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Triplet eradicates B-ALL, prolongs survival in mice
A 3-drug combination has demonstrated long-term efficacy against acute lymphoblastic leukemia (ALL) in mice, according to research published in Nature Communications.
Researchers found that when the production of nucleotides is stopped, a DNA replication stress response is activated, and this allows ALL cells to survive.
The team used these findings to devise a 3-drug regimen that blocks both of the nucleotide biosynthetic pathways and inhibits the replication stress response.
One of the drugs is triapine (3-AP), which inhibits ribonucleotide reductase (RNR) and enhances salvage nucleotide biosynthesis.
Another drug is DI-82, which inhibits the nucleoside salvage kinase deoxycytidine kinase (dCK).
And the third drug is VE-822, which inhibits the replication stress-sensing kinase ataxia telangiectasia and Rad3-related protein (ATR).
The researchers tested these 3 drugs in a mouse model of pre-B-ALL. Starting on day 7 after inoculation of pre-B-ALL, the mice received 3-AP and DI-82 twice a day and VE-822 once a day.
The team said mice in the control group succumbed to their disease within 17 days. However, all of the mice that received the 3-drug combination were still disease-free 442 days after they had stopped treatment (on day 42).
The researchers said the combination was well-tolerated, as mice maintained their body weight and enjoyed long-term survival without any detectable pathology.
The team also tested a dosing regimen in which all 3 drugs were given once a day.
Although this was less effective than the first regimen, 4 of 5 mice had no detectable disease 313 days after stopping treatment.
Two of the researchers involved in this study are co-founders and equity holders of Trethera Corp, a company developing a dCK inhibitor known as TRE-515.
The University of California (where most of the study authors work) has patented intellectual property for small-molecule dCK inhibitors, and it was licensed by Trethera. 
A 3-drug combination has demonstrated long-term efficacy against acute lymphoblastic leukemia (ALL) in mice, according to research published in Nature Communications.
Researchers found that when the production of nucleotides is stopped, a DNA replication stress response is activated, and this allows ALL cells to survive.
The team used these findings to devise a 3-drug regimen that blocks both of the nucleotide biosynthetic pathways and inhibits the replication stress response.
One of the drugs is triapine (3-AP), which inhibits ribonucleotide reductase (RNR) and enhances salvage nucleotide biosynthesis.
Another drug is DI-82, which inhibits the nucleoside salvage kinase deoxycytidine kinase (dCK).
And the third drug is VE-822, which inhibits the replication stress-sensing kinase ataxia telangiectasia and Rad3-related protein (ATR).
The researchers tested these 3 drugs in a mouse model of pre-B-ALL. Starting on day 7 after inoculation of pre-B-ALL, the mice received 3-AP and DI-82 twice a day and VE-822 once a day.
The team said mice in the control group succumbed to their disease within 17 days. However, all of the mice that received the 3-drug combination were still disease-free 442 days after they had stopped treatment (on day 42).
The researchers said the combination was well-tolerated, as mice maintained their body weight and enjoyed long-term survival without any detectable pathology.
The team also tested a dosing regimen in which all 3 drugs were given once a day.
Although this was less effective than the first regimen, 4 of 5 mice had no detectable disease 313 days after stopping treatment.
Two of the researchers involved in this study are co-founders and equity holders of Trethera Corp, a company developing a dCK inhibitor known as TRE-515.
The University of California (where most of the study authors work) has patented intellectual property for small-molecule dCK inhibitors, and it was licensed by Trethera.
A 3-drug combination has demonstrated long-term efficacy against acute lymphoblastic leukemia (ALL) in mice, according to research published in Nature Communications.
Researchers found that when the production of nucleotides is stopped, a DNA replication stress response is activated, and this allows ALL cells to survive.
The team used these findings to devise a 3-drug regimen that blocks both of the nucleotide biosynthetic pathways and inhibits the replication stress response.
One of the drugs is triapine (3-AP), which inhibits ribonucleotide reductase (RNR) and enhances salvage nucleotide biosynthesis.
Another drug is DI-82, which inhibits the nucleoside salvage kinase deoxycytidine kinase (dCK).
And the third drug is VE-822, which inhibits the replication stress-sensing kinase ataxia telangiectasia and Rad3-related protein (ATR).
The researchers tested these 3 drugs in a mouse model of pre-B-ALL. Starting on day 7 after inoculation of pre-B-ALL, the mice received 3-AP and DI-82 twice a day and VE-822 once a day.
The team said mice in the control group succumbed to their disease within 17 days. However, all of the mice that received the 3-drug combination were still disease-free 442 days after they had stopped treatment (on day 42).
The researchers said the combination was well-tolerated, as mice maintained their body weight and enjoyed long-term survival without any detectable pathology.
The team also tested a dosing regimen in which all 3 drugs were given once a day.
Although this was less effective than the first regimen, 4 of 5 mice had no detectable disease 313 days after stopping treatment.
Two of the researchers involved in this study are co-founders and equity holders of Trethera Corp, a company developing a dCK inhibitor known as TRE-515.
The University of California (where most of the study authors work) has patented intellectual property for small-molecule dCK inhibitors, and it was licensed by Trethera.
Inotuzumab ozogamicin tied to sinusoidal obstruction syndrome in ALL
Inotuzumab ozogamicin therapy significantly increased the risk of sinusoidal obstruction syndrome (veno-occlusive disease) among adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), especially when they also received follow-up hematopoietic stem cell transplantation, according to a safety analysis from the INO-VATE trial.
After a median of 9 weeks of treatment, 13% of 164 patients who received inotuzumab ozogamicin (Besponsa, Wyeth/Pfizer) developed sinusoidal obstruction syndrome, compared with less than 1% of 143 patients who received standard care, reported Hagop M. Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his associates (Lancet Haematol. 2017 Jul 4. doi: 10.1016/ S2352-3026[17]30103-5).
Follow-up treatment with HSCT increased the risk of sinusoidal obstruction syndrome in both the intervention (22%) and standard-care (3%) groups. Among patients who did not undergo HSCT, rates of this adverse event were 3% and 0%, respectively. Five patients died from sinusoidal obstruction syndrome, all of whom received both inotuzumab ozogamicin and HSCT. The findings earned the newly approved regimen a boxed warning for severe hepatotoxicity.
The open-label, phase 3, multicenter INO-VATE study included 326 adults with CD22-positive, Philadelphia chromosome–negative or Philadelphia chromosome–positive relapsed or refractory B-cell precursor ALL. The safety analysis included 305 patients. Rates of treatment-emergent hepatotoxicities, of all grades, were 51% with inotuzumab ozogamicin and 34% with standard care. Most adverse hepatic events were grade 1-2 liver-related laboratory abnormalities, but 8% of inotuzumab ozogamicin recipients developed grade 3 or higher sinusoidal obstruction syndrome, versus less than 1% of the control group.
“After follow-up HSCT, the frequency of sinusoidal obstruction syndrome was 50% or higher in the following subgroups: patients aged 65 years or older, patients with last available pre-HSCT serum bilirubin concentration more than or equal to the upper limit of normal, and patients who received conditioning regimens with two alkylating agents,” Dr. Kantarjian and his fellow investigators wrote. Conditioning regimens that included thiotepa markedly increased the risk of sinusoidal obstruction syndrome. Additional risk factors included HSCT before study enrollment, history of liver disease, and a final pre-HSCT platelet count of less than 100 × 109 platelets per L.
Rates of sinusoidal obstruction syndrome were 42% with four to six cycles of inotuzumab ozogamicin, 23% with three cycles, 19% with two cycles, and 8% with one cycle, said the investigators. In multivariate analysis, conditioning with two alkylating agents (P = .02 compared with one alkylating agent) and pre-HSCT bilirubin of at least the upper limit of normal (P = .01) significantly increased the risk of sinusoidal obstruction syndrome during or after treatment with inotuzumab ozogamicin.
Notably, inotuzumab ozogamicin did not significantly increase the chances of survival compared with standard care among patients who also received follow-up HSCT (hazard ratio, 1.3; 97.5% confidence interval, 0.66 to 2.3; P = 0.77). Among HSCT recipients, the chances of surviving to 24 months were 39% (95% CI, 28%-50%) with inotuzumab ozogamicin and 29% (11%-49%) with standard care. Nonetheless, HSCT “offers possibility of cure in the relapsed or recurrent [ALL] setting,” the researchers wrote. Clinicians should be especially wary of sinusoidal obstruction syndrome if patients are 65 years or older, received HSCT before inotuzumab ozogamicin treatment, or have a baseline history of liver disease, they said. Strategies to minimize risk include shortening the duration of inotuzumab ozogamicin treatment and avoiding conditioning regimens that contain two alkylating agents.
Pfizer funded and collaborated in the trial. Dr. Kantarjian disclosed ties to Pfizer and numerous other pharmaceutical companies.
Inotuzumab ozogamicin therapy significantly increased the risk of sinusoidal obstruction syndrome (veno-occlusive disease) among adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), especially when they also received follow-up hematopoietic stem cell transplantation, according to a safety analysis from the INO-VATE trial.
After a median of 9 weeks of treatment, 13% of 164 patients who received inotuzumab ozogamicin (Besponsa, Wyeth/Pfizer) developed sinusoidal obstruction syndrome, compared with less than 1% of 143 patients who received standard care, reported Hagop M. Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his associates (Lancet Haematol. 2017 Jul 4. doi: 10.1016/ S2352-3026[17]30103-5).
Follow-up treatment with HSCT increased the risk of sinusoidal obstruction syndrome in both the intervention (22%) and standard-care (3%) groups. Among patients who did not undergo HSCT, rates of this adverse event were 3% and 0%, respectively. Five patients died from sinusoidal obstruction syndrome, all of whom received both inotuzumab ozogamicin and HSCT. The findings earned the newly approved regimen a boxed warning for severe hepatotoxicity.
The open-label, phase 3, multicenter INO-VATE study included 326 adults with CD22-positive, Philadelphia chromosome–negative or Philadelphia chromosome–positive relapsed or refractory B-cell precursor ALL. The safety analysis included 305 patients. Rates of treatment-emergent hepatotoxicities, of all grades, were 51% with inotuzumab ozogamicin and 34% with standard care. Most adverse hepatic events were grade 1-2 liver-related laboratory abnormalities, but 8% of inotuzumab ozogamicin recipients developed grade 3 or higher sinusoidal obstruction syndrome, versus less than 1% of the control group.
“After follow-up HSCT, the frequency of sinusoidal obstruction syndrome was 50% or higher in the following subgroups: patients aged 65 years or older, patients with last available pre-HSCT serum bilirubin concentration more than or equal to the upper limit of normal, and patients who received conditioning regimens with two alkylating agents,” Dr. Kantarjian and his fellow investigators wrote. Conditioning regimens that included thiotepa markedly increased the risk of sinusoidal obstruction syndrome. Additional risk factors included HSCT before study enrollment, history of liver disease, and a final pre-HSCT platelet count of less than 100 × 109 platelets per L.
Rates of sinusoidal obstruction syndrome were 42% with four to six cycles of inotuzumab ozogamicin, 23% with three cycles, 19% with two cycles, and 8% with one cycle, said the investigators. In multivariate analysis, conditioning with two alkylating agents (P = .02 compared with one alkylating agent) and pre-HSCT bilirubin of at least the upper limit of normal (P = .01) significantly increased the risk of sinusoidal obstruction syndrome during or after treatment with inotuzumab ozogamicin.
