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MicroRNA may be therapeutic target for ALK- ALCL
SAN FRANCISCO—MicroRNA-155 (miR-155) can act as an oncogenic driver in ALK− anaplastic large-cell lymphoma (ALCL) and may therefore be a therapeutic target for the disease, according to a presentation at the 7th Annual T-cell Lymphoma Forum.
Analyzing patient samples and cell lines, researchers discovered that miR-155 is highly expressed in ALK− ALCL but is nearly absent in ALK+ ALCL.
They also found evidence suggesting that miR-155 drives tumor growth in mouse models of ALK− ALCL.
Philipp Staber, MD, PhD, of the Medical University of Vienna in Austria, presented these findings at the meeting.
Dr Staber and his colleagues previously found (Merkel et al, PNAS 2010) that miR-155 was highly expressed in ALK− ALCL. So they decided to take a closer look at the phenomenon.
They assessed miR-155 expression in samples from patients with ALK+ or ALK− ALCL, as well as 6 ALCL cell lines.
miR-155 expression was significantly higher in the ALK− patient samples than in the ALK+ samples (P<0.001). And it was significantly higher (P<0.001) in the ALK− cell lines (DL-40, Mac1, and Mac2a) than in the ALK+ cell lines (K299, SR789, and SUP-M2).
Dr Staber and his colleagues then overexpressed miR-155 in ALK+ ALCL cell lines (K299 and SR789). And they observed a decrease in known target genes of miR-155—C/EBPβ, SOCS1, and SHIP1.
The researchers also observed an inverse correlation between miR-155 host gene promoter methylation and miR-155 expression in an ALCL+ cell line, which suggested that ALK activity has no direct effect on miR-155 levels.
The team treated the K299 cell line with the ALK inhibitor crizotinib at 100 nM, 200 nM, and 400 nM doses and found that miR-155 did not increase at any dose. Dr Staber noted, however, that the researchers were only able to treat cells for a maximum of 24 hours.
The group then discovered that anti-miR-155 mimics could reduce tumor growth in mouse models of ALK- ALCL. Mice were injected with Mac1 or Mac2a cells transfected with anti-miR-155, control RNA, or pre-miR-155 oligos.
In both Mac1 and Mac2 models, tumors were substantially smaller in the anti-mir-155 mice than in the pre-miR-155 mice (P=0.038 and P=0.006, respectively). But tumor growth was not significantly reduced compared to controls.
“Immunohistochemistry in these tumors shows quite a clear picture,” Dr Staber said. “The C/EBPβ target gene is overexpressed when using anti-miR-155, and [expression is decreased] with overexpression of miR-155. And the same is true for SOCS1. STAT3 signaling is increased through overexpression of miR-155.”
The researchers observed the same effect in ALK− ALCL patient samples.
Using ALK+ cell lines (K299 and SR789), the team went on to show that miR-155 suppresses IL-8 expression and induces IL-22 expression, a finding they verified in mice.
“IL-8 is a direct target of C/EBPβ, and C/EBPβ, as shown before, is a target of miR-155, so this makes sense,” Dr Staber said. “On the other hand, IL-22 is a strong inducer of STAT3 signaling, which is strongly induced when we increase miR-155 expression.”
Dr Staber and his colleagues concluded that these findings, when taken together, suggest that miR-155 could be a therapeutic target for ALK− ALCL. 
SAN FRANCISCO—MicroRNA-155 (miR-155) can act as an oncogenic driver in ALK− anaplastic large-cell lymphoma (ALCL) and may therefore be a therapeutic target for the disease, according to a presentation at the 7th Annual T-cell Lymphoma Forum.
Analyzing patient samples and cell lines, researchers discovered that miR-155 is highly expressed in ALK− ALCL but is nearly absent in ALK+ ALCL.
They also found evidence suggesting that miR-155 drives tumor growth in mouse models of ALK− ALCL.
Philipp Staber, MD, PhD, of the Medical University of Vienna in Austria, presented these findings at the meeting.
Dr Staber and his colleagues previously found (Merkel et al, PNAS 2010) that miR-155 was highly expressed in ALK− ALCL. So they decided to take a closer look at the phenomenon.
They assessed miR-155 expression in samples from patients with ALK+ or ALK− ALCL, as well as 6 ALCL cell lines.
miR-155 expression was significantly higher in the ALK− patient samples than in the ALK+ samples (P<0.001). And it was significantly higher (P<0.001) in the ALK− cell lines (DL-40, Mac1, and Mac2a) than in the ALK+ cell lines (K299, SR789, and SUP-M2).
Dr Staber and his colleagues then overexpressed miR-155 in ALK+ ALCL cell lines (K299 and SR789). And they observed a decrease in known target genes of miR-155—C/EBPβ, SOCS1, and SHIP1.
The researchers also observed an inverse correlation between miR-155 host gene promoter methylation and miR-155 expression in an ALCL+ cell line, which suggested that ALK activity has no direct effect on miR-155 levels.
The team treated the K299 cell line with the ALK inhibitor crizotinib at 100 nM, 200 nM, and 400 nM doses and found that miR-155 did not increase at any dose. Dr Staber noted, however, that the researchers were only able to treat cells for a maximum of 24 hours.
The group then discovered that anti-miR-155 mimics could reduce tumor growth in mouse models of ALK- ALCL. Mice were injected with Mac1 or Mac2a cells transfected with anti-miR-155, control RNA, or pre-miR-155 oligos.
In both Mac1 and Mac2 models, tumors were substantially smaller in the anti-mir-155 mice than in the pre-miR-155 mice (P=0.038 and P=0.006, respectively). But tumor growth was not significantly reduced compared to controls.
“Immunohistochemistry in these tumors shows quite a clear picture,” Dr Staber said. “The C/EBPβ target gene is overexpressed when using anti-miR-155, and [expression is decreased] with overexpression of miR-155. And the same is true for SOCS1. STAT3 signaling is increased through overexpression of miR-155.”
The researchers observed the same effect in ALK− ALCL patient samples.
Using ALK+ cell lines (K299 and SR789), the team went on to show that miR-155 suppresses IL-8 expression and induces IL-22 expression, a finding they verified in mice.
“IL-8 is a direct target of C/EBPβ, and C/EBPβ, as shown before, is a target of miR-155, so this makes sense,” Dr Staber said. “On the other hand, IL-22 is a strong inducer of STAT3 signaling, which is strongly induced when we increase miR-155 expression.”
Dr Staber and his colleagues concluded that these findings, when taken together, suggest that miR-155 could be a therapeutic target for ALK− ALCL.
SAN FRANCISCO—MicroRNA-155 (miR-155) can act as an oncogenic driver in ALK− anaplastic large-cell lymphoma (ALCL) and may therefore be a therapeutic target for the disease, according to a presentation at the 7th Annual T-cell Lymphoma Forum.
Analyzing patient samples and cell lines, researchers discovered that miR-155 is highly expressed in ALK− ALCL but is nearly absent in ALK+ ALCL.
They also found evidence suggesting that miR-155 drives tumor growth in mouse models of ALK− ALCL.
Philipp Staber, MD, PhD, of the Medical University of Vienna in Austria, presented these findings at the meeting.
Dr Staber and his colleagues previously found (Merkel et al, PNAS 2010) that miR-155 was highly expressed in ALK− ALCL. So they decided to take a closer look at the phenomenon.
They assessed miR-155 expression in samples from patients with ALK+ or ALK− ALCL, as well as 6 ALCL cell lines.
miR-155 expression was significantly higher in the ALK− patient samples than in the ALK+ samples (P<0.001). And it was significantly higher (P<0.001) in the ALK− cell lines (DL-40, Mac1, and Mac2a) than in the ALK+ cell lines (K299, SR789, and SUP-M2).
Dr Staber and his colleagues then overexpressed miR-155 in ALK+ ALCL cell lines (K299 and SR789). And they observed a decrease in known target genes of miR-155—C/EBPβ, SOCS1, and SHIP1.
The researchers also observed an inverse correlation between miR-155 host gene promoter methylation and miR-155 expression in an ALCL+ cell line, which suggested that ALK activity has no direct effect on miR-155 levels.
The team treated the K299 cell line with the ALK inhibitor crizotinib at 100 nM, 200 nM, and 400 nM doses and found that miR-155 did not increase at any dose. Dr Staber noted, however, that the researchers were only able to treat cells for a maximum of 24 hours.
The group then discovered that anti-miR-155 mimics could reduce tumor growth in mouse models of ALK- ALCL. Mice were injected with Mac1 or Mac2a cells transfected with anti-miR-155, control RNA, or pre-miR-155 oligos.
In both Mac1 and Mac2 models, tumors were substantially smaller in the anti-mir-155 mice than in the pre-miR-155 mice (P=0.038 and P=0.006, respectively). But tumor growth was not significantly reduced compared to controls.
“Immunohistochemistry in these tumors shows quite a clear picture,” Dr Staber said. “The C/EBPβ target gene is overexpressed when using anti-miR-155, and [expression is decreased] with overexpression of miR-155. And the same is true for SOCS1. STAT3 signaling is increased through overexpression of miR-155.”
The researchers observed the same effect in ALK− ALCL patient samples.
Using ALK+ cell lines (K299 and SR789), the team went on to show that miR-155 suppresses IL-8 expression and induces IL-22 expression, a finding they verified in mice.
“IL-8 is a direct target of C/EBPβ, and C/EBPβ, as shown before, is a target of miR-155, so this makes sense,” Dr Staber said. “On the other hand, IL-22 is a strong inducer of STAT3 signaling, which is strongly induced when we increase miR-155 expression.”
Dr Staber and his colleagues concluded that these findings, when taken together, suggest that miR-155 could be a therapeutic target for ALK− ALCL.
Combo shows early promise for T-cell lymphomas
SAN FRANCISCO—Preclinical and early phase 1 results suggest the aurora A kinase inhibitor alisertib and the histone deacetylase (HDAC) inhibitor romidepsin have synergistic activity against T-cell lymphomas.
In the preclinical study, the drugs showed synergy in cutaneous T-cell lymphoma (CTCL) cell lines and a benefit over monotherapy in vivo.
In the phase 1 study, romidepsin and alisertib produced clinical benefits in patients with peripheral T-cell lymphoma (PTCL).
Unfortunately, there are currently no good markers for predicting which patients might benefit from this type of combination, potentially because the drugs have multivariate mechanisms of action, said Michelle Fanale, MD, of the University of Texas MD Anderson Cancer Center in Houston.
She presented data on romidepsin and alisertib in combination at the 7th Annual T-cell Lymphoma Forum.
Dr Fanale said she was inspired to test the combination (in a phase 1 trial) after researchers reported promising results with the aurora kinase inhibitors MK-0457 and MK-5108 in combination with the HDAC inhibitor vorinostat (Kretzner et al, Cancer Research 2011).
She noted that aurora kinase inhibitors work mainly through actions at the G2-M transition point, while HDAC inhibitors induce G1-S transition. HDAC inhibitors can also degrade aurora A and B kinases, and the drugs modify kinetochore assembly through hyperacetylation of pericentromeric histones.
“When you actually treat with an HDAC inhibitor by itself, you’re basically getting an increase of this sub-G1 population,” Dr Fanale said. “When you treat with your aurora kinase inhibitor by itself, you’re clearly getting an increase of cells that are arresting at G2/M.”
“When you treat with the combination, you’re actually getting a further increase in the sub-G1, denoting dead cells, and then you’re further getting some increase of cells spreading out now through the G2/M portion as well.”
Preclinical research
Dr Fanale presented preclinical results showing that alisertib is highly synergistic with romidepsin in T-cell, but not B-cell, lymphoma. She was not involved in the research, which was also presented at the recent ASH Annual Meeting (Zullo et al, ASH 2014, abst 4493).
The researchers administered romidepsin at IC10-20 concentrations, with increasing concentrations of alisertib, and incubated cells for 72 hours. A synergy coefficient less than 1 denoted synergy.
The combination demonstrated synergy in the HH (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.68 and 0.40, respectively) but not at 50 nM (1.05).
Likewise, the combination demonstrated synergy in the H9 (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.66 and 0.46, respectively) but not at 50 nM (1.1).
Romidepsin was shown to cause a mild increase in the percent of cells in G1 compared with alisertib, which significantly increased the percent of cells in G2/M arrest. And live cell imaging showed marked cytokinesis failure following treatment.
“When looking at further markers for apoptosis, when giving the combination, there’s further increase in caspase 3 and PARP cleavage, as well as other pro-apoptotic proteins, including PUMA, and a decrease in the anti-apoptotic protein Bcl-xL,” Dr Fanale noted.
She also pointed out that, in an in vivo xenograft model, alisertib and romidepsin produced significantly better results than those observed with monotherapy or in controls.
Phase 1 trial
The phase 1 trial of romidepsin and alisertib in combination included patients with aggressive B- and T-cell lymphomas (NCT01897012; Fanale et al, ASH 2014, abst 1744).
Twelve patients have been enrolled to date. Ninety-two percent of patients had primary refractory disease, they had a median of 3.5 prior lines of therapy (range, 1 to 7), and none of the patients had received a stem cell transplant.
The patients received treatment as follows:
- Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 6 mg/m2 IV on days 1 and 8
- Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 8 mg/m2 IV on days 1 and 8
- Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m2 IV on days 1 and 8
- Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m2 IV on days 1 and 8
- Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 12 mg/m2 IV on days 1 and 8
- Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 14 mg/m2 IV on days 1 and 8.
The maximum-tolerated dose has not yet been reached. The main side effect was reversible myelosuppression. In the 24 cycles administered, patients experienced grade 3/4 neutropenia (62.5%), anemia (29%), and thrombocytopenia (48%).
Dr Fanale noted that 3 of the 4 patients with T-cell lymphomas had some level of clinical benefit after therapy.
One patient, a heavily pretreated patient with PTCL who was treated at the lowest dose, had a complete response lasting 10 months. The patient had received 7 prior lines of therapy, including romidepsin alone.
Two other patients had stable disease, one with PTCL and one with an overlap diagnosis of B-cell and T-cell lymphoma. The PTCL patient went on to receive a matched, unrelated-donor transplant and is doing well, Dr Fanale said.
“We’ve taken a pause from this clinical trial,” she added. “We plan to reopen it toward T-cell lymphoma patients, potentially exclusively, . . . and also potentially to change a bit of the dosing schema with both romidepsin and alisertib.”
SAN FRANCISCO—Preclinical and early phase 1 results suggest the aurora A kinase inhibitor alisertib and the histone deacetylase (HDAC) inhibitor romidepsin have synergistic activity against T-cell lymphomas.
In the preclinical study, the drugs showed synergy in cutaneous T-cell lymphoma (CTCL) cell lines and a benefit over monotherapy in vivo.
In the phase 1 study, romidepsin and alisertib produced clinical benefits in patients with peripheral T-cell lymphoma (PTCL).
Unfortunately, there are currently no good markers for predicting which patients might benefit from this type of combination, potentially because the drugs have multivariate mechanisms of action, said Michelle Fanale, MD, of the University of Texas MD Anderson Cancer Center in Houston.
