defined as requiring vasopressors and/or mechanical ventilation for hypoxia, and just three cases of grade 3 neurotoxicity. There were no cases of grade 4 neurotoxicity, no deaths related to neurotoxicity, and no cases of cerebral edema – a serious complication that has been seen in earlier CAR T-cell studies.

Split or multiple infusions of CAR T cells or incorporation of the technique into earlier lines of therapy might generate higher response rates, Dr. Park said.

The study was supported by Juno Therapeutics. Dr. Park reported consulting for and research funding from Juno, and financial relationships with other companies.
 

SOURCE: Park JH et al. ASH 2018, Abstract 224.

SAN DIEGO – A second-generation CD19-specific “armored” chimeric antigen receptor (CAR) T-cell construct was associated with high complete remission rates in diffuse large B-cell lymphoma (DLBCL) and indolent non-Hodgkin lymphoma (NHL) in a phase 1 trial.

Neil Osterweil/ MDedge News

The CAR T construct – labeled 1928z-41BBL – also induced “encouraging” complete remission rates in patients with chronic lymphocytic leukemia (CLL) with Richter’s transformation, reported Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC), New York, and his colleagues.

“Interestingly and encouragingly, severe [cytokine release syndrome] was not seen and grade 3 neurotoxicity was observed in less than 10%, with no grade 4 neurotoxicity, so there appears to be a favorable side effect profile,” Dr. Park said at the annual meeting of the American Society of Hematology.

Just as armored cars are designed to protect their valuable contents from people with bad intent, armored CAR T cells are engineered to protect the modified T-cells from a hostile tumor microenvironment and simultaneously recruit non-modified T cells to the target to produce a more robust immune response against malignant cells.

MSKCC investigators had previously shown that in contrast to other CAR T-cell constructs, the 1928z-41BBL configuration, which consists of two signaling domains (CD28 and CD3zeta) and the 4-1BB ligand, hit the sweet spot between tumor-killing function and T-cell persistence (Cancer Cell. 2015 Oct 12;28[4]:415-28).

In the current study, they enrolled 35 adults with relapsed or refractory CD19-positive hematologic malignancies, 29 of whom eventually underwent CAR T-cell infusions. The treated population comprised 14 patients with CLL (4 of whom had Richter’s transformation), 9 with DLBCL, 5 with indolent NHL, and 1 with acute lymphoblastic leukemia.

The patients with CLL had received a median of 5.5 prior lines of therapy, including ibrutinib (Imbruvica) and venetoclax (Venclexta).

There were 15 complete remissions (CR), with CR rates of 78% in DLBCL, 20% in CLL, 67% in CLL with Richter’s transformation, 60% in patients with indolent NHL, as well as CR in the single patient with ALL.

There were eight partial remissions. One patient with CLL had stable disease, and four patients had disease progression (one patient each with DLBCL, CLL, CLL with Richter’s, and indolent NHL).

Dr. Park noted that T cells are being detected in peripheral blood more than 6 months after T-cell infusion.

There were no cases of severe cytokine release syndrome, defined as requiring vasopressors and/or mechanical ventilation for hypoxia, and just three cases of grade 3 neurotoxicity. There were no cases of grade 4 neurotoxicity, no deaths related to neurotoxicity, and no cases of cerebral edema – a serious complication that has been seen in earlier CAR T-cell studies.

Split or multiple infusions of CAR T cells or incorporation of the technique into earlier lines of therapy might generate higher response rates, Dr. Park said.

The study was supported by Juno Therapeutics. Dr. Park reported consulting for and research funding from Juno, and financial relationships with other companies.
 

SOURCE: Park JH et al. ASH 2018, Abstract 224.

SAN DIEGO – A second-generation CD19-specific “armored” chimeric antigen receptor (CAR) T-cell construct was associated with high complete remission rates in diffuse large B-cell lymphoma (DLBCL) and indolent non-Hodgkin lymphoma (NHL) in a phase 1 trial.

Neil Osterweil/ MDedge News

The CAR T construct – labeled 1928z-41BBL – also induced “encouraging” complete remission rates in patients with chronic lymphocytic leukemia (CLL) with Richter’s transformation, reported Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC), New York, and his colleagues.

“Interestingly and encouragingly, severe [cytokine release syndrome] was not seen and grade 3 neurotoxicity was observed in less than 10%, with no grade 4 neurotoxicity, so there appears to be a favorable side effect profile,” Dr. Park said at the annual meeting of the American Society of Hematology.

Just as armored cars are designed to protect their valuable contents from people with bad intent, armored CAR T cells are engineered to protect the modified T-cells from a hostile tumor microenvironment and simultaneously recruit non-modified T cells to the target to produce a more robust immune response against malignant cells.

MSKCC investigators had previously shown that in contrast to other CAR T-cell constructs, the 1928z-41BBL configuration, which consists of two signaling domains (CD28 and CD3zeta) and the 4-1BB ligand, hit the sweet spot between tumor-killing function and T-cell persistence (Cancer Cell. 2015 Oct 12;28[4]:415-28).

In the current study, they enrolled 35 adults with relapsed or refractory CD19-positive hematologic malignancies, 29 of whom eventually underwent CAR T-cell infusions. The treated population comprised 14 patients with CLL (4 of whom had Richter’s transformation), 9 with DLBCL, 5 with indolent NHL, and 1 with acute lymphoblastic leukemia.

The patients with CLL had received a median of 5.5 prior lines of therapy, including ibrutinib (Imbruvica) and venetoclax (Venclexta).

There were 15 complete remissions (CR), with CR rates of 78% in DLBCL, 20% in CLL, 67% in CLL with Richter’s transformation, 60% in patients with indolent NHL, as well as CR in the single patient with ALL.

There were eight partial remissions. One patient with CLL had stable disease, and four patients had disease progression (one patient each with DLBCL, CLL, CLL with Richter’s, and indolent NHL).

Dr. Park noted that T cells are being detected in peripheral blood more than 6 months after T-cell infusion.

There were no cases of severe cytokine release syndrome, defined as requiring vasopressors and/or mechanical ventilation for hypoxia, and just three cases of grade 3 neurotoxicity. There were no cases of grade 4 neurotoxicity, no deaths related to neurotoxicity, and no cases of cerebral edema – a serious complication that has been seen in earlier CAR T-cell studies.

Split or multiple infusions of CAR T cells or incorporation of the technique into earlier lines of therapy might generate higher response rates, Dr. Park said.

The study was supported by Juno Therapeutics. Dr. Park reported consulting for and research funding from Juno, and financial relationships with other companies.
 

SOURCE: Park JH et al. ASH 2018, Abstract 224.

SAN DIEGO – Longer-term follow-up of patients treated with CD19-targeted chimeric antigen receptor (CAR) T cells for hematologic malignancies indicates that the altered cells are generally safe, with most late events being mild in nature and possibly related to therapies delivered before or after CAR T cells, investigators reported.

Among patients treated with CD19-targeted CAR T cells for relapsed or refractory chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma (NHL), the most frequent late adverse event was hypogammaglobulinemia, which occurred in 29 of 48 patients evaluated, reported Ana Cordeiro, MD, from the Fred Hutchinson Cancer Research Center in Seattle.

“Our results suggest that CD19 CAR T cells are safe,” Dr. Cordeiro said at the annual meeting of the American Society of Hematology. “However, continuing with prospective systematic and long-term follow-up of these patients is required for better understanding of these late effects.”

Dr. Cordeiro and colleagues studied a total of 60 patients who were enrolled in a phase 1/2 trial at their center of a CD19-targeted CAR T-cell construct and survived for at least 1 year.

The goal of the study was to describe complications that occurred or persisted beyond 90 days after CAR T-cell infusion.

The cohort included 43 patients treated for NHL and 17 treated for CLL. Patients with CLL were followed for a median of 27.5 months, and patients with NHL were followed for a median of 23.8 months.

As of September 2018, 47 patients were still alive, including 15 patients with CLL (88%) and 32 patients with NHL (74%). Of the 17 patients who died, 10 died from progressive disease (2 from CLL and 8 from NHL), and 3 patients died from nonrelapse causes associated with complications from subsequent allogeneic stem cell transplantation (allo-HCT), including 1 patient from graft-versus-host disease (GVHD) and infection, 1 from infection, and 1 from cerberovascular accident/thrombotic microangiopathy.

Of 38 patients who received additional therapies, 17 had subsequent CAR T-cell infusions under the same protocol, and 16 went on to allo-HCT. Treatments for the remaining five patients were not specified.

Of the 22 patients who did not receive additional treatment for their primary malignancies, 21 were in ongoing complete remission following a single CAR T-cell infusion after a median follow-up of 28 months. However, two patients in this group did require treatment for therapy-related myelodysplastic syndrome (t-MDS). The remaining patient had a small CLL clone at last follow-up.

