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FDA approves new use for ibrutinib in WM
The US Food and Drug Administration (FDA) has approved ibrutinib (Imbruvica®) for use in combination with rituximab to treat adults with Waldenström’s macroglobulinemia (WM).
This is the ninth FDA approval for ibrutinib and the second approval for the drug in WM.
The latest approval was supported by the phase 3 iNNOVATE trial, in which researchers compared ibrutinib plus rituximab to rituximab alone in patients with previously untreated or relapsed/refractory WM.
Results from iNNOVATE were presented at the 2018 ASCO Annual Meeting (abstract 8003) and simultaneously published in NEJM.
The trial enrolled 150 patients. They received rituximab at 375 mg/m2 with weekly infusions at weeks 1 to 4 and 17 to 20. They also received either ibrutinib (420 mg) or placebo once daily continuously until criteria for permanent discontinuation were met.
Overall response rates were significantly higher in the ibrutinib arm than the placebo arm—92% and 47%, respectively (P<0.0001). Complete response rates were 3% and 1%, respectively.
The median time to next treatment was not reached for the ibrutinib arm and was 18 months for the placebo arm (hazard ratio=0.096; P<0.0001). Of the patients randomized to ibrutinib plus rituximab, 75% continued on treatment at last follow-up.
The 30-month progression-free survival rates were 82% in the ibrutinib arm and 28% in the placebo arm. The median progression-free survival was not reached in the ibrutinib arm and was 20.3 months in the placebo arm (hazard ratio=0.20; P<0.0001).
The 30-month overall survival rates were 94% in the ibrutinib arm and 92% in the placebo arm.
Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 60% of patients in the ibrutinib arm and 61% in the placebo arm. Serious AEs occurred in 43% and 33%, respectively.
There were no fatal AEs in the ibrutinib arm and 3 in the rituximab arm.
Grade 3 or higher AEs that occurred more frequently in the ibrutinib arm than the placebo arm included atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%).
AEs that occurred less frequently in the ibrutinib arm than the placebo arm included grade 3 or higher infusion reactions (1% vs 16%) and any-grade IgM flare (8% vs 47%).
About ibrutinib
Ibrutinib is a Bruton’s tyrosine kinase inhibitor that is FDA-approved to treat chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic graft-versus-host disease (cGVHD), and WM.
In November 2013, ibrutinib was approved to treat adults with MCL who have received at least one prior therapy.
In February 2014, ibrutinib was approved to treat adults with CLL who have received at least one prior therapy. In July 2014, ibrutinib received approval for adult CLL patients with 17p deletion, and, in March 2016, ibrutinib was approved as a frontline CLL treatment.
Ibrutinib was approved for use as a single agent in adults with WM in January 2015.
In May 2016, ibrutinib was approved in combination with bendamustine and rituximab for adults with previously treated CLL/SLL.
In January 2017, ibrutinib was approved for adults with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, ibrutinib was approved to treat adults with cGVHD that did not respond to one or more lines of systemic therapy.
Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.
The US Food and Drug Administration (FDA) has approved ibrutinib (Imbruvica®) for use in combination with rituximab to treat adults with Waldenström’s macroglobulinemia (WM).
This is the ninth FDA approval for ibrutinib and the second approval for the drug in WM.
The latest approval was supported by the phase 3 iNNOVATE trial, in which researchers compared ibrutinib plus rituximab to rituximab alone in patients with previously untreated or relapsed/refractory WM.
Results from iNNOVATE were presented at the 2018 ASCO Annual Meeting (abstract 8003) and simultaneously published in NEJM.
The trial enrolled 150 patients. They received rituximab at 375 mg/m2 with weekly infusions at weeks 1 to 4 and 17 to 20. They also received either ibrutinib (420 mg) or placebo once daily continuously until criteria for permanent discontinuation were met.
Overall response rates were significantly higher in the ibrutinib arm than the placebo arm—92% and 47%, respectively (P<0.0001). Complete response rates were 3% and 1%, respectively.
The median time to next treatment was not reached for the ibrutinib arm and was 18 months for the placebo arm (hazard ratio=0.096; P<0.0001). Of the patients randomized to ibrutinib plus rituximab, 75% continued on treatment at last follow-up.
The 30-month progression-free survival rates were 82% in the ibrutinib arm and 28% in the placebo arm. The median progression-free survival was not reached in the ibrutinib arm and was 20.3 months in the placebo arm (hazard ratio=0.20; P<0.0001).
The 30-month overall survival rates were 94% in the ibrutinib arm and 92% in the placebo arm.
Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 60% of patients in the ibrutinib arm and 61% in the placebo arm. Serious AEs occurred in 43% and 33%, respectively.
There were no fatal AEs in the ibrutinib arm and 3 in the rituximab arm.
Grade 3 or higher AEs that occurred more frequently in the ibrutinib arm than the placebo arm included atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%).
AEs that occurred less frequently in the ibrutinib arm than the placebo arm included grade 3 or higher infusion reactions (1% vs 16%) and any-grade IgM flare (8% vs 47%).
About ibrutinib
Ibrutinib is a Bruton’s tyrosine kinase inhibitor that is FDA-approved to treat chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic graft-versus-host disease (cGVHD), and WM.
In November 2013, ibrutinib was approved to treat adults with MCL who have received at least one prior therapy.
In February 2014, ibrutinib was approved to treat adults with CLL who have received at least one prior therapy. In July 2014, ibrutinib received approval for adult CLL patients with 17p deletion, and, in March 2016, ibrutinib was approved as a frontline CLL treatment.
Ibrutinib was approved for use as a single agent in adults with WM in January 2015.
In May 2016, ibrutinib was approved in combination with bendamustine and rituximab for adults with previously treated CLL/SLL.
In January 2017, ibrutinib was approved for adults with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, ibrutinib was approved to treat adults with cGVHD that did not respond to one or more lines of systemic therapy.
Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.
The US Food and Drug Administration (FDA) has approved ibrutinib (Imbruvica®) for use in combination with rituximab to treat adults with Waldenström’s macroglobulinemia (WM).
This is the ninth FDA approval for ibrutinib and the second approval for the drug in WM.
The latest approval was supported by the phase 3 iNNOVATE trial, in which researchers compared ibrutinib plus rituximab to rituximab alone in patients with previously untreated or relapsed/refractory WM.
Results from iNNOVATE were presented at the 2018 ASCO Annual Meeting (abstract 8003) and simultaneously published in NEJM.
The trial enrolled 150 patients. They received rituximab at 375 mg/m2 with weekly infusions at weeks 1 to 4 and 17 to 20. They also received either ibrutinib (420 mg) or placebo once daily continuously until criteria for permanent discontinuation were met.
Overall response rates were significantly higher in the ibrutinib arm than the placebo arm—92% and 47%, respectively (P<0.0001). Complete response rates were 3% and 1%, respectively.
The median time to next treatment was not reached for the ibrutinib arm and was 18 months for the placebo arm (hazard ratio=0.096; P<0.0001). Of the patients randomized to ibrutinib plus rituximab, 75% continued on treatment at last follow-up.
The 30-month progression-free survival rates were 82% in the ibrutinib arm and 28% in the placebo arm. The median progression-free survival was not reached in the ibrutinib arm and was 20.3 months in the placebo arm (hazard ratio=0.20; P<0.0001).
The 30-month overall survival rates were 94% in the ibrutinib arm and 92% in the placebo arm.
Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 60% of patients in the ibrutinib arm and 61% in the placebo arm. Serious AEs occurred in 43% and 33%, respectively.
There were no fatal AEs in the ibrutinib arm and 3 in the rituximab arm.
Grade 3 or higher AEs that occurred more frequently in the ibrutinib arm than the placebo arm included atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%).
AEs that occurred less frequently in the ibrutinib arm than the placebo arm included grade 3 or higher infusion reactions (1% vs 16%) and any-grade IgM flare (8% vs 47%).
About ibrutinib
Ibrutinib is a Bruton’s tyrosine kinase inhibitor that is FDA-approved to treat chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic graft-versus-host disease (cGVHD), and WM.
In November 2013, ibrutinib was approved to treat adults with MCL who have received at least one prior therapy.
In February 2014, ibrutinib was approved to treat adults with CLL who have received at least one prior therapy. In July 2014, ibrutinib received approval for adult CLL patients with 17p deletion, and, in March 2016, ibrutinib was approved as a frontline CLL treatment.
Ibrutinib was approved for use as a single agent in adults with WM in January 2015.
In May 2016, ibrutinib was approved in combination with bendamustine and rituximab for adults with previously treated CLL/SLL.
In January 2017, ibrutinib was approved for adults with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, ibrutinib was approved to treat adults with cGVHD that did not respond to one or more lines of systemic therapy.
Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.
Combo produces high response rate in CLL
Bendamustine followed by obinutuzumab and venetoclax produces a high overall response rate in chronic lymphocytic leukemia (CLL), according to research published in The Lancet Oncology.
In an ongoing, phase 2 study, researchers examined the outcomes of this treatment in 66 patients with CLL.
Patients underwent initial debulking with two cycles of bendamustine, received six cycles of obinutuzumab and venetoclax for induction, and could receive up to 24 months of maintenance with obinutuzumab and venetoclax.
Efficacy
Of the 63 patients included in the efficacy analysis, 34 (54%) were treatment-naïve, and 29 (46%) had relapsed or refractory disease.
At the end of induction, the overall response rate was 95% (60/63), with responses observed in 100% (34/34) of treatment-naive patients and 90% (26/29) of relapsed/refractory patients.
Five patients (8%) achieved complete remission (CR)—3 who were treatment-naïve and 2 with relapsed/refractory disease.
Twenty patients (32%) had a clinical CR or CR with incomplete bone marrow recovery—14 who were treatment-naïve and 6 with relapsed/refractory disease.
Thirty-five patients (56%) had a partial response—17 who were treatment-naïve and 18 with relapsed/refractory disease.
By 15 months, both progression-free and overall survival were 100% among treatment-naive patients.
In the relapsed/refractory patients, progression-free survival was 83%, and overall survival was 90%.
Researchers observed minimal residual disease negativity in the peripheral blood of 91% (31/34) of treatment-naive patients and 83% (24/29) of relapsed/refractory patients. (Most patients did not have data for MRD in the bone marrow.)
Study author Paula Cramer, MD, from the German CLL Study Group at University Hospital, Cologne, and her colleagues described the efficacy of the combination as “encouraging.”
Safety
Safety data were available for all 66 patients. Of the 677 AEs, 427 (63%) were deemed related to study treatment, and 69 of these were serious AEs. Twelve patients had related, serious AEs during debulking, and 23 patients had related, serious AEs during induction.
The most common serious AEs were infections and cytopenias. There were four infections during debulking and 18 infections in 11 patients during induction. The most common infections were pneumonia and sepsis.
There were two cases of neutropenia during debulking and six cases in five patients during induction. There were four cases of thrombocytopenia in three patients during induction.
Other common treatment-related, serious AEs were:
- Infusion-related reactions—six cases during induction
- Coronary artery disorder—one case during debulking and three during induction
- Tumor lysis syndrome —one case during debulking and two during induction
- Neoplasms—two squamous cell carcinomas and one malignant melanoma during induction
- Increased creatinine—two cases during debulking.
Five patients in the relapsed/refractory group died—three of sepsis related to study treatment and two from unrelated Richter’s transformation.
“With three deaths from sepsis in 66 enrolled patients, the treatment-related mortality seems high; however, in cases of low patient numbers, a few patients can have a substantial effect on the overall results,” the researchers wrote.
The study was funded by F Hoffmann-La Roche and AbbVie. Several authors reported research funding, grants, honoraria, and other support from the pharmaceutical industry, including from the study sponsors.
Bendamustine followed by obinutuzumab and venetoclax produces a high overall response rate in chronic lymphocytic leukemia (CLL), according to research published in The Lancet Oncology.