Notably, inotuzumab ozogamicin did not significantly increase the chances of survival compared with standard care among patients who also received follow-up HSCT (hazard ratio, 1.3; 97.5% confidence interval, 0.66 to 2.3; P = 0.77). Among HSCT recipients, the chances of surviving to 24 months were 39% (95% CI, 28%-50%) with inotuzumab ozogamicin and 29% (11%-49%) with standard care. Nonetheless, HSCT “offers possibility of cure in the relapsed or recurrent [ALL] setting,” the researchers wrote. Clinicians should be especially wary of sinusoidal obstruction syndrome if patients are 65 years or older, received HSCT before inotuzumab ozogamicin treatment, or have a baseline history of liver disease, they said. Strategies to minimize risk include shortening the duration of inotuzumab ozogamicin treatment and avoiding conditioning regimens that contain two alkylating agents.
Pfizer funded and collaborated in the trial. Dr. Kantarjian disclosed ties to Pfizer and numerous other pharmaceutical companies.
Inotuzumab ozogamicin therapy significantly increased the risk of sinusoidal obstruction syndrome (veno-occlusive disease) among adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), especially when they also received follow-up hematopoietic stem cell transplantation, according to a safety analysis from the INO-VATE trial.
After a median of 9 weeks of treatment, 13% of 164 patients who received inotuzumab ozogamicin (Besponsa, Wyeth/Pfizer) developed sinusoidal obstruction syndrome, compared with less than 1% of 143 patients who received standard care, reported Hagop M. Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his associates (Lancet Haematol. 2017 Jul 4. doi: 10.1016/ S2352-3026[17]30103-5).
Follow-up treatment with HSCT increased the risk of sinusoidal obstruction syndrome in both the intervention (22%) and standard-care (3%) groups. Among patients who did not undergo HSCT, rates of this adverse event were 3% and 0%, respectively. Five patients died from sinusoidal obstruction syndrome, all of whom received both inotuzumab ozogamicin and HSCT. The findings earned the newly approved regimen a boxed warning for severe hepatotoxicity.
The open-label, phase 3, multicenter INO-VATE study included 326 adults with CD22-positive, Philadelphia chromosome–negative or Philadelphia chromosome–positive relapsed or refractory B-cell precursor ALL. The safety analysis included 305 patients. Rates of treatment-emergent hepatotoxicities, of all grades, were 51% with inotuzumab ozogamicin and 34% with standard care. Most adverse hepatic events were grade 1-2 liver-related laboratory abnormalities, but 8% of inotuzumab ozogamicin recipients developed grade 3 or higher sinusoidal obstruction syndrome, versus less than 1% of the control group.
“After follow-up HSCT, the frequency of sinusoidal obstruction syndrome was 50% or higher in the following subgroups: patients aged 65 years or older, patients with last available pre-HSCT serum bilirubin concentration more than or equal to the upper limit of normal, and patients who received conditioning regimens with two alkylating agents,” Dr. Kantarjian and his fellow investigators wrote. Conditioning regimens that included thiotepa markedly increased the risk of sinusoidal obstruction syndrome. Additional risk factors included HSCT before study enrollment, history of liver disease, and a final pre-HSCT platelet count of less than 100 × 109 platelets per L.
Rates of sinusoidal obstruction syndrome were 42% with four to six cycles of inotuzumab ozogamicin, 23% with three cycles, 19% with two cycles, and 8% with one cycle, said the investigators. In multivariate analysis, conditioning with two alkylating agents (P = .02 compared with one alkylating agent) and pre-HSCT bilirubin of at least the upper limit of normal (P = .01) significantly increased the risk of sinusoidal obstruction syndrome during or after treatment with inotuzumab ozogamicin.
Notably, inotuzumab ozogamicin did not significantly increase the chances of survival compared with standard care among patients who also received follow-up HSCT (hazard ratio, 1.3; 97.5% confidence interval, 0.66 to 2.3; P = 0.77). Among HSCT recipients, the chances of surviving to 24 months were 39% (95% CI, 28%-50%) with inotuzumab ozogamicin and 29% (11%-49%) with standard care. Nonetheless, HSCT “offers possibility of cure in the relapsed or recurrent [ALL] setting,” the researchers wrote. Clinicians should be especially wary of sinusoidal obstruction syndrome if patients are 65 years or older, received HSCT before inotuzumab ozogamicin treatment, or have a baseline history of liver disease, they said. Strategies to minimize risk include shortening the duration of inotuzumab ozogamicin treatment and avoiding conditioning regimens that contain two alkylating agents.
Pfizer funded and collaborated in the trial. Dr. Kantarjian disclosed ties to Pfizer and numerous other pharmaceutical companies.
FROM LANCET HAEMATOLOGY
Key clinical point: Treatment with inotuzumab ozogamicin (Besponsa, Wyeth/Pfizer) led to sinusoidal obstructive syndrome (veno-occlusive disease), especially after follow-up hematopoietic stem cell transplantation, compared with standard care for relapsed or refractory acute lymphoblastic leukemia.
Major finding: After a median of 9 weeks of treatment, rates of sinusoidal obstructive syndrome were 13% among inotuzumab ozogamicin recipients overall, 22% among those who also received HSCT, and less than 1% in the standard-care group.
Data source: A prespecified safety analysis of INO-VATE, an open-label, phase 3, multicenter trial of 326 adults with Philadelphia chromosome–negative or Philadelphia chromosome–positive relapsed or refractory B-cell precursor ALL.
Disclosures: Pfizer funded and collaborated in the trial. Dr. Kantarjian disclosed ties to Pfizer and numerous other pharmaceutical companies.
FDA approves inotuzumab ozogamicin for rel/ref ALL
The US Food and Drug Administration (FDA) has approved inotuzumab ozogamicin (Besponsa®) for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
The labeling for inotuzumab ozogamicin includes a boxed warning stating that the drug poses a risk of hepatotoxicity, including hepatic veno-occlusive disease (or sinusoidal obstruction syndrome), as well as an increased risk of post-transplant non-relapse mortality.
The full prescribing information for inotuzumab ozogamicin is available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761040s000lbl.pdf.
Inotuzumab ozogamicin is an antibody-drug conjugate that consists of a monoclonal antibody targeting CD22 and a cytotoxic agent known as calicheamicin.
The product originates from a collaboration between Pfizer and Celltech (now UCB), but Pfizer has sole responsibility for all manufacturing and clinical development activities.
Inotuzumab ozogamicin was reviewed and approved under the FDA’s breakthrough therapy designation and priority review programs.
The application for inotuzumab ozogamicin was supported by results from the phase 3 INO-VATE trial, which were published in NEJM in June 2016.
The trial enrolled 326 adults with relapsed or refractory B-cell ALL. Patients received inotuzumab ozogamicin or 1 of 3 chemotherapy regimens (high-dose cytarabine, cytarabine plus mitoxantrone, or fludarabine, cytarabine, and granulocyte colony-stimulating factor).
The rate of complete remission, including incomplete hematologic recovery, was 80.7% in the inotuzumab arm and 29.4% in the chemotherapy arm (P<0.001). The median duration of remission was 4.6 months and 3.1 months, respectively (P=0.03).
Forty-one percent of patients treated with inotuzumab and 11% of those who received chemotherapy proceeded to stem cell transplant directly after treatment (P<0.001).
The median progression-free survival was 5.0 months in the inotuzumab arm and 1.8 months in the chemotherapy arm (P<0.001).
The median overall survival was 7.7 months and 6.7 months, respectively (P=0.04). This did not meet the prespecified boundary of significance (P=0.0208).
Liver-related adverse events were more common in the inotuzumab arm than the chemotherapy arm. The most frequent of these were increased aspartate aminotransferase level (20% vs 10%), hyperbilirubinemia (15% vs 10%), and increased alanine aminotransferase level (14% vs 11%).
Veno-occlusive liver disease occurred in 11% of patients in the inotuzumab arm and 1% in the chemotherapy arm.
There were 17 deaths during treatment in the inotuzumab arm and 11 in the chemotherapy arm. Four deaths were considered related to inotuzumab, and 2 were thought to be related to chemotherapy.
The US Food and Drug Administration (FDA) has approved inotuzumab ozogamicin (Besponsa®) for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
The labeling for inotuzumab ozogamicin includes a boxed warning stating that the drug poses a risk of hepatotoxicity, including hepatic veno-occlusive disease (or sinusoidal obstruction syndrome), as well as an increased risk of post-transplant non-relapse mortality.
The full prescribing information for inotuzumab ozogamicin is available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761040s000lbl.pdf.
Inotuzumab ozogamicin is an antibody-drug conjugate that consists of a monoclonal antibody targeting CD22 and a cytotoxic agent known as calicheamicin.
The product originates from a collaboration between Pfizer and Celltech (now UCB), but Pfizer has sole responsibility for all manufacturing and clinical development activities.
Inotuzumab ozogamicin was reviewed and approved under the FDA’s breakthrough therapy designation and priority review programs.
The application for inotuzumab ozogamicin was supported by results from the phase 3 INO-VATE trial, which were published in NEJM in June 2016.
The trial enrolled 326 adults with relapsed or refractory B-cell ALL. Patients received inotuzumab ozogamicin or 1 of 3 chemotherapy regimens (high-dose cytarabine, cytarabine plus mitoxantrone, or fludarabine, cytarabine, and granulocyte colony-stimulating factor).
The rate of complete remission, including incomplete hematologic recovery, was 80.7% in the inotuzumab arm and 29.4% in the chemotherapy arm (P<0.001). The median duration of remission was 4.6 months and 3.1 months, respectively (P=0.03).
Forty-one percent of patients treated with inotuzumab and 11% of those who received chemotherapy proceeded to stem cell transplant directly after treatment (P<0.001).
The median progression-free survival was 5.0 months in the inotuzumab arm and 1.8 months in the chemotherapy arm (P<0.001).
The median overall survival was 7.7 months and 6.7 months, respectively (P=0.04). This did not meet the prespecified boundary of significance (P=0.0208).
Liver-related adverse events were more common in the inotuzumab arm than the chemotherapy arm. The most frequent of these were increased aspartate aminotransferase level (20% vs 10%), hyperbilirubinemia (15% vs 10%), and increased alanine aminotransferase level (14% vs 11%).
Veno-occlusive liver disease occurred in 11% of patients in the inotuzumab arm and 1% in the chemotherapy arm.
There were 17 deaths during treatment in the inotuzumab arm and 11 in the chemotherapy arm. Four deaths were considered related to inotuzumab, and 2 were thought to be related to chemotherapy.
The US Food and Drug Administration (FDA) has approved inotuzumab ozogamicin (Besponsa®) for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
The labeling for inotuzumab ozogamicin includes a boxed warning stating that the drug poses a risk of hepatotoxicity, including hepatic veno-occlusive disease (or sinusoidal obstruction syndrome), as well as an increased risk of post-transplant non-relapse mortality.
The full prescribing information for inotuzumab ozogamicin is available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761040s000lbl.pdf.
Inotuzumab ozogamicin is an antibody-drug conjugate that consists of a monoclonal antibody targeting CD22 and a cytotoxic agent known as calicheamicin.
The product originates from a collaboration between Pfizer and Celltech (now UCB), but Pfizer has sole responsibility for all manufacturing and clinical development activities.
Inotuzumab ozogamicin was reviewed and approved under the FDA’s breakthrough therapy designation and priority review programs.
The application for inotuzumab ozogamicin was supported by results from the phase 3 INO-VATE trial, which were published in NEJM in June 2016.
The trial enrolled 326 adults with relapsed or refractory B-cell ALL. Patients received inotuzumab ozogamicin or 1 of 3 chemotherapy regimens (high-dose cytarabine, cytarabine plus mitoxantrone, or fludarabine, cytarabine, and granulocyte colony-stimulating factor).
The rate of complete remission, including incomplete hematologic recovery, was 80.7% in the inotuzumab arm and 29.4% in the chemotherapy arm (P<0.001). The median duration of remission was 4.6 months and 3.1 months, respectively (P=0.03).
