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Groups launch open portal for cancer models
The European Bioinformatics Institute (EMBL-EBI) and The Jackson Laboratory (JAX) have developed an open cancer research portal for patient-derived xenograft (PDX) models.
The portal, known as PDX Finder, catalogues PDX models from numerous global repositories.
At present, PDX Finder contains more than 1900 models for a range of cancers, including hematologic malignancies.
Researchers can search for PDX models and submit their own on the PDX Finder website: http://www.pdxfinder.org.
“PDX models are increasingly recognized as clinically relevant because they retain the patient tumor characteristics and imitate a specific patient’s response to drugs more accurately than other models,” said Nathalie Conte, PDX Finder project lead at EMBL-EBI.
“However, until now, there was no open central catalogue for PDX models. PDX Finder enables cancer researchers to search through a wider variety of models more quickly, saving valuable time and enabling collaborations.”
PDX Finder builds on JAX’s PDX resource, which was developed in partnership with more than 20 medical centers in the US, and EMBL-EBI’s membership of EurOPDX. This ensures the scope and reach of PDX Finder is wider than any other individual resource available, according to JAX and EMBL-EBI.
“Both EMBL-EBI and JAX received independent funding from the National Cancer Institute [NCI] for projects that included implementation of online catalogues for PDX models,” noted Carol Bult, scientific director of the JAX PDX resource.
“Both groups had the goal to help basic and clinical cancer researchers find relevant models fast. With approval from the NCI, we instead collaborated to build a single, unified portal with international scope.”
The launch of PDX Finder comes just months after EMBL-EBI and JAX published the PDX minimal information standard, which sets standards for basic information needed to describe essential properties of a PDX model.
The standard ensures that every model in PDX Finder is carefully described to help researchers choose models that are most relevant to their work.
The European Bioinformatics Institute (EMBL-EBI) and The Jackson Laboratory (JAX) have developed an open cancer research portal for patient-derived xenograft (PDX) models.
The portal, known as PDX Finder, catalogues PDX models from numerous global repositories.
At present, PDX Finder contains more than 1900 models for a range of cancers, including hematologic malignancies.
Researchers can search for PDX models and submit their own on the PDX Finder website: http://www.pdxfinder.org.
“PDX models are increasingly recognized as clinically relevant because they retain the patient tumor characteristics and imitate a specific patient’s response to drugs more accurately than other models,” said Nathalie Conte, PDX Finder project lead at EMBL-EBI.
“However, until now, there was no open central catalogue for PDX models. PDX Finder enables cancer researchers to search through a wider variety of models more quickly, saving valuable time and enabling collaborations.”
PDX Finder builds on JAX’s PDX resource, which was developed in partnership with more than 20 medical centers in the US, and EMBL-EBI’s membership of EurOPDX. This ensures the scope and reach of PDX Finder is wider than any other individual resource available, according to JAX and EMBL-EBI.
“Both EMBL-EBI and JAX received independent funding from the National Cancer Institute [NCI] for projects that included implementation of online catalogues for PDX models,” noted Carol Bult, scientific director of the JAX PDX resource.
“Both groups had the goal to help basic and clinical cancer researchers find relevant models fast. With approval from the NCI, we instead collaborated to build a single, unified portal with international scope.”
The launch of PDX Finder comes just months after EMBL-EBI and JAX published the PDX minimal information standard, which sets standards for basic information needed to describe essential properties of a PDX model.
The standard ensures that every model in PDX Finder is carefully described to help researchers choose models that are most relevant to their work.
The European Bioinformatics Institute (EMBL-EBI) and The Jackson Laboratory (JAX) have developed an open cancer research portal for patient-derived xenograft (PDX) models.
The portal, known as PDX Finder, catalogues PDX models from numerous global repositories.
At present, PDX Finder contains more than 1900 models for a range of cancers, including hematologic malignancies.
Researchers can search for PDX models and submit their own on the PDX Finder website: http://www.pdxfinder.org.
“PDX models are increasingly recognized as clinically relevant because they retain the patient tumor characteristics and imitate a specific patient’s response to drugs more accurately than other models,” said Nathalie Conte, PDX Finder project lead at EMBL-EBI.
“However, until now, there was no open central catalogue for PDX models. PDX Finder enables cancer researchers to search through a wider variety of models more quickly, saving valuable time and enabling collaborations.”
PDX Finder builds on JAX’s PDX resource, which was developed in partnership with more than 20 medical centers in the US, and EMBL-EBI’s membership of EurOPDX. This ensures the scope and reach of PDX Finder is wider than any other individual resource available, according to JAX and EMBL-EBI.
“Both EMBL-EBI and JAX received independent funding from the National Cancer Institute [NCI] for projects that included implementation of online catalogues for PDX models,” noted Carol Bult, scientific director of the JAX PDX resource.
“Both groups had the goal to help basic and clinical cancer researchers find relevant models fast. With approval from the NCI, we instead collaborated to build a single, unified portal with international scope.”
The launch of PDX Finder comes just months after EMBL-EBI and JAX published the PDX minimal information standard, which sets standards for basic information needed to describe essential properties of a PDX model.
The standard ensures that every model in PDX Finder is carefully described to help researchers choose models that are most relevant to their work.
PDPK1 could be novel target in MCL
Researchers may have found a new therapeutic approach for treating mantle cell lymphoma (MCL) by targeting 3-phosphoinositide-dependent protein kinase 1 (PDPK1).
Saori Maegawa and colleagues at Kyoto Prefectural University of Medicine in Japan, evaluated PDPK1 activity in patient-derived primary B-cell lymphoma cells by immunohistochemical staining of p-PDPK1Ser241 (p-PDPK1) in tissue specimens from seven patients with MCL, six patients with diffuse large B-cell lymphoma, and five patients with follicular lymphoma. All specimens were biopsied at initial diagnosis, before starting treatment.
“Our study showed that PDPK1 inhibition caused inactivation of RSK2-NTKD, as well as the decrease of total RSK2 protein, but not of AKT, in MCL-derived cells,” the researchers wrote in Experimental Hematology. “This implies that RSK2 activity is mainly regulated by PDPK1 at both the transcriptional expression and post-translational levels, but AKT activity is regulated by a signaling pathway that does not interact with a PDPK1-mediated pathway in MCL.”
If a PDPK1 inhibitor is pursued as clinical target, the researchers said careful monitoring for hyperglycemia may be required since impaired glucose metabolism is commonly seen with AKT inhibitors. Future research in MCL could also be directed toward the targeting of RSK2-NTKD, the researchers wrote.
SOURCE: Maegawa S et al. Exp Hematol. 2018 Mar;59:72-81.e2.
Researchers may have found a new therapeutic approach for treating mantle cell lymphoma (MCL) by targeting 3-phosphoinositide-dependent protein kinase 1 (PDPK1).
Saori Maegawa and colleagues at Kyoto Prefectural University of Medicine in Japan, evaluated PDPK1 activity in patient-derived primary B-cell lymphoma cells by immunohistochemical staining of p-PDPK1Ser241 (p-PDPK1) in tissue specimens from seven patients with MCL, six patients with diffuse large B-cell lymphoma, and five patients with follicular lymphoma. All specimens were biopsied at initial diagnosis, before starting treatment.
“Our study showed that PDPK1 inhibition caused inactivation of RSK2-NTKD, as well as the decrease of total RSK2 protein, but not of AKT, in MCL-derived cells,” the researchers wrote in Experimental Hematology. “This implies that RSK2 activity is mainly regulated by PDPK1 at both the transcriptional expression and post-translational levels, but AKT activity is regulated by a signaling pathway that does not interact with a PDPK1-mediated pathway in MCL.”
If a PDPK1 inhibitor is pursued as clinical target, the researchers said careful monitoring for hyperglycemia may be required since impaired glucose metabolism is commonly seen with AKT inhibitors. Future research in MCL could also be directed toward the targeting of RSK2-NTKD, the researchers wrote.
SOURCE: Maegawa S et al. Exp Hematol. 2018 Mar;59:72-81.e2.
Researchers may have found a new therapeutic approach for treating mantle cell lymphoma (MCL) by targeting 3-phosphoinositide-dependent protein kinase 1 (PDPK1).
Saori Maegawa and colleagues at Kyoto Prefectural University of Medicine in Japan, evaluated PDPK1 activity in patient-derived primary B-cell lymphoma cells by immunohistochemical staining of p-PDPK1Ser241 (p-PDPK1) in tissue specimens from seven patients with MCL, six patients with diffuse large B-cell lymphoma, and five patients with follicular lymphoma. All specimens were biopsied at initial diagnosis, before starting treatment.
