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Drug gets orphan designation for CTCL
The European Commission has granted orphan drug designation to synthetic hypericin, the active pharmaceutical ingredient in SGX301, for the treatment of cutaneous T-cell lymphoma (CTCL).
SGX301 is a first-in-class, photodynamic therapy utilizing safe, visible light for activation. Synthetic hypericin is a potent photosensitizer that is topically applied to skin lesions and activated by visible fluorescent light 16 to 24 hours later.
This treatment approach is intended to prevent the secondary malignancies that may occur following chemotherapy or photodynamic therapies that are dependent on ultraviolet exposure.
Combined with photoactivation, hypericin has demonstrated significant antiproliferative effects on activated, normal human lymphoid cells and inhibited the growth of malignant T cells isolated from CTCL patients.
Topical hypericin has also proven safe in a phase 1 study of healthy volunteers.
In a phase 2 trial of patients with CTCL (mycosis fungoides only) or psoriasis, topical hypericin conferred a significant improvement over placebo. Among CTCL patients, the treatment prompted a response rate of 58.3%, compared to an 8.3% response rate for placebo (P≤0.04).
Topical hypericin was also well tolerated in this trial. There were no deaths or serious adverse events related to the treatment. However, there were reports of mild to moderate burning, itching, erythema, and pruritus at the application site.
Soligenix, Inc., the company developing SGX301, is currently working with CTCL centers, the National Organization for Rare Disorders, and the Cutaneous Lymphoma Foundation to begin a 120-subject phase 3 trial of SGX301.
About orphan designation
The European Commission grants orphan designation to medicines designed to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons in the European Union and has no satisfactory treatment available.
In addition to a 10-year period of marketing exclusivity after product approval, orphan drug designation provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase, as well as direct access to the centralized authorization procedure.
SGX301 has both orphan designation and fast track designation from the US Food and Drug Administration for the first-line treatment of CTCL. 
The European Commission has granted orphan drug designation to synthetic hypericin, the active pharmaceutical ingredient in SGX301, for the treatment of cutaneous T-cell lymphoma (CTCL).
SGX301 is a first-in-class, photodynamic therapy utilizing safe, visible light for activation. Synthetic hypericin is a potent photosensitizer that is topically applied to skin lesions and activated by visible fluorescent light 16 to 24 hours later.
This treatment approach is intended to prevent the secondary malignancies that may occur following chemotherapy or photodynamic therapies that are dependent on ultraviolet exposure.
Combined with photoactivation, hypericin has demonstrated significant antiproliferative effects on activated, normal human lymphoid cells and inhibited the growth of malignant T cells isolated from CTCL patients.
Topical hypericin has also proven safe in a phase 1 study of healthy volunteers.
In a phase 2 trial of patients with CTCL (mycosis fungoides only) or psoriasis, topical hypericin conferred a significant improvement over placebo. Among CTCL patients, the treatment prompted a response rate of 58.3%, compared to an 8.3% response rate for placebo (P≤0.04).
Topical hypericin was also well tolerated in this trial. There were no deaths or serious adverse events related to the treatment. However, there were reports of mild to moderate burning, itching, erythema, and pruritus at the application site.
Soligenix, Inc., the company developing SGX301, is currently working with CTCL centers, the National Organization for Rare Disorders, and the Cutaneous Lymphoma Foundation to begin a 120-subject phase 3 trial of SGX301.
About orphan designation
The European Commission grants orphan designation to medicines designed to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons in the European Union and has no satisfactory treatment available.
In addition to a 10-year period of marketing exclusivity after product approval, orphan drug designation provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase, as well as direct access to the centralized authorization procedure.
SGX301 has both orphan designation and fast track designation from the US Food and Drug Administration for the first-line treatment of CTCL.
The European Commission has granted orphan drug designation to synthetic hypericin, the active pharmaceutical ingredient in SGX301, for the treatment of cutaneous T-cell lymphoma (CTCL).
SGX301 is a first-in-class, photodynamic therapy utilizing safe, visible light for activation. Synthetic hypericin is a potent photosensitizer that is topically applied to skin lesions and activated by visible fluorescent light 16 to 24 hours later.
This treatment approach is intended to prevent the secondary malignancies that may occur following chemotherapy or photodynamic therapies that are dependent on ultraviolet exposure.
Combined with photoactivation, hypericin has demonstrated significant antiproliferative effects on activated, normal human lymphoid cells and inhibited the growth of malignant T cells isolated from CTCL patients.
Topical hypericin has also proven safe in a phase 1 study of healthy volunteers.
In a phase 2 trial of patients with CTCL (mycosis fungoides only) or psoriasis, topical hypericin conferred a significant improvement over placebo. Among CTCL patients, the treatment prompted a response rate of 58.3%, compared to an 8.3% response rate for placebo (P≤0.04).
Topical hypericin was also well tolerated in this trial. There were no deaths or serious adverse events related to the treatment. However, there were reports of mild to moderate burning, itching, erythema, and pruritus at the application site.
Soligenix, Inc., the company developing SGX301, is currently working with CTCL centers, the National Organization for Rare Disorders, and the Cutaneous Lymphoma Foundation to begin a 120-subject phase 3 trial of SGX301.
About orphan designation
The European Commission grants orphan designation to medicines designed to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons in the European Union and has no satisfactory treatment available.
In addition to a 10-year period of marketing exclusivity after product approval, orphan drug designation provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase, as well as direct access to the centralized authorization procedure.
SGX301 has both orphan designation and fast track designation from the US Food and Drug Administration for the first-line treatment of CTCL.
Health Canada grants drug conditional approval for MCL
Photo courtesy of
Janssen Biotech, Inc.