Forty-one percent of patients treated with inotuzumab and 11% of those who received chemotherapy proceeded to stem cell transplant directly after treatment (P<0.001).
The median progression-free survival was 5.0 months in the inotuzumab arm and 1.8 months in the chemotherapy arm (P<0.001).
The median overall survival was 7.7 months and 6.7 months, respectively (P=0.04). This did not meet the prespecified boundary of significance (P=0.0208).
Liver-related adverse events were more common in the inotuzumab arm than the chemotherapy arm. The most frequent of these were increased aspartate aminotransferase level (20% vs 10%), hyperbilirubinemia (15% vs 10%), and increased alanine aminotransferase level (14% vs 11%).
Veno-occlusive liver disease occurred in 11% of patients in the inotuzumab arm and 1% in the chemotherapy arm.
There were 17 deaths during treatment in the inotuzumab arm and 11 in the chemotherapy arm. Four deaths were considered related to inotuzumab, and 2 were thought to be related to chemotherapy.
Inotuzumab ozogamicin approved for relapsed/refractory ALL
The Food and Drug Administration has approved the antibody drug conjugate inotuzumab ozogamicin for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
The treatment, to be marketed by Pfizer as Besponsa, won approval based on the results of the INO-VATE ALL trial, which randomized 326 patients to receive either inotuzumab ozogamicin (164 patients) or a chemotherapy regimen of the investigator’s choice (162 patients). To be considered for inclusion in the trial, patients with Philadelphia chromosome–negative or –positive relapsed or refractory B-cell precursor ALL were required to have at least 5% bone marrow blasts and have received one or two induction chemotherapy regimens.
Adverse events that occurred in more than 20% of patients included thrombocytopenia, neutropenia, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, abdominal pain, and hyperbilirubinemia, as well as increases in gamma-glutamyltransferase and transaminases. Adverse events that led to discontinuation of treatment were infection, thrombocytopenia, hyperbilirubinemia, hemorrhage, and increases in transaminases.
Preliminary results were published in August 2016 (N Engl J Med. 2016;375:740-53).
Inotuzumab ozogamicin was granted orphan drug and breakthrough status, as well as priority review, by the FDA in February 2017.
dfulton@frontlinemedcom.com
On Twitter @denisefulton
The Food and Drug Administration has approved the antibody drug conjugate inotuzumab ozogamicin for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
The treatment, to be marketed by Pfizer as Besponsa, won approval based on the results of the INO-VATE ALL trial, which randomized 326 patients to receive either inotuzumab ozogamicin (164 patients) or a chemotherapy regimen of the investigator’s choice (162 patients). To be considered for inclusion in the trial, patients with Philadelphia chromosome–negative or –positive relapsed or refractory B-cell precursor ALL were required to have at least 5% bone marrow blasts and have received one or two induction chemotherapy regimens.
Adverse events that occurred in more than 20% of patients included thrombocytopenia, neutropenia, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, abdominal pain, and hyperbilirubinemia, as well as increases in gamma-glutamyltransferase and transaminases. Adverse events that led to discontinuation of treatment were infection, thrombocytopenia, hyperbilirubinemia, hemorrhage, and increases in transaminases.
Preliminary results were published in August 2016 (N Engl J Med. 2016;375:740-53).
Inotuzumab ozogamicin was granted orphan drug and breakthrough status, as well as priority review, by the FDA in February 2017.
dfulton@frontlinemedcom.com
On Twitter @denisefulton
The Food and Drug Administration has approved the antibody drug conjugate inotuzumab ozogamicin for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
The treatment, to be marketed by Pfizer as Besponsa, won approval based on the results of the INO-VATE ALL trial, which randomized 326 patients to receive either inotuzumab ozogamicin (164 patients) or a chemotherapy regimen of the investigator’s choice (162 patients). To be considered for inclusion in the trial, patients with Philadelphia chromosome–negative or –positive relapsed or refractory B-cell precursor ALL were required to have at least 5% bone marrow blasts and have received one or two induction chemotherapy regimens.
Adverse events that occurred in more than 20% of patients included thrombocytopenia, neutropenia, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, abdominal pain, and hyperbilirubinemia, as well as increases in gamma-glutamyltransferase and transaminases. Adverse events that led to discontinuation of treatment were infection, thrombocytopenia, hyperbilirubinemia, hemorrhage, and increases in transaminases.
Preliminary results were published in August 2016 (N Engl J Med. 2016;375:740-53).
Inotuzumab ozogamicin was granted orphan drug and breakthrough status, as well as priority review, by the FDA in February 2017.
dfulton@frontlinemedcom.com
On Twitter @denisefulton
VSTs can treat 5 different viral infections after HSCT
New research suggests virus-specific T cells (VSTs) can protect patients from severe viral infections that sometimes occur after hematopoietic stem cell transplant (HSCT).
The VSTs proved effective against 5 different viruses—Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6).
Ifigeneia Tzannou, MD, of Baylor College of Medicine in Houston, Texas, and her colleagues reported these findings in the Journal of Clinical Oncology.
“In this study, we continued our previous work . . . in which we showed that patients who had developed an Epstein-Barr virus infection after a transplant . . . could be helped by receiving immune cells specialized in eliminating that particular virus,” Dr Tzannou said. “Then, we and others successfully targeted other viruses—namely, adenoviruses and cytomegalovirus.”
“The novel contribution of this study is that we have targeted additional viruses, the BK virus and the HHV-6 virus, which had not been targeted this way before,” added study author Bilal Omer, MD, of Baylor College of Medicine.
“This is important because the BK virus does not have an effective treatment, and the complications are significant, including severe pain and bleeding. These patients are in the hospital for weeks, months sometimes, and, now, we have a treatment option.”
The researchers tested their VSTs in a phase 2 trial of 38 HSCT recipients with at least 1 of the aforementioned viruses.
“[To prepare the VSTs,] we take blood from healthy donors who have already been exposed to these viruses and who we have confirmed have immune cells that can fight the infections,” Dr Tzannou said.
“We isolate the cells and let them multiply in culture. The final product is a mixture of cells that, together, can target all 5 viruses. We prepared 59 sets of virus-specific cells from different donors following this procedure.”
“Our strategy is to prepare a number of sets of virus-specific cells ahead of time and store them in a freezer, ready to use when a patient needs them,” Dr Omer noted. “To match patient and donor, we use elaborate matching algorithms.”
Patients
The trial included 38 patients who had undergone HSCT to treat acute myeloid leukemia/myelodysplastic syndromes (n=20), acute lymphoblastic leukemia (n=9), lymphoma/myeloma (n=3), or nonmalignant disorders (n=6).
These 38 patients had a total of 45 infections—CMV (n=17), EBV (n=2), AdV (n=7), BKV (n=16), and HHV-6 (n=3).
Response
The researchers monitored virus levels and other clinical responses in the 37 evaluable patients.
Six weeks after the first VST infusion, the overall response rate was 91.9%.
Seventeen patients received VSTs for persistent CMV. Sixteen of these patients (94.1%) responded, 6 with complete responses (CRs) and 10 with partial responses (PRs).
Two patients received VSTs for EBV, and both achieved a virologic CR.
Seven patients received VSTs for persistent AdV. The response rate was 71.4%. Four patients achieved a CR, 1 had a PR, and 2 patients did not respond.
Three patients received VSTs to treat HHV-6 reactivations. The response rate was 67%. Two patients had a PR, and 1 was not evaluable.
Sixteen patients received VSTs for BKV-associated hemorrhagic cystitis (n= 14) or BKV-associated nephritis (n=2).
All 16 patients responded. One had a clinical and virologic CR. Six had a clinical CR but a virologic PR. Seven had a virologic and clinical PR. And 2 patients had only a virologic PR.
A total of 15 patients received a second VST infusion—1 due to lack of response, 7 who had a PR, and 7 due to recurrence. Ten of these patients responded to the second infusion—1 with a CR and 9 with a PR.
Four patients received a third infusion of VSTs. Two achieved a CR, 1 had a PR, and 1 did not respond.
Toxicity
One patient developed an isolated fever within 24 hours of VST infusion, but the researchers did not observe any other immediate toxicities.
One of the patients with BKV-associated hemorrhagic cystitis experienced transient hydronephrosis and a decrease in renal function associated with a concomitant bacterial urinary tract infection.
Nineteen patients had prior grade 2 to 4 graft-versus-host disease (GVHD)—15 with grade 2 and 4 with grade 3. All GVHD was quiescent at the time of VST infusion.
One patient developed recurrent grade 3 gastrointestinal GVHD after VST infusion and rapid corticosteroid taper. Five patients developed recurrent (n=3) or de novo (n=2) grade 1 to 2 skin GVHD, which resolved with topical treatment (n=4) and reinitiation of corticosteroid treatment (n=1).
Two patients had a flare of upper-gastrointestinal GVHD, which resolved after a brief corticosteroid course.
“We didn’t have any significant toxicities,” Dr Tzannou said. “Taken together, the results of this trial suggest that it is reasonable to consider this treatment as an early option for these patients. We hope that the results of a future multicenter, phase 3 clinical trial will help raise awareness in both physicians and patients that this treatment, which is safe and effective, is available.”
New research suggests virus-specific T cells (VSTs) can protect patients from severe viral infections that sometimes occur after hematopoietic stem cell transplant (HSCT).
The VSTs proved effective against 5 different viruses—Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6).
Ifigeneia Tzannou, MD, of Baylor College of Medicine in Houston, Texas, and her colleagues reported these findings in the Journal of Clinical Oncology.
“In this study, we continued our previous work . . . in which we showed that patients who had developed an Epstein-Barr virus infection after a transplant . . . could be helped by receiving immune cells specialized in eliminating that particular virus,” Dr Tzannou said. “Then, we and others successfully targeted other viruses—namely, adenoviruses and cytomegalovirus.”
“The novel contribution of this study is that we have targeted additional viruses, the BK virus and the HHV-6 virus, which had not been targeted this way before,” added study author Bilal Omer, MD, of Baylor College of Medicine.
“This is important because the BK virus does not have an effective treatment, and the complications are significant, including severe pain and bleeding. These patients are in the hospital for weeks, months sometimes, and, now, we have a treatment option.”
The researchers tested their VSTs in a phase 2 trial of 38 HSCT recipients with at least 1 of the aforementioned viruses.
“[To prepare the VSTs,] we take blood from healthy donors who have already been exposed to these viruses and who we have confirmed have immune cells that can fight the infections,” Dr Tzannou said.
“We isolate the cells and let them multiply in culture. The final product is a mixture of cells that, together, can target all 5 viruses. We prepared 59 sets of virus-specific cells from different donors following this procedure.”
“Our strategy is to prepare a number of sets of virus-specific cells ahead of time and store them in a freezer, ready to use when a patient needs them,” Dr Omer noted. “To match patient and donor, we use elaborate matching algorithms.”
Patients
The trial included 38 patients who had undergone HSCT to treat acute myeloid leukemia/myelodysplastic syndromes (n=20), acute lymphoblastic leukemia (n=9), lymphoma/myeloma (n=3), or nonmalignant disorders (n=6).
These 38 patients had a total of 45 infections—CMV (n=17), EBV (n=2), AdV (n=7), BKV (n=16), and HHV-6 (n=3).
Response
The researchers monitored virus levels and other clinical responses in the 37 evaluable patients.
Six weeks after the first VST infusion, the overall response rate was 91.9%.
Seventeen patients received VSTs for persistent CMV. Sixteen of these patients (94.1%) responded, 6 with complete responses (CRs) and 10 with partial responses (PRs).
Two patients received VSTs for EBV, and both achieved a virologic CR.