In an ongoing, phase 2 study, researchers examined the outcomes of this treatment in 66 patients with CLL.
Patients underwent initial debulking with two cycles of bendamustine, received six cycles of obinutuzumab and venetoclax for induction, and could receive up to 24 months of maintenance with obinutuzumab and venetoclax.
Efficacy
Of the 63 patients included in the efficacy analysis, 34 (54%) were treatment-naïve, and 29 (46%) had relapsed or refractory disease.
At the end of induction, the overall response rate was 95% (60/63), with responses observed in 100% (34/34) of treatment-naive patients and 90% (26/29) of relapsed/refractory patients.
Five patients (8%) achieved complete remission (CR)—3 who were treatment-naïve and 2 with relapsed/refractory disease.
Twenty patients (32%) had a clinical CR or CR with incomplete bone marrow recovery—14 who were treatment-naïve and 6 with relapsed/refractory disease.
Thirty-five patients (56%) had a partial response—17 who were treatment-naïve and 18 with relapsed/refractory disease.
By 15 months, both progression-free and overall survival were 100% among treatment-naive patients.
In the relapsed/refractory patients, progression-free survival was 83%, and overall survival was 90%.
Researchers observed minimal residual disease negativity in the peripheral blood of 91% (31/34) of treatment-naive patients and 83% (24/29) of relapsed/refractory patients. (Most patients did not have data for MRD in the bone marrow.)
Study author Paula Cramer, MD, from the German CLL Study Group at University Hospital, Cologne, and her colleagues described the efficacy of the combination as “encouraging.”
Safety
Safety data were available for all 66 patients. Of the 677 AEs, 427 (63%) were deemed related to study treatment, and 69 of these were serious AEs. Twelve patients had related, serious AEs during debulking, and 23 patients had related, serious AEs during induction.
The most common serious AEs were infections and cytopenias. There were four infections during debulking and 18 infections in 11 patients during induction. The most common infections were pneumonia and sepsis.
There were two cases of neutropenia during debulking and six cases in five patients during induction. There were four cases of thrombocytopenia in three patients during induction.
Other common treatment-related, serious AEs were:
- Infusion-related reactions—six cases during induction
- Coronary artery disorder—one case during debulking and three during induction
- Tumor lysis syndrome —one case during debulking and two during induction
- Neoplasms—two squamous cell carcinomas and one malignant melanoma during induction
- Increased creatinine—two cases during debulking.
Five patients in the relapsed/refractory group died—three of sepsis related to study treatment and two from unrelated Richter’s transformation.
“With three deaths from sepsis in 66 enrolled patients, the treatment-related mortality seems high; however, in cases of low patient numbers, a few patients can have a substantial effect on the overall results,” the researchers wrote.
The study was funded by F Hoffmann-La Roche and AbbVie. Several authors reported research funding, grants, honoraria, and other support from the pharmaceutical industry, including from the study sponsors.
Bendamustine followed by obinutuzumab and venetoclax produces a high overall response rate in chronic lymphocytic leukemia (CLL), according to research published in The Lancet Oncology.
In an ongoing, phase 2 study, researchers examined the outcomes of this treatment in 66 patients with CLL.
Patients underwent initial debulking with two cycles of bendamustine, received six cycles of obinutuzumab and venetoclax for induction, and could receive up to 24 months of maintenance with obinutuzumab and venetoclax.
Efficacy
Of the 63 patients included in the efficacy analysis, 34 (54%) were treatment-naïve, and 29 (46%) had relapsed or refractory disease.
At the end of induction, the overall response rate was 95% (60/63), with responses observed in 100% (34/34) of treatment-naive patients and 90% (26/29) of relapsed/refractory patients.
Five patients (8%) achieved complete remission (CR)—3 who were treatment-naïve and 2 with relapsed/refractory disease.
Twenty patients (32%) had a clinical CR or CR with incomplete bone marrow recovery—14 who were treatment-naïve and 6 with relapsed/refractory disease.
Thirty-five patients (56%) had a partial response—17 who were treatment-naïve and 18 with relapsed/refractory disease.
By 15 months, both progression-free and overall survival were 100% among treatment-naive patients.
In the relapsed/refractory patients, progression-free survival was 83%, and overall survival was 90%.
Researchers observed minimal residual disease negativity in the peripheral blood of 91% (31/34) of treatment-naive patients and 83% (24/29) of relapsed/refractory patients. (Most patients did not have data for MRD in the bone marrow.)
Study author Paula Cramer, MD, from the German CLL Study Group at University Hospital, Cologne, and her colleagues described the efficacy of the combination as “encouraging.”
Safety
Safety data were available for all 66 patients. Of the 677 AEs, 427 (63%) were deemed related to study treatment, and 69 of these were serious AEs. Twelve patients had related, serious AEs during debulking, and 23 patients had related, serious AEs during induction.
The most common serious AEs were infections and cytopenias. There were four infections during debulking and 18 infections in 11 patients during induction. The most common infections were pneumonia and sepsis.
There were two cases of neutropenia during debulking and six cases in five patients during induction. There were four cases of thrombocytopenia in three patients during induction.
Other common treatment-related, serious AEs were:
- Infusion-related reactions—six cases during induction
- Coronary artery disorder—one case during debulking and three during induction
- Tumor lysis syndrome —one case during debulking and two during induction
- Neoplasms—two squamous cell carcinomas and one malignant melanoma during induction
- Increased creatinine—two cases during debulking.
Five patients in the relapsed/refractory group died—three of sepsis related to study treatment and two from unrelated Richter’s transformation.
“With three deaths from sepsis in 66 enrolled patients, the treatment-related mortality seems high; however, in cases of low patient numbers, a few patients can have a substantial effect on the overall results,” the researchers wrote.
The study was funded by F Hoffmann-La Roche and AbbVie. Several authors reported research funding, grants, honoraria, and other support from the pharmaceutical industry, including from the study sponsors.
Signal strength tied to potency of CAR T-cell therapy
Investigators found that chimeric antigen receptor (CAR) T cells with stronger signaling capabilities were less effective against lymphoma cells in a mouse model.
Intracellular signaling strength was a key determinant of T-cell fate in the study, which was published in Science Signaling.
By contrast, CAR signaling pathways could not be predicted solely by the costimulatory domains used to construct the receptor, investigators said.
These findings suggest tailoring CAR design based on signal strength might improve the efficacy and reduce the toxicity of CAR T-cell therapy, according to Alexander Salter, an MD/PhD student at Fred Hutchinson Cancer Research Center in Seattle, Wash.
For this study, Salter and his colleagues used mass spectrometry to evaluate CARs encoding CD28 or 4-1BB costimulatory domains in primary human T cells.
While CARs with CD28 domains elicited more robust intracellular signaling than those with 4-1BB domains, there was considerable overlap in activation of T-cell signaling pathways, Salter said.
That overlap was somewhat surprising, according to Salter, since researchers have generally assumed that CARs with CD28 and 4-1BB costimulatory domains will primarily signal through those respective pathways.
“No matter what costimulatory domain was encoded by the receptor, both CARs… activated both CD28 and 41BB signaling pathways,” Salter said.
The major determinant of efficacy in the study turned out to be not the domain used to construct the receptor but the speed and strength of signaling, he added.
In particular, the CARs that evoked stronger signals also had increased T-cell dysfunction, decreasing their potency in the mouse model of lymphoma.
The T cells with a CD28 CAR had very strong initial antitumor function that quickly waned in the mouse model.
By contrast, the “slower burning” 4-1BB CAR signal led to T cells that better retained their function in vivo and were associated with longer median survival in the model, Salter said.
These findings suggest tailoring CAR design based on signal strength may improve clinical efficacy and reduce toxicity.
As part of the study, Salter and his co-investigators were able to modify the CAR CD28 domain to make the signaling of the CD28 CARs less intense.
“This is a modification that we think should be considered in future CAR design,” Salter said.
While the alterations in the CD28 signaling domain were able to reduce levels of cytokines produced by T cells, the study was primarily designed to look at efficacy, noted Stanley Riddell, MD, of Fred Hutchinson Cancer Research Center.
“Our models were not set up to address the question of toxicity, so we can’t directly say this would translate to what we would see in patients,” Dr. Riddell said.
“But I think we gleaned a lot of insights as to why cytokines are produced at greater or lesser levels with various CAR designs, and insights as to how to redesign these receptors to lower the levels of cytokines they make without compromising their ability to kill.”
Dr. Riddell is a founder, shareholder, and scientific advisor of Juno Therapeutics. He and Salter have filed a patent application on the use of mutant CD28 CARs for cellular therapy. Co-author Raphael Gottardo, PhD, also with Fred Hutchinson Cancer Research Center, is a consultant for Juno Therapeutics. No other competing interests were reported.
Investigators found that chimeric antigen receptor (CAR) T cells with stronger signaling capabilities were less effective against lymphoma cells in a mouse model.
Intracellular signaling strength was a key determinant of T-cell fate in the study, which was published in Science Signaling.
By contrast, CAR signaling pathways could not be predicted solely by the costimulatory domains used to construct the receptor, investigators said.
These findings suggest tailoring CAR design based on signal strength might improve the efficacy and reduce the toxicity of CAR T-cell therapy, according to Alexander Salter, an MD/PhD student at Fred Hutchinson Cancer Research Center in Seattle, Wash.
For this study, Salter and his colleagues used mass spectrometry to evaluate CARs encoding CD28 or 4-1BB costimulatory domains in primary human T cells.
While CARs with CD28 domains elicited more robust intracellular signaling than those with 4-1BB domains, there was considerable overlap in activation of T-cell signaling pathways, Salter said.
That overlap was somewhat surprising, according to Salter, since researchers have generally assumed that CARs with CD28 and 4-1BB costimulatory domains will primarily signal through those respective pathways.
“No matter what costimulatory domain was encoded by the receptor, both CARs… activated both CD28 and 41BB signaling pathways,” Salter said.
The major determinant of efficacy in the study turned out to be not the domain used to construct the receptor but the speed and strength of signaling, he added.
In particular, the CARs that evoked stronger signals also had increased T-cell dysfunction, decreasing their potency in the mouse model of lymphoma.
The T cells with a CD28 CAR had very strong initial antitumor function that quickly waned in the mouse model.
By contrast, the “slower burning” 4-1BB CAR signal led to T cells that better retained their function in vivo and were associated with longer median survival in the model, Salter said.
These findings suggest tailoring CAR design based on signal strength may improve clinical efficacy and reduce toxicity.
As part of the study, Salter and his co-investigators were able to modify the CAR CD28 domain to make the signaling of the CD28 CARs less intense.
“This is a modification that we think should be considered in future CAR design,” Salter said.
While the alterations in the CD28 signaling domain were able to reduce levels of cytokines produced by T cells, the study was primarily designed to look at efficacy, noted Stanley Riddell, MD, of Fred Hutchinson Cancer Research Center.
“Our models were not set up to address the question of toxicity, so we can’t directly say this would translate to what we would see in patients,” Dr. Riddell said.
“But I think we gleaned a lot of insights as to why cytokines are produced at greater or lesser levels with various CAR designs, and insights as to how to redesign these receptors to lower the levels of cytokines they make without compromising their ability to kill.”
Dr. Riddell is a founder, shareholder, and scientific advisor of Juno Therapeutics. He and Salter have filed a patent application on the use of mutant CD28 CARs for cellular therapy. Co-author Raphael Gottardo, PhD, also with Fred Hutchinson Cancer Research Center, is a consultant for Juno Therapeutics. No other competing interests were reported.
Investigators found that chimeric antigen receptor (CAR) T cells with stronger signaling capabilities were less effective against lymphoma cells in a mouse model.
Intracellular signaling strength was a key determinant of T-cell fate in the study, which was published in Science Signaling.
By contrast, CAR signaling pathways could not be predicted solely by the costimulatory domains used to construct the receptor, investigators said.