Health Canada has granted conditional approval for the BTK inhibitor ibrutinib (Imbruvica) to treat patients with relapsed or refractory mantle cell lymphoma (MCL).
This approval was based on data from a phase 2 trial in which ibrutinib conferred an overall response rate of 68% in patients with relapsed/refractory MCL.
For ibrutinib to gain full approval, Health Canada must receive additional data confirming the drug provides a clinical benefit.
Ibrutinib was first approved in Canada in November 2014 for patients with chronic lymphocytic leukemia (CLL), including those with 17p deletion, who have received at least one prior therapy, or for the frontline treatment of patients with CLL with 17p deletion. For this use, ibrutinib was issued marketing authorization without conditions.
Now, Health Canada has issued ibrutinib conditional marketing authorization for the treatment of relapsed/refractory MCL. This decision was based on data from the phase 2 PCYC-1104 trial, which was presented at ASH 2012 and published in NEJM in August 2013.
The study included 111 MCL patients who had received at least one prior therapy. The primary endpoint of the study was overall response rate according to the revised International Working Group criteria for non-Hodgkin lymphoma.
The overall response rate was 68%, with a complete response rate of 21% and a partial response rate of 47%. With a median follow-up of 15.3 months, the median response duration was 17.5 months.
The estimated progression-free survival was 13.9 months, and the overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.
Common nonhematologic adverse events included diarrhea (50%), fatigue (41%), nausea (31%), peripheral edema (28%), dyspnea (27%), constipation (25%), upper respiratory tract infection (23%), vomiting (23%), and decreased appetite (21%). The most common grade 3, 4, or 5 infection was pneumonia (6%).
Grade 3 and 4 hematologic adverse events included neutropenia (16%), thrombocytopenia (11%), and anemia (10%). Grade 3 bleeding events occurred in 5 patients.
Eight patients (7%) had an adverse event that led to treatment discontinuation.
Sixteen patients (14%) died during the trial, 12 due to disease progression and 4 due to an adverse event. Two patients died of pneumonia, 1 from sepsis, and 1 from a cardiac arrest that was not considered drug-related.
Ibrutinib is co-developed by Cilag GmbH International (a member of the Janssen Pharmaceutical Companies) and Pharmacyclics LLC, an AbbVie company. Janssen Inc. markets ibrutinib as Imbruvica in Canada.
Photo courtesy of
Janssen Biotech, Inc.
Health Canada has granted conditional approval for the BTK inhibitor ibrutinib (Imbruvica) to treat patients with relapsed or refractory mantle cell lymphoma (MCL).
This approval was based on data from a phase 2 trial in which ibrutinib conferred an overall response rate of 68% in patients with relapsed/refractory MCL.
For ibrutinib to gain full approval, Health Canada must receive additional data confirming the drug provides a clinical benefit.
Ibrutinib was first approved in Canada in November 2014 for patients with chronic lymphocytic leukemia (CLL), including those with 17p deletion, who have received at least one prior therapy, or for the frontline treatment of patients with CLL with 17p deletion. For this use, ibrutinib was issued marketing authorization without conditions.
Now, Health Canada has issued ibrutinib conditional marketing authorization for the treatment of relapsed/refractory MCL. This decision was based on data from the phase 2 PCYC-1104 trial, which was presented at ASH 2012 and published in NEJM in August 2013.
The study included 111 MCL patients who had received at least one prior therapy. The primary endpoint of the study was overall response rate according to the revised International Working Group criteria for non-Hodgkin lymphoma.
The overall response rate was 68%, with a complete response rate of 21% and a partial response rate of 47%. With a median follow-up of 15.3 months, the median response duration was 17.5 months.
The estimated progression-free survival was 13.9 months, and the overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.
Common nonhematologic adverse events included diarrhea (50%), fatigue (41%), nausea (31%), peripheral edema (28%), dyspnea (27%), constipation (25%), upper respiratory tract infection (23%), vomiting (23%), and decreased appetite (21%). The most common grade 3, 4, or 5 infection was pneumonia (6%).
Grade 3 and 4 hematologic adverse events included neutropenia (16%), thrombocytopenia (11%), and anemia (10%). Grade 3 bleeding events occurred in 5 patients.
Eight patients (7%) had an adverse event that led to treatment discontinuation.
Sixteen patients (14%) died during the trial, 12 due to disease progression and 4 due to an adverse event. Two patients died of pneumonia, 1 from sepsis, and 1 from a cardiac arrest that was not considered drug-related.
Ibrutinib is co-developed by Cilag GmbH International (a member of the Janssen Pharmaceutical Companies) and Pharmacyclics LLC, an AbbVie company. Janssen Inc. markets ibrutinib as Imbruvica in Canada.
Photo courtesy of
Janssen Biotech, Inc.
Health Canada has granted conditional approval for the BTK inhibitor ibrutinib (Imbruvica) to treat patients with relapsed or refractory mantle cell lymphoma (MCL).
This approval was based on data from a phase 2 trial in which ibrutinib conferred an overall response rate of 68% in patients with relapsed/refractory MCL.
For ibrutinib to gain full approval, Health Canada must receive additional data confirming the drug provides a clinical benefit.
Ibrutinib was first approved in Canada in November 2014 for patients with chronic lymphocytic leukemia (CLL), including those with 17p deletion, who have received at least one prior therapy, or for the frontline treatment of patients with CLL with 17p deletion. For this use, ibrutinib was issued marketing authorization without conditions.
Now, Health Canada has issued ibrutinib conditional marketing authorization for the treatment of relapsed/refractory MCL. This decision was based on data from the phase 2 PCYC-1104 trial, which was presented at ASH 2012 and published in NEJM in August 2013.
The study included 111 MCL patients who had received at least one prior therapy. The primary endpoint of the study was overall response rate according to the revised International Working Group criteria for non-Hodgkin lymphoma.