Late adverse events included the following:

• Late significant cytopenias in three of 19 patients evaluated.
• Late hypogammaglobulinemia in 29 of 48 evaluated patients.
• A total of 138 late infections in 31 of the 60 patients.
• Subsequent malignancies in 10 of the 60 patients, including t-MDS, nonmelanoma skin cancer, and noninvasive bladder cancer.
• Late immune-related events in seven patients.
• Late neurogenic/psychiatric events, including one case each of transient ischemic attack at 3.8 months, encephalopathy and myoclonic seizure in the setting of chemotherapy, and a fatal cerebrovascular accident in the setting of allo-HCT and thrombotic microangiopathy. These patients did not have acute neurotoxicity after CAR T-cell therapy, Dr. Cordeiro noted. In addition, three patients experienced exacerbation of depression or anxiety following infusion.
• GVHD in nine patients at a median time from allo-HCT to first CAR T-cell infusion of 46.3 months (range, 6.7 months to 11 years).

Focusing on those patients who achieve complete remissions after CAR T-cell therapy could help investigators isolate late events that are most likely related to CAR T cells, Dr. Cordeiro said.

Dr. Cordeiro reported having no relevant conflicts of interest.

SOURCE: Cordeiro A et al. ASH 2018, Abstract 223.

SAN DIEGO – Longer-term follow-up of patients treated with CD19-targeted chimeric antigen receptor (CAR) T cells for hematologic malignancies indicates that the altered cells are generally safe, with most late events being mild in nature and possibly related to therapies delivered before or after CAR T cells, investigators reported.

Among patients treated with CD19-targeted CAR T cells for relapsed or refractory chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma (NHL), the most frequent late adverse event was hypogammaglobulinemia, which occurred in 29 of 48 patients evaluated, reported Ana Cordeiro, MD, from the Fred Hutchinson Cancer Research Center in Seattle.

“Our results suggest that CD19 CAR T cells are safe,” Dr. Cordeiro said at the annual meeting of the American Society of Hematology. “However, continuing with prospective systematic and long-term follow-up of these patients is required for better understanding of these late effects.”

Dr. Cordeiro and colleagues studied a total of 60 patients who were enrolled in a phase 1/2 trial at their center of a CD19-targeted CAR T-cell construct and survived for at least 1 year.

The goal of the study was to describe complications that occurred or persisted beyond 90 days after CAR T-cell infusion.

The cohort included 43 patients treated for NHL and 17 treated for CLL. Patients with CLL were followed for a median of 27.5 months, and patients with NHL were followed for a median of 23.8 months.

As of September 2018, 47 patients were still alive, including 15 patients with CLL (88%) and 32 patients with NHL (74%). Of the 17 patients who died, 10 died from progressive disease (2 from CLL and 8 from NHL), and 3 patients died from nonrelapse causes associated with complications from subsequent allogeneic stem cell transplantation (allo-HCT), including 1 patient from graft-versus-host disease (GVHD) and infection, 1 from infection, and 1 from cerberovascular accident/thrombotic microangiopathy.

Of 38 patients who received additional therapies, 17 had subsequent CAR T-cell infusions under the same protocol, and 16 went on to allo-HCT. Treatments for the remaining five patients were not specified.

Of the 22 patients who did not receive additional treatment for their primary malignancies, 21 were in ongoing complete remission following a single CAR T-cell infusion after a median follow-up of 28 months. However, two patients in this group did require treatment for therapy-related myelodysplastic syndrome (t-MDS). The remaining patient had a small CLL clone at last follow-up.

Late adverse events included the following:

• Late significant cytopenias in three of 19 patients evaluated.
• Late hypogammaglobulinemia in 29 of 48 evaluated patients.
• A total of 138 late infections in 31 of the 60 patients.
• Subsequent malignancies in 10 of the 60 patients, including t-MDS, nonmelanoma skin cancer, and noninvasive bladder cancer.
• Late immune-related events in seven patients.
• Late neurogenic/psychiatric events, including one case each of transient ischemic attack at 3.8 months, encephalopathy and myoclonic seizure in the setting of chemotherapy, and a fatal cerebrovascular accident in the setting of allo-HCT and thrombotic microangiopathy. These patients did not have acute neurotoxicity after CAR T-cell therapy, Dr. Cordeiro noted. In addition, three patients experienced exacerbation of depression or anxiety following infusion.
• GVHD in nine patients at a median time from allo-HCT to first CAR T-cell infusion of 46.3 months (range, 6.7 months to 11 years).

Focusing on those patients who achieve complete remissions after CAR T-cell therapy could help investigators isolate late events that are most likely related to CAR T cells, Dr. Cordeiro said.

Dr. Cordeiro reported having no relevant conflicts of interest.

SOURCE: Cordeiro A et al. ASH 2018, Abstract 223.

SAN DIEGO – Longer-term follow-up of patients treated with CD19-targeted chimeric antigen receptor (CAR) T cells for hematologic malignancies indicates that the altered cells are generally safe, with most late events being mild in nature and possibly related to therapies delivered before or after CAR T cells, investigators reported.

Among patients treated with CD19-targeted CAR T cells for relapsed or refractory chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma (NHL), the most frequent late adverse event was hypogammaglobulinemia, which occurred in 29 of 48 patients evaluated, reported Ana Cordeiro, MD, from the Fred Hutchinson Cancer Research Center in Seattle.

“Our results suggest that CD19 CAR T cells are safe,” Dr. Cordeiro said at the annual meeting of the American Society of Hematology. “However, continuing with prospective systematic and long-term follow-up of these patients is required for better understanding of these late effects.”

Dr. Cordeiro and colleagues studied a total of 60 patients who were enrolled in a phase 1/2 trial at their center of a CD19-targeted CAR T-cell construct and survived for at least 1 year.

The goal of the study was to describe complications that occurred or persisted beyond 90 days after CAR T-cell infusion.

The cohort included 43 patients treated for NHL and 17 treated for CLL. Patients with CLL were followed for a median of 27.5 months, and patients with NHL were followed for a median of 23.8 months.

As of September 2018, 47 patients were still alive, including 15 patients with CLL (88%) and 32 patients with NHL (74%). Of the 17 patients who died, 10 died from progressive disease (2 from CLL and 8 from NHL), and 3 patients died from nonrelapse causes associated with complications from subsequent allogeneic stem cell transplantation (allo-HCT), including 1 patient from graft-versus-host disease (GVHD) and infection, 1 from infection, and 1 from cerberovascular accident/thrombotic microangiopathy.

Of 38 patients who received additional therapies, 17 had subsequent CAR T-cell infusions under the same protocol, and 16 went on to allo-HCT. Treatments for the remaining five patients were not specified.

Of the 22 patients who did not receive additional treatment for their primary malignancies, 21 were in ongoing complete remission following a single CAR T-cell infusion after a median follow-up of 28 months. However, two patients in this group did require treatment for therapy-related myelodysplastic syndrome (t-MDS). The remaining patient had a small CLL clone at last follow-up.

Late adverse events included the following:

• Late significant cytopenias in three of 19 patients evaluated.
• Late hypogammaglobulinemia in 29 of 48 evaluated patients.
• A total of 138 late infections in 31 of the 60 patients.
• Subsequent malignancies in 10 of the 60 patients, including t-MDS, nonmelanoma skin cancer, and noninvasive bladder cancer.
• Late immune-related events in seven patients.
• Late neurogenic/psychiatric events, including one case each of transient ischemic attack at 3.8 months, encephalopathy and myoclonic seizure in the setting of chemotherapy, and a fatal cerebrovascular accident in the setting of allo-HCT and thrombotic microangiopathy. These patients did not have acute neurotoxicity after CAR T-cell therapy, Dr. Cordeiro noted. In addition, three patients experienced exacerbation of depression or anxiety following infusion.
• GVHD in nine patients at a median time from allo-HCT to first CAR T-cell infusion of 46.3 months (range, 6.7 months to 11 years).

Focusing on those patients who achieve complete remissions after CAR T-cell therapy could help investigators isolate late events that are most likely related to CAR T cells, Dr. Cordeiro said.

Dr. Cordeiro reported having no relevant conflicts of interest.

SOURCE: Cordeiro A et al. ASH 2018, Abstract 223.

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 by Bill Branson

Survivors of childhood Hodgkin lymphoma (HL) have a 14-fold higher risk of second cancers compared to the general population, according to new research.

The subsequent malignant neoplasms (SMNs) observed in HL survivors tended to follow specific patterns depending on the patient’s age at treatment, sex, treatment modality, and region of the body treated.

And although the risk of SMNs appears to be somewhat lower for HL patients treated in more recent decades, it is still significantly higher than the risk in the general population, according to investigators.