She presented data on romidepsin and alisertib in combination at the 7th Annual T-cell Lymphoma Forum.
Dr Fanale said she was inspired to test the combination (in a phase 1 trial) after researchers reported promising results with the aurora kinase inhibitors MK-0457 and MK-5108 in combination with the HDAC inhibitor vorinostat (Kretzner et al, Cancer Research 2011).
She noted that aurora kinase inhibitors work mainly through actions at the G2-M transition point, while HDAC inhibitors induce G1-S transition. HDAC inhibitors can also degrade aurora A and B kinases, and the drugs modify kinetochore assembly through hyperacetylation of pericentromeric histones.
“When you actually treat with an HDAC inhibitor by itself, you’re basically getting an increase of this sub-G1 population,” Dr Fanale said. “When you treat with your aurora kinase inhibitor by itself, you’re clearly getting an increase of cells that are arresting at G2/M.”
“When you treat with the combination, you’re actually getting a further increase in the sub-G1, denoting dead cells, and then you’re further getting some increase of cells spreading out now through the G2/M portion as well.”
Preclinical research
Dr Fanale presented preclinical results showing that alisertib is highly synergistic with romidepsin in T-cell, but not B-cell, lymphoma. She was not involved in the research, which was also presented at the recent ASH Annual Meeting (Zullo et al, ASH 2014, abst 4493).
The researchers administered romidepsin at IC10-20 concentrations, with increasing concentrations of alisertib, and incubated cells for 72 hours. A synergy coefficient less than 1 denoted synergy.
The combination demonstrated synergy in the HH (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.68 and 0.40, respectively) but not at 50 nM (1.05).
Likewise, the combination demonstrated synergy in the H9 (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.66 and 0.46, respectively) but not at 50 nM (1.1).
Romidepsin was shown to cause a mild increase in the percent of cells in G1 compared with alisertib, which significantly increased the percent of cells in G2/M arrest. And live cell imaging showed marked cytokinesis failure following treatment.
“When looking at further markers for apoptosis, when giving the combination, there’s further increase in caspase 3 and PARP cleavage, as well as other pro-apoptotic proteins, including PUMA, and a decrease in the anti-apoptotic protein Bcl-xL,” Dr Fanale noted.
She also pointed out that, in an in vivo xenograft model, alisertib and romidepsin produced significantly better results than those observed with monotherapy or in controls.
Phase 1 trial
The phase 1 trial of romidepsin and alisertib in combination included patients with aggressive B- and T-cell lymphomas (NCT01897012; Fanale et al, ASH 2014, abst 1744).
Twelve patients have been enrolled to date. Ninety-two percent of patients had primary refractory disease, they had a median of 3.5 prior lines of therapy (range, 1 to 7), and none of the patients had received a stem cell transplant.
The patients received treatment as follows:
- Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 6 mg/m2 IV on days 1 and 8
- Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 8 mg/m2 IV on days 1 and 8
- Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m2 IV on days 1 and 8
- Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m2 IV on days 1 and 8
- Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 12 mg/m2 IV on days 1 and 8
- Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 14 mg/m2 IV on days 1 and 8.
The maximum-tolerated dose has not yet been reached. The main side effect was reversible myelosuppression. In the 24 cycles administered, patients experienced grade 3/4 neutropenia (62.5%), anemia (29%), and thrombocytopenia (48%).
Dr Fanale noted that 3 of the 4 patients with T-cell lymphomas had some level of clinical benefit after therapy.
One patient, a heavily pretreated patient with PTCL who was treated at the lowest dose, had a complete response lasting 10 months. The patient had received 7 prior lines of therapy, including romidepsin alone.
Two other patients had stable disease, one with PTCL and one with an overlap diagnosis of B-cell and T-cell lymphoma. The PTCL patient went on to receive a matched, unrelated-donor transplant and is doing well, Dr Fanale said.
“We’ve taken a pause from this clinical trial,” she added. “We plan to reopen it toward T-cell lymphoma patients, potentially exclusively, . . . and also potentially to change a bit of the dosing schema with both romidepsin and alisertib.”
SAN FRANCISCO—Preclinical and early phase 1 results suggest the aurora A kinase inhibitor alisertib and the histone deacetylase (HDAC) inhibitor romidepsin have synergistic activity against T-cell lymphomas.
In the preclinical study, the drugs showed synergy in cutaneous T-cell lymphoma (CTCL) cell lines and a benefit over monotherapy in vivo.
In the phase 1 study, romidepsin and alisertib produced clinical benefits in patients with peripheral T-cell lymphoma (PTCL).
Unfortunately, there are currently no good markers for predicting which patients might benefit from this type of combination, potentially because the drugs have multivariate mechanisms of action, said Michelle Fanale, MD, of the University of Texas MD Anderson Cancer Center in Houston.
She presented data on romidepsin and alisertib in combination at the 7th Annual T-cell Lymphoma Forum.
Dr Fanale said she was inspired to test the combination (in a phase 1 trial) after researchers reported promising results with the aurora kinase inhibitors MK-0457 and MK-5108 in combination with the HDAC inhibitor vorinostat (Kretzner et al, Cancer Research 2011).
She noted that aurora kinase inhibitors work mainly through actions at the G2-M transition point, while HDAC inhibitors induce G1-S transition. HDAC inhibitors can also degrade aurora A and B kinases, and the drugs modify kinetochore assembly through hyperacetylation of pericentromeric histones.
“When you actually treat with an HDAC inhibitor by itself, you’re basically getting an increase of this sub-G1 population,” Dr Fanale said. “When you treat with your aurora kinase inhibitor by itself, you’re clearly getting an increase of cells that are arresting at G2/M.”
“When you treat with the combination, you’re actually getting a further increase in the sub-G1, denoting dead cells, and then you’re further getting some increase of cells spreading out now through the G2/M portion as well.”
Preclinical research
Dr Fanale presented preclinical results showing that alisertib is highly synergistic with romidepsin in T-cell, but not B-cell, lymphoma. She was not involved in the research, which was also presented at the recent ASH Annual Meeting (Zullo et al, ASH 2014, abst 4493).
The researchers administered romidepsin at IC10-20 concentrations, with increasing concentrations of alisertib, and incubated cells for 72 hours. A synergy coefficient less than 1 denoted synergy.
The combination demonstrated synergy in the HH (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.68 and 0.40, respectively) but not at 50 nM (1.05).
Likewise, the combination demonstrated synergy in the H9 (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.66 and 0.46, respectively) but not at 50 nM (1.1).
Romidepsin was shown to cause a mild increase in the percent of cells in G1 compared with alisertib, which significantly increased the percent of cells in G2/M arrest. And live cell imaging showed marked cytokinesis failure following treatment.
“When looking at further markers for apoptosis, when giving the combination, there’s further increase in caspase 3 and PARP cleavage, as well as other pro-apoptotic proteins, including PUMA, and a decrease in the anti-apoptotic protein Bcl-xL,” Dr Fanale noted.
She also pointed out that, in an in vivo xenograft model, alisertib and romidepsin produced significantly better results than those observed with monotherapy or in controls.
Phase 1 trial
The phase 1 trial of romidepsin and alisertib in combination included patients with aggressive B- and T-cell lymphomas (NCT01897012; Fanale et al, ASH 2014, abst 1744).
Twelve patients have been enrolled to date. Ninety-two percent of patients had primary refractory disease, they had a median of 3.5 prior lines of therapy (range, 1 to 7), and none of the patients had received a stem cell transplant.
The patients received treatment as follows:
- Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 6 mg/m2 IV on days 1 and 8
- Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 8 mg/m2 IV on days 1 and 8
- Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m2 IV on days 1 and 8
- Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m2 IV on days 1 and 8
- Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 12 mg/m2 IV on days 1 and 8
- Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 14 mg/m2 IV on days 1 and 8.
The maximum-tolerated dose has not yet been reached. The main side effect was reversible myelosuppression. In the 24 cycles administered, patients experienced grade 3/4 neutropenia (62.5%), anemia (29%), and thrombocytopenia (48%).
Dr Fanale noted that 3 of the 4 patients with T-cell lymphomas had some level of clinical benefit after therapy.
One patient, a heavily pretreated patient with PTCL who was treated at the lowest dose, had a complete response lasting 10 months. The patient had received 7 prior lines of therapy, including romidepsin alone.
Two other patients had stable disease, one with PTCL and one with an overlap diagnosis of B-cell and T-cell lymphoma. The PTCL patient went on to receive a matched, unrelated-donor transplant and is doing well, Dr Fanale said.
“We’ve taken a pause from this clinical trial,” she added. “We plan to reopen it toward T-cell lymphoma patients, potentially exclusively, . . . and also potentially to change a bit of the dosing schema with both romidepsin and alisertib.”
A better HDAC inhibitor for PTCL?
SAN FRANCISCO—The histone deacetylase (HDAC) inhibitor chidamide is effective and well-tolerated in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL), results of the phase 2 CHIPEL trial suggest.
The study showed that chidamide can elicit higher response rates than those previously observed with the folate analog metabolic inhibitor pralatrexate and the HDAC inhibitor romidepsin.
Chidamide also prolonged survival and posed a lower risk of toxicity compared to pralatrexate and romidepsin.
Yuankai Shi, MD, PhD, of the Chinese Academy of Medical Science & Peking Union Medical College in Beijing, China, presented these results at the 7th Annual T-cell Lymphoma Forum. The trial is sponsored by Chipscreen Biosciences Ltd.
He noted that the CHIPEL study was split into two parts: an exploratory trial and a pivotal trial.
Exploratory trial
The exploratory trial included 19 patients who had a median age of 51 and were a median of 1.41 years from diagnosis. Seventeen patients had PTCL unspecified (PTCL-U), and 2 had other subtypes of PTCL.
The patients received chidamide at 30 mg (n=9) or 50 mg (n=10) twice a week for 2 weeks of a 3-week cycle. The overall response rate was 26% (n=5), and 16% of patients (n=3) had a complete response (CR) or unconfirmed CR (CRu).
Pivotal trial
The pivotal trial included 83 patients who had a median age of 53 and were a median of 1.06 years from diagnosis.
The patients had PTCL-U (29.1%, n=23), nasal NK/T-cell lymphoma (20.3%, n=16), anaplastic large-cell lymphoma (ALCL, 20.3%, n=16), angioimmunoblastic T-cell lymphoma (AITL, 11.4%, n=9), enteropathy-type T-cell lymphoma (2.5%, n=2), CD4-positive PTCL (1.3%, n=1), Lennert-type PTCL (1.3%, n=1), transformed mycosis fungoides (1.3%, n=1), and other subtypes of PTCL (12.7%, n=10).
These patients received chidamide at 30 mg twice a week without a drug-free holiday.
The overall response rate was 29% (n=23) according to investigators and 28% (n=22) according to an independent review committee. Fourteen percent of patients (n=11) had a CR/CRu, according to both sources.
The median progression-free survival was 2.1 months for all patients, 14 months for patients who achieved CR/CRus, 7.7 months in patients with partial responses, and 2.5 months in patients with stable disease.
The median overall survival was 21.4 months in all patients and not reached in patients who had a CR/CRu, partial response, or stable disease.
Overall safety
Of all 102 patients (in both the pivotal and exploratory analyses), 80% had at least one adverse event (AE), 37% had grade 3 or higher AEs, 17% had AEs leading to treatment discontinuation, and 8% had severe AEs.
The most common AEs were thrombocytopenia (50%), leukopenia (37%), neutropenia (19%), fatigue (11%), and fever (11%).
Twenty-four percent of patients had grade 3 or higher thrombocytopenia, 13% had grade 3 or higher leukopenia, and 10% had grade 3 or higher neutropenia.
Chidamide vs other agents
Dr Shi compared response rates with chidamide in the pivotal trial to those previously observed with pralatrexate (O’Connor et al, JCO 2011) and romidepsin (Coiffier et al, J Hematol Oncol 2014).
In patients with PTCL-U, response rates were similar for all 3 drugs (≈30%). In ALCL, the response rate with chidamide was higher (≈50%) than with pralatrexate (≈30%) or romidepsin (≈25%). And in AITL, the response rate with chidamide was higher (≈45%) than with pralatrexate (≈8%) or romidepsin (≈30%).
Chidamide also conferred better overall survival than pralatrexate, romidepsin, and other treatments from previous studies.
The median overall survival was 6.5 months with chemotherapy (Mak et al, JCO 2013), 14.5 months with pralatrexate (O’Connor et al, JCO 2011), 11.3 months with romidepsin (Coiffier et al, J Hematol Oncol 2014), 7.9 months with belinostat (Hyon-Zu Lee, Clinical Review 2009), and 21.4 months with chidamide.
Finally, Dr Shi compared the rates of AEs observed in the chidamide pivotal trial to AEs observed in the pralatrexate and romidepsin trials.
At least one AE occurred in 100% of patients treated with pralatrexate, 96% of patients on romidepsin, and 82% of patients on chidamide. Grade 3 or higher AEs occurred in 74%, 66%, and 39% of patients, respectively. And at least one severe AE occurred in 44%, 46%, and 8% of patients, respectively.
The favorable results observed with chidamide support the Chinese Food and Drug Administration’s December decision to approve the drug (under the brand name Epidaza) for use in patients with PTCL.
SAN FRANCISCO—The histone deacetylase (HDAC) inhibitor chidamide is effective and well-tolerated in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL), results of the phase 2 CHIPEL trial suggest.
The study showed that chidamide can elicit higher response rates than those previously observed with the folate analog metabolic inhibitor pralatrexate and the HDAC inhibitor romidepsin.
Chidamide also prolonged survival and posed a lower risk of toxicity compared to pralatrexate and romidepsin.
Yuankai Shi, MD, PhD, of the Chinese Academy of Medical Science & Peking Union Medical College in Beijing, China, presented these results at the 7th Annual T-cell Lymphoma Forum. The trial is sponsored by Chipscreen Biosciences Ltd.
He noted that the CHIPEL study was split into two parts: an exploratory trial and a pivotal trial.
Exploratory trial
The exploratory trial included 19 patients who had a median age of 51 and were a median of 1.41 years from diagnosis. Seventeen patients had PTCL unspecified (PTCL-U), and 2 had other subtypes of PTCL.
The patients received chidamide at 30 mg (n=9) or 50 mg (n=10) twice a week for 2 weeks of a 3-week cycle. The overall response rate was 26% (n=5), and 16% of patients (n=3) had a complete response (CR) or unconfirmed CR (CRu).
Pivotal trial
The pivotal trial included 83 patients who had a median age of 53 and were a median of 1.06 years from diagnosis.
The patients had PTCL-U (29.1%, n=23), nasal NK/T-cell lymphoma (20.3%, n=16), anaplastic large-cell lymphoma (ALCL, 20.3%, n=16), angioimmunoblastic T-cell lymphoma (AITL, 11.4%, n=9), enteropathy-type T-cell lymphoma (2.5%, n=2), CD4-positive PTCL (1.3%, n=1), Lennert-type PTCL (1.3%, n=1), transformed mycosis fungoides (1.3%, n=1), and other subtypes of PTCL (12.7%, n=10).
These patients received chidamide at 30 mg twice a week without a drug-free holiday.