“Our study showed that PDPK1 inhibition caused inactivation of RSK2-NTKD, as well as the decrease of total RSK2 protein, but not of AKT, in MCL-derived cells,” the researchers wrote in Experimental Hematology. “This implies that RSK2 activity is mainly regulated by PDPK1 at both the transcriptional expression and post-translational levels, but AKT activity is regulated by a signaling pathway that does not interact with a PDPK1-mediated pathway in MCL.”
If a PDPK1 inhibitor is pursued as clinical target, the researchers said careful monitoring for hyperglycemia may be required since impaired glucose metabolism is commonly seen with AKT inhibitors. Future research in MCL could also be directed toward the targeting of RSK2-NTKD, the researchers wrote.
SOURCE: Maegawa S et al. Exp Hematol. 2018 Mar;59:72-81.e2.
FROM EXPERIMENTAL HEMATOLOGY
Research reveals new subtypes of DLBCL
New research helps explain why some patients with diffuse large B-cell lymphoma (DLBCL) respond well to immunochemotherapy and others do not.
Researchers analyzed samples from nearly 600 DLBCL patients and identified 4 new genetic subtypes of the disease.
Patients with 2 of these subtypes had overall survival (OS) rates that were roughly twice as high as OS rates in patients with the other 2 subtypes.
Louis M. Staudt, MD, PhD, of the National Cancer Institute in Bethesda, Maryland, and his colleagues described these findings in NEJM.
The researchers noted that the current subtypes of DLBCL—germinal center B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL—are associated with OS after treatment with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
Patients with ABC DLBCL have a much lower OS rate, on average, than patients with GCB DLBCL. However, even in the GCB subgroup, many patients relapse after treatment.
“The first question we wanted to tackle was whether there were other molecular features of the tumors that could help us explain why some people were well-served by chemotherapy,” Dr Staudt said.
“And the second, related question was, if we could understand who was not responding well to treatment, could we understand the genetics of these tumors to suggest new potential therapies beyond chemotherapy? The answer to both questions was ‘yes.’”
Dr Staudt and his colleagues analyzed tumor samples from 574 patients with DLBCL, performing exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to find recurrent aberrations.
The team also developed an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations.
In this way, they identified 4 genetic subtypes:
- MCD, which was named based on the co-occurrence of MYD88L265P and CD79B mutations
- BN2, whose name was based on the presence of BCL6 fusions and NOTCH2 mutations
- N1, named for NOTCH1 mutations
- EZB, named for EZH2 mutations and BCL2 translocations.
The researchers said aberrations in multiple genes distinguished each of these subtypes from other DLBCLs, and the subtypes differed phenotypically.
Patients with BN2 or EZB subtypes had much higher OS rates after receiving R-CHOP than patients with MCD or N1 subtypes. The predicted 5-year OS rates were 26% for MCD patients, 36% for N1 patients, 65% for BN2 patients, and 68% for EZB patients.
The researchers said they found evidence to suggest that MCD and BN2 DLBCLs rely on chronic active B-cell receptor signaling that is amenable to therapeutic inhibition.
The team also noted that some of the subtypes they identified can be found in both ABC and GCB DLBCLs. For example, a patient could have ABC DLBCL, which is associated with a lower OS rate after R-CHOP, but also have the BN2 genetic subtype that responds well to R-CHOP.
“This shows we’ve gone beyond where we were,” Dr Staudt said. “Before, even with our most advanced molecular diagnosis, we would have said all ABC tumors are the ‘bad’ type, and they need to be treated aggressively.”
“Now, we can implement this kind of classification and say that, even if a patient has the ‘bad’ ABC type, they have the ‘good’ genetic type, BN2. So there’s a much better chance of chemotherapy curing the disease.”
Data from this study will be shared through the National Cancer Institute’s Genomic Data Commons to make it available for future research.
Dr Staudt said he and his colleagues hope their new molecular classification will be used in clinical trials so that DLBCL treatment can move toward more targeted therapies.
“The goal is to find the right drug for the right person at the right time,” Dr Staudt said. “And we feel this genetic understanding of diffuse lymphoma is a step forward in precision therapy.”
New research helps explain why some patients with diffuse large B-cell lymphoma (DLBCL) respond well to immunochemotherapy and others do not.
Researchers analyzed samples from nearly 600 DLBCL patients and identified 4 new genetic subtypes of the disease.
Patients with 2 of these subtypes had overall survival (OS) rates that were roughly twice as high as OS rates in patients with the other 2 subtypes.
Louis M. Staudt, MD, PhD, of the National Cancer Institute in Bethesda, Maryland, and his colleagues described these findings in NEJM.
The researchers noted that the current subtypes of DLBCL—germinal center B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL—are associated with OS after treatment with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
Patients with ABC DLBCL have a much lower OS rate, on average, than patients with GCB DLBCL. However, even in the GCB subgroup, many patients relapse after treatment.
“The first question we wanted to tackle was whether there were other molecular features of the tumors that could help us explain why some people were well-served by chemotherapy,” Dr Staudt said.
“And the second, related question was, if we could understand who was not responding well to treatment, could we understand the genetics of these tumors to suggest new potential therapies beyond chemotherapy? The answer to both questions was ‘yes.’”
Dr Staudt and his colleagues analyzed tumor samples from 574 patients with DLBCL, performing exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to find recurrent aberrations.
The team also developed an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations.
In this way, they identified 4 genetic subtypes:
- MCD, which was named based on the co-occurrence of MYD88L265P and CD79B mutations
- BN2, whose name was based on the presence of BCL6 fusions and NOTCH2 mutations
- N1, named for NOTCH1 mutations
- EZB, named for EZH2 mutations and BCL2 translocations.
The researchers said aberrations in multiple genes distinguished each of these subtypes from other DLBCLs, and the subtypes differed phenotypically.
Patients with BN2 or EZB subtypes had much higher OS rates after receiving R-CHOP than patients with MCD or N1 subtypes. The predicted 5-year OS rates were 26% for MCD patients, 36% for N1 patients, 65% for BN2 patients, and 68% for EZB patients.
The researchers said they found evidence to suggest that MCD and BN2 DLBCLs rely on chronic active B-cell receptor signaling that is amenable to therapeutic inhibition.
The team also noted that some of the subtypes they identified can be found in both ABC and GCB DLBCLs. For example, a patient could have ABC DLBCL, which is associated with a lower OS rate after R-CHOP, but also have the BN2 genetic subtype that responds well to R-CHOP.
“This shows we’ve gone beyond where we were,” Dr Staudt said. “Before, even with our most advanced molecular diagnosis, we would have said all ABC tumors are the ‘bad’ type, and they need to be treated aggressively.”
“Now, we can implement this kind of classification and say that, even if a patient has the ‘bad’ ABC type, they have the ‘good’ genetic type, BN2. So there’s a much better chance of chemotherapy curing the disease.”
Data from this study will be shared through the National Cancer Institute’s Genomic Data Commons to make it available for future research.
Dr Staudt said he and his colleagues hope their new molecular classification will be used in clinical trials so that DLBCL treatment can move toward more targeted therapies.
“The goal is to find the right drug for the right person at the right time,” Dr Staudt said. “And we feel this genetic understanding of diffuse lymphoma is a step forward in precision therapy.”
New research helps explain why some patients with diffuse large B-cell lymphoma (DLBCL) respond well to immunochemotherapy and others do not.
Researchers analyzed samples from nearly 600 DLBCL patients and identified 4 new genetic subtypes of the disease.
Patients with 2 of these subtypes had overall survival (OS) rates that were roughly twice as high as OS rates in patients with the other 2 subtypes.
Louis M. Staudt, MD, PhD, of the National Cancer Institute in Bethesda, Maryland, and his colleagues described these findings in NEJM.
The researchers noted that the current subtypes of DLBCL—germinal center B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL—are associated with OS after treatment with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
Patients with ABC DLBCL have a much lower OS rate, on average, than patients with GCB DLBCL. However, even in the GCB subgroup, many patients relapse after treatment.
“The first question we wanted to tackle was whether there were other molecular features of the tumors that could help us explain why some people were well-served by chemotherapy,” Dr Staudt said.
“And the second, related question was, if we could understand who was not responding well to treatment, could we understand the genetics of these tumors to suggest new potential therapies beyond chemotherapy? The answer to both questions was ‘yes.’”
Dr Staudt and his colleagues analyzed tumor samples from 574 patients with DLBCL, performing exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to find recurrent aberrations.
The team also developed an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations.