Seven patients received VSTs for persistent AdV. The response rate was 71.4%. Four patients achieved a CR, 1 had a PR, and 2 patients did not respond.
Three patients received VSTs to treat HHV-6 reactivations. The response rate was 67%. Two patients had a PR, and 1 was not evaluable.
Sixteen patients received VSTs for BKV-associated hemorrhagic cystitis (n= 14) or BKV-associated nephritis (n=2).
All 16 patients responded. One had a clinical and virologic CR. Six had a clinical CR but a virologic PR. Seven had a virologic and clinical PR. And 2 patients had only a virologic PR.
A total of 15 patients received a second VST infusion—1 due to lack of response, 7 who had a PR, and 7 due to recurrence. Ten of these patients responded to the second infusion—1 with a CR and 9 with a PR.
Four patients received a third infusion of VSTs. Two achieved a CR, 1 had a PR, and 1 did not respond.
Toxicity
One patient developed an isolated fever within 24 hours of VST infusion, but the researchers did not observe any other immediate toxicities.
One of the patients with BKV-associated hemorrhagic cystitis experienced transient hydronephrosis and a decrease in renal function associated with a concomitant bacterial urinary tract infection.
Nineteen patients had prior grade 2 to 4 graft-versus-host disease (GVHD)—15 with grade 2 and 4 with grade 3. All GVHD was quiescent at the time of VST infusion.
One patient developed recurrent grade 3 gastrointestinal GVHD after VST infusion and rapid corticosteroid taper. Five patients developed recurrent (n=3) or de novo (n=2) grade 1 to 2 skin GVHD, which resolved with topical treatment (n=4) and reinitiation of corticosteroid treatment (n=1).
Two patients had a flare of upper-gastrointestinal GVHD, which resolved after a brief corticosteroid course.
“We didn’t have any significant toxicities,” Dr Tzannou said. “Taken together, the results of this trial suggest that it is reasonable to consider this treatment as an early option for these patients. We hope that the results of a future multicenter, phase 3 clinical trial will help raise awareness in both physicians and patients that this treatment, which is safe and effective, is available.”
New research suggests virus-specific T cells (VSTs) can protect patients from severe viral infections that sometimes occur after hematopoietic stem cell transplant (HSCT).
The VSTs proved effective against 5 different viruses—Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6).
Ifigeneia Tzannou, MD, of Baylor College of Medicine in Houston, Texas, and her colleagues reported these findings in the Journal of Clinical Oncology.
“In this study, we continued our previous work . . . in which we showed that patients who had developed an Epstein-Barr virus infection after a transplant . . . could be helped by receiving immune cells specialized in eliminating that particular virus,” Dr Tzannou said. “Then, we and others successfully targeted other viruses—namely, adenoviruses and cytomegalovirus.”
“The novel contribution of this study is that we have targeted additional viruses, the BK virus and the HHV-6 virus, which had not been targeted this way before,” added study author Bilal Omer, MD, of Baylor College of Medicine.
“This is important because the BK virus does not have an effective treatment, and the complications are significant, including severe pain and bleeding. These patients are in the hospital for weeks, months sometimes, and, now, we have a treatment option.”
The researchers tested their VSTs in a phase 2 trial of 38 HSCT recipients with at least 1 of the aforementioned viruses.
“[To prepare the VSTs,] we take blood from healthy donors who have already been exposed to these viruses and who we have confirmed have immune cells that can fight the infections,” Dr Tzannou said.
“We isolate the cells and let them multiply in culture. The final product is a mixture of cells that, together, can target all 5 viruses. We prepared 59 sets of virus-specific cells from different donors following this procedure.”
“Our strategy is to prepare a number of sets of virus-specific cells ahead of time and store them in a freezer, ready to use when a patient needs them,” Dr Omer noted. “To match patient and donor, we use elaborate matching algorithms.”
Patients
The trial included 38 patients who had undergone HSCT to treat acute myeloid leukemia/myelodysplastic syndromes (n=20), acute lymphoblastic leukemia (n=9), lymphoma/myeloma (n=3), or nonmalignant disorders (n=6).
These 38 patients had a total of 45 infections—CMV (n=17), EBV (n=2), AdV (n=7), BKV (n=16), and HHV-6 (n=3).
Response
The researchers monitored virus levels and other clinical responses in the 37 evaluable patients.
Six weeks after the first VST infusion, the overall response rate was 91.9%.
Seventeen patients received VSTs for persistent CMV. Sixteen of these patients (94.1%) responded, 6 with complete responses (CRs) and 10 with partial responses (PRs).
Two patients received VSTs for EBV, and both achieved a virologic CR.
Seven patients received VSTs for persistent AdV. The response rate was 71.4%. Four patients achieved a CR, 1 had a PR, and 2 patients did not respond.
Three patients received VSTs to treat HHV-6 reactivations. The response rate was 67%. Two patients had a PR, and 1 was not evaluable.
Sixteen patients received VSTs for BKV-associated hemorrhagic cystitis (n= 14) or BKV-associated nephritis (n=2).
All 16 patients responded. One had a clinical and virologic CR. Six had a clinical CR but a virologic PR. Seven had a virologic and clinical PR. And 2 patients had only a virologic PR.
A total of 15 patients received a second VST infusion—1 due to lack of response, 7 who had a PR, and 7 due to recurrence. Ten of these patients responded to the second infusion—1 with a CR and 9 with a PR.
Four patients received a third infusion of VSTs. Two achieved a CR, 1 had a PR, and 1 did not respond.
Toxicity
One patient developed an isolated fever within 24 hours of VST infusion, but the researchers did not observe any other immediate toxicities.
One of the patients with BKV-associated hemorrhagic cystitis experienced transient hydronephrosis and a decrease in renal function associated with a concomitant bacterial urinary tract infection.
Nineteen patients had prior grade 2 to 4 graft-versus-host disease (GVHD)—15 with grade 2 and 4 with grade 3. All GVHD was quiescent at the time of VST infusion.
One patient developed recurrent grade 3 gastrointestinal GVHD after VST infusion and rapid corticosteroid taper. Five patients developed recurrent (n=3) or de novo (n=2) grade 1 to 2 skin GVHD, which resolved with topical treatment (n=4) and reinitiation of corticosteroid treatment (n=1).
Two patients had a flare of upper-gastrointestinal GVHD, which resolved after a brief corticosteroid course.
“We didn’t have any significant toxicities,” Dr Tzannou said. “Taken together, the results of this trial suggest that it is reasonable to consider this treatment as an early option for these patients. We hope that the results of a future multicenter, phase 3 clinical trial will help raise awareness in both physicians and patients that this treatment, which is safe and effective, is available.”
Blinatumomab granted full approval to treat rel/ref BCP-ALL
The US Food and Drug Administration (FDA) has approved the supplemental biologics license application (sBLA) for blinatumomab (Blincyto®).
The aim of the sBLA was to expand the indication for blinatumomab to include all patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and to convert blinatumomab’s accelerated approval to a full approval.
Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.
In 2014, the FDA granted blinatumomab accelerated approval to treat adults with Philadelphia chromosome-negative (Ph-) relapsed or refractory BCP-ALL.
In 2016, the FDA granted the therapy accelerated approval for pediatric patients with Ph- relapsed/refractory BCP-ALL.
Now, the FDA has granted blinatumomab full approval for pediatric and adult patients with Ph- or Ph+ relapsed/refractory BCP-ALL.
The FDA also recently approved the sBLA for blinatumomab to be infused over 7 days with preservative, adding to the previously approved administration options for infusion over 24 and 48 hours (preservative-free).
The blinatumomab intravenous bag for a 7-day infusion contains Bacteriostatic 0.9% Sodium Chloride, USP (containing 0.9% benzyl alcohol), which permits continuous intravenous infusion of blinatumomab at 28 mcg/day or 15 mcg/m²/day for a total of 7 days.
The 7-day infusion is not recommended for patients weighing less than 22 kg due to the risk of serious and sometimes fatal adverse events associated with benzyl alcohol in pediatric patients. See the full prescribing information for details.
The prescribing information for blinatumomab includes a boxed warning detailing the risk of cytokine release syndrome and neurologic toxicities. Blinatumomab is also under a Risk Evaluation and Mitigation Strategy program in the US intended to inform healthcare providers about these risks.
Blinatumomab is marketed by Amgen.
Trial results
With this sBLA, Amgen sought to make blinatumomab available as a treatment for patients with Ph+ relapsed/refractory BCP-ALL (as well as Ph-).
To this end, the application included data from the ALCANTARA study, which were published in the Journal of Clinical Oncology.
In this trial, researchers evaluated blinatumomab in adults with Ph+ relapsed/refractory BCP-ALL who had failed treatment with at least 1 tyrosine kinase inhibitor.
Thirty-six percent of patients achieved a complete response or complete response with partial hematologic recovery within the first 2 cycles of blinatumomab treatment. Of these patients, 88% were minimal residual disease-negative.
The most frequent adverse events (AEs) in this trial were pyrexia (58%), neurologic events (47%), febrile neutropenia (40%), and headache (31%). Three patients had grade 1/2 cytokine release syndrome, and 3 patients had grade 3 neurologic AEs.
The sBLA also included overall survival (OS) data from the phase 3 TOWER trial, which was intended to support the conversion of blinatumomab’s accelerated approval to a full approval.
Results from the TOWER trial were published in NEJM.
In this study, researchers compared blinatumomab to standard of care (SOC) chemotherapy (4 different regimens) in adults with Ph- relapsed/refractory BCP-ALL.
Blinatumomab produced higher response rates and nearly doubled OS compared to SOC. The median OS was 7.7 months in the blinatumomab arm and 4 months in the SOC arm. The hazard ratio for death was 0.71 (P=0.012).
The incidence of grade 3 or higher AEs was higher in the SOC arm, but the incidence of serious AEs was higher in the blinatumomab arm.
The US Food and Drug Administration (FDA) has approved the supplemental biologics license application (sBLA) for blinatumomab (Blincyto®).
The aim of the sBLA was to expand the indication for blinatumomab to include all patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and to convert blinatumomab’s accelerated approval to a full approval.
Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.
In 2014, the FDA granted blinatumomab accelerated approval to treat adults with Philadelphia chromosome-negative (Ph-) relapsed or refractory BCP-ALL.
In 2016, the FDA granted the therapy accelerated approval for pediatric patients with Ph- relapsed/refractory BCP-ALL.
Now, the FDA has granted blinatumomab full approval for pediatric and adult patients with Ph- or Ph+ relapsed/refractory BCP-ALL.
The FDA also recently approved the sBLA for blinatumomab to be infused over 7 days with preservative, adding to the previously approved administration options for infusion over 24 and 48 hours (preservative-free).
The blinatumomab intravenous bag for a 7-day infusion contains Bacteriostatic 0.9% Sodium Chloride, USP (containing 0.9% benzyl alcohol), which permits continuous intravenous infusion of blinatumomab at 28 mcg/day or 15 mcg/m²/day for a total of 7 days.
The 7-day infusion is not recommended for patients weighing less than 22 kg due to the risk of serious and sometimes fatal adverse events associated with benzyl alcohol in pediatric patients. See the full prescribing information for details.
The prescribing information for blinatumomab includes a boxed warning detailing the risk of cytokine release syndrome and neurologic toxicities. Blinatumomab is also under a Risk Evaluation and Mitigation Strategy program in the US intended to inform healthcare providers about these risks.
Blinatumomab is marketed by Amgen.
Trial results
With this sBLA, Amgen sought to make blinatumomab available as a treatment for patients with Ph+ relapsed/refractory BCP-ALL (as well as Ph-).
To this end, the application included data from the ALCANTARA study, which were published in the Journal of Clinical Oncology.