Anna S. Holmqvist, MD, PhD, of the University of Lund in Sweden, and her colleagues conducted this research and reported the results in Cancer.

The investigators looked at data from the Late Effects Study Group, a multinational cohort of patients age 16 or younger who were treated for HL and other cancers from 1955 through 1986.

The current report is the third update from an expanded cohort including data on 1,136 patients with a median follow-up of 26.6 years. The median patient age at diagnosis was 11 years (range, birth to 16 years), and the patients were followed for 23,212 person-years after HL diagnosis.

In all, 162 patients developed 196 SMNs, including breast cancer (n=54), basal cell carcinoma (n=34), thyroid cancer (n=30), colorectal cancer (n=15), lung cancer (n=11), and other malignancies (n=40). The disease site was not available in 12 cases.

The cumulative incidence of any SMN 40 years after HL diagnosis was 26.4%. By age 50, the cumulative incidence of any SMN was 27.2%.

The standardized incidence ratio for the entire cohort was 14.0, compared with the general population as derived from the Surveillance, Epidemiology and End Results database.

Risk factors by cancer type

Females treated with chest radiotherapy between the ages of 10 and 16 who did not receive alkylating agents or received low doses of alkylating agents had the highest risk of developing breast cancer. The cumulative incidence of breast cancer by age 50 was 45.3% in these patients.

The patients with the highest risk for subsequent lung cancer were males treated with chest radiotherapy before age 10. The cumulative incidence of lung cancer by age 50 was 4.2% in these patients.

Patients with the highest risk for colorectal cancer had received abdominal/pelvic radiotherapy and high-dose alkylating agents. The cumulative incidence of colorectal cancer by age 50 was 9.5% in these patients.

Patients with the highest risk for thyroid cancers were females who had been treated with radiotherapy to the neck before the age of 10. The cumulative incidence of thyroid cancer by age 50 was 17.3% in these patients.

The investigators noted that HL patients treated more recently are likely to have received lower doses and volumes of radiotherapy compared to patients treated in the 1950s, ’60s and ’70s.

“However, for the cohort of patients treated between 1955 and 1986, it is clear that continued surveillance for SMNs is essential because their risk continues to increase as these survivors enter their fourth and subsequent decades of life,” the investigators wrote.

They did not report a funding source for this research or make any conflict-of-interest disclosures.

Photo by Bill Branson

Survivors of childhood Hodgkin lymphoma (HL) have a 14-fold higher risk of second cancers compared to the general population, according to new research.

The subsequent malignant neoplasms (SMNs) observed in HL survivors tended to follow specific patterns depending on the patient’s age at treatment, sex, treatment modality, and region of the body treated.

And although the risk of SMNs appears to be somewhat lower for HL patients treated in more recent decades, it is still significantly higher than the risk in the general population, according to investigators.

Anna S. Holmqvist, MD, PhD, of the University of Lund in Sweden, and her colleagues conducted this research and reported the results in Cancer.

The investigators looked at data from the Late Effects Study Group, a multinational cohort of patients age 16 or younger who were treated for HL and other cancers from 1955 through 1986.

The current report is the third update from an expanded cohort including data on 1,136 patients with a median follow-up of 26.6 years. The median patient age at diagnosis was 11 years (range, birth to 16 years), and the patients were followed for 23,212 person-years after HL diagnosis.

In all, 162 patients developed 196 SMNs, including breast cancer (n=54), basal cell carcinoma (n=34), thyroid cancer (n=30), colorectal cancer (n=15), lung cancer (n=11), and other malignancies (n=40). The disease site was not available in 12 cases.

The cumulative incidence of any SMN 40 years after HL diagnosis was 26.4%. By age 50, the cumulative incidence of any SMN was 27.2%.

The standardized incidence ratio for the entire cohort was 14.0, compared with the general population as derived from the Surveillance, Epidemiology and End Results database.

Risk factors by cancer type

Females treated with chest radiotherapy between the ages of 10 and 16 who did not receive alkylating agents or received low doses of alkylating agents had the highest risk of developing breast cancer. The cumulative incidence of breast cancer by age 50 was 45.3% in these patients.

The patients with the highest risk for subsequent lung cancer were males treated with chest radiotherapy before age 10. The cumulative incidence of lung cancer by age 50 was 4.2% in these patients.

Patients with the highest risk for colorectal cancer had received abdominal/pelvic radiotherapy and high-dose alkylating agents. The cumulative incidence of colorectal cancer by age 50 was 9.5% in these patients.

Patients with the highest risk for thyroid cancers were females who had been treated with radiotherapy to the neck before the age of 10. The cumulative incidence of thyroid cancer by age 50 was 17.3% in these patients.

The investigators noted that HL patients treated more recently are likely to have received lower doses and volumes of radiotherapy compared to patients treated in the 1950s, ’60s and ’70s.

“However, for the cohort of patients treated between 1955 and 1986, it is clear that continued surveillance for SMNs is essential because their risk continues to increase as these survivors enter their fourth and subsequent decades of life,” the investigators wrote.

They did not report a funding source for this research or make any conflict-of-interest disclosures.

Photo by Bill Branson

Survivors of childhood Hodgkin lymphoma (HL) have a 14-fold higher risk of second cancers compared to the general population, according to new research.

The subsequent malignant neoplasms (SMNs) observed in HL survivors tended to follow specific patterns depending on the patient’s age at treatment, sex, treatment modality, and region of the body treated.

And although the risk of SMNs appears to be somewhat lower for HL patients treated in more recent decades, it is still significantly higher than the risk in the general population, according to investigators.

Anna S. Holmqvist, MD, PhD, of the University of Lund in Sweden, and her colleagues conducted this research and reported the results in Cancer.

The investigators looked at data from the Late Effects Study Group, a multinational cohort of patients age 16 or younger who were treated for HL and other cancers from 1955 through 1986.

The current report is the third update from an expanded cohort including data on 1,136 patients with a median follow-up of 26.6 years. The median patient age at diagnosis was 11 years (range, birth to 16 years), and the patients were followed for 23,212 person-years after HL diagnosis.

In all, 162 patients developed 196 SMNs, including breast cancer (n=54), basal cell carcinoma (n=34), thyroid cancer (n=30), colorectal cancer (n=15), lung cancer (n=11), and other malignancies (n=40). The disease site was not available in 12 cases.

The cumulative incidence of any SMN 40 years after HL diagnosis was 26.4%. By age 50, the cumulative incidence of any SMN was 27.2%.

The standardized incidence ratio for the entire cohort was 14.0, compared with the general population as derived from the Surveillance, Epidemiology and End Results database.

Risk factors by cancer type

Females treated with chest radiotherapy between the ages of 10 and 16 who did not receive alkylating agents or received low doses of alkylating agents had the highest risk of developing breast cancer. The cumulative incidence of breast cancer by age 50 was 45.3% in these patients.

The patients with the highest risk for subsequent lung cancer were males treated with chest radiotherapy before age 10. The cumulative incidence of lung cancer by age 50 was 4.2% in these patients.

Patients with the highest risk for colorectal cancer had received abdominal/pelvic radiotherapy and high-dose alkylating agents. The cumulative incidence of colorectal cancer by age 50 was 9.5% in these patients.

Patients with the highest risk for thyroid cancers were females who had been treated with radiotherapy to the neck before the age of 10. The cumulative incidence of thyroid cancer by age 50 was 17.3% in these patients.

The investigators noted that HL patients treated more recently are likely to have received lower doses and volumes of radiotherapy compared to patients treated in the 1950s, ’60s and ’70s.

“However, for the cohort of patients treated between 1955 and 1986, it is clear that continued surveillance for SMNs is essential because their risk continues to increase as these survivors enter their fourth and subsequent decades of life,” the investigators wrote.

They did not report a funding source for this research or make any conflict-of-interest disclosures.

SAN DIEGO – Nivolumab plus brentuximab vedotin may be a new treatment option for patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL), according to investigators from the CheckMate 436 trial.

Interim results from this phase 1/2 trial revealed an overall response rate of 70%, including a complete response rate of 27%.

“It’s very promising ... to see this level of activity in this advanced, relapsed/refractory population,” said Joseph E. Eid, MD, senior vice president of Bristol-Myers Squibb, which is sponsoring CheckMate 436 in collaboration with Seattle Genetics.

Dr. Eid noted that adverse events (AEs) observed with this regimen were consistent with the safety profiles of nivolumab and brentuximab vedotin alone.

These results were presented as a poster at the annual meeting of the American Society of Hematology.

Dr. Eid noted that patients with relapsed or refractory PMBCL have limited treatment options.

“The initial therapy works well in 70% to 80% of patients but the patients who fail don’t have good options,” he said.

Prior research has shown that PMBCL is often characterized by overexpression of the PD-1 ligands PD-L1 and PD-L2, and most PMBCL expresses CD30.