These findings suggest tailoring CAR design based on signal strength might improve the efficacy and reduce the toxicity of CAR T-cell therapy, according to Alexander Salter, an MD/PhD student at Fred Hutchinson Cancer Research Center in Seattle, Wash.
For this study, Salter and his colleagues used mass spectrometry to evaluate CARs encoding CD28 or 4-1BB costimulatory domains in primary human T cells.
While CARs with CD28 domains elicited more robust intracellular signaling than those with 4-1BB domains, there was considerable overlap in activation of T-cell signaling pathways, Salter said.
That overlap was somewhat surprising, according to Salter, since researchers have generally assumed that CARs with CD28 and 4-1BB costimulatory domains will primarily signal through those respective pathways.
“No matter what costimulatory domain was encoded by the receptor, both CARs… activated both CD28 and 41BB signaling pathways,” Salter said.
The major determinant of efficacy in the study turned out to be not the domain used to construct the receptor but the speed and strength of signaling, he added.
In particular, the CARs that evoked stronger signals also had increased T-cell dysfunction, decreasing their potency in the mouse model of lymphoma.
The T cells with a CD28 CAR had very strong initial antitumor function that quickly waned in the mouse model.
By contrast, the “slower burning” 4-1BB CAR signal led to T cells that better retained their function in vivo and were associated with longer median survival in the model, Salter said.
These findings suggest tailoring CAR design based on signal strength may improve clinical efficacy and reduce toxicity.
As part of the study, Salter and his co-investigators were able to modify the CAR CD28 domain to make the signaling of the CD28 CARs less intense.
“This is a modification that we think should be considered in future CAR design,” Salter said.
While the alterations in the CD28 signaling domain were able to reduce levels of cytokines produced by T cells, the study was primarily designed to look at efficacy, noted Stanley Riddell, MD, of Fred Hutchinson Cancer Research Center.
“Our models were not set up to address the question of toxicity, so we can’t directly say this would translate to what we would see in patients,” Dr. Riddell said.
“But I think we gleaned a lot of insights as to why cytokines are produced at greater or lesser levels with various CAR designs, and insights as to how to redesign these receptors to lower the levels of cytokines they make without compromising their ability to kill.”
Dr. Riddell is a founder, shareholder, and scientific advisor of Juno Therapeutics. He and Salter have filed a patent application on the use of mutant CD28 CARs for cellular therapy. Co-author Raphael Gottardo, PhD, also with Fred Hutchinson Cancer Research Center, is a consultant for Juno Therapeutics. No other competing interests were reported.
Role of SES in childhood cancer survival disparities
Socioeconomic status (SES) may explain some racial/ethnic disparities in childhood cancer survival, according to new research.
The study showed that whites had a significant survival advantage over blacks and Hispanics for several childhood cancers.
SES significantly mediated the association between race/ethnicity and survival for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), neuroblastoma, and non-Hodgkin lymphoma (NHL).
Rebecca Kehm, PhD, of Columbia University in New York, New York, and her colleagues reported these findings in Cancer alongside a related editorial.
The researchers examined population-based cancer survival data from the Surveillance, Epidemiology, and End Results database.
The team collected information on 31,866 patients, ages 0 to 19, who were diagnosed with cancer between 2000 and 2011.
Survival differences by race/ethnicity
The researchers found that whites had a significant survival advantage over blacks for the cancers listed in the following table.
| Survival—black vs white | |||
| Cancer | Mortality hazard ratio | 95% confidence interval | P value |
| ALL | 1.43 | 1.15-1.77 | <0.01 |
| AML | 1.68 | 1.36-2.07 | <0.001 |
| Neuroblastoma | 1.38 | 1.08-1.75 | 0.01 |
| NHL | 1.53 | 1.14-2.07 | 0.01 |
| Hodgkin lymphoma | 1.66 | 1.06-2.60 | 0.03 |
| Astrocytoma | 1.95 | 1.57-2.43 | <0.001 |
| Non-astrocytoma CNS tumor | 1.53 | 1.25-1.88 | <0.001 |
| Non-rhabdomyosarcoma STS | 1.40 | 1.06-1.84 | 0.02 |
| Rhabdomyosarcoma | 1.44 | 1.10-1.88 | 0.01 |
In addition, whites had a significant survival advantage over Hispanics for the following cancers.
| Survival—Hispanic vs white | |||
| Cancer | Mortality hazard ratio | 95% confidence interval | P value |
| ALL | 1.63 | 1.43-1.86 | <0.001 |
| Neuroblastoma | 1.31 | 1.04-1.65 | 0.02 |
| NHL | 1.65 | 1.29-2.12 | <0.001 |
| Astrocytoma | 1.34 | 1.10-1.64 | <0.01 |
| Wilms tumor | 1.60 | 1.04-2.45 | 0.03 |
| Germ cell tumor | 1.63 | 1.19-2.24 | <0.01 |
Impact of SES
SES significantly mediated the association between race/ethnicity and survival for ALL, AML, neuroblastoma, and NHL but not for Hodgkin lymphoma or other cancers.
For black versus white patients, SES reduced the original association between race/ethnicity and survival by:
- 44% for ALL
- 28% for AML
- 49% for neuroblastoma
- 34% for NHL.
For Hispanics versus whites, SES reduced the original association between race/ethnicity and survival by:
- 31% for ALL
- 73% for AML
- 48% for neuroblastoma
- 28% for NHL.
“These findings provide insight for future intervention efforts aimed at closing the survival gap,” Dr Kehm said.
“For cancers in which socioeconomic status is a key factor in explaining racial and ethnic survival disparities, behavioral and supportive interventions that address social and economic barriers to effective care are warranted. However, for cancers in which survival is less influenced by socioeconomic status, more research is needed on underlying differences in tumor biology and drug processing.”
This research was supported by a grant from the National Institutes of Health, and the study’s authors made no disclosures.
Socioeconomic status (SES) may explain some racial/ethnic disparities in childhood cancer survival, according to new research.
The study showed that whites had a significant survival advantage over blacks and Hispanics for several childhood cancers.
SES significantly mediated the association between race/ethnicity and survival for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), neuroblastoma, and non-Hodgkin lymphoma (NHL).
Rebecca Kehm, PhD, of Columbia University in New York, New York, and her colleagues reported these findings in Cancer alongside a related editorial.
The researchers examined population-based cancer survival data from the Surveillance, Epidemiology, and End Results database.
The team collected information on 31,866 patients, ages 0 to 19, who were diagnosed with cancer between 2000 and 2011.
Survival differences by race/ethnicity
The researchers found that whites had a significant survival advantage over blacks for the cancers listed in the following table.
| Survival—black vs white | |||
| Cancer | Mortality hazard ratio | 95% confidence interval | P value |
| ALL | 1.43 | 1.15-1.77 | <0.01 |
| AML | 1.68 | 1.36-2.07 | <0.001 |
| Neuroblastoma | 1.38 | 1.08-1.75 | 0.01 |
| NHL | 1.53 | 1.14-2.07 | 0.01 |
| Hodgkin lymphoma | 1.66 | 1.06-2.60 | 0.03 |
| Astrocytoma | 1.95 | 1.57-2.43 | <0.001 |
| Non-astrocytoma CNS tumor | 1.53 | 1.25-1.88 | <0.001 |
| Non-rhabdomyosarcoma STS | 1.40 | 1.06-1.84 | 0.02 |
| Rhabdomyosarcoma | 1.44 | 1.10-1.88 | 0.01 |
In addition, whites had a significant survival advantage over Hispanics for the following cancers.
| Survival—Hispanic vs white | |||
| Cancer | Mortality hazard ratio | 95% confidence interval | P value |
| ALL | 1.63 | 1.43-1.86 | <0.001 |
| Neuroblastoma | 1.31 | 1.04-1.65 | 0.02 |
| NHL | 1.65 | 1.29-2.12 | <0.001 |
| Astrocytoma | 1.34 | 1.10-1.64 | <0.01 |
| Wilms tumor | 1.60 | 1.04-2.45 | 0.03 |
| Germ cell tumor | 1.63 | 1.19-2.24 | <0.01 |
Impact of SES
SES significantly mediated the association between race/ethnicity and survival for ALL, AML, neuroblastoma, and NHL but not for Hodgkin lymphoma or other cancers.
For black versus white patients, SES reduced the original association between race/ethnicity and survival by:
- 44% for ALL
- 28% for AML
- 49% for neuroblastoma
- 34% for NHL.
For Hispanics versus whites, SES reduced the original association between race/ethnicity and survival by:
- 31% for ALL
- 73% for AML
- 48% for neuroblastoma
- 28% for NHL.
“These findings provide insight for future intervention efforts aimed at closing the survival gap,” Dr Kehm said.
“For cancers in which socioeconomic status is a key factor in explaining racial and ethnic survival disparities, behavioral and supportive interventions that address social and economic barriers to effective care are warranted. However, for cancers in which survival is less influenced by socioeconomic status, more research is needed on underlying differences in tumor biology and drug processing.”
This research was supported by a grant from the National Institutes of Health, and the study’s authors made no disclosures.
Socioeconomic status (SES) may explain some racial/ethnic disparities in childhood cancer survival, according to new research.
The study showed that whites had a significant survival advantage over blacks and Hispanics for several childhood cancers.
SES significantly mediated the association between race/ethnicity and survival for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), neuroblastoma, and non-Hodgkin lymphoma (NHL).
Rebecca Kehm, PhD, of Columbia University in New York, New York, and her colleagues reported these findings in Cancer alongside a related editorial.
The researchers examined population-based cancer survival data from the Surveillance, Epidemiology, and End Results database.
The team collected information on 31,866 patients, ages 0 to 19, who were diagnosed with cancer between 2000 and 2011.
Survival differences by race/ethnicity
The researchers found that whites had a significant survival advantage over blacks for the cancers listed in the following table.
| Survival—black vs white | |||
| Cancer | Mortality hazard ratio | 95% confidence interval | P value |
| ALL | 1.43 | 1.15-1.77 | <0.01 |
| AML | 1.68 | 1.36-2.07 | <0.001 |
| Neuroblastoma | 1.38 | 1.08-1.75 | 0.01 |
| NHL | 1.53 | 1.14-2.07 | 0.01 |
| Hodgkin lymphoma | 1.66 | 1.06-2.60 | 0.03 |
| Astrocytoma | 1.95 | 1.57-2.43 | <0.001 |
| Non-astrocytoma CNS tumor | 1.53 | 1.25-1.88 | <0.001 |
| Non-rhabdomyosarcoma STS | 1.40 | 1.06-1.84 | 0.02 |
| Rhabdomyosarcoma | 1.44 | 1.10-1.88 | 0.01 |
In addition, whites had a significant survival advantage over Hispanics for the following cancers.
| Survival—Hispanic vs white | |||
| Cancer | Mortality hazard ratio | 95% confidence interval | P value |
| ALL | 1.63 | 1.43-1.86 | <0.001 |
| Neuroblastoma | 1.31 | 1.04-1.65 | 0.02 |
| NHL | 1.65 | 1.29-2.12 | <0.001 |
| Astrocytoma | 1.34 | 1.10-1.64 | <0.01 |
| Wilms tumor | 1.60 | 1.04-2.45 | 0.03 |
| Germ cell tumor | 1.63 | 1.19-2.24 | <0.01 |
Impact of SES
SES significantly mediated the association between race/ethnicity and survival for ALL, AML, neuroblastoma, and NHL but not for Hodgkin lymphoma or other cancers.
For black versus white patients, SES reduced the original association between race/ethnicity and survival by:
- 44% for ALL
- 28% for AML
- 49% for neuroblastoma
- 34% for NHL.
For Hispanics versus whites, SES reduced the original association between race/ethnicity and survival by:
- 31% for ALL
- 73% for AML
- 48% for neuroblastoma
- 28% for NHL.