In this trial, researchers evaluated blinatumomab in adults with Ph+ relapsed/refractory BCP-ALL who had failed treatment with at least 1 tyrosine kinase inhibitor.
Thirty-six percent of patients achieved a complete response or complete response with partial hematologic recovery within the first 2 cycles of blinatumomab treatment. Of these patients, 88% were minimal residual disease-negative.
The most frequent adverse events (AEs) in this trial were pyrexia (58%), neurologic events (47%), febrile neutropenia (40%), and headache (31%). Three patients had grade 1/2 cytokine release syndrome, and 3 patients had grade 3 neurologic AEs.
The sBLA also included overall survival (OS) data from the phase 3 TOWER trial, which was intended to support the conversion of blinatumomab’s accelerated approval to a full approval.
Results from the TOWER trial were published in NEJM.
In this study, researchers compared blinatumomab to standard of care (SOC) chemotherapy (4 different regimens) in adults with Ph- relapsed/refractory BCP-ALL.
Blinatumomab produced higher response rates and nearly doubled OS compared to SOC. The median OS was 7.7 months in the blinatumomab arm and 4 months in the SOC arm. The hazard ratio for death was 0.71 (P=0.012).
The incidence of grade 3 or higher AEs was higher in the SOC arm, but the incidence of serious AEs was higher in the blinatumomab arm.
The US Food and Drug Administration (FDA) has approved the supplemental biologics license application (sBLA) for blinatumomab (Blincyto®).
The aim of the sBLA was to expand the indication for blinatumomab to include all patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and to convert blinatumomab’s accelerated approval to a full approval.
Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.
In 2014, the FDA granted blinatumomab accelerated approval to treat adults with Philadelphia chromosome-negative (Ph-) relapsed or refractory BCP-ALL.
In 2016, the FDA granted the therapy accelerated approval for pediatric patients with Ph- relapsed/refractory BCP-ALL.
Now, the FDA has granted blinatumomab full approval for pediatric and adult patients with Ph- or Ph+ relapsed/refractory BCP-ALL.
The FDA also recently approved the sBLA for blinatumomab to be infused over 7 days with preservative, adding to the previously approved administration options for infusion over 24 and 48 hours (preservative-free).
The blinatumomab intravenous bag for a 7-day infusion contains Bacteriostatic 0.9% Sodium Chloride, USP (containing 0.9% benzyl alcohol), which permits continuous intravenous infusion of blinatumomab at 28 mcg/day or 15 mcg/m²/day for a total of 7 days.
The 7-day infusion is not recommended for patients weighing less than 22 kg due to the risk of serious and sometimes fatal adverse events associated with benzyl alcohol in pediatric patients. See the full prescribing information for details.
The prescribing information for blinatumomab includes a boxed warning detailing the risk of cytokine release syndrome and neurologic toxicities. Blinatumomab is also under a Risk Evaluation and Mitigation Strategy program in the US intended to inform healthcare providers about these risks.
Blinatumomab is marketed by Amgen.
Trial results
With this sBLA, Amgen sought to make blinatumomab available as a treatment for patients with Ph+ relapsed/refractory BCP-ALL (as well as Ph-).
To this end, the application included data from the ALCANTARA study, which were published in the Journal of Clinical Oncology.
In this trial, researchers evaluated blinatumomab in adults with Ph+ relapsed/refractory BCP-ALL who had failed treatment with at least 1 tyrosine kinase inhibitor.
Thirty-six percent of patients achieved a complete response or complete response with partial hematologic recovery within the first 2 cycles of blinatumomab treatment. Of these patients, 88% were minimal residual disease-negative.
The most frequent adverse events (AEs) in this trial were pyrexia (58%), neurologic events (47%), febrile neutropenia (40%), and headache (31%). Three patients had grade 1/2 cytokine release syndrome, and 3 patients had grade 3 neurologic AEs.
The sBLA also included overall survival (OS) data from the phase 3 TOWER trial, which was intended to support the conversion of blinatumomab’s accelerated approval to a full approval.
Results from the TOWER trial were published in NEJM.
In this study, researchers compared blinatumomab to standard of care (SOC) chemotherapy (4 different regimens) in adults with Ph- relapsed/refractory BCP-ALL.
Blinatumomab produced higher response rates and nearly doubled OS compared to SOC. The median OS was 7.7 months in the blinatumomab arm and 4 months in the SOC arm. The hazard ratio for death was 0.71 (P=0.012).
The incidence of grade 3 or higher AEs was higher in the SOC arm, but the incidence of serious AEs was higher in the blinatumomab arm.
ODAC recommends approval of CTL019 in rel/ref ALL
The US Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC) has unanimously recommended approval for the chimeric antigen receptor (CAR) T-cell therapy CTL019 (tisagenlecleucel).
The committee voted 10 to 0 in favor of approving CTL019 for the treatment of pediatric and young adult patients (ages 3 to 25) with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).
The FDA will consider this vote as it reviews the biologics license application (BLA) for CTL019, but the agency is not obligated to follow the ODAC’s recommendation.
The BLA for CTL019 is supported by results from 3 trials.
This includes a pilot study, which was presented at the 2015 ASH Annual Meeting; the phase 2 ENSIGN trial, which was presented at the 2016 ASH Annual Meeting; and the phase 2 ELIANA study, which was recently presented at the 22nd Congress of the European Hematology Association (EHA).
ELIANA enrolled 88 patients with relapsed/refractory B-cell ALL, and 68 of them received CTL019.
Nine patients did not receive CTL019 due to death or adverse events, 7 patients were affected by manufacturing failures, and 4 patients were pending infusion at last follow-up.
Most of the infused patients (n=65) received lymphodepleting chemotherapy prior to CTL019 (single dose). The median dose was 3.0 × 106 (range, 0.2-5.4 × 106) transduced CTL019 cells/kg.
Sixty-three patients were evaluable for efficacy.
The overall response rate—complete response (CR) plus CR with incomplete hematologic recovery (CRi)—was 83% (52/63). All patients with CR/CRis were minimal residual disease-negative in the bone marrow.
Sixty-eight patients were evaluated for safety.
Serious adverse events occurred in 69% of patients. These included life-threatening cytokine release syndrome (CRS) and hemophagocytic lymphohistiocytosis, neurological events that occurred with CRS or after CRS was resolved, coagulopathies with CRS, and life-threatening infections.
Seventy-eight percent of patients had CRS—21% with grade 3 and 27% with grade 4 CRS. There were no deaths from CRS.
Forty-four percent of patients had neurological toxicities—15% grade 3 or higher. These included encephalopathy, delirium, hallucinations, somnolence, cognitive disorder, seizure, depressed level of consciousness, mental status changes, dysphagia, muscular weakness, and dysarthria.
Severe infectious complications occurred in 26% of patients, and 3 patients died of such complications.
Eleven patients died after receiving CTL019—7 due to ALL, 1 from cerebral hemorrhage, 1 from encephalitis, 1 from a respiratory tract infection, and 1 from systemic mycosis.
The US Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC) has unanimously recommended approval for the chimeric antigen receptor (CAR) T-cell therapy CTL019 (tisagenlecleucel).
The committee voted 10 to 0 in favor of approving CTL019 for the treatment of pediatric and young adult patients (ages 3 to 25) with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).
The FDA will consider this vote as it reviews the biologics license application (BLA) for CTL019, but the agency is not obligated to follow the ODAC’s recommendation.
The BLA for CTL019 is supported by results from 3 trials.
This includes a pilot study, which was presented at the 2015 ASH Annual Meeting; the phase 2 ENSIGN trial, which was presented at the 2016 ASH Annual Meeting; and the phase 2 ELIANA study, which was recently presented at the 22nd Congress of the European Hematology Association (EHA).
ELIANA enrolled 88 patients with relapsed/refractory B-cell ALL, and 68 of them received CTL019.
Nine patients did not receive CTL019 due to death or adverse events, 7 patients were affected by manufacturing failures, and 4 patients were pending infusion at last follow-up.
Most of the infused patients (n=65) received lymphodepleting chemotherapy prior to CTL019 (single dose). The median dose was 3.0 × 106 (range, 0.2-5.4 × 106) transduced CTL019 cells/kg.
Sixty-three patients were evaluable for efficacy.
The overall response rate—complete response (CR) plus CR with incomplete hematologic recovery (CRi)—was 83% (52/63). All patients with CR/CRis were minimal residual disease-negative in the bone marrow.
Sixty-eight patients were evaluated for safety.
Serious adverse events occurred in 69% of patients. These included life-threatening cytokine release syndrome (CRS) and hemophagocytic lymphohistiocytosis, neurological events that occurred with CRS or after CRS was resolved, coagulopathies with CRS, and life-threatening infections.
Seventy-eight percent of patients had CRS—21% with grade 3 and 27% with grade 4 CRS. There were no deaths from CRS.
Forty-four percent of patients had neurological toxicities—15% grade 3 or higher. These included encephalopathy, delirium, hallucinations, somnolence, cognitive disorder, seizure, depressed level of consciousness, mental status changes, dysphagia, muscular weakness, and dysarthria.
Severe infectious complications occurred in 26% of patients, and 3 patients died of such complications.
Eleven patients died after receiving CTL019—7 due to ALL, 1 from cerebral hemorrhage, 1 from encephalitis, 1 from a respiratory tract infection, and 1 from systemic mycosis.
The US Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC) has unanimously recommended approval for the chimeric antigen receptor (CAR) T-cell therapy CTL019 (tisagenlecleucel).
The committee voted 10 to 0 in favor of approving CTL019 for the treatment of pediatric and young adult patients (ages 3 to 25) with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).
The FDA will consider this vote as it reviews the biologics license application (BLA) for CTL019, but the agency is not obligated to follow the ODAC’s recommendation.
The BLA for CTL019 is supported by results from 3 trials.
This includes a pilot study, which was presented at the 2015 ASH Annual Meeting; the phase 2 ENSIGN trial, which was presented at the 2016 ASH Annual Meeting; and the phase 2 ELIANA study, which was recently presented at the 22nd Congress of the European Hematology Association (EHA).
ELIANA enrolled 88 patients with relapsed/refractory B-cell ALL, and 68 of them received CTL019.
Nine patients did not receive CTL019 due to death or adverse events, 7 patients were affected by manufacturing failures, and 4 patients were pending infusion at last follow-up.
Most of the infused patients (n=65) received lymphodepleting chemotherapy prior to CTL019 (single dose). The median dose was 3.0 × 106 (range, 0.2-5.4 × 106) transduced CTL019 cells/kg.
Sixty-three patients were evaluable for efficacy.
The overall response rate—complete response (CR) plus CR with incomplete hematologic recovery (CRi)—was 83% (52/63). All patients with CR/CRis were minimal residual disease-negative in the bone marrow.
Sixty-eight patients were evaluated for safety.
Serious adverse events occurred in 69% of patients. These included life-threatening cytokine release syndrome (CRS) and hemophagocytic lymphohistiocytosis, neurological events that occurred with CRS or after CRS was resolved, coagulopathies with CRS, and life-threatening infections.
Seventy-eight percent of patients had CRS—21% with grade 3 and 27% with grade 4 CRS. There were no deaths from CRS.
Forty-four percent of patients had neurological toxicities—15% grade 3 or higher. These included encephalopathy, delirium, hallucinations, somnolence, cognitive disorder, seizure, depressed level of consciousness, mental status changes, dysphagia, muscular weakness, and dysarthria.
Severe infectious complications occurred in 26% of patients, and 3 patients died of such complications.
Eleven patients died after receiving CTL019—7 due to ALL, 1 from cerebral hemorrhage, 1 from encephalitis, 1 from a respiratory tract infection, and 1 from systemic mycosis.