The overall response rate was 68%, with a complete response rate of 21% and a partial response rate of 47%. With a median follow-up of 15.3 months, the median response duration was 17.5 months.
The estimated progression-free survival was 13.9 months, and the overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.
Common nonhematologic adverse events included diarrhea (50%), fatigue (41%), nausea (31%), peripheral edema (28%), dyspnea (27%), constipation (25%), upper respiratory tract infection (23%), vomiting (23%), and decreased appetite (21%). The most common grade 3, 4, or 5 infection was pneumonia (6%).
Grade 3 and 4 hematologic adverse events included neutropenia (16%), thrombocytopenia (11%), and anemia (10%). Grade 3 bleeding events occurred in 5 patients.
Eight patients (7%) had an adverse event that led to treatment discontinuation.
Sixteen patients (14%) died during the trial, 12 due to disease progression and 4 due to an adverse event. Two patients died of pneumonia, 1 from sepsis, and 1 from a cardiac arrest that was not considered drug-related.
Ibrutinib is co-developed by Cilag GmbH International (a member of the Janssen Pharmaceutical Companies) and Pharmacyclics LLC, an AbbVie company. Janssen Inc. markets ibrutinib as Imbruvica in Canada.
Tool identifies optimal TKI for cancers
Photo courtesy of the
University of Colorado
Researchers say they have developed a tool that allows us to determine which tyrosine kinase inhibitor (TKI) will be most effective against a certain type of cancer.
The tool, known as the Kinase Addiction Ranker (KAR), predicts the genetic abnormalities that are driving the cancer in any population of cells and chooses the best TKI or combination of TKIs to target these abnormalities.
The researchers described the tool in Bioinformatics.
“A lot of [TKIs] inhibit a lot more than what they’re supposed to inhibit,” said study author Aik Choon Tan, PhD, of the University of Colorado Anschutz Medical Campus in Aurora.
“Maybe drug A was designed to inhibit kinase B, but it also inhibits kinase C and D as well. Our approach centers on exploiting the promiscuity of these drugs, the ‘drug spillover.’”
For each TKI, there is a signature describing the kinases each drug fully or partially inhibits. Dr Tan and his colleagues combined these kinase inhibition signatures with the results of high-throughput screening. They used the Genomics of Drug Sensitivity in Cancer database to determine which TKIs have already proven active against which cancer cell lines.
The result is KAR, which does 2 things. For any cancer cell line, the program ranks the kinases that are most important to the growth of the disease. Then, the program recommends the combination of existing TKIs that is likely to do the most good against the implicated kinases.
Dr Tan and his colleagues tested KAR using samples from 151 leukemia patients and found that, among the kinases analyzed, FLT3 had the highest variance in sensitivity to TKIs.
But EPHA5, EPHA3, and BTK were the kinases most commonly associated with drug sensitivity. They had significant associations in 72%, 58%, and 54% of the patient samples, respectively.
The researchers said the frequency of BTK dependence they observed is interesting given the fact that the BTK inhibitor ibrutinib produced favorable results in a phase 1b/2 trial of patients with chronic lymphocytic leukemia (CLL). The progression-free survival rate at 26 months was 75% in that trial.
Dr Tan and his colleagues said this was consistent with their findings, which showed that 70% of CLL patient data had a significant association between BTK inhibition and drug sensitivity.
The researchers also found that KAR could predict TKI sensitivity in 21 lung cancer cell lines. In addition, the tool was able to recommend a combination of TKIs that hindered proliferation in the lung cancer cell line H1581. KAR suggested ponatinib and the experimental anticancer agent AZD8055, and experiments showed that these drugs synergistically reduced proliferation in H1581.
KAR is available for download on the Tan lab’s website.
Photo courtesy of the
University of Colorado
Researchers say they have developed a tool that allows us to determine which tyrosine kinase inhibitor (TKI) will be most effective against a certain type of cancer.
The tool, known as the Kinase Addiction Ranker (KAR), predicts the genetic abnormalities that are driving the cancer in any population of cells and chooses the best TKI or combination of TKIs to target these abnormalities.
The researchers described the tool in Bioinformatics.
“A lot of [TKIs] inhibit a lot more than what they’re supposed to inhibit,” said study author Aik Choon Tan, PhD, of the University of Colorado Anschutz Medical Campus in Aurora.
“Maybe drug A was designed to inhibit kinase B, but it also inhibits kinase C and D as well. Our approach centers on exploiting the promiscuity of these drugs, the ‘drug spillover.’”
For each TKI, there is a signature describing the kinases each drug fully or partially inhibits. Dr Tan and his colleagues combined these kinase inhibition signatures with the results of high-throughput screening. They used the Genomics of Drug Sensitivity in Cancer database to determine which TKIs have already proven active against which cancer cell lines.
The result is KAR, which does 2 things. For any cancer cell line, the program ranks the kinases that are most important to the growth of the disease. Then, the program recommends the combination of existing TKIs that is likely to do the most good against the implicated kinases.
Dr Tan and his colleagues tested KAR using samples from 151 leukemia patients and found that, among the kinases analyzed, FLT3 had the highest variance in sensitivity to TKIs.
But EPHA5, EPHA3, and BTK were the kinases most commonly associated with drug sensitivity. They had significant associations in 72%, 58%, and 54% of the patient samples, respectively.
The researchers said the frequency of BTK dependence they observed is interesting given the fact that the BTK inhibitor ibrutinib produced favorable results in a phase 1b/2 trial of patients with chronic lymphocytic leukemia (CLL). The progression-free survival rate at 26 months was 75% in that trial.
Dr Tan and his colleagues said this was consistent with their findings, which showed that 70% of CLL patient data had a significant association between BTK inhibition and drug sensitivity.