“These findings provide insight for future intervention efforts aimed at closing the survival gap,” Dr Kehm said.
“For cancers in which socioeconomic status is a key factor in explaining racial and ethnic survival disparities, behavioral and supportive interventions that address social and economic barriers to effective care are warranted. However, for cancers in which survival is less influenced by socioeconomic status, more research is needed on underlying differences in tumor biology and drug processing.”
This research was supported by a grant from the National Institutes of Health, and the study’s authors made no disclosures.
Access to care drives disparity between urban, rural cancer patients
New research suggests that better access to quality care may reduce disparities in survival between cancer patients living in rural areas of the US and those living in urban areas.
The study showed that urban and rural cancer patients had similar survival outcomes when they were enrolled in clinical trials.
These results, published in JAMA Network Open, cast new light on decades of research showing that cancer patients living in rural areas don’t live as long as urban cancer patients.
“These findings were a surprise, since we thought we might find the same disparities others had found,” said study author Joseph Unger, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.
“But clinical trials are a key difference here. In trials, patients are uniformly assessed, treated, and followed under a strict, guideline-driven protocol. This suggests that giving people with cancer access to uniform treatment strategies could help resolve the disparities in outcomes that we see between rural and urban patients.”
Dr Unger and his colleagues studied data on 36,995 patients who were enrolled in 44 phase 3 or phase 2/3 SWOG trials from 1986 through 2012. All 50 states were represented.
Patients had 17 different cancer types, including acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM).
Using US Department of Agriculture population classifications known as Rural-Urban Continuum Codes, the researchers categorized the patients as either rural or urban and analyzed their outcomes.
A minority of patients (19.4%, n=7184) were from rural locations. They were significantly more likely than urban patients to be 65 or older (P<0.001) and significantly less likely to be black (vs all other races; P<0.001).
However, there was no significant between-group difference in sex (P=0.53), and all major US geographic regions (West, Midwest, South, and Northeast) were represented.
Results
The researchers limited their analysis of survival to the first 5 years after trial enrollment to emphasize outcomes related to cancer and its treatment. They looked at overall survival (OS) as well as cancer-specific survival.
The team found no meaningful difference in OS or cancer-specific survival between rural and urban patients for 16 of the 17 cancer types.
The exception was estrogen receptor-negative, progesterone receptor-negative breast cancer. Rural patients with this cancer didn’t live as long as their urban counterparts. The hazard ratio (HR) was 1.27 (95% CI, 1.06-1.51; P=0.008) for OS and 1.26 (95% CI, 1.04-1.52; P=0.02) for cancer-specific survival.
The researchers believe this finding could be attributed to a few factors, including timely access to follow-up chemotherapy after patients’ first round of cancer treatment.
Although there were no significant survival differences for patients with hematologic malignancies, rural patients had slightly better OS if they had advanced indolent NHL or AML but slightly worse OS if they had MM or advanced aggressive NHL. The HRs were as follows:
- Advanced indolent NHL—HR=0.91 (95% CI, 0.64-1.29; P=0.60)
- AML—HR=0.94 (95% CI, 0.83-1.06; P=0.29)
- MM—HR=1.05 (95% CI, 0.93-1.18, P=0.46)
- Advanced aggressive NHL—HR=1.05 (95% CI, 0.87-1.27; P=0.60).
Rural patients had slightly better cancer-specific survival if they had advanced indolent NHL but slightly worse cancer-specific survival if they had AML, MM, or advanced aggressive NHL. The HRs were as follows:
- Advanced indolent NHL—HR=0.98 (95% CI, 0.66-1.45; P=0.90)
- AML—HR=1.01 (95% CI, 0.86-1.20; P=0.87)
- MM—HR=1.04 (95% CI, 0.90-1.20; P=0.60)
- Advanced aggressive NHL—HR=1.08 (95% CI, 0.87-1.34; P=0.50).
The researchers said these findings suggest it is access to care, and not other characteristics, that drive the survival disparities typically observed between urban and rural cancer patients.
“If people diagnosed with cancer, regardless of where they live, receive similar care and have similar outcomes, then a reasonable inference is that the best way to improve outcomes for rural patients is to improve their access to quality care,” Dr Unger said.
This research was supported by the National Cancer Institute and the HOPE Foundation. The researchers reported financial relationships with various pharmaceutical companies.
New research suggests that better access to quality care may reduce disparities in survival between cancer patients living in rural areas of the US and those living in urban areas.
The study showed that urban and rural cancer patients had similar survival outcomes when they were enrolled in clinical trials.
These results, published in JAMA Network Open, cast new light on decades of research showing that cancer patients living in rural areas don’t live as long as urban cancer patients.
“These findings were a surprise, since we thought we might find the same disparities others had found,” said study author Joseph Unger, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.
“But clinical trials are a key difference here. In trials, patients are uniformly assessed, treated, and followed under a strict, guideline-driven protocol. This suggests that giving people with cancer access to uniform treatment strategies could help resolve the disparities in outcomes that we see between rural and urban patients.”
Dr Unger and his colleagues studied data on 36,995 patients who were enrolled in 44 phase 3 or phase 2/3 SWOG trials from 1986 through 2012. All 50 states were represented.
Patients had 17 different cancer types, including acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM).
Using US Department of Agriculture population classifications known as Rural-Urban Continuum Codes, the researchers categorized the patients as either rural or urban and analyzed their outcomes.
A minority of patients (19.4%, n=7184) were from rural locations. They were significantly more likely than urban patients to be 65 or older (P<0.001) and significantly less likely to be black (vs all other races; P<0.001).
However, there was no significant between-group difference in sex (P=0.53), and all major US geographic regions (West, Midwest, South, and Northeast) were represented.
Results
The researchers limited their analysis of survival to the first 5 years after trial enrollment to emphasize outcomes related to cancer and its treatment. They looked at overall survival (OS) as well as cancer-specific survival.
The team found no meaningful difference in OS or cancer-specific survival between rural and urban patients for 16 of the 17 cancer types.
The exception was estrogen receptor-negative, progesterone receptor-negative breast cancer. Rural patients with this cancer didn’t live as long as their urban counterparts. The hazard ratio (HR) was 1.27 (95% CI, 1.06-1.51; P=0.008) for OS and 1.26 (95% CI, 1.04-1.52; P=0.02) for cancer-specific survival.
The researchers believe this finding could be attributed to a few factors, including timely access to follow-up chemotherapy after patients’ first round of cancer treatment.
Although there were no significant survival differences for patients with hematologic malignancies, rural patients had slightly better OS if they had advanced indolent NHL or AML but slightly worse OS if they had MM or advanced aggressive NHL. The HRs were as follows:
- Advanced indolent NHL—HR=0.91 (95% CI, 0.64-1.29; P=0.60)
- AML—HR=0.94 (95% CI, 0.83-1.06; P=0.29)
- MM—HR=1.05 (95% CI, 0.93-1.18, P=0.46)
- Advanced aggressive NHL—HR=1.05 (95% CI, 0.87-1.27; P=0.60).
Rural patients had slightly better cancer-specific survival if they had advanced indolent NHL but slightly worse cancer-specific survival if they had AML, MM, or advanced aggressive NHL. The HRs were as follows:
- Advanced indolent NHL—HR=0.98 (95% CI, 0.66-1.45; P=0.90)
- AML—HR=1.01 (95% CI, 0.86-1.20; P=0.87)
- MM—HR=1.04 (95% CI, 0.90-1.20; P=0.60)
- Advanced aggressive NHL—HR=1.08 (95% CI, 0.87-1.34; P=0.50).
The researchers said these findings suggest it is access to care, and not other characteristics, that drive the survival disparities typically observed between urban and rural cancer patients.
“If people diagnosed with cancer, regardless of where they live, receive similar care and have similar outcomes, then a reasonable inference is that the best way to improve outcomes for rural patients is to improve their access to quality care,” Dr Unger said.
This research was supported by the National Cancer Institute and the HOPE Foundation. The researchers reported financial relationships with various pharmaceutical companies.
New research suggests that better access to quality care may reduce disparities in survival between cancer patients living in rural areas of the US and those living in urban areas.
The study showed that urban and rural cancer patients had similar survival outcomes when they were enrolled in clinical trials.
These results, published in JAMA Network Open, cast new light on decades of research showing that cancer patients living in rural areas don’t live as long as urban cancer patients.
“These findings were a surprise, since we thought we might find the same disparities others had found,” said study author Joseph Unger, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.
“But clinical trials are a key difference here. In trials, patients are uniformly assessed, treated, and followed under a strict, guideline-driven protocol. This suggests that giving people with cancer access to uniform treatment strategies could help resolve the disparities in outcomes that we see between rural and urban patients.”
Dr Unger and his colleagues studied data on 36,995 patients who were enrolled in 44 phase 3 or phase 2/3 SWOG trials from 1986 through 2012. All 50 states were represented.
Patients had 17 different cancer types, including acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM).
Using US Department of Agriculture population classifications known as Rural-Urban Continuum Codes, the researchers categorized the patients as either rural or urban and analyzed their outcomes.
A minority of patients (19.4%, n=7184) were from rural locations. They were significantly more likely than urban patients to be 65 or older (P<0.001) and significantly less likely to be black (vs all other races; P<0.001).
However, there was no significant between-group difference in sex (P=0.53), and all major US geographic regions (West, Midwest, South, and Northeast) were represented.
Results
The researchers limited their analysis of survival to the first 5 years after trial enrollment to emphasize outcomes related to cancer and its treatment. They looked at overall survival (OS) as well as cancer-specific survival.
The team found no meaningful difference in OS or cancer-specific survival between rural and urban patients for 16 of the 17 cancer types.
The exception was estrogen receptor-negative, progesterone receptor-negative breast cancer. Rural patients with this cancer didn’t live as long as their urban counterparts. The hazard ratio (HR) was 1.27 (95% CI, 1.06-1.51; P=0.008) for OS and 1.26 (95% CI, 1.04-1.52; P=0.02) for cancer-specific survival.
The researchers believe this finding could be attributed to a few factors, including timely access to follow-up chemotherapy after patients’ first round of cancer treatment.
Although there were no significant survival differences for patients with hematologic malignancies, rural patients had slightly better OS if they had advanced indolent NHL or AML but slightly worse OS if they had MM or advanced aggressive NHL. The HRs were as follows:
- Advanced indolent NHL—HR=0.91 (95% CI, 0.64-1.29; P=0.60)
- AML—HR=0.94 (95% CI, 0.83-1.06; P=0.29)
- MM—HR=1.05 (95% CI, 0.93-1.18, P=0.46)
- Advanced aggressive NHL—HR=1.05 (95% CI, 0.87-1.27; P=0.60).
Rural patients had slightly better cancer-specific survival if they had advanced indolent NHL but slightly worse cancer-specific survival if they had AML, MM, or advanced aggressive NHL. The HRs were as follows:
- Advanced indolent NHL—HR=0.98 (95% CI, 0.66-1.45; P=0.90)
- AML—HR=1.01 (95% CI, 0.86-1.20; P=0.87)
- MM—HR=1.04 (95% CI, 0.90-1.20; P=0.60)
- Advanced aggressive NHL—HR=1.08 (95% CI, 0.87-1.34; P=0.50).
The researchers said these findings suggest it is access to care, and not other characteristics, that drive the survival disparities typically observed between urban and rural cancer patients.
“If people diagnosed with cancer, regardless of where they live, receive similar care and have similar outcomes, then a reasonable inference is that the best way to improve outcomes for rural patients is to improve their access to quality care,” Dr Unger said.
This research was supported by the National Cancer Institute and the HOPE Foundation. The researchers reported financial relationships with various pharmaceutical companies.
CPI-613 receives orphan designation for PTCL
The US Food and Drug Administration (FDA) has granted orphan drug designation to CPI-613 for the treatment of peripheral T-cell lymphoma (PTCL).