All FDA panel members go thumbs up for CTL019 in relapsed/refractory childhood ALL
The answer to the billion dollar question – Does the chimeric antigen receptor T-cell (CAR T) construct CTL019 (tisagenlecleucel-T) have a favorable risk-benefit profile for the treatment of children and young adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia? – was a unanimous “yes” at a July 12 meeting of the Food and Drug Administration’s Oncologic Drugs Advisory Committee.
“This is the most exciting thing I have seen in my lifetime, and probably since the introduction of ‘multiagent total cancer care,’ as it was called then, for treatment of childhood leukemia,” remarked Timothy P. Cripe, MD, PhD, from Nationwide Children’s Hospital in Columbus, Ohio, and a temporary voting member of the ODAC.
Catherine M. Bollard, MD, MBChB, from the Children’s National Medical Center in Washington, also a temporary ODAC member, said that she voted “yes” because “this is a very poor-risk patient population, this is an unmet need in the pediatric population, and as you saw in the data [presented to ODAC] today, the clinical responses are remarkable. I think Novartis [the maker of CTL019] has done a great job putting together a plan for mitigating risk going forward.”
CTL019 was shown in a pivotal phase 2 clinical trial to induce an overall remission rate of 83% in children and young adults with relapsed/refractory ALL for whom at least two prior lines of therapy had failed. Based on these results, the FDA accepted a biologics license application for the agent from Novartis.
At the meeting, panel members initially seemed favorably disposed toward recommending approval but heard concerns from FDA scientists about the potential for severe or fatal adverse events such as the cytokine release syndrome (CRS); the possible generation of replication competent retrovirus (RCR); and the potential for secondary malignancies from insertional mutagenesis, the incorporation of portions of the lentiviral vector into the patient’s genome.
In his opening remarks, Wilson W. Bryan, MD, from the FDA’s Office of Tissue and Advanced Therapies and Center for Biologics Evaluation and Drug Research, commented that “the clinical development of tisagenlecleucel suggests that this is a life-saving product.”
He went on, however, to frame the FDA’s concerns: “Clinical trials are not always a good predictor of the effectiveness and safety of a marketed product,” he said. “In particular, we are concerned that the same benefit and safety seen in clinical trials may not carry over to routine clinical use.”
The purpose of the hearing was to focus on manufacturing issues related to product quality, including replicability of the product for commercial use and safety issues such as prevention of CRS and neurotoxicities.
“We are also concerned about the hypothetical risk of secondary malignancies. Therefore, we are asking for the committee’s recommendations regarding the nature and duration of follow-up of patients who would receive this product,” Dr. Bryan said.
“CTL019 is a living drug, which demonstrates activity after a single infusion,” said Samit Hirawat, MD, head of oncology global development for Novartis.
But the nature of CTL019 as a living drug also means that it is subject to variations in the ability of autologous T cells harvested via leukapheresis to be infected with the lentiviral vector and expanded into a population of CAR T cells large enough to have therapeutic value, said Xiaobin Victor Lu, PhD, a chemistry, manufacturing, and controls reviewer for the FDA.
Mitigation plan
Novartis’ proposed plan includes specific, long-term steps for mitigating the risk of CRS and neurologic events, such as cerebral edema, the latter of which caused the FDA to call for a clinical hold of the phase 2 ROCKET trial for a different CAR T-cell construct.
Among the proposed elements of the mitigation plan are a 15-year minimum pharmacovigilance program and long-term safety follow-up for adverse events related to the therapy, efficacy, immunogenicity, transgene persistence of CD19 CAR, and the incidence of second malignancies possibly related to insertional mutagenesis.
Novartis also will train treatment center staff on processes for cell collection, cryopreservation, transport, chain of identity, safety management, and logistics for handling the CAR T-cell product. The company proposes to provide on-site training of personnel on CRS and neurotoxicity risk and management, as well as to offer information to patients and caregivers about the signs and symptoms of adverse events of concern.
Dr. Cripe expressed his concerns that Novartis’ proposal to initially limit the mitigation plan to 30 or 35 treatment sites would create problems of access and economic disparities among patients, and could cause inequities among treatment centers even with the same city.
David Lebwohl, MD, head of the CAR T global program for Novartis, said that the planned number of sites for the mitigation program would be expanded after 6 to 12 months if the CAR T construct receives final approval and clinical implementation goes well.
There was nearly unanimous agreement among the panel members that the planned 15-year follow-up and other mitigation measures would be adequate for detecting serious short- and long-term consequences of CAR T-cell therapy.
Patient/advocate perspective
In the public comment section of the proceedings, panel members were urged to vote in favor of CTL019 by parents of children with ALL, including Don McMahon, whose son Connor received the therapy after multiple relapses, and Tom Whitehead, father of Emily Whitehead, the first patient to receive CAR T cells for ALL.
Both children are alive and doing well.
CTL019 is produced by Novartis.
The unanimous recommendation by the Food and Drug Administration's Oncologic Drugs Advisory Committee means that the FDA is likely to approve CTL019 (tisagenlecleucel-T), and that approval may come quickly, possibly before the end of 2017. This approval was based on compelling data showing that 83% of children and young adults with refractory or relapsed acute lymphocytic leukemia (ALL) achieved remission with this therapy. This is exciting news for ALL patients as well as for the cell and gene therapy community. What remains to be determined are the labelling for CTL019, the cost of the therapy, and whether all patients who might benefit from this therapy will have the coverage to be able to access it.
While the response rates in patients treated in the trials presented to the FDA are very encouraging there are also concerns with the risks for cytokine release syndrome and neurotoxicity which can affect up to half of treated patients. As a result, Novartis, the manufacturer of CTL019, has proposed an extensive mitigation strategy and education process for the cell therapy centers that will offer the therapy. Initially, this is likely to be limited to around 30 centers that will be geographically distributed throughout the United States with gradual roll out to more centers as there is more experience with the use of CTL019.
Another issue for the centers is going to be operationalizing a new paradigm where CTL019 will be offered as a standard of care rather than in the context of a research study. Most of the initial pediatric centers will likely provide CTL019, within their transplant infrastructure since procurement, initial processing and infusion of cells will utilize their cell processing and collection facilities. The Foundation for Accreditation of Cell Therapy (FACT) has also anticipated this approval by publishing new standards for Immune Effectors earlier this year to promote quality practice in immune effector cell administration.
One other question is whether CTL019 will be transplant enabling or transplant replacing. While the initial response rates are very high and there are some well publicized patients who remain in remission over 5 years after CTL019 without other therapy, other responders proceeded to transplant and there is also a significant relapse rate. It is therefore an open question whether treating physicians will be happy to watch patients who attain remission after this therapy or whether they will still recommend transplant because there is not yet enough follow up on this product to know what the long-term cure rate is going to be.
Another CAR T-cell product is scheduled to come before an FDA advisory committee in October. The indication for KTE-C19 (axicabtagene ciloleucel) from Kite is for relapsed/refractory diffuse large B-cell lymphoma, a much bigger indication with a potentially much larger number of patients. The response rates for KTE-C19 in DLBCL (and indeed for CTL019 in DLBCL) are not as high as those for CTL019 in ALL and follow-up time is shorter, so it is not yet clear how many patients will have sustained long term responses. Nevertheless the response rate in patients who have failed all other therapies is high enough that this product will also likely be approved.
Helen Heslop, MD, is the Dan L. Duncan Chair and Professor of Medicine and Pediatrics at Baylor College of Medicine, Houston. She also is the Director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital. Dr. Heslop is a member of the editorial advisory board of Hematology News.
The unanimous recommendation by the Food and Drug Administration's Oncologic Drugs Advisory Committee means that the FDA is likely to approve CTL019 (tisagenlecleucel-T), and that approval may come quickly, possibly before the end of 2017. This approval was based on compelling data showing that 83% of children and young adults with refractory or relapsed acute lymphocytic leukemia (ALL) achieved remission with this therapy. This is exciting news for ALL patients as well as for the cell and gene therapy community. What remains to be determined are the labelling for CTL019, the cost of the therapy, and whether all patients who might benefit from this therapy will have the coverage to be able to access it.
While the response rates in patients treated in the trials presented to the FDA are very encouraging there are also concerns with the risks for cytokine release syndrome and neurotoxicity which can affect up to half of treated patients. As a result, Novartis, the manufacturer of CTL019, has proposed an extensive mitigation strategy and education process for the cell therapy centers that will offer the therapy. Initially, this is likely to be limited to around 30 centers that will be geographically distributed throughout the United States with gradual roll out to more centers as there is more experience with the use of CTL019.
Another issue for the centers is going to be operationalizing a new paradigm where CTL019 will be offered as a standard of care rather than in the context of a research study. Most of the initial pediatric centers will likely provide CTL019, within their transplant infrastructure since procurement, initial processing and infusion of cells will utilize their cell processing and collection facilities. The Foundation for Accreditation of Cell Therapy (FACT) has also anticipated this approval by publishing new standards for Immune Effectors earlier this year to promote quality practice in immune effector cell administration.
One other question is whether CTL019 will be transplant enabling or transplant replacing. While the initial response rates are very high and there are some well publicized patients who remain in remission over 5 years after CTL019 without other therapy, other responders proceeded to transplant and there is also a significant relapse rate. It is therefore an open question whether treating physicians will be happy to watch patients who attain remission after this therapy or whether they will still recommend transplant because there is not yet enough follow up on this product to know what the long-term cure rate is going to be.
Another CAR T-cell product is scheduled to come before an FDA advisory committee in October. The indication for KTE-C19 (axicabtagene ciloleucel) from Kite is for relapsed/refractory diffuse large B-cell lymphoma, a much bigger indication with a potentially much larger number of patients. The response rates for KTE-C19 in DLBCL (and indeed for CTL019 in DLBCL) are not as high as those for CTL019 in ALL and follow-up time is shorter, so it is not yet clear how many patients will have sustained long term responses. Nevertheless the response rate in patients who have failed all other therapies is high enough that this product will also likely be approved.
Helen Heslop, MD, is the Dan L. Duncan Chair and Professor of Medicine and Pediatrics at Baylor College of Medicine, Houston. She also is the Director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital. Dr. Heslop is a member of the editorial advisory board of Hematology News.
The unanimous recommendation by the Food and Drug Administration's Oncologic Drugs Advisory Committee means that the FDA is likely to approve CTL019 (tisagenlecleucel-T), and that approval may come quickly, possibly before the end of 2017. This approval was based on compelling data showing that 83% of children and young adults with refractory or relapsed acute lymphocytic leukemia (ALL) achieved remission with this therapy. This is exciting news for ALL patients as well as for the cell and gene therapy community. What remains to be determined are the labelling for CTL019, the cost of the therapy, and whether all patients who might benefit from this therapy will have the coverage to be able to access it.
While the response rates in patients treated in the trials presented to the FDA are very encouraging there are also concerns with the risks for cytokine release syndrome and neurotoxicity which can affect up to half of treated patients. As a result, Novartis, the manufacturer of CTL019, has proposed an extensive mitigation strategy and education process for the cell therapy centers that will offer the therapy. Initially, this is likely to be limited to around 30 centers that will be geographically distributed throughout the United States with gradual roll out to more centers as there is more experience with the use of CTL019.
Another issue for the centers is going to be operationalizing a new paradigm where CTL019 will be offered as a standard of care rather than in the context of a research study. Most of the initial pediatric centers will likely provide CTL019, within their transplant infrastructure since procurement, initial processing and infusion of cells will utilize their cell processing and collection facilities. The Foundation for Accreditation of Cell Therapy (FACT) has also anticipated this approval by publishing new standards for Immune Effectors earlier this year to promote quality practice in immune effector cell administration.