In this way, they identified 4 genetic subtypes:
- MCD, which was named based on the co-occurrence of MYD88L265P and CD79B mutations
- BN2, whose name was based on the presence of BCL6 fusions and NOTCH2 mutations
- N1, named for NOTCH1 mutations
- EZB, named for EZH2 mutations and BCL2 translocations.
The researchers said aberrations in multiple genes distinguished each of these subtypes from other DLBCLs, and the subtypes differed phenotypically.
Patients with BN2 or EZB subtypes had much higher OS rates after receiving R-CHOP than patients with MCD or N1 subtypes. The predicted 5-year OS rates were 26% for MCD patients, 36% for N1 patients, 65% for BN2 patients, and 68% for EZB patients.
The researchers said they found evidence to suggest that MCD and BN2 DLBCLs rely on chronic active B-cell receptor signaling that is amenable to therapeutic inhibition.
The team also noted that some of the subtypes they identified can be found in both ABC and GCB DLBCLs. For example, a patient could have ABC DLBCL, which is associated with a lower OS rate after R-CHOP, but also have the BN2 genetic subtype that responds well to R-CHOP.
“This shows we’ve gone beyond where we were,” Dr Staudt said. “Before, even with our most advanced molecular diagnosis, we would have said all ABC tumors are the ‘bad’ type, and they need to be treated aggressively.”
“Now, we can implement this kind of classification and say that, even if a patient has the ‘bad’ ABC type, they have the ‘good’ genetic type, BN2. So there’s a much better chance of chemotherapy curing the disease.”
Data from this study will be shared through the National Cancer Institute’s Genomic Data Commons to make it available for future research.
Dr Staudt said he and his colleagues hope their new molecular classification will be used in clinical trials so that DLBCL treatment can move toward more targeted therapies.
“The goal is to find the right drug for the right person at the right time,” Dr Staudt said. “And we feel this genetic understanding of diffuse lymphoma is a step forward in precision therapy.”
Generic antiemetic now available in US
Palonosetron Hydrochloride Injection, a generic alternative to Aloxi®, is now available in the US.
Fresenius Kabi’s Palonosetron Hydrochloride Injection is a 5-HT3 serotonin receptor that is approved for the prevention of nausea and vomiting in certain adults.
Palonosetron Hydrochloride Injection is available in a single-dose vial (0.25 mg per 5 mL).
In the US, Palonosetron Hydrochloride Injection is approved for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.
The drug is also approved for the prevention of acute nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy.
And Palonosetron Hydrochloride Injection is approved for the prevention of post-operative nausea and vomiting for up to 24 hours after surgery. Efficacy beyond 24 hours has not been demonstrated.
The full prescribing information for Palonosetron Hydrochloride Injection can be found on the Fresenius Kabi website.
Palonosetron Hydrochloride Injection, a generic alternative to Aloxi®, is now available in the US.
Fresenius Kabi’s Palonosetron Hydrochloride Injection is a 5-HT3 serotonin receptor that is approved for the prevention of nausea and vomiting in certain adults.
Palonosetron Hydrochloride Injection is available in a single-dose vial (0.25 mg per 5 mL).
In the US, Palonosetron Hydrochloride Injection is approved for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.
The drug is also approved for the prevention of acute nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy.
And Palonosetron Hydrochloride Injection is approved for the prevention of post-operative nausea and vomiting for up to 24 hours after surgery. Efficacy beyond 24 hours has not been demonstrated.
The full prescribing information for Palonosetron Hydrochloride Injection can be found on the Fresenius Kabi website.
Palonosetron Hydrochloride Injection, a generic alternative to Aloxi®, is now available in the US.
Fresenius Kabi’s Palonosetron Hydrochloride Injection is a 5-HT3 serotonin receptor that is approved for the prevention of nausea and vomiting in certain adults.
Palonosetron Hydrochloride Injection is available in a single-dose vial (0.25 mg per 5 mL).
In the US, Palonosetron Hydrochloride Injection is approved for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.
The drug is also approved for the prevention of acute nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy.
And Palonosetron Hydrochloride Injection is approved for the prevention of post-operative nausea and vomiting for up to 24 hours after surgery. Efficacy beyond 24 hours has not been demonstrated.
The full prescribing information for Palonosetron Hydrochloride Injection can be found on the Fresenius Kabi website.
New genetic subtypes could facilitate precision medicine in DLBCL
Four genetic subtypes of diffuse large B-cell lymphoma (DLBCL) showed multiple distinct mutations, gene expression signatures, and treatment responses, researchers reported.
The findings “may provide a conceptual edifice on which to develop precision therapies for these aggressive cancers,” Roland Schmitz, PhD, and his associates wrote in the New England Journal of Medicine.
Other DLBCL studies have focused on individual mutations, but therapeutic response probably hinges on “constellations of genetic aberrations,” wrote Dr. Schmitz of the National Cancer Institute and his associates.
Therefore, they used exome and transcriptome sequencing, deep amplicon resequencing of 372 genes, and DNA copy-number analysis to analyze 572 fresh-frozen DLBCL biopsy specimens, nearly all of which were treatment-naïve.
This multiplatform approach yielded four genetic subtypes: MCD, so named for its co-occurring MYD88L265P and CD79B mutations; BN2, which has BCL6 fusions and NOTCH2 mutations; N1, which has NOTCH1 mutations; and EZB, which has EZH2 mutations and BCL2 translocations. Most MCD and N1 specimens were activated B-cell–like (ABC) tumors, EZB specimens were primarily germinal-center B-cell–like (GCB) tumors, and BN2 specimens included ABC, GCB, and unclassified cases.
A closer look at 119 previously untreated patients linked genetic subtypes with significant differences in progression-free survival (P less than .0001) and overall survival (P = .0002) following R-CHOP or CHOP-like chemotherapy.
The BN2 and EZB subtypes “[had] much more favorable outcomes than the MCD and N1 subtypes,” Dr. Schmitz and his associates said. “Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on ‘chronic active’ B-cell receptor signaling that is amenable to therapeutic inhibition.”
Genetically subtyping DLBCL could help guide patients into appropriate clinical trials, the investigators wrote. For example, patients with the N1 subtype might be candidates for immune checkpoint inhibitor therapy, given N1’s prominent T-cell gene expression and poor response to R-CHOP.
Funders included the National Institutes of Health, the National Cancer Institute, the Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe), the Washington University in St. Louis, and the Kay Kendall Leukaemia Fund. Dr. Schmitz disclosed research funding from Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe).
SOURCE: Schmitz et al. New Eng J Med. 2018 Apr 11. doi: 10.1056/NEJMoa1801445.
Four genetic subtypes of diffuse large B-cell lymphoma (DLBCL) showed multiple distinct mutations, gene expression signatures, and treatment responses, researchers reported.
The findings “may provide a conceptual edifice on which to develop precision therapies for these aggressive cancers,” Roland Schmitz, PhD, and his associates wrote in the New England Journal of Medicine.
Other DLBCL studies have focused on individual mutations, but therapeutic response probably hinges on “constellations of genetic aberrations,” wrote Dr. Schmitz of the National Cancer Institute and his associates.
Therefore, they used exome and transcriptome sequencing, deep amplicon resequencing of 372 genes, and DNA copy-number analysis to analyze 572 fresh-frozen DLBCL biopsy specimens, nearly all of which were treatment-naïve.
This multiplatform approach yielded four genetic subtypes: MCD, so named for its co-occurring MYD88L265P and CD79B mutations; BN2, which has BCL6 fusions and NOTCH2 mutations; N1, which has NOTCH1 mutations; and EZB, which has EZH2 mutations and BCL2 translocations. Most MCD and N1 specimens were activated B-cell–like (ABC) tumors, EZB specimens were primarily germinal-center B-cell–like (GCB) tumors, and BN2 specimens included ABC, GCB, and unclassified cases.
A closer look at 119 previously untreated patients linked genetic subtypes with significant differences in progression-free survival (P less than .0001) and overall survival (P = .0002) following R-CHOP or CHOP-like chemotherapy.
The BN2 and EZB subtypes “[had] much more favorable outcomes than the MCD and N1 subtypes,” Dr. Schmitz and his associates said. “Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on ‘chronic active’ B-cell receptor signaling that is amenable to therapeutic inhibition.”
Genetically subtyping DLBCL could help guide patients into appropriate clinical trials, the investigators wrote. For example, patients with the N1 subtype might be candidates for immune checkpoint inhibitor therapy, given N1’s prominent T-cell gene expression and poor response to R-CHOP.
Funders included the National Institutes of Health, the National Cancer Institute, the Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe), the Washington University in St. Louis, and the Kay Kendall Leukaemia Fund. Dr. Schmitz disclosed research funding from Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe).