CPI-613 is a novel lipoic acid analogue that inhibits multiple enzyme targets within the tricarboxylic acid cycle.
Rafael Pharmaceuticals, Inc., is developing CPI-613 as a treatment for hematologic malignancies and solid tumors.
CPI-613 is currently under investigation in combination with bendamustine in a phase 1 study of patients with relapsed or refractory T-cell lymphoma or classical Hodgkin lymphoma.
Results from this trial were presented at the 2016 ASH Annual Meeting.*
CPI-613 was given at escalating doses starting at 2000 mg/m2 over 2 hours on days 1-4 as well as on days 8, 11, 15, and 18. Bendamustine was infused at 90 mg/m2 on days 4 and 5 of each 4-week treatment cycle. The treatment cycles were repeated for up to 6 cycles. There was no intra-patient dose-escalation.
The ASH presentation included safety data on 8 patients. The most common grade 3 or higher toxicities—lymphopenia and neutropenia—occurred in 4 patients.
A patient dosed at 2750 mg/m2 had a dose-limiting toxicity of grade 3 acute kidney injury and grade 4 lactic acidosis. Because of this, the study protocol was amended to discontinue dose-escalation at doses of 2750 mg/m2 or higher and to expand the 2500 mg/m2 cohort.
Six patients were evaluable for efficacy, and the overall response rate was 83% (5/6).
There were 3 complete responses in patients with PTCL not otherwise specified, a partial response in a patient with mycosis fungoides, and a partial response in a patient with angioimmunoblastic T-cell lymphoma.
One patient with T-cell acute lymphoblastic leukemia experienced progressive disease.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
*The data presented differ from the abstract.
The US Food and Drug Administration (FDA) has granted orphan drug designation to CPI-613 for the treatment of peripheral T-cell lymphoma (PTCL).
CPI-613 is a novel lipoic acid analogue that inhibits multiple enzyme targets within the tricarboxylic acid cycle.
Rafael Pharmaceuticals, Inc., is developing CPI-613 as a treatment for hematologic malignancies and solid tumors.
CPI-613 is currently under investigation in combination with bendamustine in a phase 1 study of patients with relapsed or refractory T-cell lymphoma or classical Hodgkin lymphoma.
Results from this trial were presented at the 2016 ASH Annual Meeting.*
CPI-613 was given at escalating doses starting at 2000 mg/m2 over 2 hours on days 1-4 as well as on days 8, 11, 15, and 18. Bendamustine was infused at 90 mg/m2 on days 4 and 5 of each 4-week treatment cycle. The treatment cycles were repeated for up to 6 cycles. There was no intra-patient dose-escalation.
The ASH presentation included safety data on 8 patients. The most common grade 3 or higher toxicities—lymphopenia and neutropenia—occurred in 4 patients.
A patient dosed at 2750 mg/m2 had a dose-limiting toxicity of grade 3 acute kidney injury and grade 4 lactic acidosis. Because of this, the study protocol was amended to discontinue dose-escalation at doses of 2750 mg/m2 or higher and to expand the 2500 mg/m2 cohort.
Six patients were evaluable for efficacy, and the overall response rate was 83% (5/6).
There were 3 complete responses in patients with PTCL not otherwise specified, a partial response in a patient with mycosis fungoides, and a partial response in a patient with angioimmunoblastic T-cell lymphoma.
One patient with T-cell acute lymphoblastic leukemia experienced progressive disease.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
*The data presented differ from the abstract.
The US Food and Drug Administration (FDA) has granted orphan drug designation to CPI-613 for the treatment of peripheral T-cell lymphoma (PTCL).
CPI-613 is a novel lipoic acid analogue that inhibits multiple enzyme targets within the tricarboxylic acid cycle.
Rafael Pharmaceuticals, Inc., is developing CPI-613 as a treatment for hematologic malignancies and solid tumors.
CPI-613 is currently under investigation in combination with bendamustine in a phase 1 study of patients with relapsed or refractory T-cell lymphoma or classical Hodgkin lymphoma.
Results from this trial were presented at the 2016 ASH Annual Meeting.*
CPI-613 was given at escalating doses starting at 2000 mg/m2 over 2 hours on days 1-4 as well as on days 8, 11, 15, and 18. Bendamustine was infused at 90 mg/m2 on days 4 and 5 of each 4-week treatment cycle. The treatment cycles were repeated for up to 6 cycles. There was no intra-patient dose-escalation.
The ASH presentation included safety data on 8 patients. The most common grade 3 or higher toxicities—lymphopenia and neutropenia—occurred in 4 patients.
A patient dosed at 2750 mg/m2 had a dose-limiting toxicity of grade 3 acute kidney injury and grade 4 lactic acidosis. Because of this, the study protocol was amended to discontinue dose-escalation at doses of 2750 mg/m2 or higher and to expand the 2500 mg/m2 cohort.
Six patients were evaluable for efficacy, and the overall response rate was 83% (5/6).
There were 3 complete responses in patients with PTCL not otherwise specified, a partial response in a patient with mycosis fungoides, and a partial response in a patient with angioimmunoblastic T-cell lymphoma.
One patient with T-cell acute lymphoblastic leukemia experienced progressive disease.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
*The data presented differ from the abstract.
Real-world bleeding risk with ibrutinib
The Bruton tyrosine kinase inhibitor ibrutinib has been linked to a 20-fold increased risk of major bleeding in blood cancer patients taking concomitant antiplatelet and anticoagulation therapy in a clinical setting.
Caution should be used when weighing the risks and benefits of ibrutinib for patients already taking antiplatelet or anticoagulation therapy, or both, wrote Joseph Mock, MD, of the University of Virginia Health System in Charlottesville, and his colleagues.
Their report was published in Clinical Lymphoma, Myeloma & Leukemia.
Ibrutinib had been associated with an increased risk of bleeding, albeit low, in the clinical trial setting, but the authors suggested this rate could be higher in everyday clinical practice.
“Much of the information [from clinical trials] on the bleeding risk with ibrutinib, included pooled analyses, was from patients exclusively treated in clinical trials with specific exclusion criteria,” the researchers wrote. “These criteria have generally excluded patients with significant comorbidities. However, these patients are seen in clinical practice.”
The researchers conducted a review of patients treated within the University of Virginia Health System between January 2012 and May 2016.
The team identified 70 patients, with an average age of 72, who were taking ibrutinib for chronic lymphocytic leukemia (64%), mantle cell lymphoma (27%), diffuse large B-cell lymphoma (4%), lymphoblastic lymphoma (3%), and Waldenström’s macroglobulinemia (1%).
Bleeding of any grade occurred in 56% of patients, mostly grade 1-2 bruising and epistaxis.
However, major bleeding, defined as grade 3 or higher, occurred in 19% of patients (n=13). Seven of these patients were taking combined antiplatelet and anticoagulant therapy, 4 were taking antiplatelet agents alone, 1 was taking an anticoagulant agent alone, and 1 was taking only ibrutinib.
Univariate analysis showed that the factors associated with an increased risk of major bleeding were antiplatelet or anticoagulant medication, the combination of the 2 medications, interacting medications, anemia (hemoglobin less than 12 g/dL), and an elevated international normalized ratio (INR, > 1.5).
In a multivariate analysis, only the following factors were associated with an increased risk of major bleeding:
- Concomitant antiplatelet and anticoagulant use—hazard ratio=20.0 (95% CI, 2.1-200.0; P=0.0005) vs no antiplatelet/anticoagulant therapy
- Elevated INR—hazard ratio=4.6 (95% CI, 1.1-19.6; P=0.0409).
The researchers said the risk of major bleeding in patients taking both antiplatelet and anticoagulant therapy was “unacceptably high” and “medications other than ibrutinib should be considered” in this patient population.
Overall, the team said their findings confirm “the increasingly recognized risk of major bleeding complications with ibrutinib compared with what was originally reported in the clinical trial setting.”
They noted that this study was limited by the relatively small population size. Their finding that platelet count was not associated with bleeding risk was also “counterintuitive.”
The Bruton tyrosine kinase inhibitor ibrutinib has been linked to a 20-fold increased risk of major bleeding in blood cancer patients taking concomitant antiplatelet and anticoagulation therapy in a clinical setting.
Caution should be used when weighing the risks and benefits of ibrutinib for patients already taking antiplatelet or anticoagulation therapy, or both, wrote Joseph Mock, MD, of the University of Virginia Health System in Charlottesville, and his colleagues.
Their report was published in Clinical Lymphoma, Myeloma & Leukemia.
Ibrutinib had been associated with an increased risk of bleeding, albeit low, in the clinical trial setting, but the authors suggested this rate could be higher in everyday clinical practice.
“Much of the information [from clinical trials] on the bleeding risk with ibrutinib, included pooled analyses, was from patients exclusively treated in clinical trials with specific exclusion criteria,” the researchers wrote. “These criteria have generally excluded patients with significant comorbidities. However, these patients are seen in clinical practice.”
The researchers conducted a review of patients treated within the University of Virginia Health System between January 2012 and May 2016.
The team identified 70 patients, with an average age of 72, who were taking ibrutinib for chronic lymphocytic leukemia (64%), mantle cell lymphoma (27%), diffuse large B-cell lymphoma (4%), lymphoblastic lymphoma (3%), and Waldenström’s macroglobulinemia (1%).
Bleeding of any grade occurred in 56% of patients, mostly grade 1-2 bruising and epistaxis.
However, major bleeding, defined as grade 3 or higher, occurred in 19% of patients (n=13). Seven of these patients were taking combined antiplatelet and anticoagulant therapy, 4 were taking antiplatelet agents alone, 1 was taking an anticoagulant agent alone, and 1 was taking only ibrutinib.
Univariate analysis showed that the factors associated with an increased risk of major bleeding were antiplatelet or anticoagulant medication, the combination of the 2 medications, interacting medications, anemia (hemoglobin less than 12 g/dL), and an elevated international normalized ratio (INR, > 1.5).
In a multivariate analysis, only the following factors were associated with an increased risk of major bleeding:
- Concomitant antiplatelet and anticoagulant use—hazard ratio=20.0 (95% CI, 2.1-200.0; P=0.0005) vs no antiplatelet/anticoagulant therapy
- Elevated INR—hazard ratio=4.6 (95% CI, 1.1-19.6; P=0.0409).
The researchers said the risk of major bleeding in patients taking both antiplatelet and anticoagulant therapy was “unacceptably high” and “medications other than ibrutinib should be considered” in this patient population.
Overall, the team said their findings confirm “the increasingly recognized risk of major bleeding complications with ibrutinib compared with what was originally reported in the clinical trial setting.”
They noted that this study was limited by the relatively small population size. Their finding that platelet count was not associated with bleeding risk was also “counterintuitive.”
The Bruton tyrosine kinase inhibitor ibrutinib has been linked to a 20-fold increased risk of major bleeding in blood cancer patients taking concomitant antiplatelet and anticoagulation therapy in a clinical setting.
Caution should be used when weighing the risks and benefits of ibrutinib for patients already taking antiplatelet or anticoagulation therapy, or both, wrote Joseph Mock, MD, of the University of Virginia Health System in Charlottesville, and his colleagues.
Their report was published in Clinical Lymphoma, Myeloma & Leukemia.
Ibrutinib had been associated with an increased risk of bleeding, albeit low, in the clinical trial setting, but the authors suggested this rate could be higher in everyday clinical practice.
“Much of the information [from clinical trials] on the bleeding risk with ibrutinib, included pooled analyses, was from patients exclusively treated in clinical trials with specific exclusion criteria,” the researchers wrote. “These criteria have generally excluded patients with significant comorbidities. However, these patients are seen in clinical practice.”
The researchers conducted a review of patients treated within the University of Virginia Health System between January 2012 and May 2016.