The overall response rate was 29% (n=23) according to investigators and 28% (n=22) according to an independent review committee. Fourteen percent of patients (n=11) had a CR/CRu, according to both sources.
The median progression-free survival was 2.1 months for all patients, 14 months for patients who achieved CR/CRus, 7.7 months in patients with partial responses, and 2.5 months in patients with stable disease.
The median overall survival was 21.4 months in all patients and not reached in patients who had a CR/CRu, partial response, or stable disease.
Overall safety
Of all 102 patients (in both the pivotal and exploratory analyses), 80% had at least one adverse event (AE), 37% had grade 3 or higher AEs, 17% had AEs leading to treatment discontinuation, and 8% had severe AEs.
The most common AEs were thrombocytopenia (50%), leukopenia (37%), neutropenia (19%), fatigue (11%), and fever (11%).
Twenty-four percent of patients had grade 3 or higher thrombocytopenia, 13% had grade 3 or higher leukopenia, and 10% had grade 3 or higher neutropenia.
Chidamide vs other agents
Dr Shi compared response rates with chidamide in the pivotal trial to those previously observed with pralatrexate (O’Connor et al, JCO 2011) and romidepsin (Coiffier et al, J Hematol Oncol 2014).
In patients with PTCL-U, response rates were similar for all 3 drugs (≈30%). In ALCL, the response rate with chidamide was higher (≈50%) than with pralatrexate (≈30%) or romidepsin (≈25%). And in AITL, the response rate with chidamide was higher (≈45%) than with pralatrexate (≈8%) or romidepsin (≈30%).
Chidamide also conferred better overall survival than pralatrexate, romidepsin, and other treatments from previous studies.
The median overall survival was 6.5 months with chemotherapy (Mak et al, JCO 2013), 14.5 months with pralatrexate (O’Connor et al, JCO 2011), 11.3 months with romidepsin (Coiffier et al, J Hematol Oncol 2014), 7.9 months with belinostat (Hyon-Zu Lee, Clinical Review 2009), and 21.4 months with chidamide.
Finally, Dr Shi compared the rates of AEs observed in the chidamide pivotal trial to AEs observed in the pralatrexate and romidepsin trials.
At least one AE occurred in 100% of patients treated with pralatrexate, 96% of patients on romidepsin, and 82% of patients on chidamide. Grade 3 or higher AEs occurred in 74%, 66%, and 39% of patients, respectively. And at least one severe AE occurred in 44%, 46%, and 8% of patients, respectively.
The favorable results observed with chidamide support the Chinese Food and Drug Administration’s December decision to approve the drug (under the brand name Epidaza) for use in patients with PTCL.
SAN FRANCISCO—The histone deacetylase (HDAC) inhibitor chidamide is effective and well-tolerated in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL), results of the phase 2 CHIPEL trial suggest.
The study showed that chidamide can elicit higher response rates than those previously observed with the folate analog metabolic inhibitor pralatrexate and the HDAC inhibitor romidepsin.
Chidamide also prolonged survival and posed a lower risk of toxicity compared to pralatrexate and romidepsin.
Yuankai Shi, MD, PhD, of the Chinese Academy of Medical Science & Peking Union Medical College in Beijing, China, presented these results at the 7th Annual T-cell Lymphoma Forum. The trial is sponsored by Chipscreen Biosciences Ltd.
He noted that the CHIPEL study was split into two parts: an exploratory trial and a pivotal trial.
Exploratory trial
The exploratory trial included 19 patients who had a median age of 51 and were a median of 1.41 years from diagnosis. Seventeen patients had PTCL unspecified (PTCL-U), and 2 had other subtypes of PTCL.
The patients received chidamide at 30 mg (n=9) or 50 mg (n=10) twice a week for 2 weeks of a 3-week cycle. The overall response rate was 26% (n=5), and 16% of patients (n=3) had a complete response (CR) or unconfirmed CR (CRu).
Pivotal trial
The pivotal trial included 83 patients who had a median age of 53 and were a median of 1.06 years from diagnosis.
The patients had PTCL-U (29.1%, n=23), nasal NK/T-cell lymphoma (20.3%, n=16), anaplastic large-cell lymphoma (ALCL, 20.3%, n=16), angioimmunoblastic T-cell lymphoma (AITL, 11.4%, n=9), enteropathy-type T-cell lymphoma (2.5%, n=2), CD4-positive PTCL (1.3%, n=1), Lennert-type PTCL (1.3%, n=1), transformed mycosis fungoides (1.3%, n=1), and other subtypes of PTCL (12.7%, n=10).
These patients received chidamide at 30 mg twice a week without a drug-free holiday.
The overall response rate was 29% (n=23) according to investigators and 28% (n=22) according to an independent review committee. Fourteen percent of patients (n=11) had a CR/CRu, according to both sources.
The median progression-free survival was 2.1 months for all patients, 14 months for patients who achieved CR/CRus, 7.7 months in patients with partial responses, and 2.5 months in patients with stable disease.
The median overall survival was 21.4 months in all patients and not reached in patients who had a CR/CRu, partial response, or stable disease.
Overall safety
Of all 102 patients (in both the pivotal and exploratory analyses), 80% had at least one adverse event (AE), 37% had grade 3 or higher AEs, 17% had AEs leading to treatment discontinuation, and 8% had severe AEs.
The most common AEs were thrombocytopenia (50%), leukopenia (37%), neutropenia (19%), fatigue (11%), and fever (11%).
Twenty-four percent of patients had grade 3 or higher thrombocytopenia, 13% had grade 3 or higher leukopenia, and 10% had grade 3 or higher neutropenia.
Chidamide vs other agents
Dr Shi compared response rates with chidamide in the pivotal trial to those previously observed with pralatrexate (O’Connor et al, JCO 2011) and romidepsin (Coiffier et al, J Hematol Oncol 2014).
In patients with PTCL-U, response rates were similar for all 3 drugs (≈30%). In ALCL, the response rate with chidamide was higher (≈50%) than with pralatrexate (≈30%) or romidepsin (≈25%). And in AITL, the response rate with chidamide was higher (≈45%) than with pralatrexate (≈8%) or romidepsin (≈30%).
Chidamide also conferred better overall survival than pralatrexate, romidepsin, and other treatments from previous studies.
The median overall survival was 6.5 months with chemotherapy (Mak et al, JCO 2013), 14.5 months with pralatrexate (O’Connor et al, JCO 2011), 11.3 months with romidepsin (Coiffier et al, J Hematol Oncol 2014), 7.9 months with belinostat (Hyon-Zu Lee, Clinical Review 2009), and 21.4 months with chidamide.
Finally, Dr Shi compared the rates of AEs observed in the chidamide pivotal trial to AEs observed in the pralatrexate and romidepsin trials.
At least one AE occurred in 100% of patients treated with pralatrexate, 96% of patients on romidepsin, and 82% of patients on chidamide. Grade 3 or higher AEs occurred in 74%, 66%, and 39% of patients, respectively. And at least one severe AE occurred in 44%, 46%, and 8% of patients, respectively.
The favorable results observed with chidamide support the Chinese Food and Drug Administration’s December decision to approve the drug (under the brand name Epidaza) for use in patients with PTCL.
Outcomes still dismal in PTCL, project shows
SAN FRANCISCO—Outcomes remain dismal for the majority of patients with peripheral T-cell lymphoma (PTCL), according to a speaker at the 7th Annual T-cell Lymphoma Forum.
Massimo Federico, MD, of the Università di Modena e Reggio Emilia in Italy, presented an analysis of the first 1000 patients enrolled in the prospective T-Cell Project.
The data showed no improvements in survival for these patients compared to patients included in the retrospective International Peripheral T-Cell Lymphoma
Project.
The International Peripheral T-Cell Lymphoma Project included PTCL patients treated at various institutions between 1990 and 2002.
The T-Cell Project was designed to complement this retrospective analysis, providing prospective international data on PTCL patients.
“The main aim was to verify if a prospective collection of data would allow for more accurate information to better define prognosis of the most frequent subtypes of PTCL—PTCL not otherwise specified (NOS) and angioimmunoblastic T-cell lymphoma (AITL)—and improve our knowledge of clinical and biological characteristics and outcomes of the more uncommon subtypes of PTCL,” Dr Federico said.
He reported that, as of January 12, 2015, 73 institutions were recruiting patients for the project, and 6 institutions were active but not yet recruiting.
Of the 1308 patients registered at that point, 46% were from European countries (Italy, UK, Switzerland, Slovakia, Spain, and France), 20% were from the US, 20% were from South America (Argentina, Brazil, Chile, and Uruguay), and 14% were from the Middle East or Far East (South Korea, Hong Kong, and Israel).
Dr Federico went on to present data from the first 1000 patients registered in the project. The final analysis actually included 943 patients, as some patients withdrew consent, some did not have baseline data available, and some diagnoses could not be confirmed.
So of the 943 patients, 37% had PTCL-NOS, 17% had AITL, 15% had ALK-negative anaplastic large-cell lymphoma (ALCL), 7% had ALK-positive ALCL, 11% had natural killer/T-cell lymphoma (NKTCL), 8% had T-cell receptor γδ T-cell lymphoma, and 5% had other histologies.
The patients’ median age was 56 (range, 18-89), and 61% were male. Twenty-four percent of patients had an ECOG status greater than 1, 48% had B symptoms, and 71% had disease-related discomfort. Sixty-seven percent of patients had stage III-IV disease, 27% had nodal-only disease, 6% had bulky disease, 29% had more than 1 extranodal site, and 19% had bone marrow involvement.
The median follow-up was 41 months (range, 1-91). The 5-year overall survival (OS) was 44%, and the median OS was 39 months.
The 5-year OS was 35% for patients with PTCL-NOS, 42% for those with AITL, 45% for those with ALK-negative ALCL, 80% for those with ALK-positive ALCL, 48% for those with NKTCL (56% for nasal and 33% for extranasal), and 39% for those with T-cell receptor γδ T-cell lymphoma.
In comparison, the International Peripheral T-Cell Lymphoma Project showed a 5-year OS of 32% for patients with PTCL-NOS, 70% for patients with ALK-positive ALCL, and 49% for patients with ALK-negative ALCL (K. Savage et al. Blood 2008). The 5-year OS was 40% for patients with nasal NKTCL and 15% for those with extranasal NKTCL (W. Au et al. Blood 2008).
“[T]he outcome of PTCL continues to be dismal in the majority of cases, [with] no improvement in overall survival compared to older series,” Dr Federico summarized. “Treatment remains challenging, and new therapies are welcome.”
He added that the next steps for the T-Cell Project are to continue registration (with the goal of reaching 2000 assessable cases), extend the network to additional sites (particularly in under-represented areas such as Japan, China, India, and Oceania), and expand the collection of tissue.
“In particular, we intend to create an international tissue catalogue—including paraffin-embedded samples and, if possible, frozen ones—accessible to research groups with a solid reputation in investigating PTCLs at the molecular and translation level.”
SAN FRANCISCO—Outcomes remain dismal for the majority of patients with peripheral T-cell lymphoma (PTCL), according to a speaker at the 7th Annual T-cell Lymphoma Forum.
Massimo Federico, MD, of the Università di Modena e Reggio Emilia in Italy, presented an analysis of the first 1000 patients enrolled in the prospective T-Cell Project.
The data showed no improvements in survival for these patients compared to patients included in the retrospective International Peripheral T-Cell Lymphoma
Project.
The International Peripheral T-Cell Lymphoma Project included PTCL patients treated at various institutions between 1990 and 2002.
The T-Cell Project was designed to complement this retrospective analysis, providing prospective international data on PTCL patients.
“The main aim was to verify if a prospective collection of data would allow for more accurate information to better define prognosis of the most frequent subtypes of PTCL—PTCL not otherwise specified (NOS) and angioimmunoblastic T-cell lymphoma (AITL)—and improve our knowledge of clinical and biological characteristics and outcomes of the more uncommon subtypes of PTCL,” Dr Federico said.
He reported that, as of January 12, 2015, 73 institutions were recruiting patients for the project, and 6 institutions were active but not yet recruiting.
Of the 1308 patients registered at that point, 46% were from European countries (Italy, UK, Switzerland, Slovakia, Spain, and France), 20% were from the US, 20% were from South America (Argentina, Brazil, Chile, and Uruguay), and 14% were from the Middle East or Far East (South Korea, Hong Kong, and Israel).
Dr Federico went on to present data from the first 1000 patients registered in the project. The final analysis actually included 943 patients, as some patients withdrew consent, some did not have baseline data available, and some diagnoses could not be confirmed.
So of the 943 patients, 37% had PTCL-NOS, 17% had AITL, 15% had ALK-negative anaplastic large-cell lymphoma (ALCL), 7% had ALK-positive ALCL, 11% had natural killer/T-cell lymphoma (NKTCL), 8% had T-cell receptor γδ T-cell lymphoma, and 5% had other histologies.
The patients’ median age was 56 (range, 18-89), and 61% were male. Twenty-four percent of patients had an ECOG status greater than 1, 48% had B symptoms, and 71% had disease-related discomfort. Sixty-seven percent of patients had stage III-IV disease, 27% had nodal-only disease, 6% had bulky disease, 29% had more than 1 extranodal site, and 19% had bone marrow involvement.
The median follow-up was 41 months (range, 1-91). The 5-year overall survival (OS) was 44%, and the median OS was 39 months.
The 5-year OS was 35% for patients with PTCL-NOS, 42% for those with AITL, 45% for those with ALK-negative ALCL, 80% for those with ALK-positive ALCL, 48% for those with NKTCL (56% for nasal and 33% for extranasal), and 39% for those with T-cell receptor γδ T-cell lymphoma.
In comparison, the International Peripheral T-Cell Lymphoma Project showed a 5-year OS of 32% for patients with PTCL-NOS, 70% for patients with ALK-positive ALCL, and 49% for patients with ALK-negative ALCL (K. Savage et al. Blood 2008). The 5-year OS was 40% for patients with nasal NKTCL and 15% for those with extranasal NKTCL (W. Au et al. Blood 2008).
“[T]he outcome of PTCL continues to be dismal in the majority of cases, [with] no improvement in overall survival compared to older series,” Dr Federico summarized. “Treatment remains challenging, and new therapies are welcome.”
He added that the next steps for the T-Cell Project are to continue registration (with the goal of reaching 2000 assessable cases), extend the network to additional sites (particularly in under-represented areas such as Japan, China, India, and Oceania), and expand the collection of tissue.
“In particular, we intend to create an international tissue catalogue—including paraffin-embedded samples and, if possible, frozen ones—accessible to research groups with a solid reputation in investigating PTCLs at the molecular and translation level.”
SAN FRANCISCO—Outcomes remain dismal for the majority of patients with peripheral T-cell lymphoma (PTCL), according to a speaker at the 7th Annual T-cell Lymphoma Forum.
Massimo Federico, MD, of the Università di Modena e Reggio Emilia in Italy, presented an analysis of the first 1000 patients enrolled in the prospective T-Cell Project.
The data showed no improvements in survival for these patients compared to patients included in the retrospective International Peripheral T-Cell Lymphoma
Project.
