User login
Mogamulizumab in PTCL: Europe vs Japan
SAN FRANCISCO—Two phase 2 studies testing mogamulizumab in peripheral T-cell lymphomas (PTCLs) suggest that higher response rates don’t necessarily translate to an improvement in progression-free survival (PFS).
The anti-CCR4 antibody produced a higher overall response rate (ORR) in a Japanese study than in a European study—34% and 11%, respectively.
However, median PFS times were similar—about 2 months in both studies.
This similarity is all the more interesting because the studies enrolled different types of patients and followed different dosing schedules, according to Pier Luigi Zinzani, MD, PhD, of the University of Bologna in Italy.
Dr Zinzani discussed details of the European experience testing mogamulizumab in PTCL, comparing it to the Japanese experience, in a presentation at the 7th Annual T-cell Lymphoma Forum.
Kensei Tobinai, MD, PhD, of the National Cancer Center Hospital in Tokyo, Japan, also reviewed the Japanese experience (TCLF 2013, JCO 2014) during the meeting’s keynote address and presented data from an ancillary analysis of this study (which is unpublished).
All of the research was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing mogamulizumab.
The Japanese experience
The Japanese study included 29 patients with PTCL and 8 with cutaneous T-cell lymphoma (CTCL). All patients had relapsed after their last chemotherapy regimen, and none had received an allogeneic stem cell transplant (allo-SCT). The PTCL patients had a median age of 67, and 69% were male.
All patients received mogamulizumab at 1.0 mg/kg/day weekly for 8 weeks. The ORR was 35%—34% for PTCL patients and 38% for CTCL patients.
Among PTCL patients, there were 5 complete responses (CRs) and 5 partial responses (PRs). Nine patients had stable disease (SD), and 10 progressed.
Of the 16 patients with PTCL-not otherwise specified (PTCL-NOS), 1 had a CR, 2 had a PR, 6 had SD, and 7 progressed. Of the 12 patients with angioimmunoblastic T-cell lymphoma (AITL), 3 had a CR, 3 had a PR, 3 had SD, and 3 progressed. The only patient with ALK- anaplastic large-cell lymphoma (ALCL) had an unconfirmed CR.
The ancillary analysis showed that tumor shrinkage of the target lesions occurred in 72% (21/29) of patients with PTCL. The patients’ median duration of response was 6.4 months, and the median time to response was 1.9 months.
Overall, the median PFS was 3.0 months—2.0 months in patients with PTCL and 3.4 months in patients with CTCL.
Common adverse events (for both PTCL and CTCL patients) included lymphopenia (81%), skin disorders (51%), leukopenia (43%), neutropenia (38%), thrombocytopenia (38%), pyrexia (30%), acute infusion reactions (24%), and anemia (14%).
Dr Tobinai noted that these results are not as favorable as those observed when patients with adult T-cell leukemia-lymphoma receive mogamulizumab.
“But compared to the efficacy rate of other approved agents—pralatrexate and romidepsin—this antibody has promising efficacy,” he said.
In fact, the results of this study prompted the December approval of mogamulizumab to treat PTCL and CTCL patients in Japan.
The European experience
The European study differed from the Japanese study in a few ways, Dr Zinzani pointed out. The European study only enrolled patients with PTCL. And it included patients with relapsed (49%) or refractory (51%) disease, whereas the Japanese study only included relapsed patients.
Furthermore, the Japanese study did not include any patients with an ECOG performance status of 2, while the European study did (39%). And the dosing schedule differed between the 2 studies.
In the European study, patients received mogamulizumab at 1 mg/kg once weekly for 4 weeks and then once every 2 weeks until they progressed or developed unacceptable toxicity.
There were 38 patients in the safety analysis. They had a median age of 58.5 years, and 61% were male.
Thirty-five of these patients were included in the efficacy analysis. They had a median of 2 prior treatments (range, 1-8), and 17 patients (49%) had responded to their last therapy.
The patients had PTCL-NOS (43%, 15/35), AITL (34%, 12), transformed mycosis fungoides (9%, 3), ALK- ALCL (11%, 4), and ALK+ ALCL (3%, 1).
The ORR was 11% (n=4), and 46% of patients (n=16) had SD or better. Two patients with PTCL-NOS responded, as did 2 with AITL.
Six patients with PTCL-NOS had SD, as did 3 with AITL, 1 with transformed mycosis fungoides, and 2 with ALK- ALCL.
The median duration of response (including SD) was 2.9 months. And the median PFS was 2.1 months. Two patients (1 with ALK- ALCL and 1 with PTCL-NOS) went on to allo-SCT.
The most frequent adverse events (occurring in at least 10% of patients) were drug eruption (n=12), pyrexia (n=9), pruritus (n=7), diarrhea (n=7), cough (n=6), vomiting (n=6), thrombocytopenia (n=6), hypotension (n=4), headache (n=4), peripheral edema (n=4), asthenia (n=4), nausea (n=4), anemia (n=4), and neutropenia (n=4).
“For the European experience, there were some differences from the Japanese experience,” Dr Zinzani said in closing. “It was worse in terms of overall response rate—only 11%—but roughly 50% of patients attained at least stable disease. And there was an acceptable safety profile in these really heavily pretreated, relapsed/refractory PTCL patients.” 
SAN FRANCISCO—Two phase 2 studies testing mogamulizumab in peripheral T-cell lymphomas (PTCLs) suggest that higher response rates don’t necessarily translate to an improvement in progression-free survival (PFS).
The anti-CCR4 antibody produced a higher overall response rate (ORR) in a Japanese study than in a European study—34% and 11%, respectively.
However, median PFS times were similar—about 2 months in both studies.
This similarity is all the more interesting because the studies enrolled different types of patients and followed different dosing schedules, according to Pier Luigi Zinzani, MD, PhD, of the University of Bologna in Italy.
Dr Zinzani discussed details of the European experience testing mogamulizumab in PTCL, comparing it to the Japanese experience, in a presentation at the 7th Annual T-cell Lymphoma Forum.
Kensei Tobinai, MD, PhD, of the National Cancer Center Hospital in Tokyo, Japan, also reviewed the Japanese experience (TCLF 2013, JCO 2014) during the meeting’s keynote address and presented data from an ancillary analysis of this study (which is unpublished).
All of the research was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing mogamulizumab.
The Japanese experience
The Japanese study included 29 patients with PTCL and 8 with cutaneous T-cell lymphoma (CTCL). All patients had relapsed after their last chemotherapy regimen, and none had received an allogeneic stem cell transplant (allo-SCT). The PTCL patients had a median age of 67, and 69% were male.
All patients received mogamulizumab at 1.0 mg/kg/day weekly for 8 weeks. The ORR was 35%—34% for PTCL patients and 38% for CTCL patients.
Among PTCL patients, there were 5 complete responses (CRs) and 5 partial responses (PRs). Nine patients had stable disease (SD), and 10 progressed.
Of the 16 patients with PTCL-not otherwise specified (PTCL-NOS), 1 had a CR, 2 had a PR, 6 had SD, and 7 progressed. Of the 12 patients with angioimmunoblastic T-cell lymphoma (AITL), 3 had a CR, 3 had a PR, 3 had SD, and 3 progressed. The only patient with ALK- anaplastic large-cell lymphoma (ALCL) had an unconfirmed CR.
The ancillary analysis showed that tumor shrinkage of the target lesions occurred in 72% (21/29) of patients with PTCL. The patients’ median duration of response was 6.4 months, and the median time to response was 1.9 months.
Overall, the median PFS was 3.0 months—2.0 months in patients with PTCL and 3.4 months in patients with CTCL.
Common adverse events (for both PTCL and CTCL patients) included lymphopenia (81%), skin disorders (51%), leukopenia (43%), neutropenia (38%), thrombocytopenia (38%), pyrexia (30%), acute infusion reactions (24%), and anemia (14%).
Dr Tobinai noted that these results are not as favorable as those observed when patients with adult T-cell leukemia-lymphoma receive mogamulizumab.
“But compared to the efficacy rate of other approved agents—pralatrexate and romidepsin—this antibody has promising efficacy,” he said.
In fact, the results of this study prompted the December approval of mogamulizumab to treat PTCL and CTCL patients in Japan.
The European experience
The European study differed from the Japanese study in a few ways, Dr Zinzani pointed out. The European study only enrolled patients with PTCL. And it included patients with relapsed (49%) or refractory (51%) disease, whereas the Japanese study only included relapsed patients.
Furthermore, the Japanese study did not include any patients with an ECOG performance status of 2, while the European study did (39%). And the dosing schedule differed between the 2 studies.
In the European study, patients received mogamulizumab at 1 mg/kg once weekly for 4 weeks and then once every 2 weeks until they progressed or developed unacceptable toxicity.
There were 38 patients in the safety analysis. They had a median age of 58.5 years, and 61% were male.
Thirty-five of these patients were included in the efficacy analysis. They had a median of 2 prior treatments (range, 1-8), and 17 patients (49%) had responded to their last therapy.
The patients had PTCL-NOS (43%, 15/35), AITL (34%, 12), transformed mycosis fungoides (9%, 3), ALK- ALCL (11%, 4), and ALK+ ALCL (3%, 1).
The ORR was 11% (n=4), and 46% of patients (n=16) had SD or better. Two patients with PTCL-NOS responded, as did 2 with AITL.