The team identified 70 patients, with an average age of 72, who were taking ibrutinib for chronic lymphocytic leukemia (64%), mantle cell lymphoma (27%), diffuse large B-cell lymphoma (4%), lymphoblastic lymphoma (3%), and Waldenström’s macroglobulinemia (1%).
Bleeding of any grade occurred in 56% of patients, mostly grade 1-2 bruising and epistaxis.
However, major bleeding, defined as grade 3 or higher, occurred in 19% of patients (n=13). Seven of these patients were taking combined antiplatelet and anticoagulant therapy, 4 were taking antiplatelet agents alone, 1 was taking an anticoagulant agent alone, and 1 was taking only ibrutinib.
Univariate analysis showed that the factors associated with an increased risk of major bleeding were antiplatelet or anticoagulant medication, the combination of the 2 medications, interacting medications, anemia (hemoglobin less than 12 g/dL), and an elevated international normalized ratio (INR, > 1.5).
In a multivariate analysis, only the following factors were associated with an increased risk of major bleeding:
- Concomitant antiplatelet and anticoagulant use—hazard ratio=20.0 (95% CI, 2.1-200.0; P=0.0005) vs no antiplatelet/anticoagulant therapy
- Elevated INR—hazard ratio=4.6 (95% CI, 1.1-19.6; P=0.0409).
The researchers said the risk of major bleeding in patients taking both antiplatelet and anticoagulant therapy was “unacceptably high” and “medications other than ibrutinib should be considered” in this patient population.
Overall, the team said their findings confirm “the increasingly recognized risk of major bleeding complications with ibrutinib compared with what was originally reported in the clinical trial setting.”
They noted that this study was limited by the relatively small population size. Their finding that platelet count was not associated with bleeding risk was also “counterintuitive.”
Mogamulizumab prolongs PFS in CTCL
Mogamulizumab is an effective treatment option for relapsed/refractory cutaneous T-cell lymphoma (CTCL), according to researchers.
In the phase 3 MAVORIC trial, mogamulizumab prolonged progression-free survival (PFS) and produced better overall response rates (ORRs) than vorinostat in patients with relapsed/refractory CTCL.
The most common adverse events (AEs) in patients treated with mogamulizumab were infusion-related reactions, diarrhea, fatigue, and drug eruptions.
Youn Kim MD, of the Stanford Cancer Institute in Palo Alto, California, and her colleagues reported these results in The Lancet Oncology.
The results supported the recent approval of mogamulizumab by the US Food and Drug Administration.
The study was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing/marketing mogamulizumab.
Treatment
For MAVORIC, researchers compared mogamulizumab and vorinostat in adults with mycosis fungoides (MF) or Sézary syndrome (SS) who had received at least 1 prior systemic therapy.
The trial included 372 patients who were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first cycle and then every 2 weeks) or vorinostat at 400 mg daily for 28-day cycles.
Patients were treated until disease progression or unacceptable toxicity. Patients on vorinostat who progressed or experienced intolerable toxicity after 2 cycles, despite dose reduction and appropriate management of AEs, could cross over to treatment with mogamulizumab.
There were 184 patients in the mogamulizumab arm and 186 in the vorinostat arm who received treatment.
The median duration of follow-up was 17.0 months.
Most patients (n=157) ultimately discontinued mogamulizumab. Reasons included:
- Disease progression (n=76 by CTCL criteria and 22 by clinical criteria)
- AEs (n=28)
- Withdrawn consent (n=13)
- Investigator decision (n=9)
- Patient decision (n=6)
- Death (n=2)
- Noncompliance (n=1).
Most patients (n=136) in the vorinostat arm crossed over to the mogamulizumab arm, 109 due to disease progression and 27 due to treatment intolerance.
Of the 40 patients who did not cross over to mogamulizumab, reasons for stopping vorinostat included:
- Progressive disease (n=10 by CTCL criteria and 8 by clinical criteria)
- Patient decision (n=9)
- Withdrawn consent (n=5)
- AEs (n=5)
- Death (n=2)
- Lost to follow-up (n=1).
At the data cutoff, there were 27 patients assigned to mogamulizumab and 10 assigned to vorinostat who remained on treatment. There were 31 patients still on treatment who had crossed over from vorinostat to mogamulizumab.
Patient characteristics
Baseline characteristics were similar between the treatment arms.
| Mogamulizumab (n=186) | Vorinostat (n=186) | |
| Median age | 64 (range, 54-73) | 65 (range, 56-72) |
| Male | 109 (59%) | 107 (58%) |
| Female | 77 (41%) | 79 (42%) |
| MF | 105 (56%) | 99 (53%) |
| SS | 81 (44%) | 87 (47%) |
| Time from diagnosis, months | 41.0 (range, 17.4-78.8) | 35.4 (range, 16.2-68.2) |
| Median number of previous systemic regimens | 3 (range, 2-5) | 3 (range, 2-5) |
PFS and ORR
Mogamulizumab provided a significant improvement in PFS, the study’s primary endpoint.
According to investigators, the median PFS was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).
According to independent review, the median PFS was 6.7 months and 3.8 months, respectively (hazard ratio=0.64, P<0.0007).
There was a significant improvement in ORR with mogamulizumab.
According to independent review, the global ORR was 23% (43/186) in the mogamulizumab arm and 4% (7/186) in the vorinostat arm (risk ratio=19.4, P<0.0001).
According to investigators, the global ORR was 28% (52/186) and 5% (9/186), respectively (risk ratio=23.1, P<0.0001).
For patients with MF, the investigator-assessed ORR was 21% (22/105) with mogamulizumab and 7% (7/99) with vorinostat.
For SS patients, the investigator-assessed ORR was 37% (30/81) and 2% (2/87), respectively.
Responses by disease compartment were superior with mogamulizumab as well.
The investigator-assessed blood ORR was 68% (83/122) with mogamulizumab and 19% (23/123) with vorinostat. The skin ORR was 42% (78/186) and 16% (29/186), respectively.
The lymph node ORR was 17% (21/124) and 4% (5/122), respectively. The viscera ORR was 0% in both arms.
Crossover
Among patients who crossed over from vorinostat to mogamulizumab, the ORR was 31% (41/133). In these patients, the median PFS was 8.9 months.
In the 319 patients who were assigned to mogamulizumab or crossed over to that arm, the median PFS was 8.4 months.
Safety
The most common treatment-emergent, grade 1-2 AEs, occurring in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), were:
- Thrombocytopenia (14% vs 34%)
- Diarrhea (23% vs 57%)
- Nausea (15% vs 41%)
- Fatigue (22% vs 32%)
- Increased blood creatinine (3% vs 28%)
- Decreased appetite (7% vs 24%)
- Dysgeusia (3% vs 28%)
- Drug eruptions (20% vs 1%)
- Infusion-related reactions (32% vs 1%).
Grade 3 AEs in the mogamulizumab arm included drug eruptions (n=8), hypertension (n=8), pneumonia (n=6), fatigue (n=3), cellulitis (n=3), infusion-related reactions (n=3), sepsis (n=2), decreased appetite (n=2), AST increase (n=2), weight decrease (n=1), pyrexia (n=1), constipation (n=1), nausea (n=1), and diarrhea (n=1).
Grade 4 AEs with mogamulizumab were cellulitis (n=1) and pneumonia (n=1). Grade 5 AEs included pneumonia (n=1) and sepsis (n=1).
Mogamulizumab is an effective treatment option for relapsed/refractory cutaneous T-cell lymphoma (CTCL), according to researchers.
In the phase 3 MAVORIC trial, mogamulizumab prolonged progression-free survival (PFS) and produced better overall response rates (ORRs) than vorinostat in patients with relapsed/refractory CTCL.
The most common adverse events (AEs) in patients treated with mogamulizumab were infusion-related reactions, diarrhea, fatigue, and drug eruptions.
Youn Kim MD, of the Stanford Cancer Institute in Palo Alto, California, and her colleagues reported these results in The Lancet Oncology.
The results supported the recent approval of mogamulizumab by the US Food and Drug Administration.
The study was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing/marketing mogamulizumab.
Treatment
For MAVORIC, researchers compared mogamulizumab and vorinostat in adults with mycosis fungoides (MF) or Sézary syndrome (SS) who had received at least 1 prior systemic therapy.
The trial included 372 patients who were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first cycle and then every 2 weeks) or vorinostat at 400 mg daily for 28-day cycles.
Patients were treated until disease progression or unacceptable toxicity. Patients on vorinostat who progressed or experienced intolerable toxicity after 2 cycles, despite dose reduction and appropriate management of AEs, could cross over to treatment with mogamulizumab.
There were 184 patients in the mogamulizumab arm and 186 in the vorinostat arm who received treatment.
The median duration of follow-up was 17.0 months.
Most patients (n=157) ultimately discontinued mogamulizumab. Reasons included:
- Disease progression (n=76 by CTCL criteria and 22 by clinical criteria)
- AEs (n=28)
- Withdrawn consent (n=13)
- Investigator decision (n=9)
- Patient decision (n=6)
- Death (n=2)
- Noncompliance (n=1).
Most patients (n=136) in the vorinostat arm crossed over to the mogamulizumab arm, 109 due to disease progression and 27 due to treatment intolerance.
Of the 40 patients who did not cross over to mogamulizumab, reasons for stopping vorinostat included:
- Progressive disease (n=10 by CTCL criteria and 8 by clinical criteria)
- Patient decision (n=9)
- Withdrawn consent (n=5)
- AEs (n=5)
- Death (n=2)
- Lost to follow-up (n=1).
At the data cutoff, there were 27 patients assigned to mogamulizumab and 10 assigned to vorinostat who remained on treatment. There were 31 patients still on treatment who had crossed over from vorinostat to mogamulizumab.
Patient characteristics
Baseline characteristics were similar between the treatment arms.
| Mogamulizumab (n=186) | Vorinostat (n=186) | |
| Median age | 64 (range, 54-73) | 65 (range, 56-72) |
| Male | 109 (59%) | 107 (58%) |
| Female | 77 (41%) | 79 (42%) |
| MF | 105 (56%) | 99 (53%) |
| SS | 81 (44%) | 87 (47%) |
| Time from diagnosis, months | 41.0 (range, 17.4-78.8) | 35.4 (range, 16.2-68.2) |
| Median number of previous systemic regimens | 3 (range, 2-5) | 3 (range, 2-5) |
PFS and ORR
Mogamulizumab provided a significant improvement in PFS, the study’s primary endpoint.
According to investigators, the median PFS was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).
According to independent review, the median PFS was 6.7 months and 3.8 months, respectively (hazard ratio=0.64, P<0.0007).
There was a significant improvement in ORR with mogamulizumab.
According to independent review, the global ORR was 23% (43/186) in the mogamulizumab arm and 4% (7/186) in the vorinostat arm (risk ratio=19.4, P<0.0001).
According to investigators, the global ORR was 28% (52/186) and 5% (9/186), respectively (risk ratio=23.1, P<0.0001).
For patients with MF, the investigator-assessed ORR was 21% (22/105) with mogamulizumab and 7% (7/99) with vorinostat.
For SS patients, the investigator-assessed ORR was 37% (30/81) and 2% (2/87), respectively.
Responses by disease compartment were superior with mogamulizumab as well.
The investigator-assessed blood ORR was 68% (83/122) with mogamulizumab and 19% (23/123) with vorinostat. The skin ORR was 42% (78/186) and 16% (29/186), respectively.
The lymph node ORR was 17% (21/124) and 4% (5/122), respectively. The viscera ORR was 0% in both arms.
Crossover
Among patients who crossed over from vorinostat to mogamulizumab, the ORR was 31% (41/133). In these patients, the median PFS was 8.9 months.
In the 319 patients who were assigned to mogamulizumab or crossed over to that arm, the median PFS was 8.4 months.
Safety
The most common treatment-emergent, grade 1-2 AEs, occurring in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), were:
- Thrombocytopenia (14% vs 34%)
- Diarrhea (23% vs 57%)
- Nausea (15% vs 41%)
- Fatigue (22% vs 32%)
- Increased blood creatinine (3% vs 28%)
- Decreased appetite (7% vs 24%)
- Dysgeusia (3% vs 28%)
- Drug eruptions (20% vs 1%)
- Infusion-related reactions (32% vs 1%).
Grade 3 AEs in the mogamulizumab arm included drug eruptions (n=8), hypertension (n=8), pneumonia (n=6), fatigue (n=3), cellulitis (n=3), infusion-related reactions (n=3), sepsis (n=2), decreased appetite (n=2), AST increase (n=2), weight decrease (n=1), pyrexia (n=1), constipation (n=1), nausea (n=1), and diarrhea (n=1).
Grade 4 AEs with mogamulizumab were cellulitis (n=1) and pneumonia (n=1). Grade 5 AEs included pneumonia (n=1) and sepsis (n=1).
Mogamulizumab is an effective treatment option for relapsed/refractory cutaneous T-cell lymphoma (CTCL), according to researchers.
In the phase 3 MAVORIC trial, mogamulizumab prolonged progression-free survival (PFS) and produced better overall response rates (ORRs) than vorinostat in patients with relapsed/refractory CTCL.
The most common adverse events (AEs) in patients treated with mogamulizumab were infusion-related reactions, diarrhea, fatigue, and drug eruptions.
Youn Kim MD, of the Stanford Cancer Institute in Palo Alto, California, and her colleagues reported these results in The Lancet Oncology.
The results supported the recent approval of mogamulizumab by the US Food and Drug Administration.
The study was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing/marketing mogamulizumab.
Treatment
For MAVORIC, researchers compared mogamulizumab and vorinostat in adults with mycosis fungoides (MF) or Sézary syndrome (SS) who had received at least 1 prior systemic therapy.
The trial included 372 patients who were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first cycle and then every 2 weeks) or vorinostat at 400 mg daily for 28-day cycles.
Patients were treated until disease progression or unacceptable toxicity. Patients on vorinostat who progressed or experienced intolerable toxicity after 2 cycles, despite dose reduction and appropriate management of AEs, could cross over to treatment with mogamulizumab.
There were 184 patients in the mogamulizumab arm and 186 in the vorinostat arm who received treatment.
The median duration of follow-up was 17.0 months.
Most patients (n=157) ultimately discontinued mogamulizumab. Reasons included:
- Disease progression (n=76 by CTCL criteria and 22 by clinical criteria)
- AEs (n=28)
- Withdrawn consent (n=13)
- Investigator decision (n=9)
- Patient decision (n=6)
- Death (n=2)
- Noncompliance (n=1).
Most patients (n=136) in the vorinostat arm crossed over to the mogamulizumab arm, 109 due to disease progression and 27 due to treatment intolerance.
Of the 40 patients who did not cross over to mogamulizumab, reasons for stopping vorinostat included:
- Progressive disease (n=10 by CTCL criteria and 8 by clinical criteria)
- Patient decision (n=9)
- Withdrawn consent (n=5)
- AEs (n=5)
- Death (n=2)
- Lost to follow-up (n=1).
At the data cutoff, there were 27 patients assigned to mogamulizumab and 10 assigned to vorinostat who remained on treatment. There were 31 patients still on treatment who had crossed over from vorinostat to mogamulizumab.
Patient characteristics
Baseline characteristics were similar between the treatment arms.
| Mogamulizumab (n=186) | Vorinostat (n=186) | |
| Median age | 64 (range, 54-73) | 65 (range, 56-72) |
| Male | 109 (59%) | 107 (58%) |
| Female | 77 (41%) | 79 (42%) |
| MF | 105 (56%) | 99 (53%) |
| SS | 81 (44%) | 87 (47%) |
| Time from diagnosis, months | 41.0 (range, 17.4-78.8) | 35.4 (range, 16.2-68.2) |
| Median number of previous systemic regimens | 3 (range, 2-5) | 3 (range, 2-5) |
PFS and ORR
Mogamulizumab provided a significant improvement in PFS, the study’s primary endpoint.
According to investigators, the median PFS was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).
According to independent review, the median PFS was 6.7 months and 3.8 months, respectively (hazard ratio=0.64, P<0.0007).
There was a significant improvement in ORR with mogamulizumab.
According to independent review, the global ORR was 23% (43/186) in the mogamulizumab arm and 4% (7/186) in the vorinostat arm (risk ratio=19.4, P<0.0001).
According to investigators, the global ORR was 28% (52/186) and 5% (9/186), respectively (risk ratio=23.1, P<0.0001).
For patients with MF, the investigator-assessed ORR was 21% (22/105) with mogamulizumab and 7% (7/99) with vorinostat.
For SS patients, the investigator-assessed ORR was 37% (30/81) and 2% (2/87), respectively.
Responses by disease compartment were superior with mogamulizumab as well.
The investigator-assessed blood ORR was 68% (83/122) with mogamulizumab and 19% (23/123) with vorinostat. The skin ORR was 42% (78/186) and 16% (29/186), respectively.
The lymph node ORR was 17% (21/124) and 4% (5/122), respectively. The viscera ORR was 0% in both arms.
Crossover
Among patients who crossed over from vorinostat to mogamulizumab, the ORR was 31% (41/133). In these patients, the median PFS was 8.9 months.
In the 319 patients who were assigned to mogamulizumab or crossed over to that arm, the median PFS was 8.4 months.
Safety
The most common treatment-emergent, grade 1-2 AEs, occurring in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), were:
- Thrombocytopenia (14% vs 34%)
- Diarrhea (23% vs 57%)
- Nausea (15% vs 41%)
- Fatigue (22% vs 32%)
- Increased blood creatinine (3% vs 28%)
- Decreased appetite (7% vs 24%)
- Dysgeusia (3% vs 28%)
- Drug eruptions (20% vs 1%)
- Infusion-related reactions (32% vs 1%).
Grade 3 AEs in the mogamulizumab arm included drug eruptions (n=8), hypertension (n=8), pneumonia (n=6), fatigue (n=3), cellulitis (n=3), infusion-related reactions (n=3), sepsis (n=2), decreased appetite (n=2), AST increase (n=2), weight decrease (n=1), pyrexia (n=1), constipation (n=1), nausea (n=1), and diarrhea (n=1).
Grade 4 AEs with mogamulizumab were cellulitis (n=1) and pneumonia (n=1). Grade 5 AEs included pneumonia (n=1) and sepsis (n=1).
Auto-HSCT linked to higher AML, MDS risk
Patients undergoing autologous hematopoietic stem cell transplant (auto-HSCT) for lymphoma or myeloma have an increased risk of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to a retrospective study.
The study suggested these patients have 10 to 100 times the risk of AML or MDS as the general population.
The elevated risk also exceeds that of similar lymphoma and myeloma patients largely untreated with auto-HSCT.
Tomas Radivoyevitch, PhD, of the Cleveland Clinic Foundation in Ohio, and his colleagues reported these findings in Leukemia Research.
The investigators noted that exposure to DNA-damaging drugs and ionizing radiation—both used in auto-HSCT—is known to increase the risk of AML and MDS.
With this in mind, the team analyzed data on auto-HSCT recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).
Analyses were based on 9028 patients undergoing auto-HSCT from 1995 to 2010 for Hodgkin lymphoma (n=916), non-Hodgkin lymphoma (NHL, n=3546), or plasma cell myeloma (n=4566). Their median duration of follow-up was 90 months, 110 months, and 97 months, respectively.
Overall, 3.7% of the cohort developed AML or MDS after their transplant.
More aggressive transplant protocols increased the likelihood of this outcome. The risk of developing AML or MDS was higher for:
- Hodgkin lymphoma patients who received conditioning with total body radiation versus chemotherapy alone (hazard ratio [HR], 4.0)
- NHL patients who received conditioning with total body radiation (HR, 1.7) or with busulfan and melphalan or cyclophosphamide (HR, 1.8) versus the BEAM regimen (bischloroethylnitrosourea, etoposide, cytarabine, and melphalan)
- NHL or myeloma patients who received 3 or more lines of chemotherapy versus 1 line (HR, 1.9 for NHL and 1.8 for myeloma)
- NHL patients who underwent transplant in 2005 to 2010 versus 1995 to 1999 (HR, 2.1).
Patients reported to the Surveillance, Epidemiology and End Results database with the same lymphoma and myeloma diagnoses, few of whom underwent auto-HSCT, had risks of AML and MDS that were 5 to 10 times higher than the background level in the population.
However, the study auto-HSCT cohort had a risk of AML that was 10 to 50 times higher and a relative risk of MDS that was roughly 100 times higher than the background level.
“These increases may be related to exposure to high doses of DNA-damaging drugs given for [auto-HSCT], but this hypothesis can only be tested in a prospective study,” Dr Radivoyevitch and his coinvestigators wrote.
The reason for the greater elevation of MDS risk, compared with AML risk, is unknown.
“One possible explanation is that many cases of MDS evolve to AML, and that earlier diagnosis from increased post-transplant surveillance resulted in a deficiency of AML,” the investigators wrote. “A second is based on steeper MDS versus AML incidences versus age . . . and the possibility that transplantation recipient marrow ages (ie, marrow biological ages) are perhaps decades older than calendar ages.”
The study authors said they had no relevant conflicts of interest. The CIBMTR is supported by several US government agencies and numerous pharmaceutical companies.
Patients undergoing autologous hematopoietic stem cell transplant (auto-HSCT) for lymphoma or myeloma have an increased risk of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to a retrospective study.
The study suggested these patients have 10 to 100 times the risk of AML or MDS as the general population.
The elevated risk also exceeds that of similar lymphoma and myeloma patients largely untreated with auto-HSCT.
Tomas Radivoyevitch, PhD, of the Cleveland Clinic Foundation in Ohio, and his colleagues reported these findings in Leukemia Research.
The investigators noted that exposure to DNA-damaging drugs and ionizing radiation—both used in auto-HSCT—is known to increase the risk of AML and MDS.
With this in mind, the team analyzed data on auto-HSCT recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).
Analyses were based on 9028 patients undergoing auto-HSCT from 1995 to 2010 for Hodgkin lymphoma (n=916), non-Hodgkin lymphoma (NHL, n=3546), or plasma cell myeloma (n=4566). Their median duration of follow-up was 90 months, 110 months, and 97 months, respectively.
Overall, 3.7% of the cohort developed AML or MDS after their transplant.
More aggressive transplant protocols increased the likelihood of this outcome. The risk of developing AML or MDS was higher for:
- Hodgkin lymphoma patients who received conditioning with total body radiation versus chemotherapy alone (hazard ratio [HR], 4.0)
- NHL patients who received conditioning with total body radiation (HR, 1.7) or with busulfan and melphalan or cyclophosphamide (HR, 1.8) versus the BEAM regimen (bischloroethylnitrosourea, etoposide, cytarabine, and melphalan)
- NHL or myeloma patients who received 3 or more lines of chemotherapy versus 1 line (HR, 1.9 for NHL and 1.8 for myeloma)
- NHL patients who underwent transplant in 2005 to 2010 versus 1995 to 1999 (HR, 2.1).
Patients reported to the Surveillance, Epidemiology and End Results database with the same lymphoma and myeloma diagnoses, few of whom underwent auto-HSCT, had risks of AML and MDS that were 5 to 10 times higher than the background level in the population.
However, the study auto-HSCT cohort had a risk of AML that was 10 to 50 times higher and a relative risk of MDS that was roughly 100 times higher than the background level.
“These increases may be related to exposure to high doses of DNA-damaging drugs given for [auto-HSCT], but this hypothesis can only be tested in a prospective study,” Dr Radivoyevitch and his coinvestigators wrote.
The reason for the greater elevation of MDS risk, compared with AML risk, is unknown.
“One possible explanation is that many cases of MDS evolve to AML, and that earlier diagnosis from increased post-transplant surveillance resulted in a deficiency of AML,” the investigators wrote. “A second is based on steeper MDS versus AML incidences versus age . . . and the possibility that transplantation recipient marrow ages (ie, marrow biological ages) are perhaps decades older than calendar ages.”
The study authors said they had no relevant conflicts of interest. The CIBMTR is supported by several US government agencies and numerous pharmaceutical companies.
Patients undergoing autologous hematopoietic stem cell transplant (auto-HSCT) for lymphoma or myeloma have an increased risk of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to a retrospective study.
The study suggested these patients have 10 to 100 times the risk of AML or MDS as the general population.
The elevated risk also exceeds that of similar lymphoma and myeloma patients largely untreated with auto-HSCT.
Tomas Radivoyevitch, PhD, of the Cleveland Clinic Foundation in Ohio, and his colleagues reported these findings in Leukemia Research.
The investigators noted that exposure to DNA-damaging drugs and ionizing radiation—both used in auto-HSCT—is known to increase the risk of AML and MDS.
With this in mind, the team analyzed data on auto-HSCT recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).
Analyses were based on 9028 patients undergoing auto-HSCT from 1995 to 2010 for Hodgkin lymphoma (n=916), non-Hodgkin lymphoma (NHL, n=3546), or plasma cell myeloma (n=4566). Their median duration of follow-up was 90 months, 110 months, and 97 months, respectively.
Overall, 3.7% of the cohort developed AML or MDS after their transplant.
More aggressive transplant protocols increased the likelihood of this outcome. The risk of developing AML or MDS was higher for:
- Hodgkin lymphoma patients who received conditioning with total body radiation versus chemotherapy alone (hazard ratio [HR], 4.0)
- NHL patients who received conditioning with total body radiation (HR, 1.7) or with busulfan and melphalan or cyclophosphamide (HR, 1.8) versus the BEAM regimen (bischloroethylnitrosourea, etoposide, cytarabine, and melphalan)
- NHL or myeloma patients who received 3 or more lines of chemotherapy versus 1 line (HR, 1.9 for NHL and 1.8 for myeloma)
- NHL patients who underwent transplant in 2005 to 2010 versus 1995 to 1999 (HR, 2.1).
Patients reported to the Surveillance, Epidemiology and End Results database with the same lymphoma and myeloma diagnoses, few of whom underwent auto-HSCT, had risks of AML and MDS that were 5 to 10 times higher than the background level in the population.
However, the study auto-HSCT cohort had a risk of AML that was 10 to 50 times higher and a relative risk of MDS that was roughly 100 times higher than the background level.
“These increases may be related to exposure to high doses of DNA-damaging drugs given for [auto-HSCT], but this hypothesis can only be tested in a prospective study,” Dr Radivoyevitch and his coinvestigators wrote.
The reason for the greater elevation of MDS risk, compared with AML risk, is unknown.
“One possible explanation is that many cases of MDS evolve to AML, and that earlier diagnosis from increased post-transplant surveillance resulted in a deficiency of AML,” the investigators wrote. “A second is based on steeper MDS versus AML incidences versus age . . . and the possibility that transplantation recipient marrow ages (ie, marrow biological ages) are perhaps decades older than calendar ages.”
The study authors said they had no relevant conflicts of interest. The CIBMTR is supported by several US government agencies and numerous pharmaceutical companies.
Group releases new CLL guidelines
Fludarabine, cyclophosphamide, and rituximab are recommended as initial therapy for fit patients with chronic lymphocytic leukemia (CLL) who do not have TP53 disruption, according to new guidelines from the British Society for Haematology.
The guidelines update the 2012 recommendations on CLL to include “significant” developments in treatment.
The new guidelines were published in the British Journal of Haematology.
Anna H. Schuh, MD, of the University of Oxford in the UK, and her coauthors noted that, while these guidelines apply to treatments available outside clinical trials, wherever possible, patients with CLL should be treated within the clinical trial setting.
While recommending fludarabine, cyclophosphamide, and rituximab as first-line therapy, the guideline authors acknowledged that the combination of bendamustine and rituximab is an acceptable alternative for patients who cannot take the triple therapy because of comorbidities such as advanced age, renal impairment, or issues with marrow capacity.
Similarly, less-fit patients can also be considered for chlorambucil-obinutuzumab or chlorambucil-ofatumumab combinations.
All patients diagnosed with CLL should be tested for TP53 deletions and mutations before each line of therapy, the guideline committee recommended.
TP53 disruption makes chemoimmunotherapy ineffective because of either a deletion of chromosome 17p or a mutation in the TP53 gene. However, there is compelling evidence for the efficacy of ibrutinib in these patients, or idelalisib and rituximab for those with cardiac disease or receiving vitamin K antagonists.
With respect to maintenance therapy, the guidelines noted that this was not routinely recommended in CLL as “it is unclear to what extent the progression-free survival benefit is offset by long-term toxicity.”
Patients who are refractory to chemoimmunotherapy, who have relapsed, or who cannot be retreated with chemoimmunotherapy should be treated with idelalisib plus rituximab or ibrutinib monotherapy, the guidelines suggested.
“Deciding whether ibrutinib or idelalisib with rituximab is most appropriate for an individual patient depends on a range of factors, including toxicity profile and convenience of delivery,” the authors wrote.
However, they noted that the value of adding bendamustine to either option was unclear as research had not shown significant, associated gains in median progression-free survival.
Allogeneic stem cell transplant should be considered as an option for patients who have failed chemotherapy, have a TP53 disruption and have not responded to B-cell receptor signaling pathway inhibitors such as ibrutinib, or have Richter’s transformation.
The guidelines also addressed the issue of autoimmune cytopenias, which occur in 5% to 10% of patients with CLL and can actually precede the diagnosis of CLL in about 9% of cases.
In patients where autoimmune cytopenia is the dominant clinical feature, they should be treated with corticosteroids, intravenous immunoglobulin, or rituximab. However, for patients where the cytopenia is triggered by CLL therapy, the guidelines recommended halting treatment and beginning immunosuppression.
The guideline development was supported by the British Society for Haematology. The UK CLL Forum, which was involved in development as well, is a registered charity that receives funding from a number of pharmaceutical companies.
Fludarabine, cyclophosphamide, and rituximab are recommended as initial therapy for fit patients with chronic lymphocytic leukemia (CLL) who do not have TP53 disruption, according to new guidelines from the British Society for Haematology.
The guidelines update the 2012 recommendations on CLL to include “significant” developments in treatment.
The new guidelines were published in the British Journal of Haematology.
Anna H. Schuh, MD, of the University of Oxford in the UK, and her coauthors noted that, while these guidelines apply to treatments available outside clinical trials, wherever possible, patients with CLL should be treated within the clinical trial setting.
While recommending fludarabine, cyclophosphamide, and rituximab as first-line therapy, the guideline authors acknowledged that the combination of bendamustine and rituximab is an acceptable alternative for patients who cannot take the triple therapy because of comorbidities such as advanced age, renal impairment, or issues with marrow capacity.
Similarly, less-fit patients can also be considered for chlorambucil-obinutuzumab or chlorambucil-ofatumumab combinations.
All patients diagnosed with CLL should be tested for TP53 deletions and mutations before each line of therapy, the guideline committee recommended.
TP53 disruption makes chemoimmunotherapy ineffective because of either a deletion of chromosome 17p or a mutation in the TP53 gene. However, there is compelling evidence for the efficacy of ibrutinib in these patients, or idelalisib and rituximab for those with cardiac disease or receiving vitamin K antagonists.
With respect to maintenance therapy, the guidelines noted that this was not routinely recommended in CLL as “it is unclear to what extent the progression-free survival benefit is offset by long-term toxicity.”
Patients who are refractory to chemoimmunotherapy, who have relapsed, or who cannot be retreated with chemoimmunotherapy should be treated with idelalisib plus rituximab or ibrutinib monotherapy, the guidelines suggested.
“Deciding whether ibrutinib or idelalisib with rituximab is most appropriate for an individual patient depends on a range of factors, including toxicity profile and convenience of delivery,” the authors wrote.
However, they noted that the value of adding bendamustine to either option was unclear as research had not shown significant, associated gains in median progression-free survival.
Allogeneic stem cell transplant should be considered as an option for patients who have failed chemotherapy, have a TP53 disruption and have not responded to B-cell receptor signaling pathway inhibitors such as ibrutinib, or have Richter’s transformation.
The guidelines also addressed the issue of autoimmune cytopenias, which occur in 5% to 10% of patients with CLL and can actually precede the diagnosis of CLL in about 9% of cases.
In patients where autoimmune cytopenia is the dominant clinical feature, they should be treated with corticosteroids, intravenous immunoglobulin, or rituximab. However, for patients where the cytopenia is triggered by CLL therapy, the guidelines recommended halting treatment and beginning immunosuppression.
The guideline development was supported by the British Society for Haematology. The UK CLL Forum, which was involved in development as well, is a registered charity that receives funding from a number of pharmaceutical companies.
Fludarabine, cyclophosphamide, and rituximab are recommended as initial therapy for fit patients with chronic lymphocytic leukemia (CLL) who do not have TP53 disruption, according to new guidelines from the British Society for Haematology.
The guidelines update the 2012 recommendations on CLL to include “significant” developments in treatment.
The new guidelines were published in the British Journal of Haematology.
Anna H. Schuh, MD, of the University of Oxford in the UK, and her coauthors noted that, while these guidelines apply to treatments available outside clinical trials, wherever possible, patients with CLL should be treated within the clinical trial setting.
While recommending fludarabine, cyclophosphamide, and rituximab as first-line therapy, the guideline authors acknowledged that the combination of bendamustine and rituximab is an acceptable alternative for patients who cannot take the triple therapy because of comorbidities such as advanced age, renal impairment, or issues with marrow capacity.
Similarly, less-fit patients can also be considered for chlorambucil-obinutuzumab or chlorambucil-ofatumumab combinations.
All patients diagnosed with CLL should be tested for TP53 deletions and mutations before each line of therapy, the guideline committee recommended.
TP53 disruption makes chemoimmunotherapy ineffective because of either a deletion of chromosome 17p or a mutation in the TP53 gene. However, there is compelling evidence for the efficacy of ibrutinib in these patients, or idelalisib and rituximab for those with cardiac disease or receiving vitamin K antagonists.
With respect to maintenance therapy, the guidelines noted that this was not routinely recommended in CLL as “it is unclear to what extent the progression-free survival benefit is offset by long-term toxicity.”
Patients who are refractory to chemoimmunotherapy, who have relapsed, or who cannot be retreated with chemoimmunotherapy should be treated with idelalisib plus rituximab or ibrutinib monotherapy, the guidelines suggested.
“Deciding whether ibrutinib or idelalisib with rituximab is most appropriate for an individual patient depends on a range of factors, including toxicity profile and convenience of delivery,” the authors wrote.
However, they noted that the value of adding bendamustine to either option was unclear as research had not shown significant, associated gains in median progression-free survival.
Allogeneic stem cell transplant should be considered as an option for patients who have failed chemotherapy, have a TP53 disruption and have not responded to B-cell receptor signaling pathway inhibitors such as ibrutinib, or have Richter’s transformation.
The guidelines also addressed the issue of autoimmune cytopenias, which occur in 5% to 10% of patients with CLL and can actually precede the diagnosis of CLL in about 9% of cases.
In patients where autoimmune cytopenia is the dominant clinical feature, they should be treated with corticosteroids, intravenous immunoglobulin, or rituximab. However, for patients where the cytopenia is triggered by CLL therapy, the guidelines recommended halting treatment and beginning immunosuppression.
The guideline development was supported by the British Society for Haematology. The UK CLL Forum, which was involved in development as well, is a registered charity that receives funding from a number of pharmaceutical companies.