Dr. Eid said CheckMate 436 (NCT02581631) was designed to “take advantage” of these characteristics by employing the anti-PD-1 checkpoint inhibitor nivolumab and the anti-CD30 antibody-drug conjugate brentuximab vedotin.

The interim analysis of this trial included 30 patients with relapsed/refractory PMBCL. Their median age at enrollment was 35.5 and 57% of patients were female. More than half of the patients (60%) had refractory disease, 23% had relapsed disease, and 17% had both.

The median number of prior therapies was two and 13% of patients had prior autologous stem cell transplant.

The patients received nivolumab at 240 mg and brentuximab vedotin at 1.8 mg/kg every 3 weeks until progression or unacceptable toxicity.

At a median follow-up of 6.1 months, 10 patients were still on treatment. Reasons for discontinuation included maximum clinical benefit, disease progression, AEs unrelated to treatment, patient request, and other concerns.

The rate of treatment-related AEs was 83%. The most common of these were neutropenia (27%), peripheral neuropathy (20%), hyperthyroidism (13%), rash (10%), and thrombocytopenia (10%).

Grade 3-4 treatment-related AEs included neutropenia (27%), thrombocytopenia (7%), decreased neutrophil count (7%), hypersensitivity (3%), diarrhea (3%), and maculopapular rash (3%).

The rate of serious treatment-related AEs was 10%. This included grade 3-4 diarrhea and maculopapular rash and grade 5 acute kidney injury.

The acute kidney injury was the only fatal AE considered treatment related. There were three other deaths in the trial, but they were considered unrelated to treatment.

The complete response rate was 27% (n = 8), and the partial response rate was 43% (n = 13), for an overall response rate of 70% (n = 21).

“The early indication is that 70% response is a pretty good outcome in a relapsed/refractory population that, otherwise, their outcome is pretty dismal,” Dr. Eid said.

Ten percent of patients (n = 3) had stable disease, 13% (n = 4) progressed, and investigators were unable to determine the status for 7% of patients (n = 2).

The median time to response was 1.3 months, and the median time to complete response was 3.0 months. The median duration of response and complete response were not reached.

Overall and progression-free survival data are not yet mature.

Still, the investigators concluded that nivolumab and brentuximab vedotin “may provide a new treatment option” for patients with relapsed/refractory PMBCL.

This trial is supported by Bristol-Myers Squibb in collaboration with Seattle Genetics. Investigators reported relationships with Bristol-Myers Squibb, Seattle Genetics, and a range of other companies.

[email protected]

SOURCE: Moskowitz AJ et al. ASH 2018. Abstract 1691.

SAN DIEGO – Nivolumab plus brentuximab vedotin may be a new treatment option for patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL), according to investigators from the CheckMate 436 trial.

Interim results from this phase 1/2 trial revealed an overall response rate of 70%, including a complete response rate of 27%.

“It’s very promising ... to see this level of activity in this advanced, relapsed/refractory population,” said Joseph E. Eid, MD, senior vice president of Bristol-Myers Squibb, which is sponsoring CheckMate 436 in collaboration with Seattle Genetics.

Dr. Eid noted that adverse events (AEs) observed with this regimen were consistent with the safety profiles of nivolumab and brentuximab vedotin alone.

These results were presented as a poster at the annual meeting of the American Society of Hematology.

Dr. Eid noted that patients with relapsed or refractory PMBCL have limited treatment options.

“The initial therapy works well in 70% to 80% of patients but the patients who fail don’t have good options,” he said.

Prior research has shown that PMBCL is often characterized by overexpression of the PD-1 ligands PD-L1 and PD-L2, and most PMBCL expresses CD30.

Dr. Eid said CheckMate 436 (NCT02581631) was designed to “take advantage” of these characteristics by employing the anti-PD-1 checkpoint inhibitor nivolumab and the anti-CD30 antibody-drug conjugate brentuximab vedotin.

The interim analysis of this trial included 30 patients with relapsed/refractory PMBCL. Their median age at enrollment was 35.5 and 57% of patients were female. More than half of the patients (60%) had refractory disease, 23% had relapsed disease, and 17% had both.

The median number of prior therapies was two and 13% of patients had prior autologous stem cell transplant.

The patients received nivolumab at 240 mg and brentuximab vedotin at 1.8 mg/kg every 3 weeks until progression or unacceptable toxicity.

At a median follow-up of 6.1 months, 10 patients were still on treatment. Reasons for discontinuation included maximum clinical benefit, disease progression, AEs unrelated to treatment, patient request, and other concerns.

The rate of treatment-related AEs was 83%. The most common of these were neutropenia (27%), peripheral neuropathy (20%), hyperthyroidism (13%), rash (10%), and thrombocytopenia (10%).

Grade 3-4 treatment-related AEs included neutropenia (27%), thrombocytopenia (7%), decreased neutrophil count (7%), hypersensitivity (3%), diarrhea (3%), and maculopapular rash (3%).

The rate of serious treatment-related AEs was 10%. This included grade 3-4 diarrhea and maculopapular rash and grade 5 acute kidney injury.

The acute kidney injury was the only fatal AE considered treatment related. There were three other deaths in the trial, but they were considered unrelated to treatment.

The complete response rate was 27% (n = 8), and the partial response rate was 43% (n = 13), for an overall response rate of 70% (n = 21).

“The early indication is that 70% response is a pretty good outcome in a relapsed/refractory population that, otherwise, their outcome is pretty dismal,” Dr. Eid said.

Ten percent of patients (n = 3) had stable disease, 13% (n = 4) progressed, and investigators were unable to determine the status for 7% of patients (n = 2).

The median time to response was 1.3 months, and the median time to complete response was 3.0 months. The median duration of response and complete response were not reached.

Overall and progression-free survival data are not yet mature.

Still, the investigators concluded that nivolumab and brentuximab vedotin “may provide a new treatment option” for patients with relapsed/refractory PMBCL.

This trial is supported by Bristol-Myers Squibb in collaboration with Seattle Genetics. Investigators reported relationships with Bristol-Myers Squibb, Seattle Genetics, and a range of other companies.

[email protected]

SOURCE: Moskowitz AJ et al. ASH 2018. Abstract 1691.

SAN DIEGO – Nivolumab plus brentuximab vedotin may be a new treatment option for patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL), according to investigators from the CheckMate 436 trial.

Interim results from this phase 1/2 trial revealed an overall response rate of 70%, including a complete response rate of 27%.

“It’s very promising ... to see this level of activity in this advanced, relapsed/refractory population,” said Joseph E. Eid, MD, senior vice president of Bristol-Myers Squibb, which is sponsoring CheckMate 436 in collaboration with Seattle Genetics.

Dr. Eid noted that adverse events (AEs) observed with this regimen were consistent with the safety profiles of nivolumab and brentuximab vedotin alone.

These results were presented as a poster at the annual meeting of the American Society of Hematology.

Dr. Eid noted that patients with relapsed or refractory PMBCL have limited treatment options.

“The initial therapy works well in 70% to 80% of patients but the patients who fail don’t have good options,” he said.

Prior research has shown that PMBCL is often characterized by overexpression of the PD-1 ligands PD-L1 and PD-L2, and most PMBCL expresses CD30.

Dr. Eid said CheckMate 436 (NCT02581631) was designed to “take advantage” of these characteristics by employing the anti-PD-1 checkpoint inhibitor nivolumab and the anti-CD30 antibody-drug conjugate brentuximab vedotin.

The interim analysis of this trial included 30 patients with relapsed/refractory PMBCL. Their median age at enrollment was 35.5 and 57% of patients were female. More than half of the patients (60%) had refractory disease, 23% had relapsed disease, and 17% had both.

The median number of prior therapies was two and 13% of patients had prior autologous stem cell transplant.

The patients received nivolumab at 240 mg and brentuximab vedotin at 1.8 mg/kg every 3 weeks until progression or unacceptable toxicity.

At a median follow-up of 6.1 months, 10 patients were still on treatment. Reasons for discontinuation included maximum clinical benefit, disease progression, AEs unrelated to treatment, patient request, and other concerns.

The rate of treatment-related AEs was 83%. The most common of these were neutropenia (27%), peripheral neuropathy (20%), hyperthyroidism (13%), rash (10%), and thrombocytopenia (10%).

Grade 3-4 treatment-related AEs included neutropenia (27%), thrombocytopenia (7%), decreased neutrophil count (7%), hypersensitivity (3%), diarrhea (3%), and maculopapular rash (3%).

The rate of serious treatment-related AEs was 10%. This included grade 3-4 diarrhea and maculopapular rash and grade 5 acute kidney injury.

The acute kidney injury was the only fatal AE considered treatment related. There were three other deaths in the trial, but they were considered unrelated to treatment.