The International Peripheral T-Cell Lymphoma Project included PTCL patients treated at various institutions between 1990 and 2002.
The T-Cell Project was designed to complement this retrospective analysis, providing prospective international data on PTCL patients.
“The main aim was to verify if a prospective collection of data would allow for more accurate information to better define prognosis of the most frequent subtypes of PTCL—PTCL not otherwise specified (NOS) and angioimmunoblastic T-cell lymphoma (AITL)—and improve our knowledge of clinical and biological characteristics and outcomes of the more uncommon subtypes of PTCL,” Dr Federico said.
He reported that, as of January 12, 2015, 73 institutions were recruiting patients for the project, and 6 institutions were active but not yet recruiting.
Of the 1308 patients registered at that point, 46% were from European countries (Italy, UK, Switzerland, Slovakia, Spain, and France), 20% were from the US, 20% were from South America (Argentina, Brazil, Chile, and Uruguay), and 14% were from the Middle East or Far East (South Korea, Hong Kong, and Israel).
Dr Federico went on to present data from the first 1000 patients registered in the project. The final analysis actually included 943 patients, as some patients withdrew consent, some did not have baseline data available, and some diagnoses could not be confirmed.
So of the 943 patients, 37% had PTCL-NOS, 17% had AITL, 15% had ALK-negative anaplastic large-cell lymphoma (ALCL), 7% had ALK-positive ALCL, 11% had natural killer/T-cell lymphoma (NKTCL), 8% had T-cell receptor γδ T-cell lymphoma, and 5% had other histologies.
The patients’ median age was 56 (range, 18-89), and 61% were male. Twenty-four percent of patients had an ECOG status greater than 1, 48% had B symptoms, and 71% had disease-related discomfort. Sixty-seven percent of patients had stage III-IV disease, 27% had nodal-only disease, 6% had bulky disease, 29% had more than 1 extranodal site, and 19% had bone marrow involvement.
The median follow-up was 41 months (range, 1-91). The 5-year overall survival (OS) was 44%, and the median OS was 39 months.
The 5-year OS was 35% for patients with PTCL-NOS, 42% for those with AITL, 45% for those with ALK-negative ALCL, 80% for those with ALK-positive ALCL, 48% for those with NKTCL (56% for nasal and 33% for extranasal), and 39% for those with T-cell receptor γδ T-cell lymphoma.
In comparison, the International Peripheral T-Cell Lymphoma Project showed a 5-year OS of 32% for patients with PTCL-NOS, 70% for patients with ALK-positive ALCL, and 49% for patients with ALK-negative ALCL (K. Savage et al. Blood 2008). The 5-year OS was 40% for patients with nasal NKTCL and 15% for those with extranasal NKTCL (W. Au et al. Blood 2008).
“[T]he outcome of PTCL continues to be dismal in the majority of cases, [with] no improvement in overall survival compared to older series,” Dr Federico summarized. “Treatment remains challenging, and new therapies are welcome.”
He added that the next steps for the T-Cell Project are to continue registration (with the goal of reaching 2000 assessable cases), extend the network to additional sites (particularly in under-represented areas such as Japan, China, India, and Oceania), and expand the collection of tissue.
“In particular, we intend to create an international tissue catalogue—including paraffin-embedded samples and, if possible, frozen ones—accessible to research groups with a solid reputation in investigating PTCLs at the molecular and translation level.”
Distribution of PTCL subtypes varies by race/ethnicity
SAN FRANCISCO—The distribution of peripheral T-cell lymphoma (PTCL) subtypes in the US varies greatly according to race and ethnicity, new research suggests.
The retrospective study showed that the overall incidence of PTCL and its subtypes is lower in American Indians and Alaskan Natives than in other ethnic groups.
And the black population has a significantly higher incidence of PTCL—and the most common subtype, PTCL-not otherwise specified (NOS)—than other populations.
Andrei Shustov, MD, of the University of Washington Medical Center in Seattle, presented these and other findings at the 7th Annual T-cell Lymphoma Forum.
The findings were derived from data collected by the Surveillance, Epidemiology, and End Results (SEER) Cancer Registries, which cover 28% of the US population. The data included patients older than 15 years of age who were treated at 18 centers from 2000 through 2011.
Of all cancer patients registered over the 12-year period, 60% were non-Hispanic whites (n=470,864,199), 17% were Hispanic whites (n=134,464,006), 12% were black (n=92,294,395), 10% were Asian/Pacific Islanders (n=74,973,831), and 1% were American Indian/Alaskan Natives (n=10,802,898).
The overall incidence of PTCL was highest in blacks—2.11 per 100,000 persons per year, compared to 1.63 in non-Hispanic whites, 1.53 in Hispanic whites, 1.46 in Asian/Pacific Islanders, and 0.97 in American Indian/Alaskan Natives.
Although American Indian/Alaskan Natives appear to have the lowest overall rate of PTCLs, some cases may have been misclassified, Dr Shustov noted.
“The data collected for ethnicity in the SEER registry are self-reported, and a lot of American Indian/Alaskan Natives misreport their ethnic background,” he said.
Subtype analyses
PTCL-NOS was the most common subtype among all the racial/ethnic groups. The highest rate of PTCL-NOS (per 100,000 persons per year) was in blacks—at 0.77, compared to 0.47 in non-Hispanic whites, 0.46 in Hispanic whites, 0.45 in Asian/Pacific Islanders, and 0.28 in American Indian/Alaskan Natives.
The proportion of PTCL-NOS cases was 29.5% in non-Hispanic whites, 35.7% in blacks, 29.8% in Asian/Pacific Islanders, 27% in Hispanic whites, and 23.1% in American Indian/Alaskan Natives.
The proportion of angioimmunoblastic T-cell lymphoma cases was 9.9% in non-Hispanic whites, 5.2% in blacks, 15.3% in Asian/Pacific Islanders, 9.9% in Hispanic whites, and 2.6% in American Indian/Alaskan Natives.
The proportion of anaplastic large-cell lymphoma cases was 17.6% in non-Hispanic whites, 17.3% in blacks, 12.4% in Asian/Pacific Islanders, 21.2% in Hispanic whites, and 28.2% in American Indian/Alaskan Natives.
And the proportion of NK/T-cell lymphoma cases was 3.4% in non-Hispanic whites, 2.0% in blacks, 13.9% in Asian/Pacific Islanders, 14.6% in Hispanic whites, and 14.1% in American Indian/Alaskan Natives.
“That data indicates that, given the overall incidence of T-cell lymphoma in Natives is lower than in whites, if you’re a Native American/Alaskan Native [with] T-cell lymphoma, you’re 4 times more likely to have nasal NK-cell lymphoma than non-Hispanic whites,” Dr Shustov said.
He then showed a pairwise comparison of the percentage of PTCL subtypes. All of the racial/ethnic groups were significantly different from one another (P<0.001), except when Hispanic whites were compared to American Indian/Alaskan Natives (P=0.14).
Dr Shustov said this might be explained by the fact that these two groups have similar genetic backgrounds.
SAN FRANCISCO—The distribution of peripheral T-cell lymphoma (PTCL) subtypes in the US varies greatly according to race and ethnicity, new research suggests.
The retrospective study showed that the overall incidence of PTCL and its subtypes is lower in American Indians and Alaskan Natives than in other ethnic groups.
And the black population has a significantly higher incidence of PTCL—and the most common subtype, PTCL-not otherwise specified (NOS)—than other populations.
Andrei Shustov, MD, of the University of Washington Medical Center in Seattle, presented these and other findings at the 7th Annual T-cell Lymphoma Forum.
The findings were derived from data collected by the Surveillance, Epidemiology, and End Results (SEER) Cancer Registries, which cover 28% of the US population. The data included patients older than 15 years of age who were treated at 18 centers from 2000 through 2011.
Of all cancer patients registered over the 12-year period, 60% were non-Hispanic whites (n=470,864,199), 17% were Hispanic whites (n=134,464,006), 12% were black (n=92,294,395), 10% were Asian/Pacific Islanders (n=74,973,831), and 1% were American Indian/Alaskan Natives (n=10,802,898).
The overall incidence of PTCL was highest in blacks—2.11 per 100,000 persons per year, compared to 1.63 in non-Hispanic whites, 1.53 in Hispanic whites, 1.46 in Asian/Pacific Islanders, and 0.97 in American Indian/Alaskan Natives.
Although American Indian/Alaskan Natives appear to have the lowest overall rate of PTCLs, some cases may have been misclassified, Dr Shustov noted.
“The data collected for ethnicity in the SEER registry are self-reported, and a lot of American Indian/Alaskan Natives misreport their ethnic background,” he said.
Subtype analyses
PTCL-NOS was the most common subtype among all the racial/ethnic groups. The highest rate of PTCL-NOS (per 100,000 persons per year) was in blacks—at 0.77, compared to 0.47 in non-Hispanic whites, 0.46 in Hispanic whites, 0.45 in Asian/Pacific Islanders, and 0.28 in American Indian/Alaskan Natives.
The proportion of PTCL-NOS cases was 29.5% in non-Hispanic whites, 35.7% in blacks, 29.8% in Asian/Pacific Islanders, 27% in Hispanic whites, and 23.1% in American Indian/Alaskan Natives.
The proportion of angioimmunoblastic T-cell lymphoma cases was 9.9% in non-Hispanic whites, 5.2% in blacks, 15.3% in Asian/Pacific Islanders, 9.9% in Hispanic whites, and 2.6% in American Indian/Alaskan Natives.
The proportion of anaplastic large-cell lymphoma cases was 17.6% in non-Hispanic whites, 17.3% in blacks, 12.4% in Asian/Pacific Islanders, 21.2% in Hispanic whites, and 28.2% in American Indian/Alaskan Natives.
And the proportion of NK/T-cell lymphoma cases was 3.4% in non-Hispanic whites, 2.0% in blacks, 13.9% in Asian/Pacific Islanders, 14.6% in Hispanic whites, and 14.1% in American Indian/Alaskan Natives.
“That data indicates that, given the overall incidence of T-cell lymphoma in Natives is lower than in whites, if you’re a Native American/Alaskan Native [with] T-cell lymphoma, you’re 4 times more likely to have nasal NK-cell lymphoma than non-Hispanic whites,” Dr Shustov said.
He then showed a pairwise comparison of the percentage of PTCL subtypes. All of the racial/ethnic groups were significantly different from one another (P<0.001), except when Hispanic whites were compared to American Indian/Alaskan Natives (P=0.14).
Dr Shustov said this might be explained by the fact that these two groups have similar genetic backgrounds.
SAN FRANCISCO—The distribution of peripheral T-cell lymphoma (PTCL) subtypes in the US varies greatly according to race and ethnicity, new research suggests.
The retrospective study showed that the overall incidence of PTCL and its subtypes is lower in American Indians and Alaskan Natives than in other ethnic groups.
And the black population has a significantly higher incidence of PTCL—and the most common subtype, PTCL-not otherwise specified (NOS)—than other populations.
Andrei Shustov, MD, of the University of Washington Medical Center in Seattle, presented these and other findings at the 7th Annual T-cell Lymphoma Forum.
The findings were derived from data collected by the Surveillance, Epidemiology, and End Results (SEER) Cancer Registries, which cover 28% of the US population. The data included patients older than 15 years of age who were treated at 18 centers from 2000 through 2011.
Of all cancer patients registered over the 12-year period, 60% were non-Hispanic whites (n=470,864,199), 17% were Hispanic whites (n=134,464,006), 12% were black (n=92,294,395), 10% were Asian/Pacific Islanders (n=74,973,831), and 1% were American Indian/Alaskan Natives (n=10,802,898).
The overall incidence of PTCL was highest in blacks—2.11 per 100,000 persons per year, compared to 1.63 in non-Hispanic whites, 1.53 in Hispanic whites, 1.46 in Asian/Pacific Islanders, and 0.97 in American Indian/Alaskan Natives.
Although American Indian/Alaskan Natives appear to have the lowest overall rate of PTCLs, some cases may have been misclassified, Dr Shustov noted.
“The data collected for ethnicity in the SEER registry are self-reported, and a lot of American Indian/Alaskan Natives misreport their ethnic background,” he said.
Subtype analyses
PTCL-NOS was the most common subtype among all the racial/ethnic groups. The highest rate of PTCL-NOS (per 100,000 persons per year) was in blacks—at 0.77, compared to 0.47 in non-Hispanic whites, 0.46 in Hispanic whites, 0.45 in Asian/Pacific Islanders, and 0.28 in American Indian/Alaskan Natives.
The proportion of PTCL-NOS cases was 29.5% in non-Hispanic whites, 35.7% in blacks, 29.8% in Asian/Pacific Islanders, 27% in Hispanic whites, and 23.1% in American Indian/Alaskan Natives.
The proportion of angioimmunoblastic T-cell lymphoma cases was 9.9% in non-Hispanic whites, 5.2% in blacks, 15.3% in Asian/Pacific Islanders, 9.9% in Hispanic whites, and 2.6% in American Indian/Alaskan Natives.
The proportion of anaplastic large-cell lymphoma cases was 17.6% in non-Hispanic whites, 17.3% in blacks, 12.4% in Asian/Pacific Islanders, 21.2% in Hispanic whites, and 28.2% in American Indian/Alaskan Natives.
And the proportion of NK/T-cell lymphoma cases was 3.4% in non-Hispanic whites, 2.0% in blacks, 13.9% in Asian/Pacific Islanders, 14.6% in Hispanic whites, and 14.1% in American Indian/Alaskan Natives.
“That data indicates that, given the overall incidence of T-cell lymphoma in Natives is lower than in whites, if you’re a Native American/Alaskan Native [with] T-cell lymphoma, you’re 4 times more likely to have nasal NK-cell lymphoma than non-Hispanic whites,” Dr Shustov said.
He then showed a pairwise comparison of the percentage of PTCL subtypes. All of the racial/ethnic groups were significantly different from one another (P<0.001), except when Hispanic whites were compared to American Indian/Alaskan Natives (P=0.14).
Dr Shustov said this might be explained by the fact that these two groups have similar genetic backgrounds.
New test could improve warfarin monitoring
SAN FRANCISCO—Monitoring warfarin using a modified prothrombin time (PT) test can improve anticoagulation stability and long-term clinical outcomes, result of the Fiix trial suggest.
With Fiix-PT—a test that only measures the activity of coagulation factors II and X—the effect of warfarin fluctuated less than with standard PT.
Fiix-PT also proved superior in reducing long-term, recurrent thromboembolism (TE), and it did not increase bleeding, despite the fact that the test omits factor VII activity.
However, most of these effects occurred only after the 6-month mark.
Pall T. Onundarson, MD, of Landspitali University Hospital and University of Iceland School of Medicine in Reykjavik, presented these results at the 2014 ASH Annual Meeting (abstract 347).
Dr Onundarson is a co-inventor of the Fiix-PT test and has stock in Fiix Diagnostics, a startup company with the two inventors of the test as majority shareholders.
“Why would anyone still be interested in warfarin in 2014,” Dr Onundarson asked the audience at ASH. “Even if warfarin is very efficacious . . ., managing warfarin is trouble. The dose varies between patients, and the main problem is that we have a fluctuating or unstable effect—namely, a fluctuating INR—and this leads to frequent dose adjustments and frequent testing.”
Dr Onundarson said the common wisdom is that the effect of warfarin fluctuates due to food interactions and drug interactions. But he and his colleagues speculated that the fluctuation is partly caused by conventional PT.
They noted that experiments have suggested the anticoagulation effect of warfarin is mainly influenced by a reduction in FII and FX activity, and FVII may have relatively little effect. Due to the short half-life of FVII and its strong influence on the PT, monitoring warfarin using PT may confound dosing.
With that in mind, the Fiix-PT test was designed to measure only the activity of FII and FX. And the researchers conducted the Fiix trial to compare Fiix-PT and conventional PT.
Their study included 1148 patients—573 in the Fiix-PT arm and 575 in the PT arm. Overall, about 69% of patients had atrial fibrillation, and 21% had venous thromboembolism. The median monitoring time was 1.7 years per patient in both arms.
The researchers noted that most outcomes were not significantly different between the 2 arms in the first 6 months, but, after that point, things changed. So they examined outcomes after 6 months in a secondary analysis.
From day 1 to 180, there was no significant difference between the Fiix-PT arm and the PT arm in the number of dose changes per patient year (5.3 and 6.5, respectively, P=0.08). However, from day 181 to 720, there were significantly fewer dose changes in the Fiix-PT arm (4.1 and 5.0, respectively, P=0.01).
The researchers assessed the median time within target range (TTR) during 4 periods of the study, and, although results fluctuated, there were significant differences in favor of Fiix-PT.
The median TTR was 85% in the Fiix-PT arm and 81% in the PT arm for days 1 to 180 (P=0.013); 85% and 90%, respectively, for days 181 to 360 (P<0.0003); 80% and 81%, respectively, for days 361 to 540 (P=0.34); and 87% and 79%, respectively, for days 541 to 720 (P<0.005).
Overall, there was no significant difference in the rate of TE or major bleeding between the Fiix-PT and PT arms. However, when the researchers excluded the first 6 months of observation, they noted a significant difference in the rate of TE in favor of Fiix-PT.
In the primary analysis (encompassing days 1 to 720), the TE rate per patient year was 1.2% in the Fiix-PT arm and 2.3% in the PT arm (P=0.09 for superiority, P<0.001 for non-inferiority). The major bleeding rates were 2.2% and 2.5%, respectively (P=0.8 for superiority, P<0.001 for non-inferiority).
In the secondary analysis (from day 181 to 720), Fiix-PT led to a superior long-term reduction in TE compared to conventional PT—1.1% and 2.2%, respectively (P=0.03 for superiority). But there was no significant difference in the rates of major bleeding—1.5% and 2.3%, respectively (P=0.5 for superiority).
“Compared to high-quality PT-INR monitoring, Fiix-PT increased the stability of warfarin anticoagulation,” Dr Onundarson said in closing. “Fiix-PT was clinically at least non-inferior to the INR in the primary analysis, and Fiix-PT led to superior long-term reduction in TE in the secondary analysis. Fiix-PT did not increase major bleeding, despite lowering the long-term thromboembolic rate and despite not being affected by FVII in the test sample.”
“So my overall conclusion is that a fluctuating INR during warfarin treatment is partly a confounding side effect of the PT itself. The data suggests that, if the PT is replaced with a monitoring test that is not affected by FVII, warfarin may become more stable than was previously assumed.”
SAN FRANCISCO—Monitoring warfarin using a modified prothrombin time (PT) test can improve anticoagulation stability and long-term clinical outcomes, result of the Fiix trial suggest.
With Fiix-PT—a test that only measures the activity of coagulation factors II and X—the effect of warfarin fluctuated less than with standard PT.
Fiix-PT also proved superior in reducing long-term, recurrent thromboembolism (TE), and it did not increase bleeding, despite the fact that the test omits factor VII activity.
However, most of these effects occurred only after the 6-month mark.
Pall T. Onundarson, MD, of Landspitali University Hospital and University of Iceland School of Medicine in Reykjavik, presented these results at the 2014 ASH Annual Meeting (abstract 347).
Dr Onundarson is a co-inventor of the Fiix-PT test and has stock in Fiix Diagnostics, a startup company with the two inventors of the test as majority shareholders.
“Why would anyone still be interested in warfarin in 2014,” Dr Onundarson asked the audience at ASH. “Even if warfarin is very efficacious . . ., managing warfarin is trouble. The dose varies between patients, and the main problem is that we have a fluctuating or unstable effect—namely, a fluctuating INR—and this leads to frequent dose adjustments and frequent testing.”
Dr Onundarson said the common wisdom is that the effect of warfarin fluctuates due to food interactions and drug interactions. But he and his colleagues speculated that the fluctuation is partly caused by conventional PT.
They noted that experiments have suggested the anticoagulation effect of warfarin is mainly influenced by a reduction in FII and FX activity, and FVII may have relatively little effect. Due to the short half-life of FVII and its strong influence on the PT, monitoring warfarin using PT may confound dosing.
With that in mind, the Fiix-PT test was designed to measure only the activity of FII and FX. And the researchers conducted the Fiix trial to compare Fiix-PT and conventional PT.
Their study included 1148 patients—573 in the Fiix-PT arm and 575 in the PT arm. Overall, about 69% of patients had atrial fibrillation, and 21% had venous thromboembolism. The median monitoring time was 1.7 years per patient in both arms.
The researchers noted that most outcomes were not significantly different between the 2 arms in the first 6 months, but, after that point, things changed. So they examined outcomes after 6 months in a secondary analysis.
From day 1 to 180, there was no significant difference between the Fiix-PT arm and the PT arm in the number of dose changes per patient year (5.3 and 6.5, respectively, P=0.08). However, from day 181 to 720, there were significantly fewer dose changes in the Fiix-PT arm (4.1 and 5.0, respectively, P=0.01).
The researchers assessed the median time within target range (TTR) during 4 periods of the study, and, although results fluctuated, there were significant differences in favor of Fiix-PT.
The median TTR was 85% in the Fiix-PT arm and 81% in the PT arm for days 1 to 180 (P=0.013); 85% and 90%, respectively, for days 181 to 360 (P<0.0003); 80% and 81%, respectively, for days 361 to 540 (P=0.34); and 87% and 79%, respectively, for days 541 to 720 (P<0.005).
Overall, there was no significant difference in the rate of TE or major bleeding between the Fiix-PT and PT arms. However, when the researchers excluded the first 6 months of observation, they noted a significant difference in the rate of TE in favor of Fiix-PT.
In the primary analysis (encompassing days 1 to 720), the TE rate per patient year was 1.2% in the Fiix-PT arm and 2.3% in the PT arm (P=0.09 for superiority, P<0.001 for non-inferiority). The major bleeding rates were 2.2% and 2.5%, respectively (P=0.8 for superiority, P<0.001 for non-inferiority).
In the secondary analysis (from day 181 to 720), Fiix-PT led to a superior long-term reduction in TE compared to conventional PT—1.1% and 2.2%, respectively (P=0.03 for superiority). But there was no significant difference in the rates of major bleeding—1.5% and 2.3%, respectively (P=0.5 for superiority).
“Compared to high-quality PT-INR monitoring, Fiix-PT increased the stability of warfarin anticoagulation,” Dr Onundarson said in closing. “Fiix-PT was clinically at least non-inferior to the INR in the primary analysis, and Fiix-PT led to superior long-term reduction in TE in the secondary analysis. Fiix-PT did not increase major bleeding, despite lowering the long-term thromboembolic rate and despite not being affected by FVII in the test sample.”
“So my overall conclusion is that a fluctuating INR during warfarin treatment is partly a confounding side effect of the PT itself. The data suggests that, if the PT is replaced with a monitoring test that is not affected by FVII, warfarin may become more stable than was previously assumed.”
SAN FRANCISCO—Monitoring warfarin using a modified prothrombin time (PT) test can improve anticoagulation stability and long-term clinical outcomes, result of the Fiix trial suggest.
With Fiix-PT—a test that only measures the activity of coagulation factors II and X—the effect of warfarin fluctuated less than with standard PT.
Fiix-PT also proved superior in reducing long-term, recurrent thromboembolism (TE), and it did not increase bleeding, despite the fact that the test omits factor VII activity.
However, most of these effects occurred only after the 6-month mark.
Pall T. Onundarson, MD, of Landspitali University Hospital and University of Iceland School of Medicine in Reykjavik, presented these results at the 2014 ASH Annual Meeting (abstract 347).
Dr Onundarson is a co-inventor of the Fiix-PT test and has stock in Fiix Diagnostics, a startup company with the two inventors of the test as majority shareholders.
“Why would anyone still be interested in warfarin in 2014,” Dr Onundarson asked the audience at ASH. “Even if warfarin is very efficacious . . ., managing warfarin is trouble. The dose varies between patients, and the main problem is that we have a fluctuating or unstable effect—namely, a fluctuating INR—and this leads to frequent dose adjustments and frequent testing.”
Dr Onundarson said the common wisdom is that the effect of warfarin fluctuates due to food interactions and drug interactions. But he and his colleagues speculated that the fluctuation is partly caused by conventional PT.
They noted that experiments have suggested the anticoagulation effect of warfarin is mainly influenced by a reduction in FII and FX activity, and FVII may have relatively little effect. Due to the short half-life of FVII and its strong influence on the PT, monitoring warfarin using PT may confound dosing.
With that in mind, the Fiix-PT test was designed to measure only the activity of FII and FX. And the researchers conducted the Fiix trial to compare Fiix-PT and conventional PT.
Their study included 1148 patients—573 in the Fiix-PT arm and 575 in the PT arm. Overall, about 69% of patients had atrial fibrillation, and 21% had venous thromboembolism. The median monitoring time was 1.7 years per patient in both arms.
The researchers noted that most outcomes were not significantly different between the 2 arms in the first 6 months, but, after that point, things changed. So they examined outcomes after 6 months in a secondary analysis.
From day 1 to 180, there was no significant difference between the Fiix-PT arm and the PT arm in the number of dose changes per patient year (5.3 and 6.5, respectively, P=0.08). However, from day 181 to 720, there were significantly fewer dose changes in the Fiix-PT arm (4.1 and 5.0, respectively, P=0.01).
The researchers assessed the median time within target range (TTR) during 4 periods of the study, and, although results fluctuated, there were significant differences in favor of Fiix-PT.
The median TTR was 85% in the Fiix-PT arm and 81% in the PT arm for days 1 to 180 (P=0.013); 85% and 90%, respectively, for days 181 to 360 (P<0.0003); 80% and 81%, respectively, for days 361 to 540 (P=0.34); and 87% and 79%, respectively, for days 541 to 720 (P<0.005).
Overall, there was no significant difference in the rate of TE or major bleeding between the Fiix-PT and PT arms. However, when the researchers excluded the first 6 months of observation, they noted a significant difference in the rate of TE in favor of Fiix-PT.
In the primary analysis (encompassing days 1 to 720), the TE rate per patient year was 1.2% in the Fiix-PT arm and 2.3% in the PT arm (P=0.09 for superiority, P<0.001 for non-inferiority). The major bleeding rates were 2.2% and 2.5%, respectively (P=0.8 for superiority, P<0.001 for non-inferiority).
In the secondary analysis (from day 181 to 720), Fiix-PT led to a superior long-term reduction in TE compared to conventional PT—1.1% and 2.2%, respectively (P=0.03 for superiority). But there was no significant difference in the rates of major bleeding—1.5% and 2.3%, respectively (P=0.5 for superiority).
“Compared to high-quality PT-INR monitoring, Fiix-PT increased the stability of warfarin anticoagulation,” Dr Onundarson said in closing. “Fiix-PT was clinically at least non-inferior to the INR in the primary analysis, and Fiix-PT led to superior long-term reduction in TE in the secondary analysis. Fiix-PT did not increase major bleeding, despite lowering the long-term thromboembolic rate and despite not being affected by FVII in the test sample.”
“So my overall conclusion is that a fluctuating INR during warfarin treatment is partly a confounding side effect of the PT itself. The data suggests that, if the PT is replaced with a monitoring test that is not affected by FVII, warfarin may become more stable than was previously assumed.”
Drug reverses dabigatran’s effects in elderly/impaired
Credit: CDC
SAN FRANCISCO—An investigational, humanized antibody fragment known as idarucizumab can reverse the anticoagulation effects of dabigatran, new research suggests.
In a small study, idarucizumab led to sustained reversal of dabigatran’s effects in healthy subjects, elderly volunteers, and participants with mild to moderate renal impairment.
Furthermore, dabigatran anticoagulation could be re-established 24 hours after the subjects had received idarucizumab.
Joachim Stangier, PhD, of Boehringer Ingelheim Pharma GmbH & Co KG in Biberach, Germany, presented these results at the 2014 ASH Annual Meeting as abstract 344*. Boehringer Ingelheim is the company developing idarucizumab.
Dr Stangier said idarucizumab binds dabigatran with high affinity, off-target binding is not expected, and no procoagulant effects have been observed with the drug.
In a previous study of healthy volunteers, idarucizumab provided immediate, complete, and sustained reversal of dabigatran’s anticoagulant effect. The effect was sustained when idarucizumab was given at 2 g and 4 g doses.
For the current study, Dr Stangier and his colleagues wanted to evaluate whether and to what extent doses of up to 5 g of idarucizumab would reverse the anticoagulant effects of dabigatran in healthy subjects, elderly participants, and renally impaired volunteers. The team also wanted to determine the effects of dabigatran given after subjects had received idarucizumab.
The study included 46 male and female subjects who were 45 to 80 years of age. Healthy subjects received dabigatran etexilate at 220 mg twice daily, and subjects with mild to moderate renal impairment received 150 mg twice daily, both over 4 days.
Subjects then received idarucizumab at 1 g, 2.5 g, 5 g, or 5 g given as 2 x 2.5 g 1 hour apart. They received these doses as 5-minute intravenous infusions 2 hours after their last dose of dabigatran.
The researchers found that dabigatran-prolonged clotting times—thrombin time, diluted thrombin time, ecarin clotting time, and activated partial thromboplastin time—were reversed to baseline immediately after the end of idarucizumab infusion.
And the team observed sustained reversal of dabigatran’s anticoagulant effects in all subjects.
The researchers then readministered dabigatran to healthy subjects 24 hours after idarucizumab treatment and to subjects who received placebo instead of idarucizumab.
Dabigatran-mediated anticoagulation was similar in subjects who received idarucizumab and those who received placebo. And anticoagulation was restored to levels comparable to initial levels.
Dr Stangier said there were no clinically relevant adverse events (AEs) related to idarucizumab, and there were no relevant changes in any of the investigated safety parameters. There were no AEs indicative of immunogenic reactions.
AEs and local tolerability reactions were similar for placebo and idarucizumab. And there was no relationship between the frequency of AEs and drug dose, gender, or renal function.
The researchers did observe a dose-dependent, transient increase in urine protein and low-weight proteins, but values returned to the normal range within 4 hours to 24 hours.
Based on these results, Dr Stangier said idarucizumab fulfills the requirements for a fast-acting and specific antidote to dabigatran with a favorable safety profile. Additional clinical testing of the antidote is ongoing.
*Information in the abstract differs from that presented.
Credit: CDC
SAN FRANCISCO—An investigational, humanized antibody fragment known as idarucizumab can reverse the anticoagulation effects of dabigatran, new research suggests.
In a small study, idarucizumab led to sustained reversal of dabigatran’s effects in healthy subjects, elderly volunteers, and participants with mild to moderate renal impairment.
Furthermore, dabigatran anticoagulation could be re-established 24 hours after the subjects had received idarucizumab.
Joachim Stangier, PhD, of Boehringer Ingelheim Pharma GmbH & Co KG in Biberach, Germany, presented these results at the 2014 ASH Annual Meeting as abstract 344*. Boehringer Ingelheim is the company developing idarucizumab.
Dr Stangier said idarucizumab binds dabigatran with high affinity, off-target binding is not expected, and no procoagulant effects have been observed with the drug.
In a previous study of healthy volunteers, idarucizumab provided immediate, complete, and sustained reversal of dabigatran’s anticoagulant effect. The effect was sustained when idarucizumab was given at 2 g and 4 g doses.
For the current study, Dr Stangier and his colleagues wanted to evaluate whether and to what extent doses of up to 5 g of idarucizumab would reverse the anticoagulant effects of dabigatran in healthy subjects, elderly participants, and renally impaired volunteers. The team also wanted to determine the effects of dabigatran given after subjects had received idarucizumab.
The study included 46 male and female subjects who were 45 to 80 years of age. Healthy subjects received dabigatran etexilate at 220 mg twice daily, and subjects with mild to moderate renal impairment received 150 mg twice daily, both over 4 days.
Subjects then received idarucizumab at 1 g, 2.5 g, 5 g, or 5 g given as 2 x 2.5 g 1 hour apart. They received these doses as 5-minute intravenous infusions 2 hours after their last dose of dabigatran.
The researchers found that dabigatran-prolonged clotting times—thrombin time, diluted thrombin time, ecarin clotting time, and activated partial thromboplastin time—were reversed to baseline immediately after the end of idarucizumab infusion.
And the team observed sustained reversal of dabigatran’s anticoagulant effects in all subjects.
The researchers then readministered dabigatran to healthy subjects 24 hours after idarucizumab treatment and to subjects who received placebo instead of idarucizumab.
Dabigatran-mediated anticoagulation was similar in subjects who received idarucizumab and those who received placebo. And anticoagulation was restored to levels comparable to initial levels.
Dr Stangier said there were no clinically relevant adverse events (AEs) related to idarucizumab, and there were no relevant changes in any of the investigated safety parameters. There were no AEs indicative of immunogenic reactions.
AEs and local tolerability reactions were similar for placebo and idarucizumab. And there was no relationship between the frequency of AEs and drug dose, gender, or renal function.
The researchers did observe a dose-dependent, transient increase in urine protein and low-weight proteins, but values returned to the normal range within 4 hours to 24 hours.
Based on these results, Dr Stangier said idarucizumab fulfills the requirements for a fast-acting and specific antidote to dabigatran with a favorable safety profile. Additional clinical testing of the antidote is ongoing.
*Information in the abstract differs from that presented.
Credit: CDC
SAN FRANCISCO—An investigational, humanized antibody fragment known as idarucizumab can reverse the anticoagulation effects of dabigatran, new research suggests.
In a small study, idarucizumab led to sustained reversal of dabigatran’s effects in healthy subjects, elderly volunteers, and participants with mild to moderate renal impairment.
Furthermore, dabigatran anticoagulation could be re-established 24 hours after the subjects had received idarucizumab.
Joachim Stangier, PhD, of Boehringer Ingelheim Pharma GmbH & Co KG in Biberach, Germany, presented these results at the 2014 ASH Annual Meeting as abstract 344*. Boehringer Ingelheim is the company developing idarucizumab.
Dr Stangier said idarucizumab binds dabigatran with high affinity, off-target binding is not expected, and no procoagulant effects have been observed with the drug.
In a previous study of healthy volunteers, idarucizumab provided immediate, complete, and sustained reversal of dabigatran’s anticoagulant effect. The effect was sustained when idarucizumab was given at 2 g and 4 g doses.
For the current study, Dr Stangier and his colleagues wanted to evaluate whether and to what extent doses of up to 5 g of idarucizumab would reverse the anticoagulant effects of dabigatran in healthy subjects, elderly participants, and renally impaired volunteers. The team also wanted to determine the effects of dabigatran given after subjects had received idarucizumab.
The study included 46 male and female subjects who were 45 to 80 years of age. Healthy subjects received dabigatran etexilate at 220 mg twice daily, and subjects with mild to moderate renal impairment received 150 mg twice daily, both over 4 days.
Subjects then received idarucizumab at 1 g, 2.5 g, 5 g, or 5 g given as 2 x 2.5 g 1 hour apart. They received these doses as 5-minute intravenous infusions 2 hours after their last dose of dabigatran.
The researchers found that dabigatran-prolonged clotting times—thrombin time, diluted thrombin time, ecarin clotting time, and activated partial thromboplastin time—were reversed to baseline immediately after the end of idarucizumab infusion.
And the team observed sustained reversal of dabigatran’s anticoagulant effects in all subjects.
The researchers then readministered dabigatran to healthy subjects 24 hours after idarucizumab treatment and to subjects who received placebo instead of idarucizumab.
Dabigatran-mediated anticoagulation was similar in subjects who received idarucizumab and those who received placebo. And anticoagulation was restored to levels comparable to initial levels.
Dr Stangier said there were no clinically relevant adverse events (AEs) related to idarucizumab, and there were no relevant changes in any of the investigated safety parameters. There were no AEs indicative of immunogenic reactions.
AEs and local tolerability reactions were similar for placebo and idarucizumab. And there was no relationship between the frequency of AEs and drug dose, gender, or renal function.
The researchers did observe a dose-dependent, transient increase in urine protein and low-weight proteins, but values returned to the normal range within 4 hours to 24 hours.
Based on these results, Dr Stangier said idarucizumab fulfills the requirements for a fast-acting and specific antidote to dabigatran with a favorable safety profile. Additional clinical testing of the antidote is ongoing.
*Information in the abstract differs from that presented.
HIV doesn’t hinder lymphoma patients’ response to ASCT
a cultured lymphocyte
Credit: CDC
SAN FRANCISCO—Patients with HIV-related lymphoma (HRL) should not be excluded from clinical trials of autologous stem cell transplant (ASCT) due to their HIV status, new research suggests.
Investigators found no significant difference in rates of treatment failure, disease progression, or survival between transplant-treated historical controls who had lymphoma but not HIV and patients with HRL who received the modified BEAM regimen followed by ASCT on a phase 2 trial.
This suggests patients with chemotherapy-sensitive, relapsed/refractory HRL can be treated successfully with the modified BEAM regimen, said study investigator Joseph Alvarnas, MD, of City of Hope National Medical Center in Duarte, California.
“Patients with treatment-responsive HIV infection and HIV-related lymphoma should be considered candidates for autologous transplant if they meet standard transplant criteria,” he added. “And we would argue that exclusion from clinical trials on the basis of HIV infection alone is no longer justified.”
Dr Alvarnas presented this viewpoint and the research to support it at the 2014 ASH Annual Meeting as abstract 674.
The trial enrolled 43 patients with treatable HIV-1 infection, adequate organ function, and aggressive lymphoma. Three patients were excluded because they could not undergo transplant due to lymphoma progression.
Of the 40 remaining patients, 5 were female, and their median age was 46.9 years (range, 22.5-62.2). They had diffuse large B-cell lymphoma (n=16), plasmablastic lymphoma (n=2), Burkitt/Burkitt-like lymphoma (n=7), and Hodgkin lymphoma (n=15).
The pre-ASCT HIV viral load was undetectable in 31 patients. In the patients with detectable HIV, the median viral load pre-ASCT was 84 copies/μL (range, 50-17,455). The median CD4 count was 250.5/µL (range, 39-797).
Before transplant, 30 patients (75%) were in complete remission, 8 (20%) were in partial remission, and 2 (5%) had relapsed/progressive disease.
The patients underwent ASCT after conditioning with the modified BEAM regimen—carmustine at 300 mg/m2 (day -6), etoposide at 100 mg/m2 twice daily (days -5 to -2), cytarabine at 100 mg/m2 (days -5 to -2), and melphalan at 140 mg/m2 (day -1).
Combination antiretroviral therapy (cART) was held during the preparative regimen and resumed after the resolution of gastrointestinal toxicity. The investigators switched efavirenz to an alternative agent 2 or more weeks prior to the planned interruption of cART, as the drug has a long half-life. And AZT was prohibited due to its myelosuppressive effects.
Treatment results
The median follow-up was 24 months. At 100 days post-transplant, the investigators assessed 39 patients for response. One patient was not evaluable due to early death.
Thirty-six of the patients (92.3%) were in complete remission, 1 (2.6%) was in partial remission, and 2 (5.1%) had relapsed or progressive disease.
Fifteen patients reported grade 3 or higher toxicities within a year of transplant. Of the 13 unexpected grade 3-5 adverse events (reported in 9 patients), 5 were infection/sepsis, 1 was acute appendicitis, 1 was acute coronary syndrome, 2 were deep vein thromboses, 2 were gastrointestinal toxicities, and 2 were metabolic abnormalities.
Seventeen patients reported at least 1 infectious episode, 42 events in total, 9 of which were severe. Fourteen patients required readmission to the hospital after transplant.
Within a year of transplant, 5 patients had died—3 from recurrent/persistent disease, 1 due to a fungal infection, and 1 from cardiac arrest. Two additional patients died after the 1-year mark—1 of recurrent/persistent disease and 1 of heart failure.
At 12 months, the rate of overall survival was 86.6%, progression-free survival was 82.3%, progression was 12.5%, and non-relapse mortality was 5.2%.
“In order to place this within context, we had the opportunity to compare our patient experience with 151 matched controls [without HIV] from CIBMTR,” Dr Alvarnas said. “Ninety-three percent of these patients were actually transplanted within 2 years so that they were the time-concordant group, and they were matched for performance score, disease, and disease stage.”
The investigators found no significant difference between their patient group and the HIV-free controls with regard to overall mortality (P=0.56), treatment failure (P=0.10), progression (P=0.06), and treatment-related mortality (P=0.97).
Likewise, there was no significant difference in overall survival between the HRL patients and controls—86.6% and 87.7%, respectively (P=0.56). And the same was true of progression-free survival—82.3% and 69.5%, respectively (P=0.10).
a cultured lymphocyte
Credit: CDC
SAN FRANCISCO—Patients with HIV-related lymphoma (HRL) should not be excluded from clinical trials of autologous stem cell transplant (ASCT) due to their HIV status, new research suggests.
Investigators found no significant difference in rates of treatment failure, disease progression, or survival between transplant-treated historical controls who had lymphoma but not HIV and patients with HRL who received the modified BEAM regimen followed by ASCT on a phase 2 trial.
This suggests patients with chemotherapy-sensitive, relapsed/refractory HRL can be treated successfully with the modified BEAM regimen, said study investigator Joseph Alvarnas, MD, of City of Hope National Medical Center in Duarte, California.
“Patients with treatment-responsive HIV infection and HIV-related lymphoma should be considered candidates for autologous transplant if they meet standard transplant criteria,” he added. “And we would argue that exclusion from clinical trials on the basis of HIV infection alone is no longer justified.”
Dr Alvarnas presented this viewpoint and the research to support it at the 2014 ASH Annual Meeting as abstract 674.
The trial enrolled 43 patients with treatable HIV-1 infection, adequate organ function, and aggressive lymphoma. Three patients were excluded because they could not undergo transplant due to lymphoma progression.
Of the 40 remaining patients, 5 were female, and their median age was 46.9 years (range, 22.5-62.2). They had diffuse large B-cell lymphoma (n=16), plasmablastic lymphoma (n=2), Burkitt/Burkitt-like lymphoma (n=7), and Hodgkin lymphoma (n=15).
The pre-ASCT HIV viral load was undetectable in 31 patients. In the patients with detectable HIV, the median viral load pre-ASCT was 84 copies/μL (range, 50-17,455). The median CD4 count was 250.5/µL (range, 39-797).
Before transplant, 30 patients (75%) were in complete remission, 8 (20%) were in partial remission, and 2 (5%) had relapsed/progressive disease.
The patients underwent ASCT after conditioning with the modified BEAM regimen—carmustine at 300 mg/m2 (day -6), etoposide at 100 mg/m2 twice daily (days -5 to -2), cytarabine at 100 mg/m2 (days -5 to -2), and melphalan at 140 mg/m2 (day -1).
Combination antiretroviral therapy (cART) was held during the preparative regimen and resumed after the resolution of gastrointestinal toxicity. The investigators switched efavirenz to an alternative agent 2 or more weeks prior to the planned interruption of cART, as the drug has a long half-life. And AZT was prohibited due to its myelosuppressive effects.
Treatment results
The median follow-up was 24 months. At 100 days post-transplant, the investigators assessed 39 patients for response. One patient was not evaluable due to early death.
Thirty-six of the patients (92.3%) were in complete remission, 1 (2.6%) was in partial remission, and 2 (5.1%) had relapsed or progressive disease.
Fifteen patients reported grade 3 or higher toxicities within a year of transplant. Of the 13 unexpected grade 3-5 adverse events (reported in 9 patients), 5 were infection/sepsis, 1 was acute appendicitis, 1 was acute coronary syndrome, 2 were deep vein thromboses, 2 were gastrointestinal toxicities, and 2 were metabolic abnormalities.
Seventeen patients reported at least 1 infectious episode, 42 events in total, 9 of which were severe. Fourteen patients required readmission to the hospital after transplant.
Within a year of transplant, 5 patients had died—3 from recurrent/persistent disease, 1 due to a fungal infection, and 1 from cardiac arrest. Two additional patients died after the 1-year mark—1 of recurrent/persistent disease and 1 of heart failure.
At 12 months, the rate of overall survival was 86.6%, progression-free survival was 82.3%, progression was 12.5%, and non-relapse mortality was 5.2%.
“In order to place this within context, we had the opportunity to compare our patient experience with 151 matched controls [without HIV] from CIBMTR,” Dr Alvarnas said. “Ninety-three percent of these patients were actually transplanted within 2 years so that they were the time-concordant group, and they were matched for performance score, disease, and disease stage.”
The investigators found no significant difference between their patient group and the HIV-free controls with regard to overall mortality (P=0.56), treatment failure (P=0.10), progression (P=0.06), and treatment-related mortality (P=0.97).
Likewise, there was no significant difference in overall survival between the HRL patients and controls—86.6% and 87.7%, respectively (P=0.56). And the same was true of progression-free survival—82.3% and 69.5%, respectively (P=0.10).
a cultured lymphocyte
Credit: CDC
SAN FRANCISCO—Patients with HIV-related lymphoma (HRL) should not be excluded from clinical trials of autologous stem cell transplant (ASCT) due to their HIV status, new research suggests.
Investigators found no significant difference in rates of treatment failure, disease progression, or survival between transplant-treated historical controls who had lymphoma but not HIV and patients with HRL who received the modified BEAM regimen followed by ASCT on a phase 2 trial.
This suggests patients with chemotherapy-sensitive, relapsed/refractory HRL can be treated successfully with the modified BEAM regimen, said study investigator Joseph Alvarnas, MD, of City of Hope National Medical Center in Duarte, California.
“Patients with treatment-responsive HIV infection and HIV-related lymphoma should be considered candidates for autologous transplant if they meet standard transplant criteria,” he added. “And we would argue that exclusion from clinical trials on the basis of HIV infection alone is no longer justified.”
Dr Alvarnas presented this viewpoint and the research to support it at the 2014 ASH Annual Meeting as abstract 674.
The trial enrolled 43 patients with treatable HIV-1 infection, adequate organ function, and aggressive lymphoma. Three patients were excluded because they could not undergo transplant due to lymphoma progression.
Of the 40 remaining patients, 5 were female, and their median age was 46.9 years (range, 22.5-62.2). They had diffuse large B-cell lymphoma (n=16), plasmablastic lymphoma (n=2), Burkitt/Burkitt-like lymphoma (n=7), and Hodgkin lymphoma (n=15).
The pre-ASCT HIV viral load was undetectable in 31 patients. In the patients with detectable HIV, the median viral load pre-ASCT was 84 copies/μL (range, 50-17,455). The median CD4 count was 250.5/µL (range, 39-797).
Before transplant, 30 patients (75%) were in complete remission, 8 (20%) were in partial remission, and 2 (5%) had relapsed/progressive disease.
The patients underwent ASCT after conditioning with the modified BEAM regimen—carmustine at 300 mg/m2 (day -6), etoposide at 100 mg/m2 twice daily (days -5 to -2), cytarabine at 100 mg/m2 (days -5 to -2), and melphalan at 140 mg/m2 (day -1).
Combination antiretroviral therapy (cART) was held during the preparative regimen and resumed after the resolution of gastrointestinal toxicity. The investigators switched efavirenz to an alternative agent 2 or more weeks prior to the planned interruption of cART, as the drug has a long half-life. And AZT was prohibited due to its myelosuppressive effects.
Treatment results
The median follow-up was 24 months. At 100 days post-transplant, the investigators assessed 39 patients for response. One patient was not evaluable due to early death.
Thirty-six of the patients (92.3%) were in complete remission, 1 (2.6%) was in partial remission, and 2 (5.1%) had relapsed or progressive disease.
Fifteen patients reported grade 3 or higher toxicities within a year of transplant. Of the 13 unexpected grade 3-5 adverse events (reported in 9 patients), 5 were infection/sepsis, 1 was acute appendicitis, 1 was acute coronary syndrome, 2 were deep vein thromboses, 2 were gastrointestinal toxicities, and 2 were metabolic abnormalities.
Seventeen patients reported at least 1 infectious episode, 42 events in total, 9 of which were severe. Fourteen patients required readmission to the hospital after transplant.
Within a year of transplant, 5 patients had died—3 from recurrent/persistent disease, 1 due to a fungal infection, and 1 from cardiac arrest. Two additional patients died after the 1-year mark—1 of recurrent/persistent disease and 1 of heart failure.
At 12 months, the rate of overall survival was 86.6%, progression-free survival was 82.3%, progression was 12.5%, and non-relapse mortality was 5.2%.
“In order to place this within context, we had the opportunity to compare our patient experience with 151 matched controls [without HIV] from CIBMTR,” Dr Alvarnas said. “Ninety-three percent of these patients were actually transplanted within 2 years so that they were the time-concordant group, and they were matched for performance score, disease, and disease stage.”
The investigators found no significant difference between their patient group and the HIV-free controls with regard to overall mortality (P=0.56), treatment failure (P=0.10), progression (P=0.06), and treatment-related mortality (P=0.97).
Likewise, there was no significant difference in overall survival between the HRL patients and controls—86.6% and 87.7%, respectively (P=0.56). And the same was true of progression-free survival—82.3% and 69.5%, respectively (P=0.10).
Maintenance prolongs PFS, not OS, in relapsed CLL
Credit: Linda Bartlett
SAN FRANCISCO—Maintenance therapy with the anti-CD20 monoclonal antibody ofatumumab improves progression-free survival (PFS), but not overall survival (OS), in patients with relapsed chronic lymphocytic leukemia (CLL), according to an interim analysis of the PROLONG study.
The median PFS was about 29 months in patients who received ofatumumab and about 15 months for patients who did not receive maintenance (P<0.0001).
But there was no significant difference in the median OS, which was not reached in either treatment arm.
Marinus H.J. van Oers, MD, PhD, of the Academisch Medisch Centrum and HOVON in Amsterdam, The Netherlands, reported these results at the 2014 ASH Annual Meeting (abstract 21*). The study was sponsored by GlaxoSmithKline, makers of ofatumumab.
“[A]s of 2014, still we cannot say that we are able to cure CLL,” Dr van Oers noted. “And CLL is characterized by decreasing response duration with subsequent lines of treatment. In this respect, but also a number of other respects, there are similarities in biological behavior between CLL and follicular lymphoma.”
“There is definitely a role—although it’s somewhat debated—for maintenance treatment in follicular lymphoma. Therefore, it is rational to explore safe and effective maintenance treatment in CLL as well.”
To that end, Dr van Oers and his colleagues compared ofatumumab maintenance to observation in patients who were in remission after induction treatment for relapsed CLL. The team enrolled 474 patients who were in complete or partial remission after their 2nd- or 3rd-line treatment for CLL.
Patients were randomized to observation (n=236) or to receive ofatumumab (n=238) at 300 mg, followed 1 week later by 1000 mg every 8 weeks for up to 2 years. Patients on ofatumumab also received premedication with acetaminophen, antihistamine, and glucocorticoid.
The patients were stratified by the number and type of prior therapy, as well as remission status after induction treatment, and baseline characteristics were similar between the two treatment arms.
“The median age was about 65, and about 30% of patients were older than 70 years,” Dr van Oers noted. “[There was] a male preponderance, as you would expect, and the time since diagnosis was somewhere between 5 and 6 years.”
“Most patients were in [partial response], actually 80%, and most patients had received 2 prior regimens, about 70%. As for prior treatments, 80% of patients had received effective immuno-chemotherapy.”
“In both arms, there were only a few patients with unfavorable cytogenetics—11q and 17p deletion. [As for] β2 microglobulin, two-thirds [of patients in both arms] had low levels. And, in both arms, there were almost twice as many IGVH-mutated as unmutated patients.”
Patient outcomes
The median follow-up was 19.1 months. The study’s primary endpoint was PFS, which was defined as the time from randomization to the date of disease progression or death from any cause.
The median PFS was significantly longer in the ofatumumab arm than in the observation arm, at 29.4 months and 15.2 months, respectively (hazard ratio [HR]=0.50; P<0.0001).
Similarly, the time to the start of patients’ next therapy was significantly longer in the ofatumumab arm than in the in observation arm—a median of 38 months and 31.1 months, respectively (HR=0.66, P=0.108).
However, there was no significant difference in OS, which was not reached in either arm (HR=0.85, P=0.4877).
Adverse events (AEs) occurred in 86% of patients in the ofatumumab arm and 72% of patients in the observation arm (P<0.001). Sixty percent of AEs were considered related to ofatumumab. None of the AEs led to study withdrawal.
Grade 3 or higher AEs occurred in 46% of patients in the ofatumumab arm and 28% in the observation arm. They included neutropenia (24% and 10%, respectively; P<0.001), infections (13% and 8%, respectively), thrombocytopenia (2% and 3%, respectively), and infusion-related reactions (1% and 0%, respectively).
There were 5 deaths in the observation arm—1 due to progression and 4 due to causes other than progression, infection, or secondary malignancy. There were 2 deaths in the ofatumumab arm—1 due to infection/sepsis and 1 due to an “other” cause.
“So based on this planned interim analysis, we can conclude that ofatumumab maintenance in relapsed CLL results in a highly significant and clinically meaningful improvement of progression-free survival,” Dr van Oers said in closing.
“It significantly prolongs time to next treatment, it’s well-tolerated, and it’s associated with an adverse event profile which is quite characteristic of anti-CD20 monoclonal antibodies.”
*Information in the abstract differs from that presented at the meeting.
Credit: Linda Bartlett
SAN FRANCISCO—Maintenance therapy with the anti-CD20 monoclonal antibody ofatumumab improves progression-free survival (PFS), but not overall survival (OS), in patients with relapsed chronic lymphocytic leukemia (CLL), according to an interim analysis of the PROLONG study.
The median PFS was about 29 months in patients who received ofatumumab and about 15 months for patients who did not receive maintenance (P<0.0001).
But there was no significant difference in the median OS, which was not reached in either treatment arm.
Marinus H.J. van Oers, MD, PhD, of the Academisch Medisch Centrum and HOVON in Amsterdam, The Netherlands, reported these results at the 2014 ASH Annual Meeting (abstract 21*). The study was sponsored by GlaxoSmithKline, makers of ofatumumab.
“[A]s of 2014, still we cannot say that we are able to cure CLL,” Dr van Oers noted. “And CLL is characterized by decreasing response duration with subsequent lines of treatment. In this respect, but also a number of other respects, there are similarities in biological behavior between CLL and follicular lymphoma.”
“There is definitely a role—although it’s somewhat debated—for maintenance treatment in follicular lymphoma. Therefore, it is rational to explore safe and effective maintenance treatment in CLL as well.”
To that end, Dr van Oers and his colleagues compared ofatumumab maintenance to observation in patients who were in remission after induction treatment for relapsed CLL. The team enrolled 474 patients who were in complete or partial remission after their 2nd- or 3rd-line treatment for CLL.
Patients were randomized to observation (n=236) or to receive ofatumumab (n=238) at 300 mg, followed 1 week later by 1000 mg every 8 weeks for up to 2 years. Patients on ofatumumab also received premedication with acetaminophen, antihistamine, and glucocorticoid.
The patients were stratified by the number and type of prior therapy, as well as remission status after induction treatment, and baseline characteristics were similar between the two treatment arms.
“The median age was about 65, and about 30% of patients were older than 70 years,” Dr van Oers noted. “[There was] a male preponderance, as you would expect, and the time since diagnosis was somewhere between 5 and 6 years.”
“Most patients were in [partial response], actually 80%, and most patients had received 2 prior regimens, about 70%. As for prior treatments, 80% of patients had received effective immuno-chemotherapy.”
“In both arms, there were only a few patients with unfavorable cytogenetics—11q and 17p deletion. [As for] β2 microglobulin, two-thirds [of patients in both arms] had low levels. And, in both arms, there were almost twice as many IGVH-mutated as unmutated patients.”
Patient outcomes
The median follow-up was 19.1 months. The study’s primary endpoint was PFS, which was defined as the time from randomization to the date of disease progression or death from any cause.
The median PFS was significantly longer in the ofatumumab arm than in the observation arm, at 29.4 months and 15.2 months, respectively (hazard ratio [HR]=0.50; P<0.0001).
Similarly, the time to the start of patients’ next therapy was significantly longer in the ofatumumab arm than in the in observation arm—a median of 38 months and 31.1 months, respectively (HR=0.66, P=0.108).
However, there was no significant difference in OS, which was not reached in either arm (HR=0.85, P=0.4877).
Adverse events (AEs) occurred in 86% of patients in the ofatumumab arm and 72% of patients in the observation arm (P<0.001). Sixty percent of AEs were considered related to ofatumumab. None of the AEs led to study withdrawal.
Grade 3 or higher AEs occurred in 46% of patients in the ofatumumab arm and 28% in the observation arm. They included neutropenia (24% and 10%, respectively; P<0.001), infections (13% and 8%, respectively), thrombocytopenia (2% and 3%, respectively), and infusion-related reactions (1% and 0%, respectively).
There were 5 deaths in the observation arm—1 due to progression and 4 due to causes other than progression, infection, or secondary malignancy. There were 2 deaths in the ofatumumab arm—1 due to infection/sepsis and 1 due to an “other” cause.
“So based on this planned interim analysis, we can conclude that ofatumumab maintenance in relapsed CLL results in a highly significant and clinically meaningful improvement of progression-free survival,” Dr van Oers said in closing.
“It significantly prolongs time to next treatment, it’s well-tolerated, and it’s associated with an adverse event profile which is quite characteristic of anti-CD20 monoclonal antibodies.”
*Information in the abstract differs from that presented at the meeting.
Credit: Linda Bartlett
SAN FRANCISCO—Maintenance therapy with the anti-CD20 monoclonal antibody ofatumumab improves progression-free survival (PFS), but not overall survival (OS), in patients with relapsed chronic lymphocytic leukemia (CLL), according to an interim analysis of the PROLONG study.
The median PFS was about 29 months in patients who received ofatumumab and about 15 months for patients who did not receive maintenance (P<0.0001).
But there was no significant difference in the median OS, which was not reached in either treatment arm.
Marinus H.J. van Oers, MD, PhD, of the Academisch Medisch Centrum and HOVON in Amsterdam, The Netherlands, reported these results at the 2014 ASH Annual Meeting (abstract 21*). The study was sponsored by GlaxoSmithKline, makers of ofatumumab.
“[A]s of 2014, still we cannot say that we are able to cure CLL,” Dr van Oers noted. “And CLL is characterized by decreasing response duration with subsequent lines of treatment. In this respect, but also a number of other respects, there are similarities in biological behavior between CLL and follicular lymphoma.”
“There is definitely a role—although it’s somewhat debated—for maintenance treatment in follicular lymphoma. Therefore, it is rational to explore safe and effective maintenance treatment in CLL as well.”
To that end, Dr van Oers and his colleagues compared ofatumumab maintenance to observation in patients who were in remission after induction treatment for relapsed CLL. The team enrolled 474 patients who were in complete or partial remission after their 2nd- or 3rd-line treatment for CLL.
Patients were randomized to observation (n=236) or to receive ofatumumab (n=238) at 300 mg, followed 1 week later by 1000 mg every 8 weeks for up to 2 years. Patients on ofatumumab also received premedication with acetaminophen, antihistamine, and glucocorticoid.
The patients were stratified by the number and type of prior therapy, as well as remission status after induction treatment, and baseline characteristics were similar between the two treatment arms.
“The median age was about 65, and about 30% of patients were older than 70 years,” Dr van Oers noted. “[There was] a male preponderance, as you would expect, and the time since diagnosis was somewhere between 5 and 6 years.”
“Most patients were in [partial response], actually 80%, and most patients had received 2 prior regimens, about 70%. As for prior treatments, 80% of patients had received effective immuno-chemotherapy.”
“In both arms, there were only a few patients with unfavorable cytogenetics—11q and 17p deletion. [As for] β2 microglobulin, two-thirds [of patients in both arms] had low levels. And, in both arms, there were almost twice as many IGVH-mutated as unmutated patients.”
Patient outcomes
The median follow-up was 19.1 months. The study’s primary endpoint was PFS, which was defined as the time from randomization to the date of disease progression or death from any cause.
The median PFS was significantly longer in the ofatumumab arm than in the observation arm, at 29.4 months and 15.2 months, respectively (hazard ratio [HR]=0.50; P<0.0001).
Similarly, the time to the start of patients’ next therapy was significantly longer in the ofatumumab arm than in the in observation arm—a median of 38 months and 31.1 months, respectively (HR=0.66, P=0.108).
However, there was no significant difference in OS, which was not reached in either arm (HR=0.85, P=0.4877).
Adverse events (AEs) occurred in 86% of patients in the ofatumumab arm and 72% of patients in the observation arm (P<0.001). Sixty percent of AEs were considered related to ofatumumab. None of the AEs led to study withdrawal.
Grade 3 or higher AEs occurred in 46% of patients in the ofatumumab arm and 28% in the observation arm. They included neutropenia (24% and 10%, respectively; P<0.001), infections (13% and 8%, respectively), thrombocytopenia (2% and 3%, respectively), and infusion-related reactions (1% and 0%, respectively).
There were 5 deaths in the observation arm—1 due to progression and 4 due to causes other than progression, infection, or secondary malignancy. There were 2 deaths in the ofatumumab arm—1 due to infection/sepsis and 1 due to an “other” cause.
“So based on this planned interim analysis, we can conclude that ofatumumab maintenance in relapsed CLL results in a highly significant and clinically meaningful improvement of progression-free survival,” Dr van Oers said in closing.
“It significantly prolongs time to next treatment, it’s well-tolerated, and it’s associated with an adverse event profile which is quite characteristic of anti-CD20 monoclonal antibodies.”
*Information in the abstract differs from that presented at the meeting.
Combo shows promise for rel/ref MM
Credit: Linda Bartlett
SAN FRANCISCO—Combination therapy involving a novel monoclonal antibody (mAb) produces encouraging activity in relapsed or refractory multiple myeloma (MM), according to researchers.
The team conducted a phase 1b trial testing the IgG1 mAb SAR650984 in combination with lenalidomide and dexamethasone (SAR-len-dex).
The treatment produced an overall response rate (ORR) of 58% and a higher ORR among patients who received the highest dose of SAR.
Furthermore, the combination had a “very manageable safety profile,” according to study investigator Thomas Martin, MD, of the University of California at San Francisco.
“The safety findings are really consistent with those of the individual drugs,” he said.
Dr Martin presented these findings at the 2014 ASH Annual Meeting as abstract 83.* The trial was sponsored by Sanofi (the company developing SAR), but investigators also received research funding from Karyopharm, Bristol Myers Squibb, Millennium, and Celgene.
Dr Martin explained that SAR is a humanized IgG1 mAb that binds selectively to a unique epitope on the human CD38 receptor, and it has 4 potential mechanisms of action: antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, direct apoptosis without crosslinking, and inhibition of CD38 enzyme activity.
He said there is “ample evidence” to suggest that SAR-len-dex would be active in MM. First, both lenalidomide and SAR have demonstrated single-agent activity in MM. Second, lenalidomide can increase IL-2 production, which leads to enhanced antibody-dependent cellular cytotoxicity. And finally, SAR and lenalidomide showed additive effects in a mouse model of MM.
With that in mind, Dr Martin and his colleagues decided to test SAR-len-dex in patients with relapsed or refractory MM.
The team enrolled 31 patients and administered SAR at 3 different dose levels. Patients received 3 mg/kg (n=4), 5 mg/kg (n=3), or 10 mg/kg (n=24) every 2 weeks. They received lenalidomide at 25 mg on days 1-21 per 28-day cycle and dexamethasone at 40 mg once a week on days 1, 8, 15, and 22.
The patients’ median age was 59 (range, 45-74), the median time since diagnosis was 4 years (range, 1-12), the median number of prior treatment regimens was 7 (range, 2-14), and the median number of prior lines of therapy was 4 (range, 1-11).
“The median time from the last lenalidomide-containing regimen was 9 months,” Dr Martin noted. “Ninety-four percent of the patients had prior lenalidomide, and 74% of these patients were lenalidomide refractory.”
Of the 29% of patients who had received prior pomalidomide, all were refractory to it. The same was true of the 48% of patients who received carfilzomib. And of the 94% of patients who received prior bortezomib, 52% were refractory to it.
Adverse events
The maximum-tolerated dose of SAR was not reached. Treatment-emergent adverse events occurring in 30% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, diarrhea, fatigue, insomnia, muscle spasms, nausea, pneumonia, pyrexia, and upper respiratory tract infections.
Grade 3/4 events occurring in 5% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, fatigue, insomnia, and pneumonia.
“All of these events are commonly associated with the backbone treatment of lenalidomide and dexamethasone, and no unexpected or untoward adverse events were seen,” Dr Martin noted.
The most common SAR-associated adverse events were infusion reactions. About 35% of patients experienced an infusion reaction in cycle 1, and 10% did so in cycle 2.
Most reactions were grade 1 and 2 and did not lead to treatment discontinuation. Two patients did discontinue treatment due to grade 3 infusion reactions, but both events were ultimately resolved.
Response and survival
The ORR was 58% (n=18), and the clinical benefit rate was 65% (n=20). Two patients had a stringent complete response, 7 had a very good partial response, 9 had a partial response, 2 had a minimal response, 6 had stable disease, 4 progressed, and 1 was not evaluable.
Responses were seen at all dose levels, but the best responses occurred in patients who received the highest dose of SAR. Among patients who received the highest dose, the ORR was 68%, and the clinical benefit rate was 65%.
The ORR was 50% in patients who were refractory to prior treatment with an immunomodulatory drug, 40% in patients who were refractory to carfilzomib, and 33% in patients who were refractory to pomalidomide.
At 9 months of follow-up, the median progression-free survival was 6.2 months. The median progression-free survival was not reached for patients who had received 1 to 2 prior lines of therapy, and it was 5.8 months for patients who had received 3 or more prior lines of therapy.
“SAR in combination with lenalidomide/dexamethasone showed encouraging activity in this heavily pretreated population,” Dr Martin said in closing, adding that the combination compares favorably to other treatments tested in patients who received the same number of prior lines of therapy.
*Information in the abstract differs from that presented at the meeting.
Credit: Linda Bartlett
SAN FRANCISCO—Combination therapy involving a novel monoclonal antibody (mAb) produces encouraging activity in relapsed or refractory multiple myeloma (MM), according to researchers.
The team conducted a phase 1b trial testing the IgG1 mAb SAR650984 in combination with lenalidomide and dexamethasone (SAR-len-dex).
The treatment produced an overall response rate (ORR) of 58% and a higher ORR among patients who received the highest dose of SAR.
Furthermore, the combination had a “very manageable safety profile,” according to study investigator Thomas Martin, MD, of the University of California at San Francisco.
“The safety findings are really consistent with those of the individual drugs,” he said.
Dr Martin presented these findings at the 2014 ASH Annual Meeting as abstract 83.* The trial was sponsored by Sanofi (the company developing SAR), but investigators also received research funding from Karyopharm, Bristol Myers Squibb, Millennium, and Celgene.
Dr Martin explained that SAR is a humanized IgG1 mAb that binds selectively to a unique epitope on the human CD38 receptor, and it has 4 potential mechanisms of action: antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, direct apoptosis without crosslinking, and inhibition of CD38 enzyme activity.
He said there is “ample evidence” to suggest that SAR-len-dex would be active in MM. First, both lenalidomide and SAR have demonstrated single-agent activity in MM. Second, lenalidomide can increase IL-2 production, which leads to enhanced antibody-dependent cellular cytotoxicity. And finally, SAR and lenalidomide showed additive effects in a mouse model of MM.
With that in mind, Dr Martin and his colleagues decided to test SAR-len-dex in patients with relapsed or refractory MM.
The team enrolled 31 patients and administered SAR at 3 different dose levels. Patients received 3 mg/kg (n=4), 5 mg/kg (n=3), or 10 mg/kg (n=24) every 2 weeks. They received lenalidomide at 25 mg on days 1-21 per 28-day cycle and dexamethasone at 40 mg once a week on days 1, 8, 15, and 22.
The patients’ median age was 59 (range, 45-74), the median time since diagnosis was 4 years (range, 1-12), the median number of prior treatment regimens was 7 (range, 2-14), and the median number of prior lines of therapy was 4 (range, 1-11).
“The median time from the last lenalidomide-containing regimen was 9 months,” Dr Martin noted. “Ninety-four percent of the patients had prior lenalidomide, and 74% of these patients were lenalidomide refractory.”
Of the 29% of patients who had received prior pomalidomide, all were refractory to it. The same was true of the 48% of patients who received carfilzomib. And of the 94% of patients who received prior bortezomib, 52% were refractory to it.
Adverse events
The maximum-tolerated dose of SAR was not reached. Treatment-emergent adverse events occurring in 30% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, diarrhea, fatigue, insomnia, muscle spasms, nausea, pneumonia, pyrexia, and upper respiratory tract infections.
Grade 3/4 events occurring in 5% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, fatigue, insomnia, and pneumonia.
“All of these events are commonly associated with the backbone treatment of lenalidomide and dexamethasone, and no unexpected or untoward adverse events were seen,” Dr Martin noted.
The most common SAR-associated adverse events were infusion reactions. About 35% of patients experienced an infusion reaction in cycle 1, and 10% did so in cycle 2.
Most reactions were grade 1 and 2 and did not lead to treatment discontinuation. Two patients did discontinue treatment due to grade 3 infusion reactions, but both events were ultimately resolved.
Response and survival
The ORR was 58% (n=18), and the clinical benefit rate was 65% (n=20). Two patients had a stringent complete response, 7 had a very good partial response, 9 had a partial response, 2 had a minimal response, 6 had stable disease, 4 progressed, and 1 was not evaluable.
Responses were seen at all dose levels, but the best responses occurred in patients who received the highest dose of SAR. Among patients who received the highest dose, the ORR was 68%, and the clinical benefit rate was 65%.
The ORR was 50% in patients who were refractory to prior treatment with an immunomodulatory drug, 40% in patients who were refractory to carfilzomib, and 33% in patients who were refractory to pomalidomide.
At 9 months of follow-up, the median progression-free survival was 6.2 months. The median progression-free survival was not reached for patients who had received 1 to 2 prior lines of therapy, and it was 5.8 months for patients who had received 3 or more prior lines of therapy.
“SAR in combination with lenalidomide/dexamethasone showed encouraging activity in this heavily pretreated population,” Dr Martin said in closing, adding that the combination compares favorably to other treatments tested in patients who received the same number of prior lines of therapy.
*Information in the abstract differs from that presented at the meeting.
Credit: Linda Bartlett
SAN FRANCISCO—Combination therapy involving a novel monoclonal antibody (mAb) produces encouraging activity in relapsed or refractory multiple myeloma (MM), according to researchers.
The team conducted a phase 1b trial testing the IgG1 mAb SAR650984 in combination with lenalidomide and dexamethasone (SAR-len-dex).
The treatment produced an overall response rate (ORR) of 58% and a higher ORR among patients who received the highest dose of SAR.
Furthermore, the combination had a “very manageable safety profile,” according to study investigator Thomas Martin, MD, of the University of California at San Francisco.
“The safety findings are really consistent with those of the individual drugs,” he said.
Dr Martin presented these findings at the 2014 ASH Annual Meeting as abstract 83.* The trial was sponsored by Sanofi (the company developing SAR), but investigators also received research funding from Karyopharm, Bristol Myers Squibb, Millennium, and Celgene.
Dr Martin explained that SAR is a humanized IgG1 mAb that binds selectively to a unique epitope on the human CD38 receptor, and it has 4 potential mechanisms of action: antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, direct apoptosis without crosslinking, and inhibition of CD38 enzyme activity.
He said there is “ample evidence” to suggest that SAR-len-dex would be active in MM. First, both lenalidomide and SAR have demonstrated single-agent activity in MM. Second, lenalidomide can increase IL-2 production, which leads to enhanced antibody-dependent cellular cytotoxicity. And finally, SAR and lenalidomide showed additive effects in a mouse model of MM.
With that in mind, Dr Martin and his colleagues decided to test SAR-len-dex in patients with relapsed or refractory MM.
The team enrolled 31 patients and administered SAR at 3 different dose levels. Patients received 3 mg/kg (n=4), 5 mg/kg (n=3), or 10 mg/kg (n=24) every 2 weeks. They received lenalidomide at 25 mg on days 1-21 per 28-day cycle and dexamethasone at 40 mg once a week on days 1, 8, 15, and 22.
The patients’ median age was 59 (range, 45-74), the median time since diagnosis was 4 years (range, 1-12), the median number of prior treatment regimens was 7 (range, 2-14), and the median number of prior lines of therapy was 4 (range, 1-11).
“The median time from the last lenalidomide-containing regimen was 9 months,” Dr Martin noted. “Ninety-four percent of the patients had prior lenalidomide, and 74% of these patients were lenalidomide refractory.”
Of the 29% of patients who had received prior pomalidomide, all were refractory to it. The same was true of the 48% of patients who received carfilzomib. And of the 94% of patients who received prior bortezomib, 52% were refractory to it.
Adverse events
The maximum-tolerated dose of SAR was not reached. Treatment-emergent adverse events occurring in 30% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, diarrhea, fatigue, insomnia, muscle spasms, nausea, pneumonia, pyrexia, and upper respiratory tract infections.
Grade 3/4 events occurring in 5% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, fatigue, insomnia, and pneumonia.
“All of these events are commonly associated with the backbone treatment of lenalidomide and dexamethasone, and no unexpected or untoward adverse events were seen,” Dr Martin noted.
The most common SAR-associated adverse events were infusion reactions. About 35% of patients experienced an infusion reaction in cycle 1, and 10% did so in cycle 2.
Most reactions were grade 1 and 2 and did not lead to treatment discontinuation. Two patients did discontinue treatment due to grade 3 infusion reactions, but both events were ultimately resolved.
Response and survival
The ORR was 58% (n=18), and the clinical benefit rate was 65% (n=20). Two patients had a stringent complete response, 7 had a very good partial response, 9 had a partial response, 2 had a minimal response, 6 had stable disease, 4 progressed, and 1 was not evaluable.
Responses were seen at all dose levels, but the best responses occurred in patients who received the highest dose of SAR. Among patients who received the highest dose, the ORR was 68%, and the clinical benefit rate was 65%.
The ORR was 50% in patients who were refractory to prior treatment with an immunomodulatory drug, 40% in patients who were refractory to carfilzomib, and 33% in patients who were refractory to pomalidomide.
At 9 months of follow-up, the median progression-free survival was 6.2 months. The median progression-free survival was not reached for patients who had received 1 to 2 prior lines of therapy, and it was 5.8 months for patients who had received 3 or more prior lines of therapy.
“SAR in combination with lenalidomide/dexamethasone showed encouraging activity in this heavily pretreated population,” Dr Martin said in closing, adding that the combination compares favorably to other treatments tested in patients who received the same number of prior lines of therapy.
*Information in the abstract differs from that presented at the meeting.