One other question is whether CTL019 will be transplant enabling or transplant replacing. While the initial response rates are very high and there are some well publicized patients who remain in remission over 5 years after CTL019 without other therapy, other responders proceeded to transplant and there is also a significant relapse rate. It is therefore an open question whether treating physicians will be happy to watch patients who attain remission after this therapy or whether they will still recommend transplant because there is not yet enough follow up on this product to know what the long-term cure rate is going to be.
Another CAR T-cell product is scheduled to come before an FDA advisory committee in October. The indication for KTE-C19 (axicabtagene ciloleucel) from Kite is for relapsed/refractory diffuse large B-cell lymphoma, a much bigger indication with a potentially much larger number of patients. The response rates for KTE-C19 in DLBCL (and indeed for CTL019 in DLBCL) are not as high as those for CTL019 in ALL and follow-up time is shorter, so it is not yet clear how many patients will have sustained long term responses. Nevertheless the response rate in patients who have failed all other therapies is high enough that this product will also likely be approved.
Helen Heslop, MD, is the Dan L. Duncan Chair and Professor of Medicine and Pediatrics at Baylor College of Medicine, Houston. She also is the Director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital. Dr. Heslop is a member of the editorial advisory board of Hematology News.
The answer to the billion dollar question – Does the chimeric antigen receptor T-cell (CAR T) construct CTL019 (tisagenlecleucel-T) have a favorable risk-benefit profile for the treatment of children and young adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia? – was a unanimous “yes” at a July 12 meeting of the Food and Drug Administration’s Oncologic Drugs Advisory Committee.
“This is the most exciting thing I have seen in my lifetime, and probably since the introduction of ‘multiagent total cancer care,’ as it was called then, for treatment of childhood leukemia,” remarked Timothy P. Cripe, MD, PhD, from Nationwide Children’s Hospital in Columbus, Ohio, and a temporary voting member of the ODAC.
Catherine M. Bollard, MD, MBChB, from the Children’s National Medical Center in Washington, also a temporary ODAC member, said that she voted “yes” because “this is a very poor-risk patient population, this is an unmet need in the pediatric population, and as you saw in the data [presented to ODAC] today, the clinical responses are remarkable. I think Novartis [the maker of CTL019] has done a great job putting together a plan for mitigating risk going forward.”
CTL019 was shown in a pivotal phase 2 clinical trial to induce an overall remission rate of 83% in children and young adults with relapsed/refractory ALL for whom at least two prior lines of therapy had failed. Based on these results, the FDA accepted a biologics license application for the agent from Novartis.
At the meeting, panel members initially seemed favorably disposed toward recommending approval but heard concerns from FDA scientists about the potential for severe or fatal adverse events such as the cytokine release syndrome (CRS); the possible generation of replication competent retrovirus (RCR); and the potential for secondary malignancies from insertional mutagenesis, the incorporation of portions of the lentiviral vector into the patient’s genome.
In his opening remarks, Wilson W. Bryan, MD, from the FDA’s Office of Tissue and Advanced Therapies and Center for Biologics Evaluation and Drug Research, commented that “the clinical development of tisagenlecleucel suggests that this is a life-saving product.”
He went on, however, to frame the FDA’s concerns: “Clinical trials are not always a good predictor of the effectiveness and safety of a marketed product,” he said. “In particular, we are concerned that the same benefit and safety seen in clinical trials may not carry over to routine clinical use.”
The purpose of the hearing was to focus on manufacturing issues related to product quality, including replicability of the product for commercial use and safety issues such as prevention of CRS and neurotoxicities.
“We are also concerned about the hypothetical risk of secondary malignancies. Therefore, we are asking for the committee’s recommendations regarding the nature and duration of follow-up of patients who would receive this product,” Dr. Bryan said.
“CTL019 is a living drug, which demonstrates activity after a single infusion,” said Samit Hirawat, MD, head of oncology global development for Novartis.
But the nature of CTL019 as a living drug also means that it is subject to variations in the ability of autologous T cells harvested via leukapheresis to be infected with the lentiviral vector and expanded into a population of CAR T cells large enough to have therapeutic value, said Xiaobin Victor Lu, PhD, a chemistry, manufacturing, and controls reviewer for the FDA.
Mitigation plan
Novartis’ proposed plan includes specific, long-term steps for mitigating the risk of CRS and neurologic events, such as cerebral edema, the latter of which caused the FDA to call for a clinical hold of the phase 2 ROCKET trial for a different CAR T-cell construct.
Among the proposed elements of the mitigation plan are a 15-year minimum pharmacovigilance program and long-term safety follow-up for adverse events related to the therapy, efficacy, immunogenicity, transgene persistence of CD19 CAR, and the incidence of second malignancies possibly related to insertional mutagenesis.
Novartis also will train treatment center staff on processes for cell collection, cryopreservation, transport, chain of identity, safety management, and logistics for handling the CAR T-cell product. The company proposes to provide on-site training of personnel on CRS and neurotoxicity risk and management, as well as to offer information to patients and caregivers about the signs and symptoms of adverse events of concern.
Dr. Cripe expressed his concerns that Novartis’ proposal to initially limit the mitigation plan to 30 or 35 treatment sites would create problems of access and economic disparities among patients, and could cause inequities among treatment centers even with the same city.
David Lebwohl, MD, head of the CAR T global program for Novartis, said that the planned number of sites for the mitigation program would be expanded after 6 to 12 months if the CAR T construct receives final approval and clinical implementation goes well.
There was nearly unanimous agreement among the panel members that the planned 15-year follow-up and other mitigation measures would be adequate for detecting serious short- and long-term consequences of CAR T-cell therapy.
Patient/advocate perspective
In the public comment section of the proceedings, panel members were urged to vote in favor of CTL019 by parents of children with ALL, including Don McMahon, whose son Connor received the therapy after multiple relapses, and Tom Whitehead, father of Emily Whitehead, the first patient to receive CAR T cells for ALL.
Both children are alive and doing well.
CTL019 is produced by Novartis.
The answer to the billion dollar question – Does the chimeric antigen receptor T-cell (CAR T) construct CTL019 (tisagenlecleucel-T) have a favorable risk-benefit profile for the treatment of children and young adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia? – was a unanimous “yes” at a July 12 meeting of the Food and Drug Administration’s Oncologic Drugs Advisory Committee.
“This is the most exciting thing I have seen in my lifetime, and probably since the introduction of ‘multiagent total cancer care,’ as it was called then, for treatment of childhood leukemia,” remarked Timothy P. Cripe, MD, PhD, from Nationwide Children’s Hospital in Columbus, Ohio, and a temporary voting member of the ODAC.
Catherine M. Bollard, MD, MBChB, from the Children’s National Medical Center in Washington, also a temporary ODAC member, said that she voted “yes” because “this is a very poor-risk patient population, this is an unmet need in the pediatric population, and as you saw in the data [presented to ODAC] today, the clinical responses are remarkable. I think Novartis [the maker of CTL019] has done a great job putting together a plan for mitigating risk going forward.”
CTL019 was shown in a pivotal phase 2 clinical trial to induce an overall remission rate of 83% in children and young adults with relapsed/refractory ALL for whom at least two prior lines of therapy had failed. Based on these results, the FDA accepted a biologics license application for the agent from Novartis.
At the meeting, panel members initially seemed favorably disposed toward recommending approval but heard concerns from FDA scientists about the potential for severe or fatal adverse events such as the cytokine release syndrome (CRS); the possible generation of replication competent retrovirus (RCR); and the potential for secondary malignancies from insertional mutagenesis, the incorporation of portions of the lentiviral vector into the patient’s genome.
In his opening remarks, Wilson W. Bryan, MD, from the FDA’s Office of Tissue and Advanced Therapies and Center for Biologics Evaluation and Drug Research, commented that “the clinical development of tisagenlecleucel suggests that this is a life-saving product.”
He went on, however, to frame the FDA’s concerns: “Clinical trials are not always a good predictor of the effectiveness and safety of a marketed product,” he said. “In particular, we are concerned that the same benefit and safety seen in clinical trials may not carry over to routine clinical use.”
The purpose of the hearing was to focus on manufacturing issues related to product quality, including replicability of the product for commercial use and safety issues such as prevention of CRS and neurotoxicities.
“We are also concerned about the hypothetical risk of secondary malignancies. Therefore, we are asking for the committee’s recommendations regarding the nature and duration of follow-up of patients who would receive this product,” Dr. Bryan said.
“CTL019 is a living drug, which demonstrates activity after a single infusion,” said Samit Hirawat, MD, head of oncology global development for Novartis.
But the nature of CTL019 as a living drug also means that it is subject to variations in the ability of autologous T cells harvested via leukapheresis to be infected with the lentiviral vector and expanded into a population of CAR T cells large enough to have therapeutic value, said Xiaobin Victor Lu, PhD, a chemistry, manufacturing, and controls reviewer for the FDA.
Mitigation plan
Novartis’ proposed plan includes specific, long-term steps for mitigating the risk of CRS and neurologic events, such as cerebral edema, the latter of which caused the FDA to call for a clinical hold of the phase 2 ROCKET trial for a different CAR T-cell construct.
Among the proposed elements of the mitigation plan are a 15-year minimum pharmacovigilance program and long-term safety follow-up for adverse events related to the therapy, efficacy, immunogenicity, transgene persistence of CD19 CAR, and the incidence of second malignancies possibly related to insertional mutagenesis.
Novartis also will train treatment center staff on processes for cell collection, cryopreservation, transport, chain of identity, safety management, and logistics for handling the CAR T-cell product. The company proposes to provide on-site training of personnel on CRS and neurotoxicity risk and management, as well as to offer information to patients and caregivers about the signs and symptoms of adverse events of concern.
Dr. Cripe expressed his concerns that Novartis’ proposal to initially limit the mitigation plan to 30 or 35 treatment sites would create problems of access and economic disparities among patients, and could cause inequities among treatment centers even with the same city.
David Lebwohl, MD, head of the CAR T global program for Novartis, said that the planned number of sites for the mitigation program would be expanded after 6 to 12 months if the CAR T construct receives final approval and clinical implementation goes well.
There was nearly unanimous agreement among the panel members that the planned 15-year follow-up and other mitigation measures would be adequate for detecting serious short- and long-term consequences of CAR T-cell therapy.
Patient/advocate perspective
In the public comment section of the proceedings, panel members were urged to vote in favor of CTL019 by parents of children with ALL, including Don McMahon, whose son Connor received the therapy after multiple relapses, and Tom Whitehead, father of Emily Whitehead, the first patient to receive CAR T cells for ALL.
Both children are alive and doing well.
CTL019 is produced by Novartis.
Mapping the genomic landscape of T-ALL
Researchers say they have uncovered new details of the genomic landscape of T-lineage acute lymphoblastic leukemia (T-ALL).
The team believes their findings will aid the development of drugs to target newly discovered mutations and enable researchers to engineer better mouse models to probe the leukemia’s aberrant biological machinery.
Charles Mullighan, MD, MBBS, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported their findings in Nature Genetics.
“This first comprehensive and systematic analysis in a large group of patients revealed many new mutations that are biologically significant as well as new drug targets that could be clinically important,” Dr Mullighan said.
“Leukemias typically arise from multiple genetic changes that work together. Most previous studies have not had the breadth of genomic data in enough patients to identify the constellations of mutations and recognize their associations.”
Dr Mullighan and his colleagues sequenced the genomes of 264 children and young adults with T-ALL. This revealed 106 driver genes, half of which had not been identified in childhood T-ALL.
“We went into this study knowing that we didn’t know the full genomic landscape of T-ALL,” said Stephen Hunger, MD, of the Children’s Hospital of Philadelphia in Pennsylvania.