The complete response rate was 27% (n = 8), and the partial response rate was 43% (n = 13), for an overall response rate of 70% (n = 21).

“The early indication is that 70% response is a pretty good outcome in a relapsed/refractory population that, otherwise, their outcome is pretty dismal,” Dr. Eid said.

Ten percent of patients (n = 3) had stable disease, 13% (n = 4) progressed, and investigators were unable to determine the status for 7% of patients (n = 2).

The median time to response was 1.3 months, and the median time to complete response was 3.0 months. The median duration of response and complete response were not reached.

Overall and progression-free survival data are not yet mature.

Still, the investigators concluded that nivolumab and brentuximab vedotin “may provide a new treatment option” for patients with relapsed/refractory PMBCL.

This trial is supported by Bristol-Myers Squibb in collaboration with Seattle Genetics. Investigators reported relationships with Bristol-Myers Squibb, Seattle Genetics, and a range of other companies.

[email protected]

SOURCE: Moskowitz AJ et al. ASH 2018. Abstract 1691.

SAN DIEGO – A newly approved treatment regimen provides a survival benefit over standard therapy for patients with CD30-positive peripheral T-cell lymphomas (PTCLs), according to new research presented at the annual meeting of the American Society of Hematology.

In the ECHELON-2 trial, patients who received brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone (CHP) had superior progression-free survival (PFS) and overall survival (OS), compared with patients who received standard treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

These results supported the recent U.S. approval of BV in combination with CHP for adults with previously untreated, systemic anaplastic large cell lymphoma or other CD30-expressing PTCLs.

“ECHELON-2 is the first prospective trial in peripheral T-cell lymphoma to show an overall survival benefit over CHOP,” said Steven M. Horwitz, MD, of Memorial Sloan Kettering Cancer Center, with locations in New York and New Jersey.

Dr. Horwitz presented data from this trial at the ASH meeting. Results were simultaneously published in the Lancet (2018 Dec 3. doi: 10.1016/S0140-6736[18]32984-2).

ECHELON-2 (NCT01777152) enrolled 452 patients with previously untreated, CD30-positive PTCL. Subtypes included ALK-positive or ALK-negative systemic anaplastic large-cell lymphoma, PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, enteropathy-associated T-cell lymphoma, and adult T-cell leukemia/lymphoma.

Patients were randomized to receive BV-CHP plus placebo (n = 226) or CHOP plus placebo (n = 226) every 3 weeks for six to eight cycles.

At baseline, the median age was 58 in the BV-CHP arm and the CHOP arm. The majority of patients were male – 59% in the BV-CHP arm and 67% in the CHOP arm – and most patients had stage III/IV disease, 81% and 80%, respectively.

In all, 89% of patients in the BV-CHP arm and 81% in the CHOP arm completed six or more cycles of their assigned treatment.

The overall response rate was 83% in the BV-CHP arm and 72% in the CHOP arm (P = .0032). The complete response rates were 68% and 56%, respectively (P = .0066).

At a median follow-up of 36.2 months, the median PFS was 48.2 months in the BV-CHP arm and 20.8 months in the CHOP arm. The rate of death or progression was 42% in the BV-CHP arm and 55% in the CHOP arm (hazard ratio = 0.71, P = .011).

At a median follow-up of 42.1 months, the median OS was not reached in either treatment arm. The rate of death was 23% in the BV-CHP arm and 32% in the CHOP arm (HR = 0.66, P = .0244).

Dr. Horwitz noted that this study was not powered to determine differences in PFS or OS by PTCL subtypes.

BV-CHP had a safety profile comparable with that of CHOP, Dr. Horwitz said.

The rate of adverse events (AEs) was 99% in the BV-CHP arm and 98% in the CHOP arm. Grade 3 or higher AEs occurred in 66% and 65% of patients, respectively. Serious AEs occurred in 39% and 38%, respectively.

Three percent of patients in the BV-CHP arm and 4% of those in the CHOP arm had fatal AEs.

The study was funded by Seattle Genetics, Millennium Pharmaceuticals, and the National Institutes of Health. Dr. Horwitz reported relationships with Seattle Genetics, Millennium Pharmaceuticals, and other companies.

[email protected]

SOURCE: Horwitz S et al. ASH 2018, Abstract 997.

SAN DIEGO – A newly approved treatment regimen provides a survival benefit over standard therapy for patients with CD30-positive peripheral T-cell lymphomas (PTCLs), according to new research presented at the annual meeting of the American Society of Hematology.

In the ECHELON-2 trial, patients who received brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone (CHP) had superior progression-free survival (PFS) and overall survival (OS), compared with patients who received standard treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

These results supported the recent U.S. approval of BV in combination with CHP for adults with previously untreated, systemic anaplastic large cell lymphoma or other CD30-expressing PTCLs.

“ECHELON-2 is the first prospective trial in peripheral T-cell lymphoma to show an overall survival benefit over CHOP,” said Steven M. Horwitz, MD, of Memorial Sloan Kettering Cancer Center, with locations in New York and New Jersey.

Dr. Horwitz presented data from this trial at the ASH meeting. Results were simultaneously published in the Lancet (2018 Dec 3. doi: 10.1016/S0140-6736[18]32984-2).

ECHELON-2 (NCT01777152) enrolled 452 patients with previously untreated, CD30-positive PTCL. Subtypes included ALK-positive or ALK-negative systemic anaplastic large-cell lymphoma, PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, enteropathy-associated T-cell lymphoma, and adult T-cell leukemia/lymphoma.

Patients were randomized to receive BV-CHP plus placebo (n = 226) or CHOP plus placebo (n = 226) every 3 weeks for six to eight cycles.

At baseline, the median age was 58 in the BV-CHP arm and the CHOP arm. The majority of patients were male – 59% in the BV-CHP arm and 67% in the CHOP arm – and most patients had stage III/IV disease, 81% and 80%, respectively.

In all, 89% of patients in the BV-CHP arm and 81% in the CHOP arm completed six or more cycles of their assigned treatment.

The overall response rate was 83% in the BV-CHP arm and 72% in the CHOP arm (P = .0032). The complete response rates were 68% and 56%, respectively (P = .0066).

At a median follow-up of 36.2 months, the median PFS was 48.2 months in the BV-CHP arm and 20.8 months in the CHOP arm. The rate of death or progression was 42% in the BV-CHP arm and 55% in the CHOP arm (hazard ratio = 0.71, P = .011).

At a median follow-up of 42.1 months, the median OS was not reached in either treatment arm. The rate of death was 23% in the BV-CHP arm and 32% in the CHOP arm (HR = 0.66, P = .0244).

Dr. Horwitz noted that this study was not powered to determine differences in PFS or OS by PTCL subtypes.

BV-CHP had a safety profile comparable with that of CHOP, Dr. Horwitz said.

The rate of adverse events (AEs) was 99% in the BV-CHP arm and 98% in the CHOP arm. Grade 3 or higher AEs occurred in 66% and 65% of patients, respectively. Serious AEs occurred in 39% and 38%, respectively.

Three percent of patients in the BV-CHP arm and 4% of those in the CHOP arm had fatal AEs.

The study was funded by Seattle Genetics, Millennium Pharmaceuticals, and the National Institutes of Health. Dr. Horwitz reported relationships with Seattle Genetics, Millennium Pharmaceuticals, and other companies.

[email protected]

SOURCE: Horwitz S et al. ASH 2018, Abstract 997.

SAN DIEGO – A newly approved treatment regimen provides a survival benefit over standard therapy for patients with CD30-positive peripheral T-cell lymphomas (PTCLs), according to new research presented at the annual meeting of the American Society of Hematology.

In the ECHELON-2 trial, patients who received brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone (CHP) had superior progression-free survival (PFS) and overall survival (OS), compared with patients who received standard treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

These results supported the recent U.S. approval of BV in combination with CHP for adults with previously untreated, systemic anaplastic large cell lymphoma or other CD30-expressing PTCLs.

“ECHELON-2 is the first prospective trial in peripheral T-cell lymphoma to show an overall survival benefit over CHOP,” said Steven M. Horwitz, MD, of Memorial Sloan Kettering Cancer Center, with locations in New York and New Jersey.

Dr. Horwitz presented data from this trial at the ASH meeting. Results were simultaneously published in the Lancet (2018 Dec 3. doi: 10.1016/S0140-6736[18]32984-2).

ECHELON-2 (NCT01777152) enrolled 452 patients with previously untreated, CD30-positive PTCL. Subtypes included ALK-positive or ALK-negative systemic anaplastic large-cell lymphoma, PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, enteropathy-associated T-cell lymphoma, and adult T-cell leukemia/lymphoma.

Patients were randomized to receive BV-CHP plus placebo (n = 226) or CHOP plus placebo (n = 226) every 3 weeks for six to eight cycles.