The researchers also found that KAR could predict TKI sensitivity in 21 lung cancer cell lines. In addition, the tool was able to recommend a combination of TKIs that hindered proliferation in the lung cancer cell line H1581. KAR suggested ponatinib and the experimental anticancer agent AZD8055, and experiments showed that these drugs synergistically reduced proliferation in H1581.
KAR is available for download on the Tan lab’s website.
Photo courtesy of the
University of Colorado
Researchers say they have developed a tool that allows us to determine which tyrosine kinase inhibitor (TKI) will be most effective against a certain type of cancer.
The tool, known as the Kinase Addiction Ranker (KAR), predicts the genetic abnormalities that are driving the cancer in any population of cells and chooses the best TKI or combination of TKIs to target these abnormalities.
The researchers described the tool in Bioinformatics.
“A lot of [TKIs] inhibit a lot more than what they’re supposed to inhibit,” said study author Aik Choon Tan, PhD, of the University of Colorado Anschutz Medical Campus in Aurora.
“Maybe drug A was designed to inhibit kinase B, but it also inhibits kinase C and D as well. Our approach centers on exploiting the promiscuity of these drugs, the ‘drug spillover.’”
For each TKI, there is a signature describing the kinases each drug fully or partially inhibits. Dr Tan and his colleagues combined these kinase inhibition signatures with the results of high-throughput screening. They used the Genomics of Drug Sensitivity in Cancer database to determine which TKIs have already proven active against which cancer cell lines.
The result is KAR, which does 2 things. For any cancer cell line, the program ranks the kinases that are most important to the growth of the disease. Then, the program recommends the combination of existing TKIs that is likely to do the most good against the implicated kinases.
Dr Tan and his colleagues tested KAR using samples from 151 leukemia patients and found that, among the kinases analyzed, FLT3 had the highest variance in sensitivity to TKIs.
But EPHA5, EPHA3, and BTK were the kinases most commonly associated with drug sensitivity. They had significant associations in 72%, 58%, and 54% of the patient samples, respectively.
The researchers said the frequency of BTK dependence they observed is interesting given the fact that the BTK inhibitor ibrutinib produced favorable results in a phase 1b/2 trial of patients with chronic lymphocytic leukemia (CLL). The progression-free survival rate at 26 months was 75% in that trial.
Dr Tan and his colleagues said this was consistent with their findings, which showed that 70% of CLL patient data had a significant association between BTK inhibition and drug sensitivity.
The researchers also found that KAR could predict TKI sensitivity in 21 lung cancer cell lines. In addition, the tool was able to recommend a combination of TKIs that hindered proliferation in the lung cancer cell line H1581. KAR suggested ponatinib and the experimental anticancer agent AZD8055, and experiments showed that these drugs synergistically reduced proliferation in H1581.
KAR is available for download on the Tan lab’s website.
Analysis reveals ‘distinctive biology’ of CTCL
New research suggests cutaneous T-cell lymphoma (CTCL) is driven by a plethora of genetic mutations.
Investigators conducted a genomic analysis of normal and cancer cells from patients with CTCL and identified mutations in 17 genes that are implicated in CTCL pathogenesis.
They also found that somatic copy number variants (SCNVs) driving CTCL outnumbered somatic single-nucleotide variants (SSNVs) by more than 10 to 1.
The team reported these findings in Nature Genetics.
They performed exome and whole-genome DNA sequencing and RNA sequencing on purified CTCL cells and matched normal cells. And they identified genes implicated in CTCL pathogenesis by looking for:
- Genes with recurrent SSNVs altering the same amino acid more often than expected by chance
- Genes with SSNVs previously identified as recurrent mutations in other cancers
- Genes having a significantly increased burden of protein-altering SSNVs
- SCNVs that occurred more often than expected by chance.
This revealed mutations in 17 genes that are implicated in CTCL pathogenesis—TP53, ZEB1, ARID1A, DNMT3A, CDKN2A, FAS, NFKB2, CD28, RHOA, PLCG1, STAT5B, BRAF, ATM, CTCF, TNFAIP3, PRKCQ, and IRF4.
The investigators noted that these are genes involved in T-cell activation, apoptosis, NF-κB signaling, chromatin remodeling, and DNA damage response.
The team also discovered “a striking bias” for SCNVs as drivers of CTCL. They identified 12 statistically significant chromosome-arm SCNVs and 36 significant focal SCNVs.
Collectively, these SCNVs occurred 473 times in the CTCL samples analyzed—a mean of 7.5 focal deletions, 1.6 broad deletions, 1.0 focal amplification, and 1.8 broad amplifications per CTCL.
On the other hand, there were 38 SSNVs in CTCL driver genes—1.0 per tumor.
So, according to these data, SCNVs comprise 92% of all driver mutations in CTCL—a mean of 11.8 pathogenic SCNVs vs 1.0 SSNV per CTCL.
“This cancer has a very distinctive biology,” said Jaehyuk Choi, MD, PhD, of the Yale School of Medicine in New Haven, Connecticut.
And decoding this biology has revealed potential treatment approaches, according to Dr Choi and his colleagues.
For example, the presence of mutations activating the NF-κB pathway suggests NF-κB inhibitors such as bortezomib may have therapeutic potential in CTCL, and the presence of CD28 mutations suggests inhibitors such as abatacept may be effective against the disease.
New research suggests cutaneous T-cell lymphoma (CTCL) is driven by a plethora of genetic mutations.
Investigators conducted a genomic analysis of normal and cancer cells from patients with CTCL and identified mutations in 17 genes that are implicated in CTCL pathogenesis.
They also found that somatic copy number variants (SCNVs) driving CTCL outnumbered somatic single-nucleotide variants (SSNVs) by more than 10 to 1.