Six patients with PTCL-NOS had SD, as did 3 with AITL, 1 with transformed mycosis fungoides, and 2 with ALK- ALCL.
The median duration of response (including SD) was 2.9 months. And the median PFS was 2.1 months. Two patients (1 with ALK- ALCL and 1 with PTCL-NOS) went on to allo-SCT.
The most frequent adverse events (occurring in at least 10% of patients) were drug eruption (n=12), pyrexia (n=9), pruritus (n=7), diarrhea (n=7), cough (n=6), vomiting (n=6), thrombocytopenia (n=6), hypotension (n=4), headache (n=4), peripheral edema (n=4), asthenia (n=4), nausea (n=4), anemia (n=4), and neutropenia (n=4).
“For the European experience, there were some differences from the Japanese experience,” Dr Zinzani said in closing. “It was worse in terms of overall response rate—only 11%—but roughly 50% of patients attained at least stable disease. And there was an acceptable safety profile in these really heavily pretreated, relapsed/refractory PTCL patients.”
SAN FRANCISCO—Two phase 2 studies testing mogamulizumab in peripheral T-cell lymphomas (PTCLs) suggest that higher response rates don’t necessarily translate to an improvement in progression-free survival (PFS).
The anti-CCR4 antibody produced a higher overall response rate (ORR) in a Japanese study than in a European study—34% and 11%, respectively.
However, median PFS times were similar—about 2 months in both studies.
This similarity is all the more interesting because the studies enrolled different types of patients and followed different dosing schedules, according to Pier Luigi Zinzani, MD, PhD, of the University of Bologna in Italy.
Dr Zinzani discussed details of the European experience testing mogamulizumab in PTCL, comparing it to the Japanese experience, in a presentation at the 7th Annual T-cell Lymphoma Forum.
Kensei Tobinai, MD, PhD, of the National Cancer Center Hospital in Tokyo, Japan, also reviewed the Japanese experience (TCLF 2013, JCO 2014) during the meeting’s keynote address and presented data from an ancillary analysis of this study (which is unpublished).
All of the research was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing mogamulizumab.
The Japanese experience
The Japanese study included 29 patients with PTCL and 8 with cutaneous T-cell lymphoma (CTCL). All patients had relapsed after their last chemotherapy regimen, and none had received an allogeneic stem cell transplant (allo-SCT). The PTCL patients had a median age of 67, and 69% were male.
All patients received mogamulizumab at 1.0 mg/kg/day weekly for 8 weeks. The ORR was 35%—34% for PTCL patients and 38% for CTCL patients.
Among PTCL patients, there were 5 complete responses (CRs) and 5 partial responses (PRs). Nine patients had stable disease (SD), and 10 progressed.
Of the 16 patients with PTCL-not otherwise specified (PTCL-NOS), 1 had a CR, 2 had a PR, 6 had SD, and 7 progressed. Of the 12 patients with angioimmunoblastic T-cell lymphoma (AITL), 3 had a CR, 3 had a PR, 3 had SD, and 3 progressed. The only patient with ALK- anaplastic large-cell lymphoma (ALCL) had an unconfirmed CR.
The ancillary analysis showed that tumor shrinkage of the target lesions occurred in 72% (21/29) of patients with PTCL. The patients’ median duration of response was 6.4 months, and the median time to response was 1.9 months.
Overall, the median PFS was 3.0 months—2.0 months in patients with PTCL and 3.4 months in patients with CTCL.
Common adverse events (for both PTCL and CTCL patients) included lymphopenia (81%), skin disorders (51%), leukopenia (43%), neutropenia (38%), thrombocytopenia (38%), pyrexia (30%), acute infusion reactions (24%), and anemia (14%).
Dr Tobinai noted that these results are not as favorable as those observed when patients with adult T-cell leukemia-lymphoma receive mogamulizumab.
“But compared to the efficacy rate of other approved agents—pralatrexate and romidepsin—this antibody has promising efficacy,” he said.
In fact, the results of this study prompted the December approval of mogamulizumab to treat PTCL and CTCL patients in Japan.
The European experience
The European study differed from the Japanese study in a few ways, Dr Zinzani pointed out. The European study only enrolled patients with PTCL. And it included patients with relapsed (49%) or refractory (51%) disease, whereas the Japanese study only included relapsed patients.
Furthermore, the Japanese study did not include any patients with an ECOG performance status of 2, while the European study did (39%). And the dosing schedule differed between the 2 studies.
In the European study, patients received mogamulizumab at 1 mg/kg once weekly for 4 weeks and then once every 2 weeks until they progressed or developed unacceptable toxicity.
There were 38 patients in the safety analysis. They had a median age of 58.5 years, and 61% were male.
Thirty-five of these patients were included in the efficacy analysis. They had a median of 2 prior treatments (range, 1-8), and 17 patients (49%) had responded to their last therapy.
The patients had PTCL-NOS (43%, 15/35), AITL (34%, 12), transformed mycosis fungoides (9%, 3), ALK- ALCL (11%, 4), and ALK+ ALCL (3%, 1).
The ORR was 11% (n=4), and 46% of patients (n=16) had SD or better. Two patients with PTCL-NOS responded, as did 2 with AITL.
Six patients with PTCL-NOS had SD, as did 3 with AITL, 1 with transformed mycosis fungoides, and 2 with ALK- ALCL.
The median duration of response (including SD) was 2.9 months. And the median PFS was 2.1 months. Two patients (1 with ALK- ALCL and 1 with PTCL-NOS) went on to allo-SCT.
The most frequent adverse events (occurring in at least 10% of patients) were drug eruption (n=12), pyrexia (n=9), pruritus (n=7), diarrhea (n=7), cough (n=6), vomiting (n=6), thrombocytopenia (n=6), hypotension (n=4), headache (n=4), peripheral edema (n=4), asthenia (n=4), nausea (n=4), anemia (n=4), and neutropenia (n=4).
“For the European experience, there were some differences from the Japanese experience,” Dr Zinzani said in closing. “It was worse in terms of overall response rate—only 11%—but roughly 50% of patients attained at least stable disease. And there was an acceptable safety profile in these really heavily pretreated, relapsed/refractory PTCL patients.”
Though costly, blood cancer drugs appear cost-effective
Photo by Bill Branson
A new analysis indicates that certain high-cost therapies for hematologic malignancies provide reasonable value for money spent.
Most cost-effectiveness ratios were lower than thresholds commonly used to establish cost-effectiveness in the US—$50,000 or $100,000 per quality-adjusted life year (QALY) gained.
The median cost-effectiveness ratio was highest for chronic myeloid leukemia (CML), at $55,000/QALY, and lowest for non-Hodgkin lymphoma (NHL), at $21,500/QALY.
Researchers presented these data in Blood.
“Given the increased discussion about the high cost of these treatments, we were somewhat surprised to discover that their cost-effectiveness ratios were lower than expected,” said study author Peter J. Neumann, ScD, of Tufts Medical Center in Boston.
“Our analysis had a small sample size and included both industry- and non-industry-funded studies. In addition, cost-effectiveness ratios may have changed over time as associated costs or benefits have changed. However, the study underscores that debates in healthcare should consider the value of breakthrough drugs and not just costs.”
With that issue in mind, Dr Neumann and his colleagues had conducted a systematic review of studies published between 1996 and 2012 that examined the cost utility of agents for hematologic malignancies. The cost utility of a drug was depicted as a ratio of a drug’s total cost per patient QALY gained.
The researchers identified 29 studies, 22 of which were industry-funded. Nine studies were conducted from a US perspective, 6 from the UK, 3 from Norway, 3 from Sweden, 2 from France, 1 from Canada, 1 from Finland, and 4 from “other” countries.
The team grouped studies according to malignancy—CML, chronic lymphocytic leukemia (CLL), NHL, and multiple myeloma (MM)—as well as by treatment—α interferon, alemtuzumab, bendamustine, bortezomib, dasatinib, imatinib, lenalidomide, rituximab alone or in combination, and thalidomide.
The studies reported 44 cost-effectiveness ratios, most concerning interventions for NHL (41%) or CML (30%). Most ratios pertained to rituximab (43%), α interferon (18%), or imatinib (16%), and the most common intervention-disease combination was rituximab (alone or in combination) for NHL (36%).
The median cost-effectiveness ratios fluctuated over time, rising from $35,000/QALY (1996-2002) to $52,000/QALY (2003-2006), then falling to $22,000/QALY (2007-2012).
The median cost-effectiveness ratio reported by industry-funded studies was lower ($26,000/QALY) than for non-industry-funded studies ($33,000/QALY).
Four cost-effectiveness ratios, 1 from an industry-funded study, exceeded $100,000/QALY. This included 2 studies of bortezomib in MM, 1 of α interferon in CML, and 1 of imatinib in CML.
The researchers said these results suggest that many new treatments for hematologic malignancies may confer reasonable value for money spent. The distribution of cost-effectiveness ratios is comparable to those for cancers overall and for other healthcare fields, they said.
This study was funded by internal resources at the Center for the Evaluation of Value and Risk in Health. The center receives funding from federal, private foundation, and pharmaceutical industry sources.
Photo by Bill Branson
A new analysis indicates that certain high-cost therapies for hematologic malignancies provide reasonable value for money spent.
Most cost-effectiveness ratios were lower than thresholds commonly used to establish cost-effectiveness in the US—$50,000 or $100,000 per quality-adjusted life year (QALY) gained.