At baseline, the median age was 58 in the BV-CHP arm and the CHOP arm. The majority of patients were male – 59% in the BV-CHP arm and 67% in the CHOP arm – and most patients had stage III/IV disease, 81% and 80%, respectively.

In all, 89% of patients in the BV-CHP arm and 81% in the CHOP arm completed six or more cycles of their assigned treatment.

The overall response rate was 83% in the BV-CHP arm and 72% in the CHOP arm (P = .0032). The complete response rates were 68% and 56%, respectively (P = .0066).

At a median follow-up of 36.2 months, the median PFS was 48.2 months in the BV-CHP arm and 20.8 months in the CHOP arm. The rate of death or progression was 42% in the BV-CHP arm and 55% in the CHOP arm (hazard ratio = 0.71, P = .011).

At a median follow-up of 42.1 months, the median OS was not reached in either treatment arm. The rate of death was 23% in the BV-CHP arm and 32% in the CHOP arm (HR = 0.66, P = .0244).

Dr. Horwitz noted that this study was not powered to determine differences in PFS or OS by PTCL subtypes.

BV-CHP had a safety profile comparable with that of CHOP, Dr. Horwitz said.

The rate of adverse events (AEs) was 99% in the BV-CHP arm and 98% in the CHOP arm. Grade 3 or higher AEs occurred in 66% and 65% of patients, respectively. Serious AEs occurred in 39% and 38%, respectively.

Three percent of patients in the BV-CHP arm and 4% of those in the CHOP arm had fatal AEs.

The study was funded by Seattle Genetics, Millennium Pharmaceuticals, and the National Institutes of Health. Dr. Horwitz reported relationships with Seattle Genetics, Millennium Pharmaceuticals, and other companies.

[email protected]

SOURCE: Horwitz S et al. ASH 2018, Abstract 997.

Photo from Business Wire

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for brentuximab vedotin (BV).

The CHMP has recommended approval for BV (Adcetris) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) to treat adults with previously untreated, CD30+, stage IV Hodgkin lymphoma (HL).

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of a CHMP recommendation.

BV is already EC-approved to treat adults with:

• CD30+ HL at increased risk of relapse or progression following autologous stem cell transplant (ASCT)
• Relapsed or refractory, CD30+ HL following ASCT or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option
• Relapsed or refractory systemic anaplastic large-cell lymphoma
• CD30+ cutaneous T-cell lymphoma after at least one prior systemic therapy.

Phase 3 trial

The CHMP’s recommendation to approve BV in combination with AVD is supported by the phase 3 ECHELON-1 trial (NCT01712490).

Result from ECHELON-1 were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.

In this trial, researchers compared BV plus AVD (BV+AVD) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for 1334 patients with advanced HL.

The primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.

According to an independent review committee, BV+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.

The 2-year modified PFS rate was 82.1% in the BV+AVD arm and 77.2% in the ABVD arm.

There was no significant difference between the treatment arms when it came to response rates or overall survival.

The objective response rate was 86% in the BV+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).

The interim 2-year overall survival rate was 97% in the BV+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).

The overall incidence of adverse events (AEs) was 99% in the BV+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.

Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with BV+AVD, while pulmonary toxicity was more common with ABVD.

The ECHELON-1 trial was sponsored by Millennium Pharmaceuticals, Inc. (a Takeda company) in collaboration with Seattle Genetics, Inc.

Photo from Business Wire

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for brentuximab vedotin (BV).

The CHMP has recommended approval for BV (Adcetris) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) to treat adults with previously untreated, CD30+, stage IV Hodgkin lymphoma (HL).

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of a CHMP recommendation.

BV is already EC-approved to treat adults with:

• CD30+ HL at increased risk of relapse or progression following autologous stem cell transplant (ASCT)
• Relapsed or refractory, CD30+ HL following ASCT or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option
• Relapsed or refractory systemic anaplastic large-cell lymphoma
• CD30+ cutaneous T-cell lymphoma after at least one prior systemic therapy.

Phase 3 trial

The CHMP’s recommendation to approve BV in combination with AVD is supported by the phase 3 ECHELON-1 trial (NCT01712490).

Result from ECHELON-1 were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.

In this trial, researchers compared BV plus AVD (BV+AVD) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for 1334 patients with advanced HL.

The primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.

According to an independent review committee, BV+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.

The 2-year modified PFS rate was 82.1% in the BV+AVD arm and 77.2% in the ABVD arm.

There was no significant difference between the treatment arms when it came to response rates or overall survival.

The objective response rate was 86% in the BV+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).

The interim 2-year overall survival rate was 97% in the BV+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).

The overall incidence of adverse events (AEs) was 99% in the BV+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.

Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with BV+AVD, while pulmonary toxicity was more common with ABVD.

The ECHELON-1 trial was sponsored by Millennium Pharmaceuticals, Inc. (a Takeda company) in collaboration with Seattle Genetics, Inc.

Photo from Business Wire

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for brentuximab vedotin (BV).

The CHMP has recommended approval for BV (Adcetris) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) to treat adults with previously untreated, CD30+, stage IV Hodgkin lymphoma (HL).

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of a CHMP recommendation.

BV is already EC-approved to treat adults with:

• CD30+ HL at increased risk of relapse or progression following autologous stem cell transplant (ASCT)
• Relapsed or refractory, CD30+ HL following ASCT or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option
• Relapsed or refractory systemic anaplastic large-cell lymphoma
• CD30+ cutaneous T-cell lymphoma after at least one prior systemic therapy.

Phase 3 trial

The CHMP’s recommendation to approve BV in combination with AVD is supported by the phase 3 ECHELON-1 trial (NCT01712490).

Result from ECHELON-1 were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.

In this trial, researchers compared BV plus AVD (BV+AVD) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for 1334 patients with advanced HL.

The primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.

According to an independent review committee, BV+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.

The 2-year modified PFS rate was 82.1% in the BV+AVD arm and 77.2% in the ABVD arm.

There was no significant difference between the treatment arms when it came to response rates or overall survival.

The objective response rate was 86% in the BV+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).

The interim 2-year overall survival rate was 97% in the BV+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).

The overall incidence of adverse events (AEs) was 99% in the BV+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.

Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with BV+AVD, while pulmonary toxicity was more common with ABVD.

The ECHELON-1 trial was sponsored by Millennium Pharmaceuticals, Inc. (a Takeda company) in collaboration with Seattle Genetics, Inc.

©ASH/Scott Morgan 2018

SAN DIEGO—In a phase 3 trial, ibrutinib plus rituximab (IR) improved survival when compared with standard chemoimmunotherapy in patients younger than 70 with untreated chronic lymphocytic leukemia (CLL).

Patients who received IR had superior progression-free survival (PFS) and overall survival compared to patients who received fludarabine, cyclophosphamide, and rituximab (FCR).

“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” said Tait D. Shanafelt, MD, of Stanford University in California.

In fact, the study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.

He presented the results during the late-breaking abstract session at the 2018 ASH Annual Meeting (abstract LBA-4*).

The trial (NCT02048813) included 529 patients age 70 or younger with previously untreated CLL. They were randomized on a 2:1 basis to either six cycles of FCR according to standard protocols (n=175) or IR (n=354).

IR consisted of ibrutinib given at 420 mg daily for each 28-day cycle and rituximab given at 50 mg/m² on day 1 of cycle 2, at 325 mg/m² on day 2 of cycle 2, and at 500 mg/m² on day 1 for cycles 3 to 7.

From cycle 8 on, patients in the IR arm received daily ibrutinib at 420 mg until disease progression.

Dr. Shanafelt said patient characteristics were well-balanced between the treatment arms.

He presented results from both an intent-to-treat (ITT) analysis and a per-protocol analysis excluding 22 patients in the IR arm and nine patients in the FCR arm who were randomized but later found not to meet eligibility criteria.

PFS

In the ITT analysis, there were 37 cases of progression or death in the IR arm and 40 cases in the FCR arm. This difference translated into a hazard ratio (HR) for progression or death of 0.35 with IR (P<0.00001).

In the per-protocol analysis, there were 33 cases of progression or death in the IR arm and 39 cases in the FCR arm. The HR was 0.32 favoring IR (P<0.00001).

In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.

PFS was significantly better with IR in patients with unmutated IGHV (HR= 0.26, P<0.00001) but not in patients with mutated IGHV (HR=0.44, P=0.07).

Overall survival

In the ITT analysis, there were four deaths in the IR arm and 10 in the FCR arm (HR=0.17, P<0.0003).

In the per-protocol analysis, there were three deaths in the IR arm and 10 deaths in the FCR arm (HR=0.13, P<0.0001).

Dr. Shanafelt noted that, although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning the rate of death in the FCR arm was five-fold higher than in the IR arm.