SOURCE: Schmitz et al. New Eng J Med. 2018 Apr 11. doi: 10.1056/NEJMoa1801445.
Four genetic subtypes of diffuse large B-cell lymphoma (DLBCL) showed multiple distinct mutations, gene expression signatures, and treatment responses, researchers reported.
The findings “may provide a conceptual edifice on which to develop precision therapies for these aggressive cancers,” Roland Schmitz, PhD, and his associates wrote in the New England Journal of Medicine.
Other DLBCL studies have focused on individual mutations, but therapeutic response probably hinges on “constellations of genetic aberrations,” wrote Dr. Schmitz of the National Cancer Institute and his associates.
Therefore, they used exome and transcriptome sequencing, deep amplicon resequencing of 372 genes, and DNA copy-number analysis to analyze 572 fresh-frozen DLBCL biopsy specimens, nearly all of which were treatment-naïve.
This multiplatform approach yielded four genetic subtypes: MCD, so named for its co-occurring MYD88L265P and CD79B mutations; BN2, which has BCL6 fusions and NOTCH2 mutations; N1, which has NOTCH1 mutations; and EZB, which has EZH2 mutations and BCL2 translocations. Most MCD and N1 specimens were activated B-cell–like (ABC) tumors, EZB specimens were primarily germinal-center B-cell–like (GCB) tumors, and BN2 specimens included ABC, GCB, and unclassified cases.
A closer look at 119 previously untreated patients linked genetic subtypes with significant differences in progression-free survival (P less than .0001) and overall survival (P = .0002) following R-CHOP or CHOP-like chemotherapy.
The BN2 and EZB subtypes “[had] much more favorable outcomes than the MCD and N1 subtypes,” Dr. Schmitz and his associates said. “Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on ‘chronic active’ B-cell receptor signaling that is amenable to therapeutic inhibition.”
Genetically subtyping DLBCL could help guide patients into appropriate clinical trials, the investigators wrote. For example, patients with the N1 subtype might be candidates for immune checkpoint inhibitor therapy, given N1’s prominent T-cell gene expression and poor response to R-CHOP.
Funders included the National Institutes of Health, the National Cancer Institute, the Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe), the Washington University in St. Louis, and the Kay Kendall Leukaemia Fund. Dr. Schmitz disclosed research funding from Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe).
SOURCE: Schmitz et al. New Eng J Med. 2018 Apr 11. doi: 10.1056/NEJMoa1801445.
FROM NEJM
Key clinical point: Multiplatform analyses identified four new genetic subtypes of DLBCL.
Major finding: The subtypes were distinguishable based on multiple genetic aberrations, phenotypes, and treatment responses.
Study details: Study of 574 DLBCL samples using exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes.
Disclosures: Funders included the National Institutes of Health, the National Cancer Institute, the Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe), the Washington University in St. Louis, and the Kay Kendall Leukaemia Fund. Dr. Schmitz disclosed research funding from Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe).
Source: Schmitz et al. New Eng J Med. 2018 Apr 11. doi: 10.1056/NEJMoa1801445.
FDA grants priority review of follicular lymphoma drug
by the Food and Drug Administration.
The biopharmaceutical company Verastem is seeking full approval for duvelisib for the treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and accelerated approval for the treatment of relapsed/refractory follicular lymphoma. The FDA has set Oct. 5, 2018, as the target action date, according to Verastem.
by the Food and Drug Administration.
The biopharmaceutical company Verastem is seeking full approval for duvelisib for the treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and accelerated approval for the treatment of relapsed/refractory follicular lymphoma. The FDA has set Oct. 5, 2018, as the target action date, according to Verastem.
by the Food and Drug Administration.
The biopharmaceutical company Verastem is seeking full approval for duvelisib for the treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and accelerated approval for the treatment of relapsed/refractory follicular lymphoma. The FDA has set Oct. 5, 2018, as the target action date, according to Verastem.
Tazemetostat exhibits antitumor activity in phase 1 trial
The EZH2 inhibitor tazemetostat demonstrated a “favorable safety profile and antitumor activity” in a phase 1 study, according to researchers.
The drug produced responses in 8 of 21 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), including 3 complete responses (CRs).
The maximum tolerated dose of tazemetostat was not reached, and there were no fatal adverse events (AEs) related to treatment.
Grade 3/4 treatment-related AEs included thrombocytopenia, neutropenia, hepatocellular injury, and hypertension.
Antoine Italiano, MD, PhD, of Institut Bergonié in Bordeaux, France, and his colleagues reported these results in The Lancet Oncology. The trial was sponsored by Epizyme and Eisai.
The study enrolled 64 patients—43 with solid tumors and 21 with B-cell NHL. The following characteristics and dosing information pertain only to the patients with NHL.
Thirteen patients had diffuse large B-cell lymphoma (DLBCL), 7 had follicular lymphoma (FL), and 1 had marginal zone lymphoma (MZL).
The patients’ median age was 62 (range, 53-70), and 71% were male. They had an ECOG performance status of 0 (62%) or 1 (38%).
Most patients had received at least 3 prior therapies—38% had 3, 14% had 4, and 33% had 5 or more prior therapies. Forty-eight percent had prior hematopoietic stem cell transplant.
The patients received escalating doses of tazemetostat twice daily—100 mg (n=1), 200 mg (n=2), 400 mg (n=1), 800 mg (n=8), and 1600 mg (n=4).
The remaining 5 patients were enrolled in a substudy to evaluate food effect. These patients received a single 200 mg dose on day -8 and day -1, with or without food, followed by 400 mg twice daily starting on day 1. Specific results on the food effects were not included in the paper.
Safety
In the entire study cohort, there was 1 dose-limiting toxicity—grade 4 thrombocytopenia—at the 1600 mg dose. The maximum tolerated dose of tazemetostat was not reached, but the researchers decided upon 800 mg twice daily as the recommended phase 2 dose.
Overall, 77% (n=49) of patients had treatment-related AEs. Grade 3/4 treatment-related AEs included thrombocytopenia (4%, n=2), neutropenia (4%, n=2), hepatocellular injury (2%, n=1), and hypertension (2%, n=1).
Serious treatment-related AEs were neutropenia in 1 patient (800 mg group) and anemia and thrombocytopenia in another patient (1600 mg group).
Seven patients (11%) had fatal AEs, but none were considered treatment-related. They included general physical health deterioration (1 at 200 mg, 1 at 1600 mg, and 2 at 400 mg), respiratory distress (2 at 400 mg), and septic shock (1 at 1600 mg).
Efficacy
Eight of the 21 NHL patients responded to treatment. Three patients had a CR—1 with DLBCL and 2 with FL. Of the 5 partial responders, 3 had DLBCL, 1 had FL, and 1 had MZL.
The median time to first response was 3.5 months, and the median duration of response was 12.4 months.
The 3 complete responders remained on tazemetostat beyond 27.6 months (FL patient), 28.8 months (FL patient), and 33.6 months (DLBCL patient).
Two of the 43 patients with solid tumors responded to tazemetostat—1 with a CR and 1 with a partial response.
The complete responder had an INI1-negative malignant rhabdoid tumor, and the partial responder had a SMARCA4-negative malignant rhabdoid tumor of the ovary.
“Today’s publication in The Lancet Oncology reports the safety and tolerability endpoints for tazemetostat in this study, which enabled further evaluation of EZH2 inhibition in INI1- and SMARCA4-negative solid tumors and NHL,” Dr Italiano said. “I’m also encouraged by the preliminary antitumor activity observed in this study.”
The EZH2 inhibitor tazemetostat demonstrated a “favorable safety profile and antitumor activity” in a phase 1 study, according to researchers.
The drug produced responses in 8 of 21 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), including 3 complete responses (CRs).
The maximum tolerated dose of tazemetostat was not reached, and there were no fatal adverse events (AEs) related to treatment.
Grade 3/4 treatment-related AEs included thrombocytopenia, neutropenia, hepatocellular injury, and hypertension.
Antoine Italiano, MD, PhD, of Institut Bergonié in Bordeaux, France, and his colleagues reported these results in The Lancet Oncology. The trial was sponsored by Epizyme and Eisai.
The study enrolled 64 patients—43 with solid tumors and 21 with B-cell NHL. The following characteristics and dosing information pertain only to the patients with NHL.
Thirteen patients had diffuse large B-cell lymphoma (DLBCL), 7 had follicular lymphoma (FL), and 1 had marginal zone lymphoma (MZL).
The patients’ median age was 62 (range, 53-70), and 71% were male. They had an ECOG performance status of 0 (62%) or 1 (38%).
Most patients had received at least 3 prior therapies—38% had 3, 14% had 4, and 33% had 5 or more prior therapies. Forty-eight percent had prior hematopoietic stem cell transplant.
The patients received escalating doses of tazemetostat twice daily—100 mg (n=1), 200 mg (n=2), 400 mg (n=1), 800 mg (n=8), and 1600 mg (n=4).
The remaining 5 patients were enrolled in a substudy to evaluate food effect. These patients received a single 200 mg dose on day -8 and day -1, with or without food, followed by 400 mg twice daily starting on day 1. Specific results on the food effects were not included in the paper.
Safety
In the entire study cohort, there was 1 dose-limiting toxicity—grade 4 thrombocytopenia—at the 1600 mg dose. The maximum tolerated dose of tazemetostat was not reached, but the researchers decided upon 800 mg twice daily as the recommended phase 2 dose.
Overall, 77% (n=49) of patients had treatment-related AEs. Grade 3/4 treatment-related AEs included thrombocytopenia (4%, n=2), neutropenia (4%, n=2), hepatocellular injury (2%, n=1), and hypertension (2%, n=1).
Serious treatment-related AEs were neutropenia in 1 patient (800 mg group) and anemia and thrombocytopenia in another patient (1600 mg group).
Seven patients (11%) had fatal AEs, but none were considered treatment-related. They included general physical health deterioration (1 at 200 mg, 1 at 1600 mg, and 2 at 400 mg), respiratory distress (2 at 400 mg), and septic shock (1 at 1600 mg).
Efficacy
Eight of the 21 NHL patients responded to treatment. Three patients had a CR—1 with DLBCL and 2 with FL. Of the 5 partial responders, 3 had DLBCL, 1 had FL, and 1 had MZL.
The median time to first response was 3.5 months, and the median duration of response was 12.4 months.
The 3 complete responders remained on tazemetostat beyond 27.6 months (FL patient), 28.8 months (FL patient), and 33.6 months (DLBCL patient).
Two of the 43 patients with solid tumors responded to tazemetostat—1 with a CR and 1 with a partial response.
The complete responder had an INI1-negative malignant rhabdoid tumor, and the partial responder had a SMARCA4-negative malignant rhabdoid tumor of the ovary.
“Today’s publication in The Lancet Oncology reports the safety and tolerability endpoints for tazemetostat in this study, which enabled further evaluation of EZH2 inhibition in INI1- and SMARCA4-negative solid tumors and NHL,” Dr Italiano said. “I’m also encouraged by the preliminary antitumor activity observed in this study.”
The EZH2 inhibitor tazemetostat demonstrated a “favorable safety profile and antitumor activity” in a phase 1 study, according to researchers.
The drug produced responses in 8 of 21 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), including 3 complete responses (CRs).
The maximum tolerated dose of tazemetostat was not reached, and there were no fatal adverse events (AEs) related to treatment.
Grade 3/4 treatment-related AEs included thrombocytopenia, neutropenia, hepatocellular injury, and hypertension.
Antoine Italiano, MD, PhD, of Institut Bergonié in Bordeaux, France, and his colleagues reported these results in The Lancet Oncology. The trial was sponsored by Epizyme and Eisai.
The study enrolled 64 patients—43 with solid tumors and 21 with B-cell NHL. The following characteristics and dosing information pertain only to the patients with NHL.
Thirteen patients had diffuse large B-cell lymphoma (DLBCL), 7 had follicular lymphoma (FL), and 1 had marginal zone lymphoma (MZL).
The patients’ median age was 62 (range, 53-70), and 71% were male. They had an ECOG performance status of 0 (62%) or 1 (38%).
Most patients had received at least 3 prior therapies—38% had 3, 14% had 4, and 33% had 5 or more prior therapies. Forty-eight percent had prior hematopoietic stem cell transplant.
The patients received escalating doses of tazemetostat twice daily—100 mg (n=1), 200 mg (n=2), 400 mg (n=1), 800 mg (n=8), and 1600 mg (n=4).
The remaining 5 patients were enrolled in a substudy to evaluate food effect. These patients received a single 200 mg dose on day -8 and day -1, with or without food, followed by 400 mg twice daily starting on day 1. Specific results on the food effects were not included in the paper.
Safety
In the entire study cohort, there was 1 dose-limiting toxicity—grade 4 thrombocytopenia—at the 1600 mg dose. The maximum tolerated dose of tazemetostat was not reached, but the researchers decided upon 800 mg twice daily as the recommended phase 2 dose.
Overall, 77% (n=49) of patients had treatment-related AEs. Grade 3/4 treatment-related AEs included thrombocytopenia (4%, n=2), neutropenia (4%, n=2), hepatocellular injury (2%, n=1), and hypertension (2%, n=1).
Serious treatment-related AEs were neutropenia in 1 patient (800 mg group) and anemia and thrombocytopenia in another patient (1600 mg group).
Seven patients (11%) had fatal AEs, but none were considered treatment-related. They included general physical health deterioration (1 at 200 mg, 1 at 1600 mg, and 2 at 400 mg), respiratory distress (2 at 400 mg), and septic shock (1 at 1600 mg).
Efficacy
Eight of the 21 NHL patients responded to treatment. Three patients had a CR—1 with DLBCL and 2 with FL. Of the 5 partial responders, 3 had DLBCL, 1 had FL, and 1 had MZL.
The median time to first response was 3.5 months, and the median duration of response was 12.4 months.
The 3 complete responders remained on tazemetostat beyond 27.6 months (FL patient), 28.8 months (FL patient), and 33.6 months (DLBCL patient).
Two of the 43 patients with solid tumors responded to tazemetostat—1 with a CR and 1 with a partial response.
The complete responder had an INI1-negative malignant rhabdoid tumor, and the partial responder had a SMARCA4-negative malignant rhabdoid tumor of the ovary.
“Today’s publication in The Lancet Oncology reports the safety and tolerability endpoints for tazemetostat in this study, which enabled further evaluation of EZH2 inhibition in INI1- and SMARCA4-negative solid tumors and NHL,” Dr Italiano said. “I’m also encouraged by the preliminary antitumor activity observed in this study.”
Combo improves outcomes in MCL
A 2-drug combination can improve outcomes in patients with mantle cell lymphoma (MCL), according to researchers.
In a phase 2 trial of MCL patients, the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax produced an overall response rate of 71% and a complete response (CR) rate of 62%.
“This was in patients who we expected to have a poor outcome on conventional therapy, and in which treatment with either ibrutinib or venetoclax alone was expected to see only 21% of patients show a complete response,” said Constantine Tam, MBBS, MD, of the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.
The most common adverse events (AEs) in patients receiving venetoclax and ibrutinib were diarrhea (83%), fatigue (75%), and nausea/vomiting (71%). Fourteen patients (58%) had serious AEs, including 2 with tumor lysis syndrome.
Dr Tam and his colleagues reported these results in NEJM.
The study included 24 patients—23 with relapsed/refractory MCL and 1 with previously untreated MCL. They had a median age of 68 (range, 47-81).
Most patients had high-risk (75%) or intermediate-risk (21%) disease, according to the MCL International Prognostic Index. Half of patients (including the previously untreated patient) had a TP53 aberration, and 25% had an NF-κB pathway mutation.
The relapsed/refractory patients had a median of 2 prior therapies (range, 1-6), and 48% were refractory to their most recent therapy.
Patients received ibrutinib monotherapy at 560 mg daily for 4 weeks. Then, patients began receiving venetoclax as well, in increasing doses, up to 400 mg per day. Patients received treatment until progression or unacceptable toxicity.
Efficacy
The study’s primary endpoint was CR at week 16, as assessed without PET. This was to allow the researchers to compare CR results in this trial to CR results in the PCYC-1104-CA study, a phase 2 trial of ibrutinib monotherapy in MCL.
According to CT, the CR rate was 42% in patients who received venetoclax and ibrutinib. This is significantly higher than the 9% CR rate observed in the patients treated with ibrutinib alone (P<0.001).
However, according to PET/CT, the 16-week CR rate was 62% in patients who received venetoclax and ibrutinib, and the overall response rate was 71%.
Overall, the rate of minimal residual disease (MRD) negativity was 67% (n=16) in the bone marrow according to flow cytometry and 38% (n=9) in the blood according to allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR). However, not all patients were evaluable for MRD.
Among evaluable patients with a CR, 93% (14/15) were MRD negative according to flow cytometry, and 82% (9/11) were negative according to ASO-PCR.
The median progression-free survival was not reached at a median follow-up of 15.9 months. The estimated progression-free survival was 75% at 12 months and 57% at 18 months.
The rate of overall survival was 79% at 12 months and 74% at 18 months.
“These very promising results have triggered additional and larger studies to better understand the synergistic benefits of the venetoclax-ibrutinib treatment combination in MCL patients,” Dr Tam said.
Safety
The most common AEs were diarrhea (83%); fatigue (75%); nausea/vomiting (71%); bleeding, bruising, or postoperative hemorrhage (54%); musculoskeletal or connective-tissue pain (50%); cough or dyspnea (46%); soft-tissue infection (42%); upper respiratory tract infection (42%); neutropenia (33%); and lower respiratory tract infection (33%).
Grade 3/4 AEs included neutropenia (33%), thrombocytopenia (17%), anemia (12%), diarrhea (12%), tumor lysis syndrome (8%), atrial fibrillation (8%), lower respiratory tract infection (8%), soft-tissue infection (8%), cough or dyspnea (4%), musculoskeletal or connective-tissue pain (4%), and bleeding, bruising, or postoperative hemorrhage (4%).
Serious AEs included diarrhea (12%), tumor lysis syndrome (8%), atrial fibrillation (8%), pyrexia (8%), pleural effusion (8%), cardiac failure (4%), and soft-tissue infection (4%).
The patients who developed tumor lysis syndrome were among the first 15 patients who started venetoclax at a dose of 50 mg per day. Because of these cases, the study protocol was amended to lower the starting dose of venetoclax to 20 mg daily. After that, there were no additional cases of tumor lysis syndrome.
There were 6 deaths during the study. Four were attributed to disease progression, 1 to malignant otitis externa, and 1 to cardiac failure in a patient in CR.
A 2-drug combination can improve outcomes in patients with mantle cell lymphoma (MCL), according to researchers.
In a phase 2 trial of MCL patients, the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax produced an overall response rate of 71% and a complete response (CR) rate of 62%.
“This was in patients who we expected to have a poor outcome on conventional therapy, and in which treatment with either ibrutinib or venetoclax alone was expected to see only 21% of patients show a complete response,” said Constantine Tam, MBBS, MD, of the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.
The most common adverse events (AEs) in patients receiving venetoclax and ibrutinib were diarrhea (83%), fatigue (75%), and nausea/vomiting (71%). Fourteen patients (58%) had serious AEs, including 2 with tumor lysis syndrome.
Dr Tam and his colleagues reported these results in NEJM.
The study included 24 patients—23 with relapsed/refractory MCL and 1 with previously untreated MCL. They had a median age of 68 (range, 47-81).
Most patients had high-risk (75%) or intermediate-risk (21%) disease, according to the MCL International Prognostic Index. Half of patients (including the previously untreated patient) had a TP53 aberration, and 25% had an NF-κB pathway mutation.
The relapsed/refractory patients had a median of 2 prior therapies (range, 1-6), and 48% were refractory to their most recent therapy.
Patients received ibrutinib monotherapy at 560 mg daily for 4 weeks. Then, patients began receiving venetoclax as well, in increasing doses, up to 400 mg per day. Patients received treatment until progression or unacceptable toxicity.
Efficacy
The study’s primary endpoint was CR at week 16, as assessed without PET. This was to allow the researchers to compare CR results in this trial to CR results in the PCYC-1104-CA study, a phase 2 trial of ibrutinib monotherapy in MCL.
According to CT, the CR rate was 42% in patients who received venetoclax and ibrutinib. This is significantly higher than the 9% CR rate observed in the patients treated with ibrutinib alone (P<0.001).
However, according to PET/CT, the 16-week CR rate was 62% in patients who received venetoclax and ibrutinib, and the overall response rate was 71%.
Overall, the rate of minimal residual disease (MRD) negativity was 67% (n=16) in the bone marrow according to flow cytometry and 38% (n=9) in the blood according to allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR). However, not all patients were evaluable for MRD.
Among evaluable patients with a CR, 93% (14/15) were MRD negative according to flow cytometry, and 82% (9/11) were negative according to ASO-PCR.
The median progression-free survival was not reached at a median follow-up of 15.9 months. The estimated progression-free survival was 75% at 12 months and 57% at 18 months.
The rate of overall survival was 79% at 12 months and 74% at 18 months.
“These very promising results have triggered additional and larger studies to better understand the synergistic benefits of the venetoclax-ibrutinib treatment combination in MCL patients,” Dr Tam said.
Safety
The most common AEs were diarrhea (83%); fatigue (75%); nausea/vomiting (71%); bleeding, bruising, or postoperative hemorrhage (54%); musculoskeletal or connective-tissue pain (50%); cough or dyspnea (46%); soft-tissue infection (42%); upper respiratory tract infection (42%); neutropenia (33%); and lower respiratory tract infection (33%).
Grade 3/4 AEs included neutropenia (33%), thrombocytopenia (17%), anemia (12%), diarrhea (12%), tumor lysis syndrome (8%), atrial fibrillation (8%), lower respiratory tract infection (8%), soft-tissue infection (8%), cough or dyspnea (4%), musculoskeletal or connective-tissue pain (4%), and bleeding, bruising, or postoperative hemorrhage (4%).
Serious AEs included diarrhea (12%), tumor lysis syndrome (8%), atrial fibrillation (8%), pyrexia (8%), pleural effusion (8%), cardiac failure (4%), and soft-tissue infection (4%).
The patients who developed tumor lysis syndrome were among the first 15 patients who started venetoclax at a dose of 50 mg per day. Because of these cases, the study protocol was amended to lower the starting dose of venetoclax to 20 mg daily. After that, there were no additional cases of tumor lysis syndrome.
There were 6 deaths during the study. Four were attributed to disease progression, 1 to malignant otitis externa, and 1 to cardiac failure in a patient in CR.
A 2-drug combination can improve outcomes in patients with mantle cell lymphoma (MCL), according to researchers.
In a phase 2 trial of MCL patients, the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax produced an overall response rate of 71% and a complete response (CR) rate of 62%.
“This was in patients who we expected to have a poor outcome on conventional therapy, and in which treatment with either ibrutinib or venetoclax alone was expected to see only 21% of patients show a complete response,” said Constantine Tam, MBBS, MD, of the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.
The most common adverse events (AEs) in patients receiving venetoclax and ibrutinib were diarrhea (83%), fatigue (75%), and nausea/vomiting (71%). Fourteen patients (58%) had serious AEs, including 2 with tumor lysis syndrome.
Dr Tam and his colleagues reported these results in NEJM.
The study included 24 patients—23 with relapsed/refractory MCL and 1 with previously untreated MCL. They had a median age of 68 (range, 47-81).
Most patients had high-risk (75%) or intermediate-risk (21%) disease, according to the MCL International Prognostic Index. Half of patients (including the previously untreated patient) had a TP53 aberration, and 25% had an NF-κB pathway mutation.
The relapsed/refractory patients had a median of 2 prior therapies (range, 1-6), and 48% were refractory to their most recent therapy.
Patients received ibrutinib monotherapy at 560 mg daily for 4 weeks. Then, patients began receiving venetoclax as well, in increasing doses, up to 400 mg per day. Patients received treatment until progression or unacceptable toxicity.
Efficacy
The study’s primary endpoint was CR at week 16, as assessed without PET. This was to allow the researchers to compare CR results in this trial to CR results in the PCYC-1104-CA study, a phase 2 trial of ibrutinib monotherapy in MCL.
According to CT, the CR rate was 42% in patients who received venetoclax and ibrutinib. This is significantly higher than the 9% CR rate observed in the patients treated with ibrutinib alone (P<0.001).
However, according to PET/CT, the 16-week CR rate was 62% in patients who received venetoclax and ibrutinib, and the overall response rate was 71%.
Overall, the rate of minimal residual disease (MRD) negativity was 67% (n=16) in the bone marrow according to flow cytometry and 38% (n=9) in the blood according to allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR). However, not all patients were evaluable for MRD.
Among evaluable patients with a CR, 93% (14/15) were MRD negative according to flow cytometry, and 82% (9/11) were negative according to ASO-PCR.
The median progression-free survival was not reached at a median follow-up of 15.9 months. The estimated progression-free survival was 75% at 12 months and 57% at 18 months.
The rate of overall survival was 79% at 12 months and 74% at 18 months.
“These very promising results have triggered additional and larger studies to better understand the synergistic benefits of the venetoclax-ibrutinib treatment combination in MCL patients,” Dr Tam said.
Safety
The most common AEs were diarrhea (83%); fatigue (75%); nausea/vomiting (71%); bleeding, bruising, or postoperative hemorrhage (54%); musculoskeletal or connective-tissue pain (50%); cough or dyspnea (46%); soft-tissue infection (42%); upper respiratory tract infection (42%); neutropenia (33%); and lower respiratory tract infection (33%).
Grade 3/4 AEs included neutropenia (33%), thrombocytopenia (17%), anemia (12%), diarrhea (12%), tumor lysis syndrome (8%), atrial fibrillation (8%), lower respiratory tract infection (8%), soft-tissue infection (8%), cough or dyspnea (4%), musculoskeletal or connective-tissue pain (4%), and bleeding, bruising, or postoperative hemorrhage (4%).
Serious AEs included diarrhea (12%), tumor lysis syndrome (8%), atrial fibrillation (8%), pyrexia (8%), pleural effusion (8%), cardiac failure (4%), and soft-tissue infection (4%).
The patients who developed tumor lysis syndrome were among the first 15 patients who started venetoclax at a dose of 50 mg per day. Because of these cases, the study protocol was amended to lower the starting dose of venetoclax to 20 mg daily. After that, there were no additional cases of tumor lysis syndrome.
There were 6 deaths during the study. Four were attributed to disease progression, 1 to malignant otitis externa, and 1 to cardiac failure in a patient in CR.
Tenalisib receives orphan designation for CTCL
The US Food and Drug Administration (FDA) has granted orphan drug designation to tenalisib for treatment of cutaneous T-cell lymphoma (CTCL).
Tenalisib (formerly RP6530) is a dual PI3K delta/gamma inhibitor under development by Rhizen Pharmaceuticals SA.
The FDA previously granted tenalisib fast track and orphan drug designations for the treatment of peripheral T-cell lymphoma (PTCL).
Tenalisib has been investigated in a phase 1 trial of patients with relapsed/refractory PTCL and CTCL. Results from this trial were presented at the 10th Annual T-cell Lymphoma Forum in February.
The data included 55 patients—28 with CTCL and 27 with PTCL—who received varying doses of tenalisib. The maximum tolerated dose was an 800 mg daily fasting dose.
Fourteen PTCL patients were evaluable for efficacy, and 7 responded (50%) to treatment. Three patients had a complete response, and 4 had a partial response.
Eighteen CTCL patients were evaluable for efficacy. Eight patients responded (44%), all with partial responses.
In the entire cohort, treatment-related adverse events (AEs) of grade 3 or higher included transaminitis (20%), rash (5%), neutropenia (2%), hypophosphatemia (2%), international normalized ratio increase (2%), sepsis (2%), pyrexia (2%), and diplopia secondary to neuropathy (2%).
Four CTCL patients stopped tenalisib due to a treatment-related AE—transaminitis, sepsis, diarrhea, and diplopia secondary to neuropathy. One PTCL patient stopped treatment due to a related AE, which was transaminitis.
About orphan and fast track designations
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The FDA’s fast track drug development program is designed to expedite clinical development and submission of new drug applications for medicines with the potential to treat serious or life-threatening conditions and address unmet medical needs.
Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss all aspects of development to support a drug’s approval, and also provides the opportunity to submit sections of a new drug application on a rolling basis as data become available.
The US Food and Drug Administration (FDA) has granted orphan drug designation to tenalisib for treatment of cutaneous T-cell lymphoma (CTCL).
Tenalisib (formerly RP6530) is a dual PI3K delta/gamma inhibitor under development by Rhizen Pharmaceuticals SA.
The FDA previously granted tenalisib fast track and orphan drug designations for the treatment of peripheral T-cell lymphoma (PTCL).
Tenalisib has been investigated in a phase 1 trial of patients with relapsed/refractory PTCL and CTCL. Results from this trial were presented at the 10th Annual T-cell Lymphoma Forum in February.
The data included 55 patients—28 with CTCL and 27 with PTCL—who received varying doses of tenalisib. The maximum tolerated dose was an 800 mg daily fasting dose.
Fourteen PTCL patients were evaluable for efficacy, and 7 responded (50%) to treatment. Three patients had a complete response, and 4 had a partial response.
Eighteen CTCL patients were evaluable for efficacy. Eight patients responded (44%), all with partial responses.
In the entire cohort, treatment-related adverse events (AEs) of grade 3 or higher included transaminitis (20%), rash (5%), neutropenia (2%), hypophosphatemia (2%), international normalized ratio increase (2%), sepsis (2%), pyrexia (2%), and diplopia secondary to neuropathy (2%).
Four CTCL patients stopped tenalisib due to a treatment-related AE—transaminitis, sepsis, diarrhea, and diplopia secondary to neuropathy. One PTCL patient stopped treatment due to a related AE, which was transaminitis.
About orphan and fast track designations
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The FDA’s fast track drug development program is designed to expedite clinical development and submission of new drug applications for medicines with the potential to treat serious or life-threatening conditions and address unmet medical needs.
Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss all aspects of development to support a drug’s approval, and also provides the opportunity to submit sections of a new drug application on a rolling basis as data become available.
The US Food and Drug Administration (FDA) has granted orphan drug designation to tenalisib for treatment of cutaneous T-cell lymphoma (CTCL).
Tenalisib (formerly RP6530) is a dual PI3K delta/gamma inhibitor under development by Rhizen Pharmaceuticals SA.
The FDA previously granted tenalisib fast track and orphan drug designations for the treatment of peripheral T-cell lymphoma (PTCL).
Tenalisib has been investigated in a phase 1 trial of patients with relapsed/refractory PTCL and CTCL. Results from this trial were presented at the 10th Annual T-cell Lymphoma Forum in February.
The data included 55 patients—28 with CTCL and 27 with PTCL—who received varying doses of tenalisib. The maximum tolerated dose was an 800 mg daily fasting dose.
Fourteen PTCL patients were evaluable for efficacy, and 7 responded (50%) to treatment. Three patients had a complete response, and 4 had a partial response.
Eighteen CTCL patients were evaluable for efficacy. Eight patients responded (44%), all with partial responses.
In the entire cohort, treatment-related adverse events (AEs) of grade 3 or higher included transaminitis (20%), rash (5%), neutropenia (2%), hypophosphatemia (2%), international normalized ratio increase (2%), sepsis (2%), pyrexia (2%), and diplopia secondary to neuropathy (2%).
Four CTCL patients stopped tenalisib due to a treatment-related AE—transaminitis, sepsis, diarrhea, and diplopia secondary to neuropathy. One PTCL patient stopped treatment due to a related AE, which was transaminitis.
About orphan and fast track designations
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The FDA’s fast track drug development program is designed to expedite clinical development and submission of new drug applications for medicines with the potential to treat serious or life-threatening conditions and address unmet medical needs.
Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss all aspects of development to support a drug’s approval, and also provides the opportunity to submit sections of a new drug application on a rolling basis as data become available.
Duvelisib NDA granted priority review
The US Food and Drug Administration (FDA) has accepted for priority review the new drug application (NDA) for duvelisib, a dual PI3K delta/gamma inhibitor.
With this NDA, Verastem, Inc., is seeking full approval of duvelisib for the treatment of relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and accelerated approval of the drug for the treatment of relapsed or refractory follicular lymphoma (FL).
The FDA expects to make a decision on the NDA by October 5, 2018.
The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The agency grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The application for duvelisib is supported by data from DUO™, a randomized, phase 3 study of patients with relapsed or refractory CLL/SLL, and DYNAMO™, a phase 2 study of patients with refractory indolent non-Hodgkin lymphoma.
Phase 3 DUO trial
Results from DUO were presented at the 2017 ASH Annual Meeting in December.
This study included 319 CLL/SLL patients who were randomized 1:1 to receive either duvelisib (25 mg orally twice daily) or ofatumumab (initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2000 mg).
The study’s primary endpoint was met, as duvelisib conferred a significant improvement in median progression-free survival (PFS) over ofatumumab.
Per an independent review committee, the median PFS was 13.3 months with duvelisib and 9.9 months with ofatumumab (hazard ratio=0.52; P<0.0001). Duvelisib maintained a PFS advantage in all patient subgroups analyzed.
The overall response rate was 73.8% with duvelisib and 45.3% with ofatumumab (P<0.0001). The complete response rate was 0.6% in both arms.
Overall survival (OS) was similar in the duvelisib and ofatumumab arms (hazard ratio=0.99; P=0.4807). The median OS was not reached in either arm.
The most common grade 3 or higher adverse events (AEs)—in the duvelisib and ofatumumab arms, respectively—were neutropenia (30% vs 17%), anemia (13% vs 5%), diarrhea (15% vs 1%), pneumonia (14% vs 1%), and colitis (12% vs 1%).
Thirty-five percent of patients discontinued duvelisib due to an AE.
Severe opportunistic infections occurred in 6% of duvelisib recipients—bronchopulmonary aspergillosis (n=4), fungal infection (n=2), Pneumocystis jirovecii pneumonia (n=2), and cytomegalovirus colitis (n=1).
There were 4 deaths related to duvelisib—staphylococcal pneumonia (n=2), general physical health deterioration (n=1), and sepsis (n=1).
Phase 2 DYNAMO trial
Results from DYNAMO were presented at the 22nd EHA Congress (abstract S777) in June 2017.
This trial enrolled patients with indolent non-Hodgkin lymphoma whose disease was refractory to both rituximab and chemotherapy or radioimmunotherapy.
There were 83 patients with FL. They had a median of 3 prior anticancer regimens (range, 1-10).
The patients received duvelisib at 25 mg orally twice daily until disease progression or unacceptable toxicity.
The overall response rate, per an independent review committee, was 43%. One patient achieved a complete response, and 35 had a partial response. The median duration of response was 7.9 months.
The median PFS was 8.3 months, and the median OS was 27.8 months.
The most common grade 3 or higher AEs were neutropenia (22%), anemia (13%), diarrhea (16%), lipase increase (10%), and thrombocytopenia (9%).
There were 2 serious opportunistic infections—Pneumocystis pneumonia and fungal pneumonia.
There were 3 deaths attributed to duvelisib—toxic epidermal necrolysis/sepsis syndrome (n=1), drug reaction/eosinophilia/systemic symptoms (n=1), and pneumonitis/pneumonia (n=1).
The US Food and Drug Administration (FDA) has accepted for priority review the new drug application (NDA) for duvelisib, a dual PI3K delta/gamma inhibitor.
With this NDA, Verastem, Inc., is seeking full approval of duvelisib for the treatment of relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and accelerated approval of the drug for the treatment of relapsed or refractory follicular lymphoma (FL).
The FDA expects to make a decision on the NDA by October 5, 2018.
The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The agency grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The application for duvelisib is supported by data from DUO™, a randomized, phase 3 study of patients with relapsed or refractory CLL/SLL, and DYNAMO™, a phase 2 study of patients with refractory indolent non-Hodgkin lymphoma.
Phase 3 DUO trial
Results from DUO were presented at the 2017 ASH Annual Meeting in December.
This study included 319 CLL/SLL patients who were randomized 1:1 to receive either duvelisib (25 mg orally twice daily) or ofatumumab (initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2000 mg).
The study’s primary endpoint was met, as duvelisib conferred a significant improvement in median progression-free survival (PFS) over ofatumumab.
Per an independent review committee, the median PFS was 13.3 months with duvelisib and 9.9 months with ofatumumab (hazard ratio=0.52; P<0.0001). Duvelisib maintained a PFS advantage in all patient subgroups analyzed.
The overall response rate was 73.8% with duvelisib and 45.3% with ofatumumab (P<0.0001). The complete response rate was 0.6% in both arms.
Overall survival (OS) was similar in the duvelisib and ofatumumab arms (hazard ratio=0.99; P=0.4807). The median OS was not reached in either arm.
The most common grade 3 or higher adverse events (AEs)—in the duvelisib and ofatumumab arms, respectively—were neutropenia (30% vs 17%), anemia (13% vs 5%), diarrhea (15% vs 1%), pneumonia (14% vs 1%), and colitis (12% vs 1%).
Thirty-five percent of patients discontinued duvelisib due to an AE.
Severe opportunistic infections occurred in 6% of duvelisib recipients—bronchopulmonary aspergillosis (n=4), fungal infection (n=2), Pneumocystis jirovecii pneumonia (n=2), and cytomegalovirus colitis (n=1).
There were 4 deaths related to duvelisib—staphylococcal pneumonia (n=2), general physical health deterioration (n=1), and sepsis (n=1).
Phase 2 DYNAMO trial
Results from DYNAMO were presented at the 22nd EHA Congress (abstract S777) in June 2017.
This trial enrolled patients with indolent non-Hodgkin lymphoma whose disease was refractory to both rituximab and chemotherapy or radioimmunotherapy.
There were 83 patients with FL. They had a median of 3 prior anticancer regimens (range, 1-10).
The patients received duvelisib at 25 mg orally twice daily until disease progression or unacceptable toxicity.
The overall response rate, per an independent review committee, was 43%. One patient achieved a complete response, and 35 had a partial response. The median duration of response was 7.9 months.
The median PFS was 8.3 months, and the median OS was 27.8 months.
The most common grade 3 or higher AEs were neutropenia (22%), anemia (13%), diarrhea (16%), lipase increase (10%), and thrombocytopenia (9%).
There were 2 serious opportunistic infections—Pneumocystis pneumonia and fungal pneumonia.
There were 3 deaths attributed to duvelisib—toxic epidermal necrolysis/sepsis syndrome (n=1), drug reaction/eosinophilia/systemic symptoms (n=1), and pneumonitis/pneumonia (n=1).
The US Food and Drug Administration (FDA) has accepted for priority review the new drug application (NDA) for duvelisib, a dual PI3K delta/gamma inhibitor.
With this NDA, Verastem, Inc., is seeking full approval of duvelisib for the treatment of relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and accelerated approval of the drug for the treatment of relapsed or refractory follicular lymphoma (FL).
The FDA expects to make a decision on the NDA by October 5, 2018.
The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The agency grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The application for duvelisib is supported by data from DUO™, a randomized, phase 3 study of patients with relapsed or refractory CLL/SLL, and DYNAMO™, a phase 2 study of patients with refractory indolent non-Hodgkin lymphoma.
Phase 3 DUO trial
Results from DUO were presented at the 2017 ASH Annual Meeting in December.
This study included 319 CLL/SLL patients who were randomized 1:1 to receive either duvelisib (25 mg orally twice daily) or ofatumumab (initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2000 mg).
The study’s primary endpoint was met, as duvelisib conferred a significant improvement in median progression-free survival (PFS) over ofatumumab.
Per an independent review committee, the median PFS was 13.3 months with duvelisib and 9.9 months with ofatumumab (hazard ratio=0.52; P<0.0001). Duvelisib maintained a PFS advantage in all patient subgroups analyzed.
The overall response rate was 73.8% with duvelisib and 45.3% with ofatumumab (P<0.0001). The complete response rate was 0.6% in both arms.
Overall survival (OS) was similar in the duvelisib and ofatumumab arms (hazard ratio=0.99; P=0.4807). The median OS was not reached in either arm.
The most common grade 3 or higher adverse events (AEs)—in the duvelisib and ofatumumab arms, respectively—were neutropenia (30% vs 17%), anemia (13% vs 5%), diarrhea (15% vs 1%), pneumonia (14% vs 1%), and colitis (12% vs 1%).
Thirty-five percent of patients discontinued duvelisib due to an AE.
Severe opportunistic infections occurred in 6% of duvelisib recipients—bronchopulmonary aspergillosis (n=4), fungal infection (n=2), Pneumocystis jirovecii pneumonia (n=2), and cytomegalovirus colitis (n=1).
There were 4 deaths related to duvelisib—staphylococcal pneumonia (n=2), general physical health deterioration (n=1), and sepsis (n=1).
Phase 2 DYNAMO trial
Results from DYNAMO were presented at the 22nd EHA Congress (abstract S777) in June 2017.
This trial enrolled patients with indolent non-Hodgkin lymphoma whose disease was refractory to both rituximab and chemotherapy or radioimmunotherapy.
There were 83 patients with FL. They had a median of 3 prior anticancer regimens (range, 1-10).
The patients received duvelisib at 25 mg orally twice daily until disease progression or unacceptable toxicity.
The overall response rate, per an independent review committee, was 43%. One patient achieved a complete response, and 35 had a partial response. The median duration of response was 7.9 months.
The median PFS was 8.3 months, and the median OS was 27.8 months.
The most common grade 3 or higher AEs were neutropenia (22%), anemia (13%), diarrhea (16%), lipase increase (10%), and thrombocytopenia (9%).
There were 2 serious opportunistic infections—Pneumocystis pneumonia and fungal pneumonia.
There were 3 deaths attributed to duvelisib—toxic epidermal necrolysis/sepsis syndrome (n=1), drug reaction/eosinophilia/systemic symptoms (n=1), and pneumonitis/pneumonia (n=1).