The median cost-effectiveness ratio was highest for chronic myeloid leukemia (CML), at $55,000/QALY, and lowest for non-Hodgkin lymphoma (NHL), at $21,500/QALY.
Researchers presented these data in Blood.
“Given the increased discussion about the high cost of these treatments, we were somewhat surprised to discover that their cost-effectiveness ratios were lower than expected,” said study author Peter J. Neumann, ScD, of Tufts Medical Center in Boston.
“Our analysis had a small sample size and included both industry- and non-industry-funded studies. In addition, cost-effectiveness ratios may have changed over time as associated costs or benefits have changed. However, the study underscores that debates in healthcare should consider the value of breakthrough drugs and not just costs.”
With that issue in mind, Dr Neumann and his colleagues had conducted a systematic review of studies published between 1996 and 2012 that examined the cost utility of agents for hematologic malignancies. The cost utility of a drug was depicted as a ratio of a drug’s total cost per patient QALY gained.
The researchers identified 29 studies, 22 of which were industry-funded. Nine studies were conducted from a US perspective, 6 from the UK, 3 from Norway, 3 from Sweden, 2 from France, 1 from Canada, 1 from Finland, and 4 from “other” countries.
The team grouped studies according to malignancy—CML, chronic lymphocytic leukemia (CLL), NHL, and multiple myeloma (MM)—as well as by treatment—α interferon, alemtuzumab, bendamustine, bortezomib, dasatinib, imatinib, lenalidomide, rituximab alone or in combination, and thalidomide.
The studies reported 44 cost-effectiveness ratios, most concerning interventions for NHL (41%) or CML (30%). Most ratios pertained to rituximab (43%), α interferon (18%), or imatinib (16%), and the most common intervention-disease combination was rituximab (alone or in combination) for NHL (36%).
The median cost-effectiveness ratios fluctuated over time, rising from $35,000/QALY (1996-2002) to $52,000/QALY (2003-2006), then falling to $22,000/QALY (2007-2012).
The median cost-effectiveness ratio reported by industry-funded studies was lower ($26,000/QALY) than for non-industry-funded studies ($33,000/QALY).
Four cost-effectiveness ratios, 1 from an industry-funded study, exceeded $100,000/QALY. This included 2 studies of bortezomib in MM, 1 of α interferon in CML, and 1 of imatinib in CML.
The researchers said these results suggest that many new treatments for hematologic malignancies may confer reasonable value for money spent. The distribution of cost-effectiveness ratios is comparable to those for cancers overall and for other healthcare fields, they said.
This study was funded by internal resources at the Center for the Evaluation of Value and Risk in Health. The center receives funding from federal, private foundation, and pharmaceutical industry sources.
Photo by Bill Branson
A new analysis indicates that certain high-cost therapies for hematologic malignancies provide reasonable value for money spent.
Most cost-effectiveness ratios were lower than thresholds commonly used to establish cost-effectiveness in the US—$50,000 or $100,000 per quality-adjusted life year (QALY) gained.
The median cost-effectiveness ratio was highest for chronic myeloid leukemia (CML), at $55,000/QALY, and lowest for non-Hodgkin lymphoma (NHL), at $21,500/QALY.
Researchers presented these data in Blood.
“Given the increased discussion about the high cost of these treatments, we were somewhat surprised to discover that their cost-effectiveness ratios were lower than expected,” said study author Peter J. Neumann, ScD, of Tufts Medical Center in Boston.
“Our analysis had a small sample size and included both industry- and non-industry-funded studies. In addition, cost-effectiveness ratios may have changed over time as associated costs or benefits have changed. However, the study underscores that debates in healthcare should consider the value of breakthrough drugs and not just costs.”
With that issue in mind, Dr Neumann and his colleagues had conducted a systematic review of studies published between 1996 and 2012 that examined the cost utility of agents for hematologic malignancies. The cost utility of a drug was depicted as a ratio of a drug’s total cost per patient QALY gained.
The researchers identified 29 studies, 22 of which were industry-funded. Nine studies were conducted from a US perspective, 6 from the UK, 3 from Norway, 3 from Sweden, 2 from France, 1 from Canada, 1 from Finland, and 4 from “other” countries.
The team grouped studies according to malignancy—CML, chronic lymphocytic leukemia (CLL), NHL, and multiple myeloma (MM)—as well as by treatment—α interferon, alemtuzumab, bendamustine, bortezomib, dasatinib, imatinib, lenalidomide, rituximab alone or in combination, and thalidomide.
The studies reported 44 cost-effectiveness ratios, most concerning interventions for NHL (41%) or CML (30%). Most ratios pertained to rituximab (43%), α interferon (18%), or imatinib (16%), and the most common intervention-disease combination was rituximab (alone or in combination) for NHL (36%).
The median cost-effectiveness ratios fluctuated over time, rising from $35,000/QALY (1996-2002) to $52,000/QALY (2003-2006), then falling to $22,000/QALY (2007-2012).
The median cost-effectiveness ratio reported by industry-funded studies was lower ($26,000/QALY) than for non-industry-funded studies ($33,000/QALY).
Four cost-effectiveness ratios, 1 from an industry-funded study, exceeded $100,000/QALY. This included 2 studies of bortezomib in MM, 1 of α interferon in CML, and 1 of imatinib in CML.
The researchers said these results suggest that many new treatments for hematologic malignancies may confer reasonable value for money spent. The distribution of cost-effectiveness ratios is comparable to those for cancers overall and for other healthcare fields, they said.
This study was funded by internal resources at the Center for the Evaluation of Value and Risk in Health. The center receives funding from federal, private foundation, and pharmaceutical industry sources.
EC approves bortezomib for MCL
Photo courtesy of Millennium
The European Commission (EC) has approved bortezomib (Velcade) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) to treat adults with previously untreated mantle cell lymphoma (MCL) in whom hematopoietic stem cell transplant (HSCT) is considered unsuitable.
Now, bortezomib can be marketed for this indication in all 28 countries of the European Union (EU).
Bortezomib is already approved in the EU to treat multiple myeloma (MM), either as monotherapy or in combination with other agents.
The EC’s approval of bortezomib in MCL is based on data from a phase 3 study known as LYM-3002.
This randomized trial included 487 patients with newly diagnosed MCL who were ineligible, or not considered, for HSCT. Patients were randomized to receive VR-CAP or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
The VR-CAP regimen significantly improved progression-free survival (PFS), the primary endpoint, when compared to R-CHOP.
According to an independent review committee, there was a 59% improvement in PFS for the VR-CAP arm compared to the R-CHOP arm, with median times of 24.7 months and 14.4 months, respectively (hazard ratio=0.63; P<0.001).
Study investigators reported a 96% increase in PFS with VR-CAP compared to R-CHOP, with median times of 30.7 months and 16.1 months, respectively (hazard ratio=0.51, P<0.001).
VR-CAP was associated with additional, but manageable, toxicity when compared to R-CHOP. Serious adverse events (AEs) were reported in 38% and 30% of patients, respectively. And grade 3 or higher AEs were reported in 93% and 85% of patients, respectively.
Treatment discontinuation due to AEs occurred in 9% of patients in the VR-CAP arm and 7% in the R-CHOP arm. On-treatment, drug-related deaths occurred in 2% and 3% of patients, respectively.
About bortezomib
Bortezomib works by reversibly interrupting the normal working of cell proteasomes, inducing cancerous cells to stop growing and die.
In addition to the new MCL indication, the drug is approved in the EU to treat various stages of MM. It’s approved in combination with melphalan and prednisone to treat previously untreated adults with MM who are unsuitable for high-dose chemotherapy with HSCT.
Bortezomib is also approved in combination with dexamethasone, or with dexamethasone plus thalidomide, to treat previously untreated MM patients set to receive high-dose chemotherapy followed by HSCT.
And the drug is approved as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone to treat adults with MM whose disease has progressed after at least one other treatment and who have already had, or cannot undergo, HSCT.
Bortezomib is approved in more than 90 countries and has been used to treat more than 550,000 patients worldwide.
The product is co-developed by Millennium, the Takeda Oncology Company, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, and Janssen Pharmaceutical Companies.
Millennium is responsible for commercialization in the US. Janssen Pharmaceutical Companies are responsible for commercialization in Europe and the rest of the world. Takeda Pharmaceutical Company Limited and Janssen Pharmaceutical K.K. co-promote the drug in Japan.
Photo courtesy of Millennium
The European Commission (EC) has approved bortezomib (Velcade) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) to treat adults with previously untreated mantle cell lymphoma (MCL) in whom hematopoietic stem cell transplant (HSCT) is considered unsuitable.
Now, bortezomib can be marketed for this indication in all 28 countries of the European Union (EU).
Bortezomib is already approved in the EU to treat multiple myeloma (MM), either as monotherapy or in combination with other agents.
The EC’s approval of bortezomib in MCL is based on data from a phase 3 study known as LYM-3002.
This randomized trial included 487 patients with newly diagnosed MCL who were ineligible, or not considered, for HSCT. Patients were randomized to receive VR-CAP or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
The VR-CAP regimen significantly improved progression-free survival (PFS), the primary endpoint, when compared to R-CHOP.
According to an independent review committee, there was a 59% improvement in PFS for the VR-CAP arm compared to the R-CHOP arm, with median times of 24.7 months and 14.4 months, respectively (hazard ratio=0.63; P<0.001).