Safety and cost

Grade 3 or greater treatment-related adverse events (AEs) occurred in 58.5% of patients in the IR arm and 72.1% of patients in the FCR arm (P=0.004).

Specific AEs that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P<0.001 for all comparisons).

AEs that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P=0.04) and hypertension (7.4% vs. 1.9%, P=0.01).

Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost. The monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.

“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.

The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, AbbVie, Pharmacyclics, and Janssen.

*Data in the abstract differ from the presentation.

©ASH/Scott Morgan 2018

SAN DIEGO—In a phase 3 trial, ibrutinib plus rituximab (IR) improved survival when compared with standard chemoimmunotherapy in patients younger than 70 with untreated chronic lymphocytic leukemia (CLL).

Patients who received IR had superior progression-free survival (PFS) and overall survival compared to patients who received fludarabine, cyclophosphamide, and rituximab (FCR).

“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” said Tait D. Shanafelt, MD, of Stanford University in California.

In fact, the study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.

He presented the results during the late-breaking abstract session at the 2018 ASH Annual Meeting (abstract LBA-4*).

The trial (NCT02048813) included 529 patients age 70 or younger with previously untreated CLL. They were randomized on a 2:1 basis to either six cycles of FCR according to standard protocols (n=175) or IR (n=354).

IR consisted of ibrutinib given at 420 mg daily for each 28-day cycle and rituximab given at 50 mg/m² on day 1 of cycle 2, at 325 mg/m² on day 2 of cycle 2, and at 500 mg/m² on day 1 for cycles 3 to 7.

From cycle 8 on, patients in the IR arm received daily ibrutinib at 420 mg until disease progression.

Dr. Shanafelt said patient characteristics were well-balanced between the treatment arms.

He presented results from both an intent-to-treat (ITT) analysis and a per-protocol analysis excluding 22 patients in the IR arm and nine patients in the FCR arm who were randomized but later found not to meet eligibility criteria.

PFS

In the ITT analysis, there were 37 cases of progression or death in the IR arm and 40 cases in the FCR arm. This difference translated into a hazard ratio (HR) for progression or death of 0.35 with IR (P<0.00001).

In the per-protocol analysis, there were 33 cases of progression or death in the IR arm and 39 cases in the FCR arm. The HR was 0.32 favoring IR (P<0.00001).

In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.

PFS was significantly better with IR in patients with unmutated IGHV (HR= 0.26, P<0.00001) but not in patients with mutated IGHV (HR=0.44, P=0.07).

Overall survival

In the ITT analysis, there were four deaths in the IR arm and 10 in the FCR arm (HR=0.17, P<0.0003).

In the per-protocol analysis, there were three deaths in the IR arm and 10 deaths in the FCR arm (HR=0.13, P<0.0001).

Dr. Shanafelt noted that, although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning the rate of death in the FCR arm was five-fold higher than in the IR arm.

Safety and cost

Grade 3 or greater treatment-related adverse events (AEs) occurred in 58.5% of patients in the IR arm and 72.1% of patients in the FCR arm (P=0.004).

Specific AEs that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P<0.001 for all comparisons).

AEs that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P=0.04) and hypertension (7.4% vs. 1.9%, P=0.01).

Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost. The monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.

“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.

The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, AbbVie, Pharmacyclics, and Janssen.

*Data in the abstract differ from the presentation.

©ASH/Scott Morgan 2018

SAN DIEGO—In a phase 3 trial, ibrutinib plus rituximab (IR) improved survival when compared with standard chemoimmunotherapy in patients younger than 70 with untreated chronic lymphocytic leukemia (CLL).

Patients who received IR had superior progression-free survival (PFS) and overall survival compared to patients who received fludarabine, cyclophosphamide, and rituximab (FCR).

“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” said Tait D. Shanafelt, MD, of Stanford University in California.

In fact, the study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.

He presented the results during the late-breaking abstract session at the 2018 ASH Annual Meeting (abstract LBA-4*).

The trial (NCT02048813) included 529 patients age 70 or younger with previously untreated CLL. They were randomized on a 2:1 basis to either six cycles of FCR according to standard protocols (n=175) or IR (n=354).

IR consisted of ibrutinib given at 420 mg daily for each 28-day cycle and rituximab given at 50 mg/m² on day 1 of cycle 2, at 325 mg/m² on day 2 of cycle 2, and at 500 mg/m² on day 1 for cycles 3 to 7.

From cycle 8 on, patients in the IR arm received daily ibrutinib at 420 mg until disease progression.

Dr. Shanafelt said patient characteristics were well-balanced between the treatment arms.

He presented results from both an intent-to-treat (ITT) analysis and a per-protocol analysis excluding 22 patients in the IR arm and nine patients in the FCR arm who were randomized but later found not to meet eligibility criteria.

PFS

In the ITT analysis, there were 37 cases of progression or death in the IR arm and 40 cases in the FCR arm. This difference translated into a hazard ratio (HR) for progression or death of 0.35 with IR (P<0.00001).

In the per-protocol analysis, there were 33 cases of progression or death in the IR arm and 39 cases in the FCR arm. The HR was 0.32 favoring IR (P<0.00001).

In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.

PFS was significantly better with IR in patients with unmutated IGHV (HR= 0.26, P<0.00001) but not in patients with mutated IGHV (HR=0.44, P=0.07).

Overall survival

In the ITT analysis, there were four deaths in the IR arm and 10 in the FCR arm (HR=0.17, P<0.0003).

In the per-protocol analysis, there were three deaths in the IR arm and 10 deaths in the FCR arm (HR=0.13, P<0.0001).

Dr. Shanafelt noted that, although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning the rate of death in the FCR arm was five-fold higher than in the IR arm.

Safety and cost

Grade 3 or greater treatment-related adverse events (AEs) occurred in 58.5% of patients in the IR arm and 72.1% of patients in the FCR arm (P=0.004).

Specific AEs that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P<0.001 for all comparisons).

AEs that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P=0.04) and hypertension (7.4% vs. 1.9%, P=0.01).

Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost. The monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.

“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.

The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, AbbVie, Pharmacyclics, and Janssen.

*Data in the abstract differ from the presentation.

SAN DIEGO – The combination of ibrutinib and rituximab was associated with a two-thirds reduction in chronic lymphocytic leukemia (CLL) progression, compared with standard chemoimmunotherapy in patients younger than 70 years old, interim results of a phase 3 randomized trial showed.

Among 529 patients with previously untreated, symptomatic CLL randomly assigned to ibrutinib-rituximab (IR) or to chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR), the IR regimen was associated with a 65% reduction in risk for disease progression, which was the trial’s primary endpoint.

The IR regimen was also associated with better overall survival out to 4 years of follow-up, reported Tait D. Shanafelt, MD, of Stanford (Calif.) University.

“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” he said at a media briefing prior at the annual meeting of the American Society of Hematology.

The study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.

In the ECOG-ACRIN Cancer Research Group E1912 trial, 529 patients aged 70 or younger with previously untreated CLL were enrolled and randomly assigned on a 2:1 basis to either standard therapy with six cycles of FCR according to standard protocols (175 patients), or IR, with ibrutinib 420 mg daily for each cycle, and rituximab delivered 50 mg/m² intravenously on day 1 of cycle 2, and 325 mg/m² on day 2 of the same cycle, and 500 mg/m² on day 1 for all remaining cycles (354 patients).

From cycle 8 until progression, patients in the IR arm received daily ibrutinib 420 mg.

Dr. Shanafelt presented results from both an intention-to-treat analysis and a per-protocol analysis excluding 22 patients in the IR arm and 9 patients in the FCR arm who were randomized but later found not to meet eligibility criteria.

After a mean follow-up of 34 months, there were 37 PFS events in the IR arm, compared with 40 events in the FCR arm in an intention-to-treat analysis. The difference translated into a hazard ratio for progression of 0.35 with IR (P less than .00001).

The results were similar in the per-protocol analysis, with an HR of 0.32 favoring IR (P less than .00001).*

There were four deaths in the IR arm, compared with 10 in the FCR arm at the time of the data lock, translating into a hazard ratio (HR) for overall survival of 0.17 (P less than .0003) in the intention-to-treat analysis, and 0.13 in the per-protocol analysis (P less than .0001).

Dr. Shanafelt noted that although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning that the rate of deaths in the FCR arm was fivefold higher than in the IR arm.

In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.

PFS was also significantly better with IR in patients with unmutated immunoglobulin heavy chain variable (IGHV) regions (HR 0.26, P less than .00001), but not in patients with mutated IGHV.*

Grade 3 or greater treatment-related adverse events occurred in 58.5% of patients in the IR arm, compared with 72.1% of patients in the FCR arm. Specific events that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P less than .001 for all comparisons).