“But we were surprised that over half of the new targets and mutations were previously unrecognized. It was particularly unexpected and very striking that some mutations were exclusively found in some subtypes of T-ALL but not others.”
The researchers’ analysis confirmed that T-ALL was driven by mutations in known signaling pathways, including JAK-STAT, Ras, and PTEN-PI3K. However, the study also revealed new mutations in those known pathways.
In addition, the researchers identified cases in which the same T-ALL subtype had mutations in different pathways triggered by the same founding mutation.
“We believe this finding suggests we can target such subtypes with an inhibitor drug for one of the pathways, and it’s likely to be effective,” Dr Mullighan said.
He and his colleagues also believe the mutations uncovered in this study will enable researchers to create mouse models that more accurately reflect human T-ALL.
“We now have a launching pad, if you will, to design mouse models that include multiple genetic mutations to more faithfully reflect the leukemias we see in humans,” Dr Mullighan said.
Data from this study are available to researchers through the St. Jude PeCan data portal and the TARGET Data Matrix.
Researchers say they have uncovered new details of the genomic landscape of T-lineage acute lymphoblastic leukemia (T-ALL).
The team believes their findings will aid the development of drugs to target newly discovered mutations and enable researchers to engineer better mouse models to probe the leukemia’s aberrant biological machinery.
Charles Mullighan, MD, MBBS, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported their findings in Nature Genetics.
“This first comprehensive and systematic analysis in a large group of patients revealed many new mutations that are biologically significant as well as new drug targets that could be clinically important,” Dr Mullighan said.
“Leukemias typically arise from multiple genetic changes that work together. Most previous studies have not had the breadth of genomic data in enough patients to identify the constellations of mutations and recognize their associations.”
Dr Mullighan and his colleagues sequenced the genomes of 264 children and young adults with T-ALL. This revealed 106 driver genes, half of which had not been identified in childhood T-ALL.
“We went into this study knowing that we didn’t know the full genomic landscape of T-ALL,” said Stephen Hunger, MD, of the Children’s Hospital of Philadelphia in Pennsylvania.
“But we were surprised that over half of the new targets and mutations were previously unrecognized. It was particularly unexpected and very striking that some mutations were exclusively found in some subtypes of T-ALL but not others.”
The researchers’ analysis confirmed that T-ALL was driven by mutations in known signaling pathways, including JAK-STAT, Ras, and PTEN-PI3K. However, the study also revealed new mutations in those known pathways.
In addition, the researchers identified cases in which the same T-ALL subtype had mutations in different pathways triggered by the same founding mutation.
“We believe this finding suggests we can target such subtypes with an inhibitor drug for one of the pathways, and it’s likely to be effective,” Dr Mullighan said.
He and his colleagues also believe the mutations uncovered in this study will enable researchers to create mouse models that more accurately reflect human T-ALL.
“We now have a launching pad, if you will, to design mouse models that include multiple genetic mutations to more faithfully reflect the leukemias we see in humans,” Dr Mullighan said.
Data from this study are available to researchers through the St. Jude PeCan data portal and the TARGET Data Matrix.
Researchers say they have uncovered new details of the genomic landscape of T-lineage acute lymphoblastic leukemia (T-ALL).
The team believes their findings will aid the development of drugs to target newly discovered mutations and enable researchers to engineer better mouse models to probe the leukemia’s aberrant biological machinery.
Charles Mullighan, MD, MBBS, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported their findings in Nature Genetics.
“This first comprehensive and systematic analysis in a large group of patients revealed many new mutations that are biologically significant as well as new drug targets that could be clinically important,” Dr Mullighan said.
“Leukemias typically arise from multiple genetic changes that work together. Most previous studies have not had the breadth of genomic data in enough patients to identify the constellations of mutations and recognize their associations.”
Dr Mullighan and his colleagues sequenced the genomes of 264 children and young adults with T-ALL. This revealed 106 driver genes, half of which had not been identified in childhood T-ALL.
“We went into this study knowing that we didn’t know the full genomic landscape of T-ALL,” said Stephen Hunger, MD, of the Children’s Hospital of Philadelphia in Pennsylvania.
“But we were surprised that over half of the new targets and mutations were previously unrecognized. It was particularly unexpected and very striking that some mutations were exclusively found in some subtypes of T-ALL but not others.”
The researchers’ analysis confirmed that T-ALL was driven by mutations in known signaling pathways, including JAK-STAT, Ras, and PTEN-PI3K. However, the study also revealed new mutations in those known pathways.
In addition, the researchers identified cases in which the same T-ALL subtype had mutations in different pathways triggered by the same founding mutation.
“We believe this finding suggests we can target such subtypes with an inhibitor drug for one of the pathways, and it’s likely to be effective,” Dr Mullighan said.
He and his colleagues also believe the mutations uncovered in this study will enable researchers to create mouse models that more accurately reflect human T-ALL.
“We now have a launching pad, if you will, to design mouse models that include multiple genetic mutations to more faithfully reflect the leukemias we see in humans,” Dr Mullighan said.
Data from this study are available to researchers through the St. Jude PeCan data portal and the TARGET Data Matrix.
EC approves therapy for relapsed/refractory BCP-ALL
The European Commission (EC) has approved inotuzumab ozogamicin (BESPONSA®) as monotherapy for adults with relapsed or refractory, CD22-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
Adults with Philadelphia chromosome-positive, relapsed/refractory, CD22-positive BCP-ALL should have failed treatment with at least one tyrosine kinase inhibitor before receiving inotuzumab ozogamicin.
Inotuzumab ozogamicin is an antibody-drug conjugate that consists of a monoclonal antibody targeting CD22 and a cytotoxic agent known as calicheamicin.
The product originates from a collaboration between Pfizer and Celltech (now UCB), but Pfizer has sole responsibility for all manufacturing and clinical development activities.
The EC’s approval of inotuzumab ozogamicin is supported by results from a phase 3 trial, which were published in NEJM in June 2016.
The trial enrolled 326 adult patients with relapsed or refractory BCP-ALL and compared inotuzumab ozogamicin to standard of care chemotherapy.
The rate of complete remission, including incomplete hematologic recovery, was 80.7% in the inotuzumab ozogamicin arm and 29.4% in the chemotherapy arm (P<0.001). The median duration of remission was 4.6 months and 3.1 months, respectively (P=0.03).
Forty-one percent of patients treated with inotuzumab ozogamicin and 11% of those who received chemotherapy proceeded to stem cell transplant directly after treatment (P<0.001).
The median progression-free survival was 5.0 months in the inotuzumab ozogamicin arm and 1.8 months in the chemotherapy arm (P<0.001).
The median overall survival was 7.7 months and 6.7 months, respectively (P=0.04). This did not meet the prespecified boundary of significance (P=0.0208).
Liver-related adverse events were more common in the inotuzumab ozogamicin arm than the chemotherapy arm. The most frequent of these were increased aspartate aminotransferase level (20% vs 10%), hyperbilirubinemia (15% vs 10%), and increased alanine aminotransferase level (14% vs 11%).
Veno-occlusive liver disease occurred in 11% of patients in the inotuzumab ozogamicin arm and 1% in the chemotherapy arm.
There were 17 deaths during treatment in the inotuzumab ozogamicin arm and 11 in the chemotherapy arm. Four deaths were considered related to inotuzumab ozogamicin, and 2 were thought to be related to chemotherapy.
The European Commission (EC) has approved inotuzumab ozogamicin (BESPONSA®) as monotherapy for adults with relapsed or refractory, CD22-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
Adults with Philadelphia chromosome-positive, relapsed/refractory, CD22-positive BCP-ALL should have failed treatment with at least one tyrosine kinase inhibitor before receiving inotuzumab ozogamicin.
Inotuzumab ozogamicin is an antibody-drug conjugate that consists of a monoclonal antibody targeting CD22 and a cytotoxic agent known as calicheamicin.
The product originates from a collaboration between Pfizer and Celltech (now UCB), but Pfizer has sole responsibility for all manufacturing and clinical development activities.
The EC’s approval of inotuzumab ozogamicin is supported by results from a phase 3 trial, which were published in NEJM in June 2016.
The trial enrolled 326 adult patients with relapsed or refractory BCP-ALL and compared inotuzumab ozogamicin to standard of care chemotherapy.
The rate of complete remission, including incomplete hematologic recovery, was 80.7% in the inotuzumab ozogamicin arm and 29.4% in the chemotherapy arm (P<0.001). The median duration of remission was 4.6 months and 3.1 months, respectively (P=0.03).
Forty-one percent of patients treated with inotuzumab ozogamicin and 11% of those who received chemotherapy proceeded to stem cell transplant directly after treatment (P<0.001).
The median progression-free survival was 5.0 months in the inotuzumab ozogamicin arm and 1.8 months in the chemotherapy arm (P<0.001).
The median overall survival was 7.7 months and 6.7 months, respectively (P=0.04). This did not meet the prespecified boundary of significance (P=0.0208).
Liver-related adverse events were more common in the inotuzumab ozogamicin arm than the chemotherapy arm. The most frequent of these were increased aspartate aminotransferase level (20% vs 10%), hyperbilirubinemia (15% vs 10%), and increased alanine aminotransferase level (14% vs 11%).
Veno-occlusive liver disease occurred in 11% of patients in the inotuzumab ozogamicin arm and 1% in the chemotherapy arm.
There were 17 deaths during treatment in the inotuzumab ozogamicin arm and 11 in the chemotherapy arm. Four deaths were considered related to inotuzumab ozogamicin, and 2 were thought to be related to chemotherapy.
The European Commission (EC) has approved inotuzumab ozogamicin (BESPONSA®) as monotherapy for adults with relapsed or refractory, CD22-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
Adults with Philadelphia chromosome-positive, relapsed/refractory, CD22-positive BCP-ALL should have failed treatment with at least one tyrosine kinase inhibitor before receiving inotuzumab ozogamicin.
Inotuzumab ozogamicin is an antibody-drug conjugate that consists of a monoclonal antibody targeting CD22 and a cytotoxic agent known as calicheamicin.
The product originates from a collaboration between Pfizer and Celltech (now UCB), but Pfizer has sole responsibility for all manufacturing and clinical development activities.
The EC’s approval of inotuzumab ozogamicin is supported by results from a phase 3 trial, which were published in NEJM in June 2016.
The trial enrolled 326 adult patients with relapsed or refractory BCP-ALL and compared inotuzumab ozogamicin to standard of care chemotherapy.
The rate of complete remission, including incomplete hematologic recovery, was 80.7% in the inotuzumab ozogamicin arm and 29.4% in the chemotherapy arm (P<0.001). The median duration of remission was 4.6 months and 3.1 months, respectively (P=0.03).
Forty-one percent of patients treated with inotuzumab ozogamicin and 11% of those who received chemotherapy proceeded to stem cell transplant directly after treatment (P<0.001).
The median progression-free survival was 5.0 months in the inotuzumab ozogamicin arm and 1.8 months in the chemotherapy arm (P<0.001).
The median overall survival was 7.7 months and 6.7 months, respectively (P=0.04). This did not meet the prespecified boundary of significance (P=0.0208).
Liver-related adverse events were more common in the inotuzumab ozogamicin arm than the chemotherapy arm. The most frequent of these were increased aspartate aminotransferase level (20% vs 10%), hyperbilirubinemia (15% vs 10%), and increased alanine aminotransferase level (14% vs 11%).
Veno-occlusive liver disease occurred in 11% of patients in the inotuzumab ozogamicin arm and 1% in the chemotherapy arm.
There were 17 deaths during treatment in the inotuzumab ozogamicin arm and 11 in the chemotherapy arm. Four deaths were considered related to inotuzumab ozogamicin, and 2 were thought to be related to chemotherapy.