Study investigators reported a 96% increase in PFS with VR-CAP compared to R-CHOP, with median times of 30.7 months and 16.1 months, respectively (hazard ratio=0.51, P<0.001).
VR-CAP was associated with additional, but manageable, toxicity when compared to R-CHOP. Serious adverse events (AEs) were reported in 38% and 30% of patients, respectively. And grade 3 or higher AEs were reported in 93% and 85% of patients, respectively.
Treatment discontinuation due to AEs occurred in 9% of patients in the VR-CAP arm and 7% in the R-CHOP arm. On-treatment, drug-related deaths occurred in 2% and 3% of patients, respectively.
About bortezomib
Bortezomib works by reversibly interrupting the normal working of cell proteasomes, inducing cancerous cells to stop growing and die.
In addition to the new MCL indication, the drug is approved in the EU to treat various stages of MM. It’s approved in combination with melphalan and prednisone to treat previously untreated adults with MM who are unsuitable for high-dose chemotherapy with HSCT.
Bortezomib is also approved in combination with dexamethasone, or with dexamethasone plus thalidomide, to treat previously untreated MM patients set to receive high-dose chemotherapy followed by HSCT.
And the drug is approved as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone to treat adults with MM whose disease has progressed after at least one other treatment and who have already had, or cannot undergo, HSCT.
Bortezomib is approved in more than 90 countries and has been used to treat more than 550,000 patients worldwide.
The product is co-developed by Millennium, the Takeda Oncology Company, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, and Janssen Pharmaceutical Companies.
Millennium is responsible for commercialization in the US. Janssen Pharmaceutical Companies are responsible for commercialization in Europe and the rest of the world. Takeda Pharmaceutical Company Limited and Janssen Pharmaceutical K.K. co-promote the drug in Japan.
Photo courtesy of Millennium
The European Commission (EC) has approved bortezomib (Velcade) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) to treat adults with previously untreated mantle cell lymphoma (MCL) in whom hematopoietic stem cell transplant (HSCT) is considered unsuitable.
Now, bortezomib can be marketed for this indication in all 28 countries of the European Union (EU).
Bortezomib is already approved in the EU to treat multiple myeloma (MM), either as monotherapy or in combination with other agents.
The EC’s approval of bortezomib in MCL is based on data from a phase 3 study known as LYM-3002.
This randomized trial included 487 patients with newly diagnosed MCL who were ineligible, or not considered, for HSCT. Patients were randomized to receive VR-CAP or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
The VR-CAP regimen significantly improved progression-free survival (PFS), the primary endpoint, when compared to R-CHOP.
According to an independent review committee, there was a 59% improvement in PFS for the VR-CAP arm compared to the R-CHOP arm, with median times of 24.7 months and 14.4 months, respectively (hazard ratio=0.63; P<0.001).
Study investigators reported a 96% increase in PFS with VR-CAP compared to R-CHOP, with median times of 30.7 months and 16.1 months, respectively (hazard ratio=0.51, P<0.001).
VR-CAP was associated with additional, but manageable, toxicity when compared to R-CHOP. Serious adverse events (AEs) were reported in 38% and 30% of patients, respectively. And grade 3 or higher AEs were reported in 93% and 85% of patients, respectively.
Treatment discontinuation due to AEs occurred in 9% of patients in the VR-CAP arm and 7% in the R-CHOP arm. On-treatment, drug-related deaths occurred in 2% and 3% of patients, respectively.
About bortezomib
Bortezomib works by reversibly interrupting the normal working of cell proteasomes, inducing cancerous cells to stop growing and die.
In addition to the new MCL indication, the drug is approved in the EU to treat various stages of MM. It’s approved in combination with melphalan and prednisone to treat previously untreated adults with MM who are unsuitable for high-dose chemotherapy with HSCT.
Bortezomib is also approved in combination with dexamethasone, or with dexamethasone plus thalidomide, to treat previously untreated MM patients set to receive high-dose chemotherapy followed by HSCT.
And the drug is approved as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone to treat adults with MM whose disease has progressed after at least one other treatment and who have already had, or cannot undergo, HSCT.
Bortezomib is approved in more than 90 countries and has been used to treat more than 550,000 patients worldwide.
The product is co-developed by Millennium, the Takeda Oncology Company, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, and Janssen Pharmaceutical Companies.
Millennium is responsible for commercialization in the US. Janssen Pharmaceutical Companies are responsible for commercialization in Europe and the rest of the world. Takeda Pharmaceutical Company Limited and Janssen Pharmaceutical K.K. co-promote the drug in Japan.
Aggressiveness of CLL linked to genetic variability
The genetic variability of chronic lymphocytic leukemia (CLL) appears to predict its aggressiveness, according to a study published in Genome Medicine.
Investigators found evidence suggesting that greater variability in gene expression is associated with more aggressive disease.
The team analyzed gene expression in two cohorts of CLL patients—those with IgVH mutations and a good prognosis and those with unmutated CLL who have more aggressive disease.
The researchers examined 70 mutated and 52 unmutated CLL samples, as well as 20 control samples taken from healthy individuals.
Unmutated, aggressive CLL showed increased gene expression variability across individuals, whereas gene expression variability was lower in less aggressive, mutated CLL.
The investigators validated these observations by comparing them against a second sample group consisting of 24 mutated and 36 unmutated CLL samples.
The results suggested that CLL aggressiveness is specifically determined by a set of 500 genes showing increased expression variability across individuals. The genes are involved in processes such as adaptation to the environment, cell death, tumor growth, and drug resistance.
“Our conclusion is that the coefficient of variation for gene expression in CLL efficiently predicts its aggressiveness,” said study author Alfonso Valencia, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain.
“More importantly, if further research confirms these findings, a classifier based on the measurement of gene expression variability could be created to predict the disease subtype of CLL patients.”
The researchers said their next step is to discover the mechanisms responsible for the high levels of expression variability for a given gene across individuals.
Understanding the mechanisms underlying this phenomenon is of crucial relevance for oncology research, the investigators said, as it is linked to tumor heterogeneity, a key feature of cancer progression and drug resistance.
The greater the genetic variability in a tumor, the better it will adapt to its environment, and the more probabilities for this tumor to spread, develop resistance to cancer therapies, and metastasize to distant organs.
The genetic variability of chronic lymphocytic leukemia (CLL) appears to predict its aggressiveness, according to a study published in Genome Medicine.
Investigators found evidence suggesting that greater variability in gene expression is associated with more aggressive disease.
The team analyzed gene expression in two cohorts of CLL patients—those with IgVH mutations and a good prognosis and those with unmutated CLL who have more aggressive disease.
The researchers examined 70 mutated and 52 unmutated CLL samples, as well as 20 control samples taken from healthy individuals.
Unmutated, aggressive CLL showed increased gene expression variability across individuals, whereas gene expression variability was lower in less aggressive, mutated CLL.
The investigators validated these observations by comparing them against a second sample group consisting of 24 mutated and 36 unmutated CLL samples.
The results suggested that CLL aggressiveness is specifically determined by a set of 500 genes showing increased expression variability across individuals. The genes are involved in processes such as adaptation to the environment, cell death, tumor growth, and drug resistance.
“Our conclusion is that the coefficient of variation for gene expression in CLL efficiently predicts its aggressiveness,” said study author Alfonso Valencia, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain.
“More importantly, if further research confirms these findings, a classifier based on the measurement of gene expression variability could be created to predict the disease subtype of CLL patients.”
The researchers said their next step is to discover the mechanisms responsible for the high levels of expression variability for a given gene across individuals.
Understanding the mechanisms underlying this phenomenon is of crucial relevance for oncology research, the investigators said, as it is linked to tumor heterogeneity, a key feature of cancer progression and drug resistance.
The greater the genetic variability in a tumor, the better it will adapt to its environment, and the more probabilities for this tumor to spread, develop resistance to cancer therapies, and metastasize to distant organs.
The genetic variability of chronic lymphocytic leukemia (CLL) appears to predict its aggressiveness, according to a study published in Genome Medicine.
Investigators found evidence suggesting that greater variability in gene expression is associated with more aggressive disease.
The team analyzed gene expression in two cohorts of CLL patients—those with IgVH mutations and a good prognosis and those with unmutated CLL who have more aggressive disease.
The researchers examined 70 mutated and 52 unmutated CLL samples, as well as 20 control samples taken from healthy individuals.
Unmutated, aggressive CLL showed increased gene expression variability across individuals, whereas gene expression variability was lower in less aggressive, mutated CLL.
The investigators validated these observations by comparing them against a second sample group consisting of 24 mutated and 36 unmutated CLL samples.
The results suggested that CLL aggressiveness is specifically determined by a set of 500 genes showing increased expression variability across individuals. The genes are involved in processes such as adaptation to the environment, cell death, tumor growth, and drug resistance.
“Our conclusion is that the coefficient of variation for gene expression in CLL efficiently predicts its aggressiveness,” said study author Alfonso Valencia, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain.
“More importantly, if further research confirms these findings, a classifier based on the measurement of gene expression variability could be created to predict the disease subtype of CLL patients.”
The researchers said their next step is to discover the mechanisms responsible for the high levels of expression variability for a given gene across individuals.
Understanding the mechanisms underlying this phenomenon is of crucial relevance for oncology research, the investigators said, as it is linked to tumor heterogeneity, a key feature of cancer progression and drug resistance.
The greater the genetic variability in a tumor, the better it will adapt to its environment, and the more probabilities for this tumor to spread, develop resistance to cancer therapies, and metastasize to distant organs.
Risk of HBV reactivation ‘underappreciated’
Credit: CDC
Reactivation of the hepatitis B virus (HBV) may be more of a risk than we anticipated, investigators have reported in Hepatology.
Their research indicates that HBV reactivation is associated with the use of chemotherapy, high-dose corticosteroids, biologics targeting tumor necrosis factor-alpha (TNF-α), and agents that aren’t really considered immunosuppressive.
HBV reactivation is also fairly common after organ transplant and hematopoietic stem cell transplant (HSCT).
As reactivation of HBV can be fatal, the study authors suggest routine screening of HBV in all patients prior to the start of these treatments.
The researchers noted that, in September 2013, the US Food and Drug Administration (FDA) issued a Drug Safety Communication in an attempt to decrease the risk of HBV reactivation. The communication advised healthcare professionals to screen patients for HBV prior to the administration of ofatumumab or rituximab.
“[T]his may be just the tip of the iceberg,” said Adrian Di Bisceglie, MD, of Saint Louis University School of Medicine in Missouri.
“Our research suggests that the issue of HBV reactivation may be an underappreciated clinical challenge that extends well beyond the use of just two anti-CD20 medications.”
After a systematic literature review, Dr Di Bisceglie and his colleagues identified 504 studies pertaining to reactivation of HBV.
The investigators reviewed 14 studies in which the antiviral agent lamivudine was used to prevent HBV reactivation in HBsAg-positive patients receiving chemotherapy. Among patients who did not receive lamivudine, HBV reactivation occurred in 32%. Thirteen percent of patients experienced liver failure, and 7% died.
The researchers also looked at patients undergoing HSCT. In one study, 61 patients had resolved HBV infection before HSCT. But 12 of these patients (20%) developed reverse seroconversion (reappearance of HBsAg in a person who was HBsAg-negative, anti-HBc-positive prior to HSCT).
The cumulative probability of reverse seroconversion was 9% a year after HSCT, 21.7% at 2 years, and 42.9% at 4 years.
The investigators also noted that high-dose corticosteroids carry a significant risk of HBV reactivation, both as part of combination treatment for malignancies and when used alone to treat benign conditions.
In addition, the researchers found data showing that HBV reactivation has occurred with antitumor agents that are not thought to be particularly immunosuppressive, such as imatinib and thalidomide. The team said this raises questions about the mechanisms by which drugs are causing HBV reactivation.
The investigators also looked at data from 257 patients with active or recovered HBV infection who received treatment with biological therapies targeting TNF-α.
Forty-two percent of the patients had elevations in serum aminotransferase levels, 39% had reappearance of HBV DNA, 16% had signs and symptoms of liver disease, and 5% died of liver failure.
HBV reactivation was more frequent among patients receiving infliximab than etanercept. It was 7-fold higher among patients who were HBsAg-positive (38%) than those who were HBsAg-negative but anti-HBc-positive (5%).
While it remains unclear how HBV reactivation occurs, experts believe a loss of immune control over viral replication may trigger the process.
“Further study and cooperation between various medical disciplines will help broaden understanding of HBV reactivation,” Dr Di Bisceglie concluded.
Credit: CDC
Reactivation of the hepatitis B virus (HBV) may be more of a risk than we anticipated, investigators have reported in Hepatology.
Their research indicates that HBV reactivation is associated with the use of chemotherapy, high-dose corticosteroids, biologics targeting tumor necrosis factor-alpha (TNF-α), and agents that aren’t really considered immunosuppressive.
HBV reactivation is also fairly common after organ transplant and hematopoietic stem cell transplant (HSCT).
As reactivation of HBV can be fatal, the study authors suggest routine screening of HBV in all patients prior to the start of these treatments.
The researchers noted that, in September 2013, the US Food and Drug Administration (FDA) issued a Drug Safety Communication in an attempt to decrease the risk of HBV reactivation. The communication advised healthcare professionals to screen patients for HBV prior to the administration of ofatumumab or rituximab.
“[T]his may be just the tip of the iceberg,” said Adrian Di Bisceglie, MD, of Saint Louis University School of Medicine in Missouri.
“Our research suggests that the issue of HBV reactivation may be an underappreciated clinical challenge that extends well beyond the use of just two anti-CD20 medications.”
After a systematic literature review, Dr Di Bisceglie and his colleagues identified 504 studies pertaining to reactivation of HBV.
The investigators reviewed 14 studies in which the antiviral agent lamivudine was used to prevent HBV reactivation in HBsAg-positive patients receiving chemotherapy. Among patients who did not receive lamivudine, HBV reactivation occurred in 32%. Thirteen percent of patients experienced liver failure, and 7% died.
The researchers also looked at patients undergoing HSCT. In one study, 61 patients had resolved HBV infection before HSCT. But 12 of these patients (20%) developed reverse seroconversion (reappearance of HBsAg in a person who was HBsAg-negative, anti-HBc-positive prior to HSCT).
The cumulative probability of reverse seroconversion was 9% a year after HSCT, 21.7% at 2 years, and 42.9% at 4 years.
The investigators also noted that high-dose corticosteroids carry a significant risk of HBV reactivation, both as part of combination treatment for malignancies and when used alone to treat benign conditions.
In addition, the researchers found data showing that HBV reactivation has occurred with antitumor agents that are not thought to be particularly immunosuppressive, such as imatinib and thalidomide. The team said this raises questions about the mechanisms by which drugs are causing HBV reactivation.
The investigators also looked at data from 257 patients with active or recovered HBV infection who received treatment with biological therapies targeting TNF-α.
Forty-two percent of the patients had elevations in serum aminotransferase levels, 39% had reappearance of HBV DNA, 16% had signs and symptoms of liver disease, and 5% died of liver failure.
HBV reactivation was more frequent among patients receiving infliximab than etanercept. It was 7-fold higher among patients who were HBsAg-positive (38%) than those who were HBsAg-negative but anti-HBc-positive (5%).
While it remains unclear how HBV reactivation occurs, experts believe a loss of immune control over viral replication may trigger the process.
“Further study and cooperation between various medical disciplines will help broaden understanding of HBV reactivation,” Dr Di Bisceglie concluded.
Credit: CDC
Reactivation of the hepatitis B virus (HBV) may be more of a risk than we anticipated, investigators have reported in Hepatology.
Their research indicates that HBV reactivation is associated with the use of chemotherapy, high-dose corticosteroids, biologics targeting tumor necrosis factor-alpha (TNF-α), and agents that aren’t really considered immunosuppressive.
HBV reactivation is also fairly common after organ transplant and hematopoietic stem cell transplant (HSCT).
As reactivation of HBV can be fatal, the study authors suggest routine screening of HBV in all patients prior to the start of these treatments.
The researchers noted that, in September 2013, the US Food and Drug Administration (FDA) issued a Drug Safety Communication in an attempt to decrease the risk of HBV reactivation. The communication advised healthcare professionals to screen patients for HBV prior to the administration of ofatumumab or rituximab.
“[T]his may be just the tip of the iceberg,” said Adrian Di Bisceglie, MD, of Saint Louis University School of Medicine in Missouri.
“Our research suggests that the issue of HBV reactivation may be an underappreciated clinical challenge that extends well beyond the use of just two anti-CD20 medications.”
After a systematic literature review, Dr Di Bisceglie and his colleagues identified 504 studies pertaining to reactivation of HBV.
The investigators reviewed 14 studies in which the antiviral agent lamivudine was used to prevent HBV reactivation in HBsAg-positive patients receiving chemotherapy. Among patients who did not receive lamivudine, HBV reactivation occurred in 32%. Thirteen percent of patients experienced liver failure, and 7% died.
The researchers also looked at patients undergoing HSCT. In one study, 61 patients had resolved HBV infection before HSCT. But 12 of these patients (20%) developed reverse seroconversion (reappearance of HBsAg in a person who was HBsAg-negative, anti-HBc-positive prior to HSCT).
The cumulative probability of reverse seroconversion was 9% a year after HSCT, 21.7% at 2 years, and 42.9% at 4 years.
The investigators also noted that high-dose corticosteroids carry a significant risk of HBV reactivation, both as part of combination treatment for malignancies and when used alone to treat benign conditions.
In addition, the researchers found data showing that HBV reactivation has occurred with antitumor agents that are not thought to be particularly immunosuppressive, such as imatinib and thalidomide. The team said this raises questions about the mechanisms by which drugs are causing HBV reactivation.
The investigators also looked at data from 257 patients with active or recovered HBV infection who received treatment with biological therapies targeting TNF-α.
Forty-two percent of the patients had elevations in serum aminotransferase levels, 39% had reappearance of HBV DNA, 16% had signs and symptoms of liver disease, and 5% died of liver failure.
HBV reactivation was more frequent among patients receiving infliximab than etanercept. It was 7-fold higher among patients who were HBsAg-positive (38%) than those who were HBsAg-negative but anti-HBc-positive (5%).
While it remains unclear how HBV reactivation occurs, experts believe a loss of immune control over viral replication may trigger the process.
“Further study and cooperation between various medical disciplines will help broaden understanding of HBV reactivation,” Dr Di Bisceglie concluded.
Vaccine gets orphan designation for ATLL
The European Medicines Agency (EMA) has granted orphan drug designation for a therapeutic vaccine candidate known as THV02 to treat adult T-cell leukemia/lymphoma (ATLL).
THV02 is an experimental treatment composed of 2 lentiviral vectors to be used in a prime/boost regimen in ATLL patients infected by the HTLV-1 virus.
Both investigational drugs encode the same antigens, derived from 4 proteins of the HTLV-1 virus.
THV02 is intended to induce an immune response against HTLV antigens born by ATLL with the aim of enabling the patients’ immune system to fight leukemic cells.
Preclinical evaluation has suggested that THV02 is safe, and the vaccine has presented an “unprecedented” immunogenicity profile in several models, according to THERAVECTYS, the company developing THV02.
“Preclinical immunogenicity results obtained to date are very promising, and we are really excited by the prospect of bringing a safe and better-tolerated alternative to patients who are desperately in need of a treatment,” said Déborah Revaud, the senior scientist in charge of developing THV02.
The EMA grants orphan designation to drugs in development intended for the treatment, prevention, or diagnosis of life-threatening or chronically debilitating diseases occurring in fewer than 5 in 10,000 people.
The designation allows sponsors to benefit from an accelerated development process, financial incentives, and a 10-year period of market exclusivity once the drug is on the market.
“We are extremely pleased that the European Medicines Agency has granted an orphan drug status to our vaccine candidate against ATLL,” said Emmanuelle Sabbah-Petrover, PhD, head of regulatory affairs at THERAVECTYS.
“We expect to recruit our first patients towards the end of Q3 2015 in Europe and advance further developments in the US and in Japan in 2016.”
Should THV02 demonstrate a convincing safety and efficacy profile during its development against ATLL, THERAVECTYS said it will consider developing the vaccine for HTLV-related infections as treatment and possibly as prophylaxis.
The European Medicines Agency (EMA) has granted orphan drug designation for a therapeutic vaccine candidate known as THV02 to treat adult T-cell leukemia/lymphoma (ATLL).
THV02 is an experimental treatment composed of 2 lentiviral vectors to be used in a prime/boost regimen in ATLL patients infected by the HTLV-1 virus.
Both investigational drugs encode the same antigens, derived from 4 proteins of the HTLV-1 virus.
THV02 is intended to induce an immune response against HTLV antigens born by ATLL with the aim of enabling the patients’ immune system to fight leukemic cells.
Preclinical evaluation has suggested that THV02 is safe, and the vaccine has presented an “unprecedented” immunogenicity profile in several models, according to THERAVECTYS, the company developing THV02.
“Preclinical immunogenicity results obtained to date are very promising, and we are really excited by the prospect of bringing a safe and better-tolerated alternative to patients who are desperately in need of a treatment,” said Déborah Revaud, the senior scientist in charge of developing THV02.
The EMA grants orphan designation to drugs in development intended for the treatment, prevention, or diagnosis of life-threatening or chronically debilitating diseases occurring in fewer than 5 in 10,000 people.
The designation allows sponsors to benefit from an accelerated development process, financial incentives, and a 10-year period of market exclusivity once the drug is on the market.
“We are extremely pleased that the European Medicines Agency has granted an orphan drug status to our vaccine candidate against ATLL,” said Emmanuelle Sabbah-Petrover, PhD, head of regulatory affairs at THERAVECTYS.
“We expect to recruit our first patients towards the end of Q3 2015 in Europe and advance further developments in the US and in Japan in 2016.”
Should THV02 demonstrate a convincing safety and efficacy profile during its development against ATLL, THERAVECTYS said it will consider developing the vaccine for HTLV-related infections as treatment and possibly as prophylaxis.
The European Medicines Agency (EMA) has granted orphan drug designation for a therapeutic vaccine candidate known as THV02 to treat adult T-cell leukemia/lymphoma (ATLL).
THV02 is an experimental treatment composed of 2 lentiviral vectors to be used in a prime/boost regimen in ATLL patients infected by the HTLV-1 virus.
Both investigational drugs encode the same antigens, derived from 4 proteins of the HTLV-1 virus.
THV02 is intended to induce an immune response against HTLV antigens born by ATLL with the aim of enabling the patients’ immune system to fight leukemic cells.
Preclinical evaluation has suggested that THV02 is safe, and the vaccine has presented an “unprecedented” immunogenicity profile in several models, according to THERAVECTYS, the company developing THV02.
“Preclinical immunogenicity results obtained to date are very promising, and we are really excited by the prospect of bringing a safe and better-tolerated alternative to patients who are desperately in need of a treatment,” said Déborah Revaud, the senior scientist in charge of developing THV02.
The EMA grants orphan designation to drugs in development intended for the treatment, prevention, or diagnosis of life-threatening or chronically debilitating diseases occurring in fewer than 5 in 10,000 people.
The designation allows sponsors to benefit from an accelerated development process, financial incentives, and a 10-year period of market exclusivity once the drug is on the market.
“We are extremely pleased that the European Medicines Agency has granted an orphan drug status to our vaccine candidate against ATLL,” said Emmanuelle Sabbah-Petrover, PhD, head of regulatory affairs at THERAVECTYS.
“We expect to recruit our first patients towards the end of Q3 2015 in Europe and advance further developments in the US and in Japan in 2016.”
Should THV02 demonstrate a convincing safety and efficacy profile during its development against ATLL, THERAVECTYS said it will consider developing the vaccine for HTLV-related infections as treatment and possibly as prophylaxis.
Team creates new cells for modeling malaria
infection in iPSC-derived liver
cells 8 days after infection
Credit: Shengyong Ng et al.
Researchers say they’ve found a way to grow liver-like cells from induced pluripotent stem cells (iPSCs).
The liver-like cells can be infected with several strains of the malaria parasite and respond to existing drugs the same way mature human liver cells do.
The new cells, described in Stem Cell Reports, could allow scientists to test drugs on cells from people with different genetic backgrounds, who may respond differently to malaria infection and treatment.
Modeling infection
Until now, malaria researchers have not had many reliable ways to test new drugs in liver tissue.
“What’s historically been done is people have tried to make do with the systems that were available,” said study author Sangeeta Bhatia, MD, PhD, of the Massachusetts Institute of Technology in Cambridge.
In 2013, Dr Bhatia and her colleagues showed they could model malaria infection in hepatocytes from human donors. However, this generates only a limited supply from each donor, and not all of the cells work well for drug studies.
The researchers then turned to iPSCs, which can be generated from human skin cells by adding reprogramming factors. To create liver cells, the researchers added a series of growth factors, including hepatocyte growth factor, to the iPSCs.
The team generated these cells in 2012 and used them to model infection of hepatitis C. However, these cells, known as hepatocyte-like cells, did not seem to be as mature as real adult liver cells.
In the current study, the researchers found these cells could be infected with several strains of malaria. But, initially, the cells did not respond to drugs in the same way as adult liver cells.
In particular, they were not sensitive to primaquine, which works only if cells have a certain set of drug-metabolism enzymes found in mature liver cells.
To induce the cells to become more mature and turn on these metabolic enzymes, the researchers added a molecule they had identified in a previous study. This compound, which the researchers call a “maturin,” stimulated the cells to turn on those enzymes, which made them sensitive to primaquine.
Toward better drugs
The team is now working with the nonprofit foundation Medical Malaria Ventures to test about 10 potential malaria drugs that are in the pipeline, first using adult donor liver cells and then the hepatocyte-like cells generated in this study.
These cells could also prove useful to help identify new drug targets, the researchers said. In this study, they found the liver-like cells can be infected with malaria when they are still in the equivalent of fetal stages of development, when they become hepatoblasts, which are precursors to hepatocytes.
In future studies, the researchers plan to investigate which genes get turned on when the cells become susceptible to infection, which may suggest new targets for malaria drugs.
They also hope to compare the genes needed for malaria infection with those needed for hepatitis infection, in hopes of identifying common pathways to target for both diseases.
infection in iPSC-derived liver
cells 8 days after infection
Credit: Shengyong Ng et al.
Researchers say they’ve found a way to grow liver-like cells from induced pluripotent stem cells (iPSCs).
The liver-like cells can be infected with several strains of the malaria parasite and respond to existing drugs the same way mature human liver cells do.
The new cells, described in Stem Cell Reports, could allow scientists to test drugs on cells from people with different genetic backgrounds, who may respond differently to malaria infection and treatment.
Modeling infection
Until now, malaria researchers have not had many reliable ways to test new drugs in liver tissue.
“What’s historically been done is people have tried to make do with the systems that were available,” said study author Sangeeta Bhatia, MD, PhD, of the Massachusetts Institute of Technology in Cambridge.
In 2013, Dr Bhatia and her colleagues showed they could model malaria infection in hepatocytes from human donors. However, this generates only a limited supply from each donor, and not all of the cells work well for drug studies.
The researchers then turned to iPSCs, which can be generated from human skin cells by adding reprogramming factors. To create liver cells, the researchers added a series of growth factors, including hepatocyte growth factor, to the iPSCs.
The team generated these cells in 2012 and used them to model infection of hepatitis C. However, these cells, known as hepatocyte-like cells, did not seem to be as mature as real adult liver cells.
In the current study, the researchers found these cells could be infected with several strains of malaria. But, initially, the cells did not respond to drugs in the same way as adult liver cells.
In particular, they were not sensitive to primaquine, which works only if cells have a certain set of drug-metabolism enzymes found in mature liver cells.
To induce the cells to become more mature and turn on these metabolic enzymes, the researchers added a molecule they had identified in a previous study. This compound, which the researchers call a “maturin,” stimulated the cells to turn on those enzymes, which made them sensitive to primaquine.
Toward better drugs
The team is now working with the nonprofit foundation Medical Malaria Ventures to test about 10 potential malaria drugs that are in the pipeline, first using adult donor liver cells and then the hepatocyte-like cells generated in this study.
These cells could also prove useful to help identify new drug targets, the researchers said. In this study, they found the liver-like cells can be infected with malaria when they are still in the equivalent of fetal stages of development, when they become hepatoblasts, which are precursors to hepatocytes.
In future studies, the researchers plan to investigate which genes get turned on when the cells become susceptible to infection, which may suggest new targets for malaria drugs.
They also hope to compare the genes needed for malaria infection with those needed for hepatitis infection, in hopes of identifying common pathways to target for both diseases.
infection in iPSC-derived liver
cells 8 days after infection
Credit: Shengyong Ng et al.
Researchers say they’ve found a way to grow liver-like cells from induced pluripotent stem cells (iPSCs).
The liver-like cells can be infected with several strains of the malaria parasite and respond to existing drugs the same way mature human liver cells do.
The new cells, described in Stem Cell Reports, could allow scientists to test drugs on cells from people with different genetic backgrounds, who may respond differently to malaria infection and treatment.
Modeling infection
Until now, malaria researchers have not had many reliable ways to test new drugs in liver tissue.
“What’s historically been done is people have tried to make do with the systems that were available,” said study author Sangeeta Bhatia, MD, PhD, of the Massachusetts Institute of Technology in Cambridge.
In 2013, Dr Bhatia and her colleagues showed they could model malaria infection in hepatocytes from human donors. However, this generates only a limited supply from each donor, and not all of the cells work well for drug studies.
The researchers then turned to iPSCs, which can be generated from human skin cells by adding reprogramming factors. To create liver cells, the researchers added a series of growth factors, including hepatocyte growth factor, to the iPSCs.
The team generated these cells in 2012 and used them to model infection of hepatitis C. However, these cells, known as hepatocyte-like cells, did not seem to be as mature as real adult liver cells.
In the current study, the researchers found these cells could be infected with several strains of malaria. But, initially, the cells did not respond to drugs in the same way as adult liver cells.
In particular, they were not sensitive to primaquine, which works only if cells have a certain set of drug-metabolism enzymes found in mature liver cells.
To induce the cells to become more mature and turn on these metabolic enzymes, the researchers added a molecule they had identified in a previous study. This compound, which the researchers call a “maturin,” stimulated the cells to turn on those enzymes, which made them sensitive to primaquine.
Toward better drugs
The team is now working with the nonprofit foundation Medical Malaria Ventures to test about 10 potential malaria drugs that are in the pipeline, first using adult donor liver cells and then the hepatocyte-like cells generated in this study.
These cells could also prove useful to help identify new drug targets, the researchers said. In this study, they found the liver-like cells can be infected with malaria when they are still in the equivalent of fetal stages of development, when they become hepatoblasts, which are precursors to hepatocytes.
In future studies, the researchers plan to investigate which genes get turned on when the cells become susceptible to infection, which may suggest new targets for malaria drugs.
They also hope to compare the genes needed for malaria infection with those needed for hepatitis infection, in hopes of identifying common pathways to target for both diseases.
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.
Memory T cells can fight CMV infection
CMV infection
Transplanting a small number of antiviral memory T cells along with donor hematopoietic stem cells can fight and may even prevent cytomegalovirus (CMV) disease in transplant recipients, according to preclinical research published in the Journal of Immunology.
To date, researchers have focused on developing anti-CMV immunotherapy with effector-phenotype CD8+ T cells (TEFF cells), which attack and kill virally infected host cells.
But Christopher Snyder, PhD, of Thomas Jefferson University in Philadelphia, Pennsylvania, and his colleagues found that CMV-specific TEFF cells divide poorly in response to CMV infection or reactivation in mouse models.
So they wondered if CMV-specific memory-phenotype CD8+ T cells (TM cells)—which act more like stem cells—could help control the infection long-term.
The group showed that a small number of TM cells were enough to produce and repeatedly replenish all of the TEFF cells needed to fight CMV.
The infused TM cells became major contributors to the recipient antiviral immune response, persisting for at least 3 months’ time and producing TEFF cells at a steady stream.
To determine whether these cells have counterparts in humans, Dr Snyder and his colleagues compared the genomic fingerprints of mouse and human TM cells that were specific for CMV. Results showed the two had similar profiles.
“This suggested that human and mouse CMV-specific memory T cells are very similar populations,” said study author Michael Quinn, an MD/PhD student at Thomas Jefferson University.
“Therefore, infusing similar cells into humans could improve on immunotherapeutic methods for controlling CMV infection. This may be a valuable approach to keep the disease from emerging in people.”
Dr Snyder added, “Our data argue for developing new clinical trials focused specifically on using these T memory cells, in order to determine if it would indeed be better than current therapeutic options.”
CMV infection
Transplanting a small number of antiviral memory T cells along with donor hematopoietic stem cells can fight and may even prevent cytomegalovirus (CMV) disease in transplant recipients, according to preclinical research published in the Journal of Immunology.
To date, researchers have focused on developing anti-CMV immunotherapy with effector-phenotype CD8+ T cells (TEFF cells), which attack and kill virally infected host cells.
But Christopher Snyder, PhD, of Thomas Jefferson University in Philadelphia, Pennsylvania, and his colleagues found that CMV-specific TEFF cells divide poorly in response to CMV infection or reactivation in mouse models.
So they wondered if CMV-specific memory-phenotype CD8+ T cells (TM cells)—which act more like stem cells—could help control the infection long-term.
The group showed that a small number of TM cells were enough to produce and repeatedly replenish all of the TEFF cells needed to fight CMV.
The infused TM cells became major contributors to the recipient antiviral immune response, persisting for at least 3 months’ time and producing TEFF cells at a steady stream.
To determine whether these cells have counterparts in humans, Dr Snyder and his colleagues compared the genomic fingerprints of mouse and human TM cells that were specific for CMV. Results showed the two had similar profiles.
“This suggested that human and mouse CMV-specific memory T cells are very similar populations,” said study author Michael Quinn, an MD/PhD student at Thomas Jefferson University.
“Therefore, infusing similar cells into humans could improve on immunotherapeutic methods for controlling CMV infection. This may be a valuable approach to keep the disease from emerging in people.”
Dr Snyder added, “Our data argue for developing new clinical trials focused specifically on using these T memory cells, in order to determine if it would indeed be better than current therapeutic options.”
CMV infection
Transplanting a small number of antiviral memory T cells along with donor hematopoietic stem cells can fight and may even prevent cytomegalovirus (CMV) disease in transplant recipients, according to preclinical research published in the Journal of Immunology.
To date, researchers have focused on developing anti-CMV immunotherapy with effector-phenotype CD8+ T cells (TEFF cells), which attack and kill virally infected host cells.
But Christopher Snyder, PhD, of Thomas Jefferson University in Philadelphia, Pennsylvania, and his colleagues found that CMV-specific TEFF cells divide poorly in response to CMV infection or reactivation in mouse models.
So they wondered if CMV-specific memory-phenotype CD8+ T cells (TM cells)—which act more like stem cells—could help control the infection long-term.
The group showed that a small number of TM cells were enough to produce and repeatedly replenish all of the TEFF cells needed to fight CMV.
The infused TM cells became major contributors to the recipient antiviral immune response, persisting for at least 3 months’ time and producing TEFF cells at a steady stream.
To determine whether these cells have counterparts in humans, Dr Snyder and his colleagues compared the genomic fingerprints of mouse and human TM cells that were specific for CMV. Results showed the two had similar profiles.
“This suggested that human and mouse CMV-specific memory T cells are very similar populations,” said study author Michael Quinn, an MD/PhD student at Thomas Jefferson University.
“Therefore, infusing similar cells into humans could improve on immunotherapeutic methods for controlling CMV infection. This may be a valuable approach to keep the disease from emerging in people.”
Dr Snyder added, “Our data argue for developing new clinical trials focused specifically on using these T memory cells, in order to determine if it would indeed be better than current therapeutic options.”
mAb shows ‘modest activity’ in rel/ref MM
Photo by Linda Bartlett
The monoclonal IgM antibody PAT-SM6 was “well-tolerated” and showed “modest clinical activity” in patients with relapsed or refractory multiple myeloma (MM), researchers reported in haematologica.
Adverse events occurred in all 12 patients enrolled in the phase 1/2a study, but most were considered unrelated to treatment.
A third of patients, all of whom had progressive disease upon study entry, achieved stable disease after receiving PAT-SM6. The remaining patients progressed.
Leo Rasche, MD, of University Hospital Wurzburg in Germany, and his colleagues conducted this study. It was funded, in part, by Patrys Limited, the company developing PAT-SM6.
The study included 12 heavily pretreated MM patients. They had a median age of 69.5 years and a long-standing history of MM (range, 3.25 to 15.75 years). They had received a median of 3.9 prior lines of therapy (range, 2-7).
Patients received 4 escalating doses of PAT-SM6, over a period of 2 weeks, via intravenous infusions at 0.3 mg/kg, 1 mg/kg, 3 mg/kg, and 6 mg/kg.
Safety data
There were 54 treatment-emergent adverse events in all 12 patients. However, there were no dose-limiting toxicities and no deaths. The maximum tolerated dose has not been reached.
More than 80% of the adverse events were of mild to moderate intensity. Two patients (16.6%) each experienced a single serious event. One patient had acute back pain, and one had a bile duct stone. Neither of these events was considered treatment-related.
Twenty-one adverse events were considered treatment-related. This included leukopenia (66.6%), neutropenia (50%), hypertension (16.6%), catheter-related thrombophlebitis (8.3%), injection site erythema (8.3%), slight headache (8.3%), C-reactive protein increase (8.3%), and hypertriglyceridemia (8.3%).
Efficacy data
Most patients progressed following treatment, but 4 (33.3%) had stable disease. The investigators noted that stable disease is not necessarily connected with a clinical benefit, so they analyzed the 4 patients in detail.
Patient 4, who received PAT-SM6 at 1 mg/kg, entered the study with high-risk disease. The patient had 13q deletion and 1q21 gain, had received 5 prior lines of therapy, and was refractory to novel agents, including pomalidomide and bortezomib.
The patient was treatment-free for 1 month prior to receiving PAT-SM6. During treatment, there were no symptoms of active myeloma, and the patient asked to continue salvage therapy 1 week after the end of the study.
Patient 7, who received PAT-SM6 at 3 mg/kg, had been diagnosed with MM for 15 years and had received 4 prior lines of therapy.
The patient’s treatment-free interval before receiving PAT-SM6 was 30 months. After PAT-SM6, the patient was therapy-free for 4.6 months.
Patient 10, who received PAT-SM6 at 6mg/kg, had 6 prior lines of therapy, including tandem autologous stem cell transplant and several polychemotherapeutic regimens.
The patient was therapy-free for 4 months prior to receiving PAT-SM6. The patient requested salvage therapy 1 month after receiving PAT-SM6.
Patient 11, who received PAT-SM6 at 6mg/kg, had 4 prior lines of therapy and was refractory to both lenalidomide and thalidomide.
The patient’s treatment-free interval prior to PAT-SM6 was 12 months. After PAT-SM6, the patient was therapy-free for 5.2 months.
The researchers said additional trials testing PAT-SM6 in combination with other MM therapies are planned. PAT-SM6 has received orphan drug designation for MM in the US and the European Union.
Photo by Linda Bartlett
The monoclonal IgM antibody PAT-SM6 was “well-tolerated” and showed “modest clinical activity” in patients with relapsed or refractory multiple myeloma (MM), researchers reported in haematologica.
Adverse events occurred in all 12 patients enrolled in the phase 1/2a study, but most were considered unrelated to treatment.
A third of patients, all of whom had progressive disease upon study entry, achieved stable disease after receiving PAT-SM6. The remaining patients progressed.
Leo Rasche, MD, of University Hospital Wurzburg in Germany, and his colleagues conducted this study. It was funded, in part, by Patrys Limited, the company developing PAT-SM6.
The study included 12 heavily pretreated MM patients. They had a median age of 69.5 years and a long-standing history of MM (range, 3.25 to 15.75 years). They had received a median of 3.9 prior lines of therapy (range, 2-7).
Patients received 4 escalating doses of PAT-SM6, over a period of 2 weeks, via intravenous infusions at 0.3 mg/kg, 1 mg/kg, 3 mg/kg, and 6 mg/kg.
Safety data
There were 54 treatment-emergent adverse events in all 12 patients. However, there were no dose-limiting toxicities and no deaths. The maximum tolerated dose has not been reached.
More than 80% of the adverse events were of mild to moderate intensity. Two patients (16.6%) each experienced a single serious event. One patient had acute back pain, and one had a bile duct stone. Neither of these events was considered treatment-related.
Twenty-one adverse events were considered treatment-related. This included leukopenia (66.6%), neutropenia (50%), hypertension (16.6%), catheter-related thrombophlebitis (8.3%), injection site erythema (8.3%), slight headache (8.3%), C-reactive protein increase (8.3%), and hypertriglyceridemia (8.3%).
Efficacy data
Most patients progressed following treatment, but 4 (33.3%) had stable disease. The investigators noted that stable disease is not necessarily connected with a clinical benefit, so they analyzed the 4 patients in detail.
Patient 4, who received PAT-SM6 at 1 mg/kg, entered the study with high-risk disease. The patient had 13q deletion and 1q21 gain, had received 5 prior lines of therapy, and was refractory to novel agents, including pomalidomide and bortezomib.
The patient was treatment-free for 1 month prior to receiving PAT-SM6. During treatment, there were no symptoms of active myeloma, and the patient asked to continue salvage therapy 1 week after the end of the study.
Patient 7, who received PAT-SM6 at 3 mg/kg, had been diagnosed with MM for 15 years and had received 4 prior lines of therapy.
The patient’s treatment-free interval before receiving PAT-SM6 was 30 months. After PAT-SM6, the patient was therapy-free for 4.6 months.
Patient 10, who received PAT-SM6 at 6mg/kg, had 6 prior lines of therapy, including tandem autologous stem cell transplant and several polychemotherapeutic regimens.
The patient was therapy-free for 4 months prior to receiving PAT-SM6. The patient requested salvage therapy 1 month after receiving PAT-SM6.
Patient 11, who received PAT-SM6 at 6mg/kg, had 4 prior lines of therapy and was refractory to both lenalidomide and thalidomide.
The patient’s treatment-free interval prior to PAT-SM6 was 12 months. After PAT-SM6, the patient was therapy-free for 5.2 months.
The researchers said additional trials testing PAT-SM6 in combination with other MM therapies are planned. PAT-SM6 has received orphan drug designation for MM in the US and the European Union.
Photo by Linda Bartlett
The monoclonal IgM antibody PAT-SM6 was “well-tolerated” and showed “modest clinical activity” in patients with relapsed or refractory multiple myeloma (MM), researchers reported in haematologica.
Adverse events occurred in all 12 patients enrolled in the phase 1/2a study, but most were considered unrelated to treatment.
A third of patients, all of whom had progressive disease upon study entry, achieved stable disease after receiving PAT-SM6. The remaining patients progressed.
Leo Rasche, MD, of University Hospital Wurzburg in Germany, and his colleagues conducted this study. It was funded, in part, by Patrys Limited, the company developing PAT-SM6.
The study included 12 heavily pretreated MM patients. They had a median age of 69.5 years and a long-standing history of MM (range, 3.25 to 15.75 years). They had received a median of 3.9 prior lines of therapy (range, 2-7).
Patients received 4 escalating doses of PAT-SM6, over a period of 2 weeks, via intravenous infusions at 0.3 mg/kg, 1 mg/kg, 3 mg/kg, and 6 mg/kg.
Safety data
There were 54 treatment-emergent adverse events in all 12 patients. However, there were no dose-limiting toxicities and no deaths. The maximum tolerated dose has not been reached.
More than 80% of the adverse events were of mild to moderate intensity. Two patients (16.6%) each experienced a single serious event. One patient had acute back pain, and one had a bile duct stone. Neither of these events was considered treatment-related.
Twenty-one adverse events were considered treatment-related. This included leukopenia (66.6%), neutropenia (50%), hypertension (16.6%), catheter-related thrombophlebitis (8.3%), injection site erythema (8.3%), slight headache (8.3%), C-reactive protein increase (8.3%), and hypertriglyceridemia (8.3%).
Efficacy data
Most patients progressed following treatment, but 4 (33.3%) had stable disease. The investigators noted that stable disease is not necessarily connected with a clinical benefit, so they analyzed the 4 patients in detail.
Patient 4, who received PAT-SM6 at 1 mg/kg, entered the study with high-risk disease. The patient had 13q deletion and 1q21 gain, had received 5 prior lines of therapy, and was refractory to novel agents, including pomalidomide and bortezomib.
The patient was treatment-free for 1 month prior to receiving PAT-SM6. During treatment, there were no symptoms of active myeloma, and the patient asked to continue salvage therapy 1 week after the end of the study.
Patient 7, who received PAT-SM6 at 3 mg/kg, had been diagnosed with MM for 15 years and had received 4 prior lines of therapy.
The patient’s treatment-free interval before receiving PAT-SM6 was 30 months. After PAT-SM6, the patient was therapy-free for 4.6 months.
Patient 10, who received PAT-SM6 at 6mg/kg, had 6 prior lines of therapy, including tandem autologous stem cell transplant and several polychemotherapeutic regimens.
The patient was therapy-free for 4 months prior to receiving PAT-SM6. The patient requested salvage therapy 1 month after receiving PAT-SM6.
Patient 11, who received PAT-SM6 at 6mg/kg, had 4 prior lines of therapy and was refractory to both lenalidomide and thalidomide.
The patient’s treatment-free interval prior to PAT-SM6 was 12 months. After PAT-SM6, the patient was therapy-free for 5.2 months.
The researchers said additional trials testing PAT-SM6 in combination with other MM therapies are planned. PAT-SM6 has received orphan drug designation for MM in the US and the European Union.