Events that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P = .04), and hypertension (7.4% vs. 1.9%, P = .01).

Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost; the monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.

“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.

The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, Abbvie, Pharmacyclics, and Janssen.

SOURCE: Shanafelt TD et al. ASH 2018, Abstract LBA-4.

*Correction, 12/12/2018: An earlier version of this story misstated the P value in two comparisons.

SAN DIEGO – The combination of ibrutinib and rituximab was associated with a two-thirds reduction in chronic lymphocytic leukemia (CLL) progression, compared with standard chemoimmunotherapy in patients younger than 70 years old, interim results of a phase 3 randomized trial showed.

Among 529 patients with previously untreated, symptomatic CLL randomly assigned to ibrutinib-rituximab (IR) or to chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR), the IR regimen was associated with a 65% reduction in risk for disease progression, which was the trial’s primary endpoint.

The IR regimen was also associated with better overall survival out to 4 years of follow-up, reported Tait D. Shanafelt, MD, of Stanford (Calif.) University.

“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” he said at a media briefing prior at the annual meeting of the American Society of Hematology.

The study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.

In the ECOG-ACRIN Cancer Research Group E1912 trial, 529 patients aged 70 or younger with previously untreated CLL were enrolled and randomly assigned on a 2:1 basis to either standard therapy with six cycles of FCR according to standard protocols (175 patients), or IR, with ibrutinib 420 mg daily for each cycle, and rituximab delivered 50 mg/m² intravenously on day 1 of cycle 2, and 325 mg/m² on day 2 of the same cycle, and 500 mg/m² on day 1 for all remaining cycles (354 patients).

From cycle 8 until progression, patients in the IR arm received daily ibrutinib 420 mg.

Dr. Shanafelt presented results from both an intention-to-treat analysis and a per-protocol analysis excluding 22 patients in the IR arm and 9 patients in the FCR arm who were randomized but later found not to meet eligibility criteria.

After a mean follow-up of 34 months, there were 37 PFS events in the IR arm, compared with 40 events in the FCR arm in an intention-to-treat analysis. The difference translated into a hazard ratio for progression of 0.35 with IR (P less than .00001).

The results were similar in the per-protocol analysis, with an HR of 0.32 favoring IR (P less than .00001).*

There were four deaths in the IR arm, compared with 10 in the FCR arm at the time of the data lock, translating into a hazard ratio (HR) for overall survival of 0.17 (P less than .0003) in the intention-to-treat analysis, and 0.13 in the per-protocol analysis (P less than .0001).

Dr. Shanafelt noted that although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning that the rate of deaths in the FCR arm was fivefold higher than in the IR arm.

In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.

PFS was also significantly better with IR in patients with unmutated immunoglobulin heavy chain variable (IGHV) regions (HR 0.26, P less than .00001), but not in patients with mutated IGHV.*

Grade 3 or greater treatment-related adverse events occurred in 58.5% of patients in the IR arm, compared with 72.1% of patients in the FCR arm. Specific events that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P less than .001 for all comparisons).

Events that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P = .04), and hypertension (7.4% vs. 1.9%, P = .01).

Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost; the monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.

“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.

The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, Abbvie, Pharmacyclics, and Janssen.

SOURCE: Shanafelt TD et al. ASH 2018, Abstract LBA-4.

*Correction, 12/12/2018: An earlier version of this story misstated the P value in two comparisons.

SAN DIEGO – The combination of ibrutinib and rituximab was associated with a two-thirds reduction in chronic lymphocytic leukemia (CLL) progression, compared with standard chemoimmunotherapy in patients younger than 70 years old, interim results of a phase 3 randomized trial showed.

Among 529 patients with previously untreated, symptomatic CLL randomly assigned to ibrutinib-rituximab (IR) or to chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR), the IR regimen was associated with a 65% reduction in risk for disease progression, which was the trial’s primary endpoint.

The IR regimen was also associated with better overall survival out to 4 years of follow-up, reported Tait D. Shanafelt, MD, of Stanford (Calif.) University.

“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” he said at a media briefing prior at the annual meeting of the American Society of Hematology.

The study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.

In the ECOG-ACRIN Cancer Research Group E1912 trial, 529 patients aged 70 or younger with previously untreated CLL were enrolled and randomly assigned on a 2:1 basis to either standard therapy with six cycles of FCR according to standard protocols (175 patients), or IR, with ibrutinib 420 mg daily for each cycle, and rituximab delivered 50 mg/m² intravenously on day 1 of cycle 2, and 325 mg/m² on day 2 of the same cycle, and 500 mg/m² on day 1 for all remaining cycles (354 patients).

From cycle 8 until progression, patients in the IR arm received daily ibrutinib 420 mg.

Dr. Shanafelt presented results from both an intention-to-treat analysis and a per-protocol analysis excluding 22 patients in the IR arm and 9 patients in the FCR arm who were randomized but later found not to meet eligibility criteria.

After a mean follow-up of 34 months, there were 37 PFS events in the IR arm, compared with 40 events in the FCR arm in an intention-to-treat analysis. The difference translated into a hazard ratio for progression of 0.35 with IR (P less than .00001).

The results were similar in the per-protocol analysis, with an HR of 0.32 favoring IR (P less than .00001).*

There were four deaths in the IR arm, compared with 10 in the FCR arm at the time of the data lock, translating into a hazard ratio (HR) for overall survival of 0.17 (P less than .0003) in the intention-to-treat analysis, and 0.13 in the per-protocol analysis (P less than .0001).

Dr. Shanafelt noted that although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning that the rate of deaths in the FCR arm was fivefold higher than in the IR arm.

In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.

PFS was also significantly better with IR in patients with unmutated immunoglobulin heavy chain variable (IGHV) regions (HR 0.26, P less than .00001), but not in patients with mutated IGHV.*

Grade 3 or greater treatment-related adverse events occurred in 58.5% of patients in the IR arm, compared with 72.1% of patients in the FCR arm. Specific events that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P less than .001 for all comparisons).

Events that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P = .04), and hypertension (7.4% vs. 1.9%, P = .01).

Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost; the monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.

“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.

The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, Abbvie, Pharmacyclics, and Janssen.

SOURCE: Shanafelt TD et al. ASH 2018, Abstract LBA-4.

*Correction, 12/12/2018: An earlier version of this story misstated the P value in two comparisons.

Photo courtesy of ASH

SAN DIEGO—A recurrent mutation in BCL2, the therapeutic target of venetoclax, appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.

The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, according to Piers Blombery, MBBS, of the Peter MacCallum Cancer Center in Melbourne, Victoria, Australia.

“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said during the late-breaking abstracts session at the 2018 ASH Annual Meeting.

The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” Dr. Blombery added.

A paper on the mutation was published in Cancer Discovery to coincide with the presentation at ASH (abstract LBA-7).

Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.

To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.

In seven patients, the investigators identified a novel mutation that showed up at the time of progression but was absent from the pre-venetoclax samples.

The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.

They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies.

Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.

In other experiments, the investigators determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and, in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage compared with wild-type cells.

Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.

“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.

He added that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.

Dr. Blombery reported having no relevant disclosures. The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation.

Photo courtesy of ASH

SAN DIEGO—A recurrent mutation in BCL2, the therapeutic target of venetoclax, appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.

The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, according to Piers Blombery, MBBS, of the Peter MacCallum Cancer Center in Melbourne, Victoria, Australia.

“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said during the late-breaking abstracts session at the 2018 ASH Annual Meeting.

The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” Dr. Blombery added.

A paper on the mutation was published in Cancer Discovery to coincide with the presentation at ASH (abstract LBA-7).

Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.

To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.

In seven patients, the investigators identified a novel mutation that showed up at the time of progression but was absent from the pre-venetoclax samples.

The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.

They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies.

Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.

In other experiments, the investigators determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and, in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage compared with wild-type cells.

Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.

“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.

He added that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.

Dr. Blombery reported having no relevant disclosures. The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation.

Photo courtesy of ASH

SAN DIEGO—A recurrent mutation in BCL2, the therapeutic target of venetoclax, appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.

The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, according to Piers Blombery, MBBS, of the Peter MacCallum Cancer Center in Melbourne, Victoria, Australia.

“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said during the late-breaking abstracts session at the 2018 ASH Annual Meeting.

The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” Dr. Blombery added.

A paper on the mutation was published in Cancer Discovery to coincide with the presentation at ASH (abstract LBA-7).

Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.

To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.

In seven patients, the investigators identified a novel mutation that showed up at the time of progression but was absent from the pre-venetoclax samples.

The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.

They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies.

Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.

In other experiments, the investigators determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and, in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage compared with wild-type cells.

Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.

“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.

He added that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.

Dr. Blombery reported having no relevant disclosures. The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation.