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OMS721 receives orphan designation for use in HSCT
The European Commission has granted orphan designation to OMS721 for use in the setting of hematopoietic stem cell transplant (HSCT).
OMS721 is a monoclonal antibody targeting MASP-2, the effector enzyme of the lectin pathway of the complement system.
Omeros Corporation is developing OMS721 as a treatment for HSCT-associated thrombotic microangiopathy (TMA) and other conditions.
OMS721 is currently under evaluation in a phase 2 trial (NCT02222545) of patients with HSCT-TMA, and Omeros released some results from this study in February.
Results were reported for 18 adults with HSCT-TMA persisting for at least 2 weeks following immunosuppressive regimen modification or more than 30 days post-transplant.
The patients received weekly OMS721 treatments for 4 to 8 weeks at the discretion of the investigator.
These patients had a significantly longer median overall survival than historical controls—347 days and 21 days, respectively (P<0.0001).
Omeros also reported that markers of TMA activity significantly improved following OMS721 treatment.
The mean platelet count increased from 18,100 x 106/mL at baseline to 52,300 x 106/mL (P=0.017). The mean LDH decreased from 591 U/L to 250 U/L (P<0.001). And the mean haptoglobin increased from 8 mg/dL to 141 mg/dL (P=0.003).
Mean creatinine remained stable—at approximately 120 μmol/L—but a majority of patients had co-existing conditions for which they were receiving nephrotoxic medications. These conditions included graft-versus-host disease, cytomegalovirus and human herpes virus 6 infections, prior sepsis, diffuse alveolar hemorrhage, and residual underlying malignancies.
The most commonly reported adverse events in this trial were diarrhea and neutropenia.
Four deaths occurred. One of these—due to acute renal and respiratory failure—was considered possibly related to OMS721.
The other deaths were due to progression of acute myeloid leukemia (n=1) and neutropenic sepsis (n=2).
About orphan designation
Orphan designation from the European Commission is available to companies developing products intended to treat a life-threatening or chronically debilitating condition that affects fewer than 5 in 10,000 people in the European Union.
The designation allows for financial and regulatory incentives that include 10 years of marketing exclusivity in the European Union after product approval, protocol assistance from the European Medicines Agency at reduced fees during the product development phase, and access to centralized marketing authorization.
The European Commission has granted orphan designation to OMS721 for use in the setting of hematopoietic stem cell transplant (HSCT).
OMS721 is a monoclonal antibody targeting MASP-2, the effector enzyme of the lectin pathway of the complement system.
Omeros Corporation is developing OMS721 as a treatment for HSCT-associated thrombotic microangiopathy (TMA) and other conditions.
OMS721 is currently under evaluation in a phase 2 trial (NCT02222545) of patients with HSCT-TMA, and Omeros released some results from this study in February.
Results were reported for 18 adults with HSCT-TMA persisting for at least 2 weeks following immunosuppressive regimen modification or more than 30 days post-transplant.
The patients received weekly OMS721 treatments for 4 to 8 weeks at the discretion of the investigator.
These patients had a significantly longer median overall survival than historical controls—347 days and 21 days, respectively (P<0.0001).
Omeros also reported that markers of TMA activity significantly improved following OMS721 treatment.
The mean platelet count increased from 18,100 x 106/mL at baseline to 52,300 x 106/mL (P=0.017). The mean LDH decreased from 591 U/L to 250 U/L (P<0.001). And the mean haptoglobin increased from 8 mg/dL to 141 mg/dL (P=0.003).
Mean creatinine remained stable—at approximately 120 μmol/L—but a majority of patients had co-existing conditions for which they were receiving nephrotoxic medications. These conditions included graft-versus-host disease, cytomegalovirus and human herpes virus 6 infections, prior sepsis, diffuse alveolar hemorrhage, and residual underlying malignancies.
The most commonly reported adverse events in this trial were diarrhea and neutropenia.
Four deaths occurred. One of these—due to acute renal and respiratory failure—was considered possibly related to OMS721.
The other deaths were due to progression of acute myeloid leukemia (n=1) and neutropenic sepsis (n=2).
About orphan designation
Orphan designation from the European Commission is available to companies developing products intended to treat a life-threatening or chronically debilitating condition that affects fewer than 5 in 10,000 people in the European Union.
The designation allows for financial and regulatory incentives that include 10 years of marketing exclusivity in the European Union after product approval, protocol assistance from the European Medicines Agency at reduced fees during the product development phase, and access to centralized marketing authorization.
The European Commission has granted orphan designation to OMS721 for use in the setting of hematopoietic stem cell transplant (HSCT).
OMS721 is a monoclonal antibody targeting MASP-2, the effector enzyme of the lectin pathway of the complement system.
Omeros Corporation is developing OMS721 as a treatment for HSCT-associated thrombotic microangiopathy (TMA) and other conditions.
OMS721 is currently under evaluation in a phase 2 trial (NCT02222545) of patients with HSCT-TMA, and Omeros released some results from this study in February.
Results were reported for 18 adults with HSCT-TMA persisting for at least 2 weeks following immunosuppressive regimen modification or more than 30 days post-transplant.
The patients received weekly OMS721 treatments for 4 to 8 weeks at the discretion of the investigator.
These patients had a significantly longer median overall survival than historical controls—347 days and 21 days, respectively (P<0.0001).
Omeros also reported that markers of TMA activity significantly improved following OMS721 treatment.
The mean platelet count increased from 18,100 x 106/mL at baseline to 52,300 x 106/mL (P=0.017). The mean LDH decreased from 591 U/L to 250 U/L (P<0.001). And the mean haptoglobin increased from 8 mg/dL to 141 mg/dL (P=0.003).
Mean creatinine remained stable—at approximately 120 μmol/L—but a majority of patients had co-existing conditions for which they were receiving nephrotoxic medications. These conditions included graft-versus-host disease, cytomegalovirus and human herpes virus 6 infections, prior sepsis, diffuse alveolar hemorrhage, and residual underlying malignancies.
The most commonly reported adverse events in this trial were diarrhea and neutropenia.
Four deaths occurred. One of these—due to acute renal and respiratory failure—was considered possibly related to OMS721.
The other deaths were due to progression of acute myeloid leukemia (n=1) and neutropenic sepsis (n=2).
About orphan designation
Orphan designation from the European Commission is available to companies developing products intended to treat a life-threatening or chronically debilitating condition that affects fewer than 5 in 10,000 people in the European Union.
The designation allows for financial and regulatory incentives that include 10 years of marketing exclusivity in the European Union after product approval, protocol assistance from the European Medicines Agency at reduced fees during the product development phase, and access to centralized marketing authorization.
Predicting early outcomes in DLBCL
Measurement of circulating tumor DNA (ctDNA) could be a new and useful tool for predicting survival outcomes and response to therapy in patients with diffuse large B-cell lymphoma (DLBCL), according to researchers.
Pretreatment ctDNA levels predicted 24-month event-free survival as well as overall survival in a prospective study.
Changes in ctDNA during treatment were prognostic for outcomes as early as 21 days into therapy.
Ash A. Alizadeh, MD, PhD, of Stanford University in California, and his colleagues reported these findings in the Journal of Clinical Oncology.
ctDNA was detected in 98% of the 217 patients evaluated, which demonstrated the “potentially universal applicability” of this approach, the researchers wrote.
In an evaluation of pretreatment ctDNA levels, the researchers found a 2.5 log haploid genome equivalents per milliliter threshold stratified patient outcomes. Event-free survival was significantly inferior at 24 months in patients with ctDNA above that threshold, with hazard ratios of 2.6 (P=0.007) for frontline treatment and 2.9 (P=0.01) for salvage therapy.
On-treatment ctDNA levels were favorably prognostic for outcomes in patients receiving frontline therapy.
An early molecular response (EMR), defined as a 2-log decrease in ctDNA levels after one cycle of treatment, was associated with a 24-month event-free survival of 83% versus 50% for no EMR (P=0.0015).
Major molecular response (MMR), defined as a 2.5-log drop in ctDNA after two cycles of treatment, was associated with a 24-month event-free survival of 82% versus 46% for no MMR in patients on frontline therapy (P<0.001).
In one cohort of patients receiving salvage therapy, EMR also predicted superior 24-month event-free survival.
The EMR measure was also favorably prognostic for overall survival in both the frontline and salvage settings.
The prognostic value of measuring ctDNA was independent of International Prognostic Index and interim PET/CT studies, results of multivariable analyses showed.
Patients had “excellent outcomes” if they had both molecular response and favorable interim PET results, according to researchers. Conversely, patients were at “extremely high risk” for treatment failure if they had no molecular response and a positive PET scan.
“The identification of patients at exceptionally high risk (i.e., interim PET/CT positive and not achieving EMR/MMR) could provide an opportunity for early intervention with alternative treatments, including autologous bone marrow transplantation or chimeric antigen receptor T cells,” the researchers wrote.
Patients in the study were all treated with combination immunochemotherapy according to local standards.
Dr. Alizadeh reported disclosures related to CiberMed, Forty Seven, Janssen Oncology, Celgene, Roche/Genentech, and Gilead, as well as patent filings on ctDNA detection assigned to Stanford University.
Measurement of circulating tumor DNA (ctDNA) could be a new and useful tool for predicting survival outcomes and response to therapy in patients with diffuse large B-cell lymphoma (DLBCL), according to researchers.
Pretreatment ctDNA levels predicted 24-month event-free survival as well as overall survival in a prospective study.
Changes in ctDNA during treatment were prognostic for outcomes as early as 21 days into therapy.
Ash A. Alizadeh, MD, PhD, of Stanford University in California, and his colleagues reported these findings in the Journal of Clinical Oncology.
ctDNA was detected in 98% of the 217 patients evaluated, which demonstrated the “potentially universal applicability” of this approach, the researchers wrote.
In an evaluation of pretreatment ctDNA levels, the researchers found a 2.5 log haploid genome equivalents per milliliter threshold stratified patient outcomes. Event-free survival was significantly inferior at 24 months in patients with ctDNA above that threshold, with hazard ratios of 2.6 (P=0.007) for frontline treatment and 2.9 (P=0.01) for salvage therapy.
On-treatment ctDNA levels were favorably prognostic for outcomes in patients receiving frontline therapy.
An early molecular response (EMR), defined as a 2-log decrease in ctDNA levels after one cycle of treatment, was associated with a 24-month event-free survival of 83% versus 50% for no EMR (P=0.0015).
Major molecular response (MMR), defined as a 2.5-log drop in ctDNA after two cycles of treatment, was associated with a 24-month event-free survival of 82% versus 46% for no MMR in patients on frontline therapy (P<0.001).
In one cohort of patients receiving salvage therapy, EMR also predicted superior 24-month event-free survival.
The EMR measure was also favorably prognostic for overall survival in both the frontline and salvage settings.
The prognostic value of measuring ctDNA was independent of International Prognostic Index and interim PET/CT studies, results of multivariable analyses showed.
Patients had “excellent outcomes” if they had both molecular response and favorable interim PET results, according to researchers. Conversely, patients were at “extremely high risk” for treatment failure if they had no molecular response and a positive PET scan.
“The identification of patients at exceptionally high risk (i.e., interim PET/CT positive and not achieving EMR/MMR) could provide an opportunity for early intervention with alternative treatments, including autologous bone marrow transplantation or chimeric antigen receptor T cells,” the researchers wrote.
Patients in the study were all treated with combination immunochemotherapy according to local standards.
Dr. Alizadeh reported disclosures related to CiberMed, Forty Seven, Janssen Oncology, Celgene, Roche/Genentech, and Gilead, as well as patent filings on ctDNA detection assigned to Stanford University.
Measurement of circulating tumor DNA (ctDNA) could be a new and useful tool for predicting survival outcomes and response to therapy in patients with diffuse large B-cell lymphoma (DLBCL), according to researchers.
Pretreatment ctDNA levels predicted 24-month event-free survival as well as overall survival in a prospective study.
Changes in ctDNA during treatment were prognostic for outcomes as early as 21 days into therapy.
Ash A. Alizadeh, MD, PhD, of Stanford University in California, and his colleagues reported these findings in the Journal of Clinical Oncology.
ctDNA was detected in 98% of the 217 patients evaluated, which demonstrated the “potentially universal applicability” of this approach, the researchers wrote.
In an evaluation of pretreatment ctDNA levels, the researchers found a 2.5 log haploid genome equivalents per milliliter threshold stratified patient outcomes. Event-free survival was significantly inferior at 24 months in patients with ctDNA above that threshold, with hazard ratios of 2.6 (P=0.007) for frontline treatment and 2.9 (P=0.01) for salvage therapy.
On-treatment ctDNA levels were favorably prognostic for outcomes in patients receiving frontline therapy.
An early molecular response (EMR), defined as a 2-log decrease in ctDNA levels after one cycle of treatment, was associated with a 24-month event-free survival of 83% versus 50% for no EMR (P=0.0015).
Major molecular response (MMR), defined as a 2.5-log drop in ctDNA after two cycles of treatment, was associated with a 24-month event-free survival of 82% versus 46% for no MMR in patients on frontline therapy (P<0.001).
In one cohort of patients receiving salvage therapy, EMR also predicted superior 24-month event-free survival.
The EMR measure was also favorably prognostic for overall survival in both the frontline and salvage settings.
The prognostic value of measuring ctDNA was independent of International Prognostic Index and interim PET/CT studies, results of multivariable analyses showed.
Patients had “excellent outcomes” if they had both molecular response and favorable interim PET results, according to researchers. Conversely, patients were at “extremely high risk” for treatment failure if they had no molecular response and a positive PET scan.
“The identification of patients at exceptionally high risk (i.e., interim PET/CT positive and not achieving EMR/MMR) could provide an opportunity for early intervention with alternative treatments, including autologous bone marrow transplantation or chimeric antigen receptor T cells,” the researchers wrote.
Patients in the study were all treated with combination immunochemotherapy according to local standards.
Dr. Alizadeh reported disclosures related to CiberMed, Forty Seven, Janssen Oncology, Celgene, Roche/Genentech, and Gilead, as well as patent filings on ctDNA detection assigned to Stanford University.
Restrictive transfusion will likely be standard, doc says
MUNICH—A restrictive transfusion strategy during cardiovascular surgery will likely become the standard of care, according to an investigator from the TRICS III trial.
The study showed that a restrictive approach to transfusion did not increase the risk of poor outcomes at 6 months after cardiac surgery.
David Mazer, MD, of St. Michael’s Hospital, University of Toronto in Ontario, Canada, presented these findings at the 2018 ESC Congress. The results were published simultaneously in NEJM.
Dr. Mazer and his colleagues previously reported results from the TRICS III trial showing that 28-day outcomes were similar whether patients undergoing cardiac surgery were treated with a restrictive or a liberal transfusion strategy.
However, the team wanted to look into 6-month results to rule out latent problems, such as sequelae from perioperative organ hypoxia.
“Our research question was, ‘At what point does the risk of anemia, or the risk of a lower hemoglobin, outweigh the risk of transfusion?’” Dr. Mazer said. “We wanted to know whether it is safe to let your hemoglobin go to a lower level before you transfuse. The answer is yes. It’ll save blood, make blood more available, reduce costs of transfusion, and result in similar or better outcomes.”
Patients
The trial included 2317 patients who were randomized to a restrictive transfusion strategy, which meant they received red cell transfusions if their hemoglobin concentrations fell below 7.5 g/dL intraoperatively or postoperatively.
Another 2347 patients were randomized to the liberal approach, which meant they received transfusions if their hemoglobin fell below 9.5 g/dL in the operating room and intensive care unit (ICU) and below 8.5 g/dL outside the ICU.
Baseline characteristics were well balanced between the arms. Patients were a mean of 72 years old, and 35% were female. The majority of patients in both arms underwent coronary artery bypass surgery, valve surgery, or both. Heart transplants were excluded.
Results
At 6 months, 17.4% of patients in the restrictive arm and 17.1% in the liberal arm met the primary composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis (P=0.006 for noninferiority).
Unexpectedly, patients age 75 and older had a lower risk of the primary outcome with the restrictive strategy, while the liberal strategy was associated with lower risk in younger patients.
For all age groups, there were no significant differences between the treatment arms for the individual components of the primary composite outcome or for secondary outcomes.
The mortality rate was 6.2% in the restrictive arm and 6.4% in the liberal arm. The rate of myocardial infarction was 7.3% in both arms.
The rate of stroke was 4% in the restrictive arm and 3.3% in the liberal arm. The incidence of new-onset renal failure with dialysis was 3.9% and 4.2%, respectively.
The secondary composite outcome included the components of the primary outcome plus hospital readmissions, emergency department visits, and coronary revascularization. This outcome occurred in 43.8% of patients in the restrictive arm and 42.8% in the liberal arm.
The incidence of hospital readmissions/emergency visits was 35.5% in the restrictive arm and 33.6% in the liberal arm. The incidence of coronary revascularization was 0.7% and 0.9%, respectively.
The investigators also found the restrictive transfusion strategy effectively saved blood. Just over half of patients (52.3%) in the restrictive arm and almost three-quarters (72.6%) of those in the liberal arm were transfused after randomization.
“This research has already started to change transfusion practice around the world,” Dr. Mazer said. “With this data at six months, we’ve proven the longer-term safety of restrictive therapy. This approach has already been adopted into guidelines and will likely become the standard of care worldwide.”
This study was funded by the Canadian Institutes of Health Research, Canadian Blood Services, the National Health and Medical Research Council in Australia, and the Health Research Council of New Zealand. Dr. Mazer had no relevant disclosures.
MUNICH—A restrictive transfusion strategy during cardiovascular surgery will likely become the standard of care, according to an investigator from the TRICS III trial.
The study showed that a restrictive approach to transfusion did not increase the risk of poor outcomes at 6 months after cardiac surgery.
David Mazer, MD, of St. Michael’s Hospital, University of Toronto in Ontario, Canada, presented these findings at the 2018 ESC Congress. The results were published simultaneously in NEJM.
Dr. Mazer and his colleagues previously reported results from the TRICS III trial showing that 28-day outcomes were similar whether patients undergoing cardiac surgery were treated with a restrictive or a liberal transfusion strategy.
However, the team wanted to look into 6-month results to rule out latent problems, such as sequelae from perioperative organ hypoxia.
“Our research question was, ‘At what point does the risk of anemia, or the risk of a lower hemoglobin, outweigh the risk of transfusion?’” Dr. Mazer said. “We wanted to know whether it is safe to let your hemoglobin go to a lower level before you transfuse. The answer is yes. It’ll save blood, make blood more available, reduce costs of transfusion, and result in similar or better outcomes.”
Patients
The trial included 2317 patients who were randomized to a restrictive transfusion strategy, which meant they received red cell transfusions if their hemoglobin concentrations fell below 7.5 g/dL intraoperatively or postoperatively.
Another 2347 patients were randomized to the liberal approach, which meant they received transfusions if their hemoglobin fell below 9.5 g/dL in the operating room and intensive care unit (ICU) and below 8.5 g/dL outside the ICU.
Baseline characteristics were well balanced between the arms. Patients were a mean of 72 years old, and 35% were female. The majority of patients in both arms underwent coronary artery bypass surgery, valve surgery, or both. Heart transplants were excluded.
Results
At 6 months, 17.4% of patients in the restrictive arm and 17.1% in the liberal arm met the primary composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis (P=0.006 for noninferiority).
Unexpectedly, patients age 75 and older had a lower risk of the primary outcome with the restrictive strategy, while the liberal strategy was associated with lower risk in younger patients.
For all age groups, there were no significant differences between the treatment arms for the individual components of the primary composite outcome or for secondary outcomes.
The mortality rate was 6.2% in the restrictive arm and 6.4% in the liberal arm. The rate of myocardial infarction was 7.3% in both arms.
The rate of stroke was 4% in the restrictive arm and 3.3% in the liberal arm. The incidence of new-onset renal failure with dialysis was 3.9% and 4.2%, respectively.
The secondary composite outcome included the components of the primary outcome plus hospital readmissions, emergency department visits, and coronary revascularization. This outcome occurred in 43.8% of patients in the restrictive arm and 42.8% in the liberal arm.
The incidence of hospital readmissions/emergency visits was 35.5% in the restrictive arm and 33.6% in the liberal arm. The incidence of coronary revascularization was 0.7% and 0.9%, respectively.
The investigators also found the restrictive transfusion strategy effectively saved blood. Just over half of patients (52.3%) in the restrictive arm and almost three-quarters (72.6%) of those in the liberal arm were transfused after randomization.
“This research has already started to change transfusion practice around the world,” Dr. Mazer said. “With this data at six months, we’ve proven the longer-term safety of restrictive therapy. This approach has already been adopted into guidelines and will likely become the standard of care worldwide.”
This study was funded by the Canadian Institutes of Health Research, Canadian Blood Services, the National Health and Medical Research Council in Australia, and the Health Research Council of New Zealand. Dr. Mazer had no relevant disclosures.
MUNICH—A restrictive transfusion strategy during cardiovascular surgery will likely become the standard of care, according to an investigator from the TRICS III trial.
The study showed that a restrictive approach to transfusion did not increase the risk of poor outcomes at 6 months after cardiac surgery.
David Mazer, MD, of St. Michael’s Hospital, University of Toronto in Ontario, Canada, presented these findings at the 2018 ESC Congress. The results were published simultaneously in NEJM.
Dr. Mazer and his colleagues previously reported results from the TRICS III trial showing that 28-day outcomes were similar whether patients undergoing cardiac surgery were treated with a restrictive or a liberal transfusion strategy.
However, the team wanted to look into 6-month results to rule out latent problems, such as sequelae from perioperative organ hypoxia.
“Our research question was, ‘At what point does the risk of anemia, or the risk of a lower hemoglobin, outweigh the risk of transfusion?’” Dr. Mazer said. “We wanted to know whether it is safe to let your hemoglobin go to a lower level before you transfuse. The answer is yes. It’ll save blood, make blood more available, reduce costs of transfusion, and result in similar or better outcomes.”
Patients
The trial included 2317 patients who were randomized to a restrictive transfusion strategy, which meant they received red cell transfusions if their hemoglobin concentrations fell below 7.5 g/dL intraoperatively or postoperatively.
Another 2347 patients were randomized to the liberal approach, which meant they received transfusions if their hemoglobin fell below 9.5 g/dL in the operating room and intensive care unit (ICU) and below 8.5 g/dL outside the ICU.
Baseline characteristics were well balanced between the arms. Patients were a mean of 72 years old, and 35% were female. The majority of patients in both arms underwent coronary artery bypass surgery, valve surgery, or both. Heart transplants were excluded.
Results
At 6 months, 17.4% of patients in the restrictive arm and 17.1% in the liberal arm met the primary composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis (P=0.006 for noninferiority).
Unexpectedly, patients age 75 and older had a lower risk of the primary outcome with the restrictive strategy, while the liberal strategy was associated with lower risk in younger patients.
For all age groups, there were no significant differences between the treatment arms for the individual components of the primary composite outcome or for secondary outcomes.
The mortality rate was 6.2% in the restrictive arm and 6.4% in the liberal arm. The rate of myocardial infarction was 7.3% in both arms.
The rate of stroke was 4% in the restrictive arm and 3.3% in the liberal arm. The incidence of new-onset renal failure with dialysis was 3.9% and 4.2%, respectively.
The secondary composite outcome included the components of the primary outcome plus hospital readmissions, emergency department visits, and coronary revascularization. This outcome occurred in 43.8% of patients in the restrictive arm and 42.8% in the liberal arm.
The incidence of hospital readmissions/emergency visits was 35.5% in the restrictive arm and 33.6% in the liberal arm. The incidence of coronary revascularization was 0.7% and 0.9%, respectively.
The investigators also found the restrictive transfusion strategy effectively saved blood. Just over half of patients (52.3%) in the restrictive arm and almost three-quarters (72.6%) of those in the liberal arm were transfused after randomization.
“This research has already started to change transfusion practice around the world,” Dr. Mazer said. “With this data at six months, we’ve proven the longer-term safety of restrictive therapy. This approach has already been adopted into guidelines and will likely become the standard of care worldwide.”
This study was funded by the Canadian Institutes of Health Research, Canadian Blood Services, the National Health and Medical Research Council in Australia, and the Health Research Council of New Zealand. Dr. Mazer had no relevant disclosures.
NICE says CAR T-cell therapy isn’t cost-effective
The National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending against the use of axicabtagene ciloleucel (Yescarta) in England.
Axicabtagene ciloleucel is a chimeric antigen receptor (CAR) T-cell therapy that was just approved by the European Commission to treat patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) or primary mediastinal B-cell lymphoma (PMBCL) who have received two or more lines of systemic therapy.
However, NICE has said it isn’t clear how much of a benefit axicabtagene ciloleucel may provide over salvage chemotherapy.
Additionally, the cost of axicabtagene ciloleucel is too high for the therapy to be considered a cost-effective use of National Health Service (NHS) resources.
NICE’s draft guidance points out that there is no standard treatment for patients with relapsed or refractory DLBCL or PMBCL who have received two or more systemic therapies. These patients receive best supportive care, which usually includes salvage chemotherapy.
Results from the ZUMA-1 trial suggest the majority of DLBCL/PMBCL patients given axicabtagene ciloleucel do respond to treatment.
However, there is no direct data comparing axicabtagene ciloleucel with salvage chemotherapy, so the benefit of the CAR T-cell therapy over chemotherapy is unknown.
The draft guidance also notes that axicabtagene ciloleucel meets NICE’s criteria to be considered a life-extending treatment at the end of life.
However, the CAR T-cell therapy cannot be considered a cost-effective use of NHS resources. The cost-effectiveness estimates for axicabtagene ciloleucel, compared with salvage chemotherapy, were above £50,000 per year of quality adjusted life gained, the upper limit of the specially extended range of cost-effectiveness for cancer treatments.
Furthermore, axicabtagene ciloleucel does not meet the criteria for inclusion in the Cancer Drugs Fund. NICE said axicabtagene ciloleucel does not have the plausible potential to be cost effective, which would be necessary for inclusion in the fund while further evidence of the treatment’s longer-term benefits is collected.
“Although promising, there is still much more we need to know about CAR-T, and, unfortunately, in this case, we are not able to recommend axicabtagene ciloleucel for use in the NHS in England at the cost per patient set by Kite Pharma,” said Meindert Boysen, director of the centre for health technology evaluation at NICE.
The consultation period for the draft guidance runs until September 18, 2018.
The National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending against the use of axicabtagene ciloleucel (Yescarta) in England.
Axicabtagene ciloleucel is a chimeric antigen receptor (CAR) T-cell therapy that was just approved by the European Commission to treat patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) or primary mediastinal B-cell lymphoma (PMBCL) who have received two or more lines of systemic therapy.
However, NICE has said it isn’t clear how much of a benefit axicabtagene ciloleucel may provide over salvage chemotherapy.
Additionally, the cost of axicabtagene ciloleucel is too high for the therapy to be considered a cost-effective use of National Health Service (NHS) resources.
NICE’s draft guidance points out that there is no standard treatment for patients with relapsed or refractory DLBCL or PMBCL who have received two or more systemic therapies. These patients receive best supportive care, which usually includes salvage chemotherapy.
Results from the ZUMA-1 trial suggest the majority of DLBCL/PMBCL patients given axicabtagene ciloleucel do respond to treatment.
However, there is no direct data comparing axicabtagene ciloleucel with salvage chemotherapy, so the benefit of the CAR T-cell therapy over chemotherapy is unknown.
The draft guidance also notes that axicabtagene ciloleucel meets NICE’s criteria to be considered a life-extending treatment at the end of life.
However, the CAR T-cell therapy cannot be considered a cost-effective use of NHS resources. The cost-effectiveness estimates for axicabtagene ciloleucel, compared with salvage chemotherapy, were above £50,000 per year of quality adjusted life gained, the upper limit of the specially extended range of cost-effectiveness for cancer treatments.
Furthermore, axicabtagene ciloleucel does not meet the criteria for inclusion in the Cancer Drugs Fund. NICE said axicabtagene ciloleucel does not have the plausible potential to be cost effective, which would be necessary for inclusion in the fund while further evidence of the treatment’s longer-term benefits is collected.
“Although promising, there is still much more we need to know about CAR-T, and, unfortunately, in this case, we are not able to recommend axicabtagene ciloleucel for use in the NHS in England at the cost per patient set by Kite Pharma,” said Meindert Boysen, director of the centre for health technology evaluation at NICE.
The consultation period for the draft guidance runs until September 18, 2018.
The National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending against the use of axicabtagene ciloleucel (Yescarta) in England.
Axicabtagene ciloleucel is a chimeric antigen receptor (CAR) T-cell therapy that was just approved by the European Commission to treat patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) or primary mediastinal B-cell lymphoma (PMBCL) who have received two or more lines of systemic therapy.
However, NICE has said it isn’t clear how much of a benefit axicabtagene ciloleucel may provide over salvage chemotherapy.
Additionally, the cost of axicabtagene ciloleucel is too high for the therapy to be considered a cost-effective use of National Health Service (NHS) resources.
NICE’s draft guidance points out that there is no standard treatment for patients with relapsed or refractory DLBCL or PMBCL who have received two or more systemic therapies. These patients receive best supportive care, which usually includes salvage chemotherapy.
Results from the ZUMA-1 trial suggest the majority of DLBCL/PMBCL patients given axicabtagene ciloleucel do respond to treatment.
However, there is no direct data comparing axicabtagene ciloleucel with salvage chemotherapy, so the benefit of the CAR T-cell therapy over chemotherapy is unknown.
The draft guidance also notes that axicabtagene ciloleucel meets NICE’s criteria to be considered a life-extending treatment at the end of life.
However, the CAR T-cell therapy cannot be considered a cost-effective use of NHS resources. The cost-effectiveness estimates for axicabtagene ciloleucel, compared with salvage chemotherapy, were above £50,000 per year of quality adjusted life gained, the upper limit of the specially extended range of cost-effectiveness for cancer treatments.
Furthermore, axicabtagene ciloleucel does not meet the criteria for inclusion in the Cancer Drugs Fund. NICE said axicabtagene ciloleucel does not have the plausible potential to be cost effective, which would be necessary for inclusion in the fund while further evidence of the treatment’s longer-term benefits is collected.
“Although promising, there is still much more we need to know about CAR-T, and, unfortunately, in this case, we are not able to recommend axicabtagene ciloleucel for use in the NHS in England at the cost per patient set by Kite Pharma,” said Meindert Boysen, director of the centre for health technology evaluation at NICE.
The consultation period for the draft guidance runs until September 18, 2018.
Lots of blood collection system recalled
The US Food and Drug Administration (FDA) has announced a recall of 10 lots of the Leukotrap RC System with RC2D Filter, a blood collection system for leukoreduced red blood cells.
Haemonetics Corporation issued the recall due to reports of higher than expected residual white blood cells in blood processed with certain lot numbers of Leukotrap RC Systems with RC2D Filter.
The FDA said the problem is the result of a manufacturing assembly issue, and use of the affected lots may result in a higher than expected level of leukocytes in transfused blood.
Therefore, these lots should not be used, unused product can be returned to Haemonetics, and the company will replace these recalled lots. Customers can contact their local customer service representative to coordinate returns and shipments of replacement product.
The FDA said blood processed using the affected lots should not be re-filtered. If blood products processed by the affected lots are shown to have levels of leukocytes above recognized standards, the products should be labeled as non-leukoreduced. However, if the blood products have levels of leukocytes within recognized standards, they can still be labeled as leukoreduced.
The affected lots, which were shipped between April 2018 and July 2018, are:
- 1856199, Product ID 129-62
- 1856113, Product ID 129-63
- 1856114, Product ID 129-63
- 1856131, Product ID 129-63
- 1856134, Product ID 129-63
- 1856135, Product ID 129-63
- 1856183, Product ID 129-63
- 1856185, Product ID 129-63
- 1856186, Product ID 129-63
- 1856201, Product ID 129-63.
The US Food and Drug Administration (FDA) has announced a recall of 10 lots of the Leukotrap RC System with RC2D Filter, a blood collection system for leukoreduced red blood cells.
Haemonetics Corporation issued the recall due to reports of higher than expected residual white blood cells in blood processed with certain lot numbers of Leukotrap RC Systems with RC2D Filter.
The FDA said the problem is the result of a manufacturing assembly issue, and use of the affected lots may result in a higher than expected level of leukocytes in transfused blood.
Therefore, these lots should not be used, unused product can be returned to Haemonetics, and the company will replace these recalled lots. Customers can contact their local customer service representative to coordinate returns and shipments of replacement product.
The FDA said blood processed using the affected lots should not be re-filtered. If blood products processed by the affected lots are shown to have levels of leukocytes above recognized standards, the products should be labeled as non-leukoreduced. However, if the blood products have levels of leukocytes within recognized standards, they can still be labeled as leukoreduced.
The affected lots, which were shipped between April 2018 and July 2018, are:
- 1856199, Product ID 129-62
- 1856113, Product ID 129-63
- 1856114, Product ID 129-63
- 1856131, Product ID 129-63
- 1856134, Product ID 129-63
- 1856135, Product ID 129-63
- 1856183, Product ID 129-63
- 1856185, Product ID 129-63
- 1856186, Product ID 129-63
- 1856201, Product ID 129-63.
The US Food and Drug Administration (FDA) has announced a recall of 10 lots of the Leukotrap RC System with RC2D Filter, a blood collection system for leukoreduced red blood cells.
Haemonetics Corporation issued the recall due to reports of higher than expected residual white blood cells in blood processed with certain lot numbers of Leukotrap RC Systems with RC2D Filter.
The FDA said the problem is the result of a manufacturing assembly issue, and use of the affected lots may result in a higher than expected level of leukocytes in transfused blood.
Therefore, these lots should not be used, unused product can be returned to Haemonetics, and the company will replace these recalled lots. Customers can contact their local customer service representative to coordinate returns and shipments of replacement product.
The FDA said blood processed using the affected lots should not be re-filtered. If blood products processed by the affected lots are shown to have levels of leukocytes above recognized standards, the products should be labeled as non-leukoreduced. However, if the blood products have levels of leukocytes within recognized standards, they can still be labeled as leukoreduced.
The affected lots, which were shipped between April 2018 and July 2018, are:
- 1856199, Product ID 129-62
- 1856113, Product ID 129-63
- 1856114, Product ID 129-63
- 1856131, Product ID 129-63
- 1856134, Product ID 129-63
- 1856135, Product ID 129-63
- 1856183, Product ID 129-63
- 1856185, Product ID 129-63
- 1856186, Product ID 129-63
- 1856201, Product ID 129-63.
EC approves CAR T-cell therapy for DLBCL, PMBCL
The European Commission (EC) has approved the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (Yescarta®) to treat two types of lymphoma.
Axicabtagene ciloleucel is now approved to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL) after two or more lines of systemic therapy.
The approval extends to all member countries of the European Union, as well as Norway, Iceland, and Liechtenstein.
The EC’s approval of axicabtagene ciloleucel is supported by data from the ZUMA-1 trial.
Results from this phase 2 trial were presented at the 2017 ASH Annual Meeting and published simultaneously in NEJM.
The trial enrolled 111 patients with relapsed/refractory B-cell lymphomas. There were 101 patients who received axicabtagene ciloleucel—77 with DLBCL, 8 with PMBCL, and 16 with transformed follicular lymphoma (TFL).
Patients received conditioning with low-dose cyclophosphamide and fludarabine, followed by axicabtagene ciloleucel.
The objective response rate (ORR) was 82% (n=83), and the complete response (CR) rate was 54% (n=55).
Among the DLBCL patients, the ORR was 82% (63/77), and the CR rate was 49% (38/77). In the patients with PMBCL or TFL, the ORR was 83% (20/24), and the CR rate was 71% (17/24).
With a median follow-up of 15.4 months, 42% of patients retained their response, and 40% retained a CR.
At 18 months, the overall survival rate was 52%. Most deaths were due to disease progression.
However, 2 patients died of adverse events related to axicabtagene ciloleucel, both cytokine release syndrome.
The most common grade 3 or higher adverse events were neutropenia (78%), anemia (43%), thrombocytopenia (38%), and febrile neutropenia (31%).
Grade 3 or higher cytokine release syndrome occurred in 13% of patients, and grade 3 or higher neurologic events occurred in 28%.
The European Commission (EC) has approved the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (Yescarta®) to treat two types of lymphoma.
Axicabtagene ciloleucel is now approved to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL) after two or more lines of systemic therapy.
The approval extends to all member countries of the European Union, as well as Norway, Iceland, and Liechtenstein.
The EC’s approval of axicabtagene ciloleucel is supported by data from the ZUMA-1 trial.
Results from this phase 2 trial were presented at the 2017 ASH Annual Meeting and published simultaneously in NEJM.
The trial enrolled 111 patients with relapsed/refractory B-cell lymphomas. There were 101 patients who received axicabtagene ciloleucel—77 with DLBCL, 8 with PMBCL, and 16 with transformed follicular lymphoma (TFL).
Patients received conditioning with low-dose cyclophosphamide and fludarabine, followed by axicabtagene ciloleucel.
The objective response rate (ORR) was 82% (n=83), and the complete response (CR) rate was 54% (n=55).
Among the DLBCL patients, the ORR was 82% (63/77), and the CR rate was 49% (38/77). In the patients with PMBCL or TFL, the ORR was 83% (20/24), and the CR rate was 71% (17/24).
With a median follow-up of 15.4 months, 42% of patients retained their response, and 40% retained a CR.
At 18 months, the overall survival rate was 52%. Most deaths were due to disease progression.
However, 2 patients died of adverse events related to axicabtagene ciloleucel, both cytokine release syndrome.
The most common grade 3 or higher adverse events were neutropenia (78%), anemia (43%), thrombocytopenia (38%), and febrile neutropenia (31%).
Grade 3 or higher cytokine release syndrome occurred in 13% of patients, and grade 3 or higher neurologic events occurred in 28%.
The European Commission (EC) has approved the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (Yescarta®) to treat two types of lymphoma.
Axicabtagene ciloleucel is now approved to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL) after two or more lines of systemic therapy.
The approval extends to all member countries of the European Union, as well as Norway, Iceland, and Liechtenstein.
The EC’s approval of axicabtagene ciloleucel is supported by data from the ZUMA-1 trial.
Results from this phase 2 trial were presented at the 2017 ASH Annual Meeting and published simultaneously in NEJM.
The trial enrolled 111 patients with relapsed/refractory B-cell lymphomas. There were 101 patients who received axicabtagene ciloleucel—77 with DLBCL, 8 with PMBCL, and 16 with transformed follicular lymphoma (TFL).
Patients received conditioning with low-dose cyclophosphamide and fludarabine, followed by axicabtagene ciloleucel.
The objective response rate (ORR) was 82% (n=83), and the complete response (CR) rate was 54% (n=55).
Among the DLBCL patients, the ORR was 82% (63/77), and the CR rate was 49% (38/77). In the patients with PMBCL or TFL, the ORR was 83% (20/24), and the CR rate was 71% (17/24).
With a median follow-up of 15.4 months, 42% of patients retained their response, and 40% retained a CR.
At 18 months, the overall survival rate was 52%. Most deaths were due to disease progression.
However, 2 patients died of adverse events related to axicabtagene ciloleucel, both cytokine release syndrome.
The most common grade 3 or higher adverse events were neutropenia (78%), anemia (43%), thrombocytopenia (38%), and febrile neutropenia (31%).
Grade 3 or higher cytokine release syndrome occurred in 13% of patients, and grade 3 or higher neurologic events occurred in 28%.
EC approves product for high-risk AML
The European Commission (EC) has approved CPX-351 (Vyxeos), a liposomal formulation that delivers a fixed ratio of daunorubicin and cytarabine (44 mg/100 mg).
CPX-351 is approved to treat adults with newly diagnosed, therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes.
The approval extends to all European Union member states as well as Iceland, Norway, and Liechtenstein.
The EC’s approval is supported by data from 5 studies, including a phase 3 trial.
Data from the phase 3 trial were published in the Journal of Clinical Oncology in July.
The trial enrolled 309 patients, ages 60 to 75, with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.
Patients received CPX-351 (n=153) or cytarabine and daunorubicin (7+3; n=156).
The overall remission rate—the rate of complete response (CR) plus CR with incomplete count recovery—was 47.7% in the CPX-351 arm and 33.3% in the 7+3 arm (P=0.016). The CR rate was 37.3% and 25.6%, respectively (P=0.040).
About 30% of patients went on to allogeneic hematopoietic stem cell transplant—34% in the CPX-351 arm and 25% in the 7+3 arm (P=0.098).
The median overall survival was 9.56 months in the CPX-351 arm and 5.95 months in the 7+3 arm (P=0.003). The median event-free survival was 2.53 months and 1.31 months, respectively (P=0.021).
Adverse events (AEs) that led to treatment discontinuation in the CPX-351 arm were cardiac failure (n=1), cardiomyopathy (n=1), and acute renal failure (n=1). AEs that led to treatment discontinuation in the 7+3 arm were decreased ejection fraction in 2 patients.
The most common grade 3 to 5 AEs (in the CPX-351 and 7+3 arms, respectively) were infection-related events (83.7% and 86.1%), febrile neutropenia (68.0% and 70.9%), pneumonia (19.6% and 14.6%), hypoxia (13.1% and 15.2%), and bleeding events (11.8% and 8.6%).
Ultimately, 69.3% of patients in the CPX-351 arm and 84.8% of those in the 7+3 arm died.
Deaths (in the CPX-351 and 7+3 cohorts, respectively) were due to progressive disease (n=65 and 67), AEs (n=15 and 19), cancer-related organ failure in the absence of progressive disease (n=0 and 5), and unknown/other causes (n=26 and 37).
The European Commission (EC) has approved CPX-351 (Vyxeos), a liposomal formulation that delivers a fixed ratio of daunorubicin and cytarabine (44 mg/100 mg).
CPX-351 is approved to treat adults with newly diagnosed, therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes.
The approval extends to all European Union member states as well as Iceland, Norway, and Liechtenstein.
The EC’s approval is supported by data from 5 studies, including a phase 3 trial.
Data from the phase 3 trial were published in the Journal of Clinical Oncology in July.
The trial enrolled 309 patients, ages 60 to 75, with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.
Patients received CPX-351 (n=153) or cytarabine and daunorubicin (7+3; n=156).
The overall remission rate—the rate of complete response (CR) plus CR with incomplete count recovery—was 47.7% in the CPX-351 arm and 33.3% in the 7+3 arm (P=0.016). The CR rate was 37.3% and 25.6%, respectively (P=0.040).
About 30% of patients went on to allogeneic hematopoietic stem cell transplant—34% in the CPX-351 arm and 25% in the 7+3 arm (P=0.098).
The median overall survival was 9.56 months in the CPX-351 arm and 5.95 months in the 7+3 arm (P=0.003). The median event-free survival was 2.53 months and 1.31 months, respectively (P=0.021).
Adverse events (AEs) that led to treatment discontinuation in the CPX-351 arm were cardiac failure (n=1), cardiomyopathy (n=1), and acute renal failure (n=1). AEs that led to treatment discontinuation in the 7+3 arm were decreased ejection fraction in 2 patients.
The most common grade 3 to 5 AEs (in the CPX-351 and 7+3 arms, respectively) were infection-related events (83.7% and 86.1%), febrile neutropenia (68.0% and 70.9%), pneumonia (19.6% and 14.6%), hypoxia (13.1% and 15.2%), and bleeding events (11.8% and 8.6%).
Ultimately, 69.3% of patients in the CPX-351 arm and 84.8% of those in the 7+3 arm died.
Deaths (in the CPX-351 and 7+3 cohorts, respectively) were due to progressive disease (n=65 and 67), AEs (n=15 and 19), cancer-related organ failure in the absence of progressive disease (n=0 and 5), and unknown/other causes (n=26 and 37).
The European Commission (EC) has approved CPX-351 (Vyxeos), a liposomal formulation that delivers a fixed ratio of daunorubicin and cytarabine (44 mg/100 mg).
CPX-351 is approved to treat adults with newly diagnosed, therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes.
The approval extends to all European Union member states as well as Iceland, Norway, and Liechtenstein.
The EC’s approval is supported by data from 5 studies, including a phase 3 trial.
Data from the phase 3 trial were published in the Journal of Clinical Oncology in July.
The trial enrolled 309 patients, ages 60 to 75, with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.
Patients received CPX-351 (n=153) or cytarabine and daunorubicin (7+3; n=156).
The overall remission rate—the rate of complete response (CR) plus CR with incomplete count recovery—was 47.7% in the CPX-351 arm and 33.3% in the 7+3 arm (P=0.016). The CR rate was 37.3% and 25.6%, respectively (P=0.040).
About 30% of patients went on to allogeneic hematopoietic stem cell transplant—34% in the CPX-351 arm and 25% in the 7+3 arm (P=0.098).
The median overall survival was 9.56 months in the CPX-351 arm and 5.95 months in the 7+3 arm (P=0.003). The median event-free survival was 2.53 months and 1.31 months, respectively (P=0.021).
Adverse events (AEs) that led to treatment discontinuation in the CPX-351 arm were cardiac failure (n=1), cardiomyopathy (n=1), and acute renal failure (n=1). AEs that led to treatment discontinuation in the 7+3 arm were decreased ejection fraction in 2 patients.
The most common grade 3 to 5 AEs (in the CPX-351 and 7+3 arms, respectively) were infection-related events (83.7% and 86.1%), febrile neutropenia (68.0% and 70.9%), pneumonia (19.6% and 14.6%), hypoxia (13.1% and 15.2%), and bleeding events (11.8% and 8.6%).
Ultimately, 69.3% of patients in the CPX-351 arm and 84.8% of those in the 7+3 arm died.
Deaths (in the CPX-351 and 7+3 cohorts, respectively) were due to progressive disease (n=65 and 67), AEs (n=15 and 19), cancer-related organ failure in the absence of progressive disease (n=0 and 5), and unknown/other causes (n=26 and 37).
FDA grants fast track designation to CX-01 for AML
The US Food and Drug Administration (FDA) has granted fast track designation to CX-01 as a treatment for patients older than 60 receiving induction therapy for newly diagnosed acute myeloid leukemia (AML).
CX-01 also has orphan drug designation from the FDA.
CX-01 is a polysaccharide derived from heparin that is thought to enhance chemotherapy by disrupting the adhesion of leukemia cells in the bone marrow.
CX-01 inhibits the activity of HMGB1, disrupts the CXCL12/CXCR4 axis, and neutralizes the activity of platelet factor 4. HMGB1 has been implicated in autophagy, a mechanism by which cells withstand the effects of chemotherapy.
The CXCL12/CXCR4 axis is thought to be involved in protecting leukemia cells from chemotherapy. And platelet factor 4 inhibits bone marrow recovery after chemotherapy.
CX-01 research
Cantex Pharmaceuticals, Inc., is conducting a randomized, phase 2b study to determine whether CX-01 can improve the efficacy of frontline chemotherapy in patients with AML.
This study builds upon results of a pilot study, which were published in Blood Advances in February.
The study enrolled 12 adults with newly diagnosed AML. Patients had good-risk (n=3), intermediate-risk (n=5), and poor-risk (n=4) disease.
They received CX-01 as a 7-day continuous infusion, along with standard induction chemotherapy (cytarabine and idarubicin).
Eleven patients (92%) achieved morphologic complete remission after one cycle of induction. This includes two patients who did not complete induction. All patients received subsequent therapy—consolidation, salvage, or transplant—on- or off-study.
At a median follow-up of 24 months, 8 patients were still alive. Two patients died of transplant-related complications, one died of infectious complications, and one died of cerebral hemorrhage.
The median disease-free survival was 14.8 months, and the median overall survival was not reached.
There were five serious adverse events (AEs) in five patients. Most of these AEs were considered unrelated to CX-01, but a case of grade 4 sepsis was considered possibly related to CX-01.
Transient, asymptomatic, low-grade elevations of liver transaminases observed during induction were considered possibly related to CX-01. There were also transient, asymptomatic, grade 3-4 liver transaminase elevations observed during consolidation that were considered possibly related to CX-01.
The researchers said the most frequent nonserious AEs were hematologic toxicities, infectious complications, and organ toxicity complications resulting from treatment and/or the underlying leukemia.
About fast track, orphan designations
The FDA’s fast track development program is designed to expedite clinical development and submission of applications for products with the potential to treat serious or life-threatening conditions and address unmet medical needs.
Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the product’s development plan and written communications about issues such as trial design and use of biomarkers.
Products that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Such products may also be eligible for rolling review, which allows a developer to submit individual sections of a product’s application for review as they are ready, rather than waiting until all sections are complete.
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted fast track designation to CX-01 as a treatment for patients older than 60 receiving induction therapy for newly diagnosed acute myeloid leukemia (AML).
CX-01 also has orphan drug designation from the FDA.
CX-01 is a polysaccharide derived from heparin that is thought to enhance chemotherapy by disrupting the adhesion of leukemia cells in the bone marrow.
CX-01 inhibits the activity of HMGB1, disrupts the CXCL12/CXCR4 axis, and neutralizes the activity of platelet factor 4. HMGB1 has been implicated in autophagy, a mechanism by which cells withstand the effects of chemotherapy.
The CXCL12/CXCR4 axis is thought to be involved in protecting leukemia cells from chemotherapy. And platelet factor 4 inhibits bone marrow recovery after chemotherapy.
CX-01 research
Cantex Pharmaceuticals, Inc., is conducting a randomized, phase 2b study to determine whether CX-01 can improve the efficacy of frontline chemotherapy in patients with AML.
This study builds upon results of a pilot study, which were published in Blood Advances in February.
The study enrolled 12 adults with newly diagnosed AML. Patients had good-risk (n=3), intermediate-risk (n=5), and poor-risk (n=4) disease.
They received CX-01 as a 7-day continuous infusion, along with standard induction chemotherapy (cytarabine and idarubicin).
Eleven patients (92%) achieved morphologic complete remission after one cycle of induction. This includes two patients who did not complete induction. All patients received subsequent therapy—consolidation, salvage, or transplant—on- or off-study.
At a median follow-up of 24 months, 8 patients were still alive. Two patients died of transplant-related complications, one died of infectious complications, and one died of cerebral hemorrhage.
The median disease-free survival was 14.8 months, and the median overall survival was not reached.
There were five serious adverse events (AEs) in five patients. Most of these AEs were considered unrelated to CX-01, but a case of grade 4 sepsis was considered possibly related to CX-01.
Transient, asymptomatic, low-grade elevations of liver transaminases observed during induction were considered possibly related to CX-01. There were also transient, asymptomatic, grade 3-4 liver transaminase elevations observed during consolidation that were considered possibly related to CX-01.
The researchers said the most frequent nonserious AEs were hematologic toxicities, infectious complications, and organ toxicity complications resulting from treatment and/or the underlying leukemia.
About fast track, orphan designations
The FDA’s fast track development program is designed to expedite clinical development and submission of applications for products with the potential to treat serious or life-threatening conditions and address unmet medical needs.
Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the product’s development plan and written communications about issues such as trial design and use of biomarkers.
Products that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Such products may also be eligible for rolling review, which allows a developer to submit individual sections of a product’s application for review as they are ready, rather than waiting until all sections are complete.
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted fast track designation to CX-01 as a treatment for patients older than 60 receiving induction therapy for newly diagnosed acute myeloid leukemia (AML).
CX-01 also has orphan drug designation from the FDA.
CX-01 is a polysaccharide derived from heparin that is thought to enhance chemotherapy by disrupting the adhesion of leukemia cells in the bone marrow.
CX-01 inhibits the activity of HMGB1, disrupts the CXCL12/CXCR4 axis, and neutralizes the activity of platelet factor 4. HMGB1 has been implicated in autophagy, a mechanism by which cells withstand the effects of chemotherapy.
The CXCL12/CXCR4 axis is thought to be involved in protecting leukemia cells from chemotherapy. And platelet factor 4 inhibits bone marrow recovery after chemotherapy.
CX-01 research
Cantex Pharmaceuticals, Inc., is conducting a randomized, phase 2b study to determine whether CX-01 can improve the efficacy of frontline chemotherapy in patients with AML.
This study builds upon results of a pilot study, which were published in Blood Advances in February.
The study enrolled 12 adults with newly diagnosed AML. Patients had good-risk (n=3), intermediate-risk (n=5), and poor-risk (n=4) disease.
They received CX-01 as a 7-day continuous infusion, along with standard induction chemotherapy (cytarabine and idarubicin).
Eleven patients (92%) achieved morphologic complete remission after one cycle of induction. This includes two patients who did not complete induction. All patients received subsequent therapy—consolidation, salvage, or transplant—on- or off-study.
At a median follow-up of 24 months, 8 patients were still alive. Two patients died of transplant-related complications, one died of infectious complications, and one died of cerebral hemorrhage.
The median disease-free survival was 14.8 months, and the median overall survival was not reached.
There were five serious adverse events (AEs) in five patients. Most of these AEs were considered unrelated to CX-01, but a case of grade 4 sepsis was considered possibly related to CX-01.
Transient, asymptomatic, low-grade elevations of liver transaminases observed during induction were considered possibly related to CX-01. There were also transient, asymptomatic, grade 3-4 liver transaminase elevations observed during consolidation that were considered possibly related to CX-01.
The researchers said the most frequent nonserious AEs were hematologic toxicities, infectious complications, and organ toxicity complications resulting from treatment and/or the underlying leukemia.
About fast track, orphan designations
The FDA’s fast track development program is designed to expedite clinical development and submission of applications for products with the potential to treat serious or life-threatening conditions and address unmet medical needs.
Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the product’s development plan and written communications about issues such as trial design and use of biomarkers.
Products that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Such products may also be eligible for rolling review, which allows a developer to submit individual sections of a product’s application for review as they are ready, rather than waiting until all sections are complete.
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
EC approves CAR T-cell therapy for ALL, DLBCL
The European Commission (EC) has granted approval for tisagenlecleucel (Kymriah®), a chimeric antigen receptor (CAR) T-cell therapy targeting CD19.
Tisagenlecleucel (formerly CTL019) is now approved for use in pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse.
Tisagenlecleucel is also approved to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received two or more lines of systemic therapy.
The EC’s approval extends to all member countries of the European Union, as well as Norway, Iceland, and Liechtenstein.
Novartis expects to launch tisagenlecleucel initially for pediatric ALL. The company said timing for tisagenlecleucel availability in each country will depend on multiple factors, including the onboarding of qualified treatment centers for the appropriate indications, as well as the completion of national reimbursement procedures.
The EC’s approval of tisagenlecleucel is based on results from the phase 2 JULIET and ELIANA trials.
JULIET trial
Updated results from JULIET were presented at the 23rd Annual Congress of the European Hematology Association in June (abstract S799).
The trial enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Most of the patients who discontinued before dosing did so due to disease progression or clinical deterioration. The patients’ median age at baseline was 56 (range, 22-76).
Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.
The median time from infusion to data cutoff was 13.9 months.
The overall response rate was 52%, and the complete response (CR) rate was 40%. The median duration of response was not reached.
At the time of data cutoff, none of the responders had gone on to receive a stem cell transplant.
For all infused patients (n=111), the 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.
Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Fifteen percent of patients received tocilizumab for CRS, including 3% of patients with grade 2 CRS and 50% of patients with grade 3 CRS.
Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).
ELIANA trial
Updated results from ELIANA were published in NEJM in February.
The trial included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).
All 75 patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.
The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.
The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.
All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
Eight patients proceeded to transplant while in remission. At last follow-up, 4 were still in remission, and 4 had unknown disease status.
At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.
All patients experienced at least one AE, and 95% had AEs thought to be related to tisagenlecleucel. The rate of grade 3/4 AEs was 88%, and the rate of related grade 3/4 AEs was 73%.
AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).
The European Commission (EC) has granted approval for tisagenlecleucel (Kymriah®), a chimeric antigen receptor (CAR) T-cell therapy targeting CD19.
Tisagenlecleucel (formerly CTL019) is now approved for use in pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse.
Tisagenlecleucel is also approved to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received two or more lines of systemic therapy.
The EC’s approval extends to all member countries of the European Union, as well as Norway, Iceland, and Liechtenstein.
Novartis expects to launch tisagenlecleucel initially for pediatric ALL. The company said timing for tisagenlecleucel availability in each country will depend on multiple factors, including the onboarding of qualified treatment centers for the appropriate indications, as well as the completion of national reimbursement procedures.
The EC’s approval of tisagenlecleucel is based on results from the phase 2 JULIET and ELIANA trials.
JULIET trial
Updated results from JULIET were presented at the 23rd Annual Congress of the European Hematology Association in June (abstract S799).
The trial enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Most of the patients who discontinued before dosing did so due to disease progression or clinical deterioration. The patients’ median age at baseline was 56 (range, 22-76).
Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.
The median time from infusion to data cutoff was 13.9 months.
The overall response rate was 52%, and the complete response (CR) rate was 40%. The median duration of response was not reached.
At the time of data cutoff, none of the responders had gone on to receive a stem cell transplant.
For all infused patients (n=111), the 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.
Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Fifteen percent of patients received tocilizumab for CRS, including 3% of patients with grade 2 CRS and 50% of patients with grade 3 CRS.
Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).
ELIANA trial
Updated results from ELIANA were published in NEJM in February.
The trial included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).
All 75 patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.
The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.
The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.
All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
Eight patients proceeded to transplant while in remission. At last follow-up, 4 were still in remission, and 4 had unknown disease status.
At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.
All patients experienced at least one AE, and 95% had AEs thought to be related to tisagenlecleucel. The rate of grade 3/4 AEs was 88%, and the rate of related grade 3/4 AEs was 73%.
AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).
The European Commission (EC) has granted approval for tisagenlecleucel (Kymriah®), a chimeric antigen receptor (CAR) T-cell therapy targeting CD19.
Tisagenlecleucel (formerly CTL019) is now approved for use in pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse.
Tisagenlecleucel is also approved to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received two or more lines of systemic therapy.
The EC’s approval extends to all member countries of the European Union, as well as Norway, Iceland, and Liechtenstein.
Novartis expects to launch tisagenlecleucel initially for pediatric ALL. The company said timing for tisagenlecleucel availability in each country will depend on multiple factors, including the onboarding of qualified treatment centers for the appropriate indications, as well as the completion of national reimbursement procedures.
The EC’s approval of tisagenlecleucel is based on results from the phase 2 JULIET and ELIANA trials.
JULIET trial
Updated results from JULIET were presented at the 23rd Annual Congress of the European Hematology Association in June (abstract S799).
The trial enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Most of the patients who discontinued before dosing did so due to disease progression or clinical deterioration. The patients’ median age at baseline was 56 (range, 22-76).
Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.
The median time from infusion to data cutoff was 13.9 months.
The overall response rate was 52%, and the complete response (CR) rate was 40%. The median duration of response was not reached.
At the time of data cutoff, none of the responders had gone on to receive a stem cell transplant.
For all infused patients (n=111), the 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.
Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Fifteen percent of patients received tocilizumab for CRS, including 3% of patients with grade 2 CRS and 50% of patients with grade 3 CRS.
Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).
ELIANA trial
Updated results from ELIANA were published in NEJM in February.
The trial included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).
All 75 patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.
The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.
The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.
All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
Eight patients proceeded to transplant while in remission. At last follow-up, 4 were still in remission, and 4 had unknown disease status.
At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.
All patients experienced at least one AE, and 95% had AEs thought to be related to tisagenlecleucel. The rate of grade 3/4 AEs was 88%, and the rate of related grade 3/4 AEs was 73%.
AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).
FDA approves new use for ibrutinib in WM
The US Food and Drug Administration (FDA) has approved ibrutinib (Imbruvica®) for use in combination with rituximab to treat adults with Waldenström’s macroglobulinemia (WM).
This is the ninth FDA approval for ibrutinib and the second approval for the drug in WM.
The latest approval was supported by the phase 3 iNNOVATE trial, in which researchers compared ibrutinib plus rituximab to rituximab alone in patients with previously untreated or relapsed/refractory WM.
Results from iNNOVATE were presented at the 2018 ASCO Annual Meeting (abstract 8003) and simultaneously published in NEJM.
The trial enrolled 150 patients. They received rituximab at 375 mg/m2 with weekly infusions at weeks 1 to 4 and 17 to 20. They also received either ibrutinib (420 mg) or placebo once daily continuously until criteria for permanent discontinuation were met.
Overall response rates were significantly higher in the ibrutinib arm than the placebo arm—92% and 47%, respectively (P<0.0001). Complete response rates were 3% and 1%, respectively.
The median time to next treatment was not reached for the ibrutinib arm and was 18 months for the placebo arm (hazard ratio=0.096; P<0.0001). Of the patients randomized to ibrutinib plus rituximab, 75% continued on treatment at last follow-up.
The 30-month progression-free survival rates were 82% in the ibrutinib arm and 28% in the placebo arm. The median progression-free survival was not reached in the ibrutinib arm and was 20.3 months in the placebo arm (hazard ratio=0.20; P<0.0001).
The 30-month overall survival rates were 94% in the ibrutinib arm and 92% in the placebo arm.
Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 60% of patients in the ibrutinib arm and 61% in the placebo arm. Serious AEs occurred in 43% and 33%, respectively.
There were no fatal AEs in the ibrutinib arm and 3 in the rituximab arm.
Grade 3 or higher AEs that occurred more frequently in the ibrutinib arm than the placebo arm included atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%).
AEs that occurred less frequently in the ibrutinib arm than the placebo arm included grade 3 or higher infusion reactions (1% vs 16%) and any-grade IgM flare (8% vs 47%).
About ibrutinib
Ibrutinib is a Bruton’s tyrosine kinase inhibitor that is FDA-approved to treat chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic graft-versus-host disease (cGVHD), and WM.
In November 2013, ibrutinib was approved to treat adults with MCL who have received at least one prior therapy.
In February 2014, ibrutinib was approved to treat adults with CLL who have received at least one prior therapy. In July 2014, ibrutinib received approval for adult CLL patients with 17p deletion, and, in March 2016, ibrutinib was approved as a frontline CLL treatment.
Ibrutinib was approved for use as a single agent in adults with WM in January 2015.
In May 2016, ibrutinib was approved in combination with bendamustine and rituximab for adults with previously treated CLL/SLL.
In January 2017, ibrutinib was approved for adults with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, ibrutinib was approved to treat adults with cGVHD that did not respond to one or more lines of systemic therapy.
Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.
The US Food and Drug Administration (FDA) has approved ibrutinib (Imbruvica®) for use in combination with rituximab to treat adults with Waldenström’s macroglobulinemia (WM).
This is the ninth FDA approval for ibrutinib and the second approval for the drug in WM.
The latest approval was supported by the phase 3 iNNOVATE trial, in which researchers compared ibrutinib plus rituximab to rituximab alone in patients with previously untreated or relapsed/refractory WM.
Results from iNNOVATE were presented at the 2018 ASCO Annual Meeting (abstract 8003) and simultaneously published in NEJM.
The trial enrolled 150 patients. They received rituximab at 375 mg/m2 with weekly infusions at weeks 1 to 4 and 17 to 20. They also received either ibrutinib (420 mg) or placebo once daily continuously until criteria for permanent discontinuation were met.
Overall response rates were significantly higher in the ibrutinib arm than the placebo arm—92% and 47%, respectively (P<0.0001). Complete response rates were 3% and 1%, respectively.
The median time to next treatment was not reached for the ibrutinib arm and was 18 months for the placebo arm (hazard ratio=0.096; P<0.0001). Of the patients randomized to ibrutinib plus rituximab, 75% continued on treatment at last follow-up.
The 30-month progression-free survival rates were 82% in the ibrutinib arm and 28% in the placebo arm. The median progression-free survival was not reached in the ibrutinib arm and was 20.3 months in the placebo arm (hazard ratio=0.20; P<0.0001).
The 30-month overall survival rates were 94% in the ibrutinib arm and 92% in the placebo arm.
Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 60% of patients in the ibrutinib arm and 61% in the placebo arm. Serious AEs occurred in 43% and 33%, respectively.
There were no fatal AEs in the ibrutinib arm and 3 in the rituximab arm.
Grade 3 or higher AEs that occurred more frequently in the ibrutinib arm than the placebo arm included atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%).
AEs that occurred less frequently in the ibrutinib arm than the placebo arm included grade 3 or higher infusion reactions (1% vs 16%) and any-grade IgM flare (8% vs 47%).
About ibrutinib
Ibrutinib is a Bruton’s tyrosine kinase inhibitor that is FDA-approved to treat chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic graft-versus-host disease (cGVHD), and WM.
In November 2013, ibrutinib was approved to treat adults with MCL who have received at least one prior therapy.
In February 2014, ibrutinib was approved to treat adults with CLL who have received at least one prior therapy. In July 2014, ibrutinib received approval for adult CLL patients with 17p deletion, and, in March 2016, ibrutinib was approved as a frontline CLL treatment.
Ibrutinib was approved for use as a single agent in adults with WM in January 2015.
In May 2016, ibrutinib was approved in combination with bendamustine and rituximab for adults with previously treated CLL/SLL.
In January 2017, ibrutinib was approved for adults with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, ibrutinib was approved to treat adults with cGVHD that did not respond to one or more lines of systemic therapy.
Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.
The US Food and Drug Administration (FDA) has approved ibrutinib (Imbruvica®) for use in combination with rituximab to treat adults with Waldenström’s macroglobulinemia (WM).
This is the ninth FDA approval for ibrutinib and the second approval for the drug in WM.
The latest approval was supported by the phase 3 iNNOVATE trial, in which researchers compared ibrutinib plus rituximab to rituximab alone in patients with previously untreated or relapsed/refractory WM.
Results from iNNOVATE were presented at the 2018 ASCO Annual Meeting (abstract 8003) and simultaneously published in NEJM.
The trial enrolled 150 patients. They received rituximab at 375 mg/m2 with weekly infusions at weeks 1 to 4 and 17 to 20. They also received either ibrutinib (420 mg) or placebo once daily continuously until criteria for permanent discontinuation were met.
Overall response rates were significantly higher in the ibrutinib arm than the placebo arm—92% and 47%, respectively (P<0.0001). Complete response rates were 3% and 1%, respectively.
The median time to next treatment was not reached for the ibrutinib arm and was 18 months for the placebo arm (hazard ratio=0.096; P<0.0001). Of the patients randomized to ibrutinib plus rituximab, 75% continued on treatment at last follow-up.
The 30-month progression-free survival rates were 82% in the ibrutinib arm and 28% in the placebo arm. The median progression-free survival was not reached in the ibrutinib arm and was 20.3 months in the placebo arm (hazard ratio=0.20; P<0.0001).
The 30-month overall survival rates were 94% in the ibrutinib arm and 92% in the placebo arm.
Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 60% of patients in the ibrutinib arm and 61% in the placebo arm. Serious AEs occurred in 43% and 33%, respectively.
There were no fatal AEs in the ibrutinib arm and 3 in the rituximab arm.
Grade 3 or higher AEs that occurred more frequently in the ibrutinib arm than the placebo arm included atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%).
AEs that occurred less frequently in the ibrutinib arm than the placebo arm included grade 3 or higher infusion reactions (1% vs 16%) and any-grade IgM flare (8% vs 47%).
About ibrutinib
Ibrutinib is a Bruton’s tyrosine kinase inhibitor that is FDA-approved to treat chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic graft-versus-host disease (cGVHD), and WM.
In November 2013, ibrutinib was approved to treat adults with MCL who have received at least one prior therapy.
In February 2014, ibrutinib was approved to treat adults with CLL who have received at least one prior therapy. In July 2014, ibrutinib received approval for adult CLL patients with 17p deletion, and, in March 2016, ibrutinib was approved as a frontline CLL treatment.
Ibrutinib was approved for use as a single agent in adults with WM in January 2015.
In May 2016, ibrutinib was approved in combination with bendamustine and rituximab for adults with previously treated CLL/SLL.
In January 2017, ibrutinib was approved for adults with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, ibrutinib was approved to treat adults with cGVHD that did not respond to one or more lines of systemic therapy.
Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.