The team reported these findings in Nature Genetics.
They performed exome and whole-genome DNA sequencing and RNA sequencing on purified CTCL cells and matched normal cells. And they identified genes implicated in CTCL pathogenesis by looking for:
- Genes with recurrent SSNVs altering the same amino acid more often than expected by chance
- Genes with SSNVs previously identified as recurrent mutations in other cancers
- Genes having a significantly increased burden of protein-altering SSNVs
- SCNVs that occurred more often than expected by chance.
This revealed mutations in 17 genes that are implicated in CTCL pathogenesis—TP53, ZEB1, ARID1A, DNMT3A, CDKN2A, FAS, NFKB2, CD28, RHOA, PLCG1, STAT5B, BRAF, ATM, CTCF, TNFAIP3, PRKCQ, and IRF4.
The investigators noted that these are genes involved in T-cell activation, apoptosis, NF-κB signaling, chromatin remodeling, and DNA damage response.
The team also discovered “a striking bias” for SCNVs as drivers of CTCL. They identified 12 statistically significant chromosome-arm SCNVs and 36 significant focal SCNVs.
Collectively, these SCNVs occurred 473 times in the CTCL samples analyzed—a mean of 7.5 focal deletions, 1.6 broad deletions, 1.0 focal amplification, and 1.8 broad amplifications per CTCL.
On the other hand, there were 38 SSNVs in CTCL driver genes—1.0 per tumor.
So, according to these data, SCNVs comprise 92% of all driver mutations in CTCL—a mean of 11.8 pathogenic SCNVs vs 1.0 SSNV per CTCL.
“This cancer has a very distinctive biology,” said Jaehyuk Choi, MD, PhD, of the Yale School of Medicine in New Haven, Connecticut.
And decoding this biology has revealed potential treatment approaches, according to Dr Choi and his colleagues.
For example, the presence of mutations activating the NF-κB pathway suggests NF-κB inhibitors such as bortezomib may have therapeutic potential in CTCL, and the presence of CD28 mutations suggests inhibitors such as abatacept may be effective against the disease.
New research suggests cutaneous T-cell lymphoma (CTCL) is driven by a plethora of genetic mutations.
Investigators conducted a genomic analysis of normal and cancer cells from patients with CTCL and identified mutations in 17 genes that are implicated in CTCL pathogenesis.
They also found that somatic copy number variants (SCNVs) driving CTCL outnumbered somatic single-nucleotide variants (SSNVs) by more than 10 to 1.
The team reported these findings in Nature Genetics.
They performed exome and whole-genome DNA sequencing and RNA sequencing on purified CTCL cells and matched normal cells. And they identified genes implicated in CTCL pathogenesis by looking for:
- Genes with recurrent SSNVs altering the same amino acid more often than expected by chance
- Genes with SSNVs previously identified as recurrent mutations in other cancers
- Genes having a significantly increased burden of protein-altering SSNVs
- SCNVs that occurred more often than expected by chance.
This revealed mutations in 17 genes that are implicated in CTCL pathogenesis—TP53, ZEB1, ARID1A, DNMT3A, CDKN2A, FAS, NFKB2, CD28, RHOA, PLCG1, STAT5B, BRAF, ATM, CTCF, TNFAIP3, PRKCQ, and IRF4.
The investigators noted that these are genes involved in T-cell activation, apoptosis, NF-κB signaling, chromatin remodeling, and DNA damage response.
The team also discovered “a striking bias” for SCNVs as drivers of CTCL. They identified 12 statistically significant chromosome-arm SCNVs and 36 significant focal SCNVs.
Collectively, these SCNVs occurred 473 times in the CTCL samples analyzed—a mean of 7.5 focal deletions, 1.6 broad deletions, 1.0 focal amplification, and 1.8 broad amplifications per CTCL.
On the other hand, there were 38 SSNVs in CTCL driver genes—1.0 per tumor.
So, according to these data, SCNVs comprise 92% of all driver mutations in CTCL—a mean of 11.8 pathogenic SCNVs vs 1.0 SSNV per CTCL.
“This cancer has a very distinctive biology,” said Jaehyuk Choi, MD, PhD, of the Yale School of Medicine in New Haven, Connecticut.
And decoding this biology has revealed potential treatment approaches, according to Dr Choi and his colleagues.
For example, the presence of mutations activating the NF-κB pathway suggests NF-κB inhibitors such as bortezomib may have therapeutic potential in CTCL, and the presence of CD28 mutations suggests inhibitors such as abatacept may be effective against the disease.
DLBCL tied to metabolic disruption
Researchers say they have found evidence linking disrupted metabolism and diffuse large B-cell lymphoma (DLBCL).
“The link between metabolism and cancer has been proposed or inferred to exist for a long time, but what is more scarce is evidence for a direct connection—genetic mutations in metabolic enzymes,” said Ricardo C.T. Aguiar, MD, PhD, of the University of Texas Health Science Center at San Antonio.
“We have discovered a metabolic imbalance that is oncogenic or pro-cancer.”
Dr Aguiar and his colleagues described this discovery in Nature Communications.
The team found that the gene encoding the enzyme D2-hydroxyglutarate dehydrogenase (D2HGDH) is mutated in DLBCL.
The mutated lymphoma cell displays a deficiency of a metabolite called alpha-ketoglutarate (α-KG), which is needed in steady levels for cells to be healthy.
“When the levels of α-KG are abnormally low, another class of enzymes called dioxygenases don‘t function properly, resulting in a host of additional disturbances,” Dr Aguiar said.
He added that α-KG has been identified as a critical regulator of aging and stem cell maintenance. So the implications of his group’s findings are not limited to cancer biology.
Researchers say they have found evidence linking disrupted metabolism and diffuse large B-cell lymphoma (DLBCL).
“The link between metabolism and cancer has been proposed or inferred to exist for a long time, but what is more scarce is evidence for a direct connection—genetic mutations in metabolic enzymes,” said Ricardo C.T. Aguiar, MD, PhD, of the University of Texas Health Science Center at San Antonio.
“We have discovered a metabolic imbalance that is oncogenic or pro-cancer.”
Dr Aguiar and his colleagues described this discovery in Nature Communications.
The team found that the gene encoding the enzyme D2-hydroxyglutarate dehydrogenase (D2HGDH) is mutated in DLBCL.
The mutated lymphoma cell displays a deficiency of a metabolite called alpha-ketoglutarate (α-KG), which is needed in steady levels for cells to be healthy.
“When the levels of α-KG are abnormally low, another class of enzymes called dioxygenases don‘t function properly, resulting in a host of additional disturbances,” Dr Aguiar said.
He added that α-KG has been identified as a critical regulator of aging and stem cell maintenance. So the implications of his group’s findings are not limited to cancer biology.
Researchers say they have found evidence linking disrupted metabolism and diffuse large B-cell lymphoma (DLBCL).
“The link between metabolism and cancer has been proposed or inferred to exist for a long time, but what is more scarce is evidence for a direct connection—genetic mutations in metabolic enzymes,” said Ricardo C.T. Aguiar, MD, PhD, of the University of Texas Health Science Center at San Antonio.
“We have discovered a metabolic imbalance that is oncogenic or pro-cancer.”
Dr Aguiar and his colleagues described this discovery in Nature Communications.
The team found that the gene encoding the enzyme D2-hydroxyglutarate dehydrogenase (D2HGDH) is mutated in DLBCL.
The mutated lymphoma cell displays a deficiency of a metabolite called alpha-ketoglutarate (α-KG), which is needed in steady levels for cells to be healthy.
“When the levels of α-KG are abnormally low, another class of enzymes called dioxygenases don‘t function properly, resulting in a host of additional disturbances,” Dr Aguiar said.
He added that α-KG has been identified as a critical regulator of aging and stem cell maintenance. So the implications of his group’s findings are not limited to cancer biology.
Response to ibrutinib varies by DLBCL subtype
Photo by Larry Young
Responses to the BTK inhibitor ibrutinib differ according to a patient’s subtype of diffuse large B-cell lymphoma (DLBCL), results of a phase 1/2 trial suggest.
The study showed that patients with activated B-cell-like (ABC) DLBCL were more likely to respond to ibrutinib than patients with germinal center B-cell-like (GCB) DLBCL.
“This is the first clinical study to demonstrate the importance of precision medicine in lymphomas,” said Wyndham Wilson, MD, PhD, of the National Cancer Institute in Bethesda, Maryland.
Dr Wilson and his colleagues described the trial in Nature Medicine. The research, which was sponsored by Pharmacyclics, Inc. (the company developing ibrutinib), was previously presented at EHA 2013.
The trial enrolled 80 patients with relapsed or refractory DLBCL. All patients received ibrutinib. Tumor responses occurred in 25% of patients. There were 8 complete responses and 12 partial responses.
After a median follow-up of 11.5 months, the median progression-free survival was 1.6 months, and the median overall survival was 6.4 months.
An analysis of outcomes by disease subtype showed that ibrutinib produced complete or partial responses in 37% (14/38) of patients with ABC DLBCL but only 5% (1/20) of patients with GCB DLBCL.
The researchers speculated that ABC tumors may produce abnormal B-cell receptor signals that promote the survival of cancer cells by activating BTK, which would account for the sensitivity of ABC tumors to ibrutinib.
Based on this study’s results, researchers are conducting an international phase 3 trial of standard chemotherapy with or without ibrutinib in patients with DLBCL, excluding the GCB subtype (NCT01855750).
This is the first time a phase 3 trial has been designed to selectively enroll patients with a particular molecular subtype of DLBCL. The study’s objective is to determine if the addition of ibrutinib to standard chemotherapy can increase the cure rate of patients with ABC DLBCL.
Photo by Larry Young
Responses to the BTK inhibitor ibrutinib differ according to a patient’s subtype of diffuse large B-cell lymphoma (DLBCL), results of a phase 1/2 trial suggest.
The study showed that patients with activated B-cell-like (ABC) DLBCL were more likely to respond to ibrutinib than patients with germinal center B-cell-like (GCB) DLBCL.
“This is the first clinical study to demonstrate the importance of precision medicine in lymphomas,” said Wyndham Wilson, MD, PhD, of the National Cancer Institute in Bethesda, Maryland.
Dr Wilson and his colleagues described the trial in Nature Medicine. The research, which was sponsored by Pharmacyclics, Inc. (the company developing ibrutinib), was previously presented at EHA 2013.
The trial enrolled 80 patients with relapsed or refractory DLBCL. All patients received ibrutinib. Tumor responses occurred in 25% of patients. There were 8 complete responses and 12 partial responses.
After a median follow-up of 11.5 months, the median progression-free survival was 1.6 months, and the median overall survival was 6.4 months.
An analysis of outcomes by disease subtype showed that ibrutinib produced complete or partial responses in 37% (14/38) of patients with ABC DLBCL but only 5% (1/20) of patients with GCB DLBCL.
The researchers speculated that ABC tumors may produce abnormal B-cell receptor signals that promote the survival of cancer cells by activating BTK, which would account for the sensitivity of ABC tumors to ibrutinib.
Based on this study’s results, researchers are conducting an international phase 3 trial of standard chemotherapy with or without ibrutinib in patients with DLBCL, excluding the GCB subtype (NCT01855750).
This is the first time a phase 3 trial has been designed to selectively enroll patients with a particular molecular subtype of DLBCL. The study’s objective is to determine if the addition of ibrutinib to standard chemotherapy can increase the cure rate of patients with ABC DLBCL.
Photo by Larry Young
Responses to the BTK inhibitor ibrutinib differ according to a patient’s subtype of diffuse large B-cell lymphoma (DLBCL), results of a phase 1/2 trial suggest.
The study showed that patients with activated B-cell-like (ABC) DLBCL were more likely to respond to ibrutinib than patients with germinal center B-cell-like (GCB) DLBCL.
“This is the first clinical study to demonstrate the importance of precision medicine in lymphomas,” said Wyndham Wilson, MD, PhD, of the National Cancer Institute in Bethesda, Maryland.
Dr Wilson and his colleagues described the trial in Nature Medicine. The research, which was sponsored by Pharmacyclics, Inc. (the company developing ibrutinib), was previously presented at EHA 2013.
The trial enrolled 80 patients with relapsed or refractory DLBCL. All patients received ibrutinib. Tumor responses occurred in 25% of patients. There were 8 complete responses and 12 partial responses.
After a median follow-up of 11.5 months, the median progression-free survival was 1.6 months, and the median overall survival was 6.4 months.
An analysis of outcomes by disease subtype showed that ibrutinib produced complete or partial responses in 37% (14/38) of patients with ABC DLBCL but only 5% (1/20) of patients with GCB DLBCL.
The researchers speculated that ABC tumors may produce abnormal B-cell receptor signals that promote the survival of cancer cells by activating BTK, which would account for the sensitivity of ABC tumors to ibrutinib.
Based on this study’s results, researchers are conducting an international phase 3 trial of standard chemotherapy with or without ibrutinib in patients with DLBCL, excluding the GCB subtype (NCT01855750).
This is the first time a phase 3 trial has been designed to selectively enroll patients with a particular molecular subtype of DLBCL. The study’s objective is to determine if the addition of ibrutinib to standard chemotherapy can increase the cure rate of patients with ABC DLBCL.
Ibrutinib approved to treat WM in EU
The European Commission has granted marketing authorization for ibrutinib (Imbruvica) to treat Waldenstrom’s macroglobulinemia (WM).
The Bruton’s tyrosine kinase inhibitor is now approved to treat adults with WM who have received at least one prior therapy or as first-line treatment for patients considered unsuitable for chemo-immunotherapy.
Ibrutinib is the first therapy approved specifically for WM in the European Union (EU). The approval applies to all 28 EU member states, plus Iceland, Norway, and Liechtenstein.
Ibrutinib is already approved to treat WM in the US. The drug is also approved in the EU, the US, and other countries to treat chronic lymphocytic leukemia and mantle cell lymphoma.
Janssen-Cilag International NV holds the marketing authorization for ibrutinib in Europe, and its affiliates market the drug in Europe and the rest of the world. In the US, ibrutinib is under joint development by Pharmacyclics and Janssen Biotech, Inc.
Phase 2 study
The European Commission’s approval of ibrutinib was based on a multicenter, phase 2 study in which researchers tested the drug (given at 420 mg once daily) in 63 patients with previously treated WM.
Initial data showed an overall response rate of 87.3% in patients who received the drug for a median of 11.7 months.
Updated results from the study were published in NEJM in April. After a median treatment duration of 19.1 months, the overall response rate was 91%.
At 24 months, the estimated rate of progression-free survival was 69%, and the estimated rate of overall survival was 95%.
The most common grade 2-4 adverse events were neutropenia (22%) and thrombocytopenia (14%). Ibrutinib-related neutropenia and thrombocytopenia were reversible but required a dose reduction in 3 patients and treatment discontinuation in 4 patients.
Grade 2 or higher bleeding events occurred in 4 patients, and there were 15 infections considered possibly related to ibrutinib.
Treatment-related atrial fibrillation (AFib) occurred in 3 patients, all of whom had a prior history of paroxysmal AFib. AFib resolved when treatment was withheld, and all 3 patients were able to continue on therapy per protocol without an additional event.
The European Commission has granted marketing authorization for ibrutinib (Imbruvica) to treat Waldenstrom’s macroglobulinemia (WM).
The Bruton’s tyrosine kinase inhibitor is now approved to treat adults with WM who have received at least one prior therapy or as first-line treatment for patients considered unsuitable for chemo-immunotherapy.
Ibrutinib is the first therapy approved specifically for WM in the European Union (EU). The approval applies to all 28 EU member states, plus Iceland, Norway, and Liechtenstein.
Ibrutinib is already approved to treat WM in the US. The drug is also approved in the EU, the US, and other countries to treat chronic lymphocytic leukemia and mantle cell lymphoma.
Janssen-Cilag International NV holds the marketing authorization for ibrutinib in Europe, and its affiliates market the drug in Europe and the rest of the world. In the US, ibrutinib is under joint development by Pharmacyclics and Janssen Biotech, Inc.
Phase 2 study
The European Commission’s approval of ibrutinib was based on a multicenter, phase 2 study in which researchers tested the drug (given at 420 mg once daily) in 63 patients with previously treated WM.
Initial data showed an overall response rate of 87.3% in patients who received the drug for a median of 11.7 months.
Updated results from the study were published in NEJM in April. After a median treatment duration of 19.1 months, the overall response rate was 91%.
At 24 months, the estimated rate of progression-free survival was 69%, and the estimated rate of overall survival was 95%.
The most common grade 2-4 adverse events were neutropenia (22%) and thrombocytopenia (14%). Ibrutinib-related neutropenia and thrombocytopenia were reversible but required a dose reduction in 3 patients and treatment discontinuation in 4 patients.
Grade 2 or higher bleeding events occurred in 4 patients, and there were 15 infections considered possibly related to ibrutinib.
Treatment-related atrial fibrillation (AFib) occurred in 3 patients, all of whom had a prior history of paroxysmal AFib. AFib resolved when treatment was withheld, and all 3 patients were able to continue on therapy per protocol without an additional event.
The European Commission has granted marketing authorization for ibrutinib (Imbruvica) to treat Waldenstrom’s macroglobulinemia (WM).
The Bruton’s tyrosine kinase inhibitor is now approved to treat adults with WM who have received at least one prior therapy or as first-line treatment for patients considered unsuitable for chemo-immunotherapy.
Ibrutinib is the first therapy approved specifically for WM in the European Union (EU). The approval applies to all 28 EU member states, plus Iceland, Norway, and Liechtenstein.
Ibrutinib is already approved to treat WM in the US. The drug is also approved in the EU, the US, and other countries to treat chronic lymphocytic leukemia and mantle cell lymphoma.
Janssen-Cilag International NV holds the marketing authorization for ibrutinib in Europe, and its affiliates market the drug in Europe and the rest of the world. In the US, ibrutinib is under joint development by Pharmacyclics and Janssen Biotech, Inc.
Phase 2 study
The European Commission’s approval of ibrutinib was based on a multicenter, phase 2 study in which researchers tested the drug (given at 420 mg once daily) in 63 patients with previously treated WM.
Initial data showed an overall response rate of 87.3% in patients who received the drug for a median of 11.7 months.
Updated results from the study were published in NEJM in April. After a median treatment duration of 19.1 months, the overall response rate was 91%.
At 24 months, the estimated rate of progression-free survival was 69%, and the estimated rate of overall survival was 95%.
The most common grade 2-4 adverse events were neutropenia (22%) and thrombocytopenia (14%). Ibrutinib-related neutropenia and thrombocytopenia were reversible but required a dose reduction in 3 patients and treatment discontinuation in 4 patients.
Grade 2 or higher bleeding events occurred in 4 patients, and there were 15 infections considered possibly related to ibrutinib.
Treatment-related atrial fibrillation (AFib) occurred in 3 patients, all of whom had a prior history of paroxysmal AFib. AFib resolved when treatment was withheld, and all 3 patients were able to continue on therapy per protocol without an additional event.
How B-cell lymphoma evades NK cells
Image by Joshua Strokes
Researchers say they have determined how lymphoma cells evade natural killer (NK) cells, and this discovery has revealed potential solutions to the problem.
The team found that NK-cell activation and a second, “triggering” event are both necessary for NK cells to exhibit cytotoxicity in the presence of B-cell lymphoma.
Previous research demonstrated this 2-step process in vitro. Now, researchers have shown that it occurs in vivo.
Dr Ralph Mocikat, of Helmholtz Zentrum München in Munich, Germany, and his colleagues described this research in the European Journal of Immunology.
The team conducted experiments using transplantable tumors, a λ-myc-transgenic model of endogenously arising lymphoma that mimics human Burkitt lymphoma, and mice deficient in the NK group 2 D (NKG2D) receptor.
The experiments showed that NK cells could eliminate lymphoma cells after receiving 2 signals. The first was NK-cell activation, which gave rise to IFN-γ expression.
The researchers found that NK cells could be activated in the presence of MHC class Ilow tumor cells or by injecting bone marrow-derived dendritic cells. Previous research had shown that interleukin 2 (IL-2) and IL-15 could activate NK cells.
The second step involved the NKG2D receptor and its ligands. NKG2D ligands are located on the surface of tumor cells and bind to NK cells. The researchers found that, if these ligands are down-regulated, the NK cells cannot carry out cytotoxic activity.
However, the team found they could increase NKG2D ligand levels. They introduced bortezomib to the tumor cell line 291 and saw a roughly 4-fold increase in NKG2D ligand levels.
“Our results show that the transfer of NK cells is a possible strategic option to treat B-cell lymphoma,” Dr Mocikat said. “According to our findings, this therapeutic approach can be optimized when transferred NK cells are already activated in vitro prior to their injection, thus bypassing the missing activation potential in the tumor microenvironment. An additional injection of IFN-γ or of antibodies against IL-10 could further support the immune activity.”
Image by Joshua Strokes
Researchers say they have determined how lymphoma cells evade natural killer (NK) cells, and this discovery has revealed potential solutions to the problem.
The team found that NK-cell activation and a second, “triggering” event are both necessary for NK cells to exhibit cytotoxicity in the presence of B-cell lymphoma.
Previous research demonstrated this 2-step process in vitro. Now, researchers have shown that it occurs in vivo.
Dr Ralph Mocikat, of Helmholtz Zentrum München in Munich, Germany, and his colleagues described this research in the European Journal of Immunology.
The team conducted experiments using transplantable tumors, a λ-myc-transgenic model of endogenously arising lymphoma that mimics human Burkitt lymphoma, and mice deficient in the NK group 2 D (NKG2D) receptor.
The experiments showed that NK cells could eliminate lymphoma cells after receiving 2 signals. The first was NK-cell activation, which gave rise to IFN-γ expression.
The researchers found that NK cells could be activated in the presence of MHC class Ilow tumor cells or by injecting bone marrow-derived dendritic cells. Previous research had shown that interleukin 2 (IL-2) and IL-15 could activate NK cells.
The second step involved the NKG2D receptor and its ligands. NKG2D ligands are located on the surface of tumor cells and bind to NK cells. The researchers found that, if these ligands are down-regulated, the NK cells cannot carry out cytotoxic activity.
However, the team found they could increase NKG2D ligand levels. They introduced bortezomib to the tumor cell line 291 and saw a roughly 4-fold increase in NKG2D ligand levels.
“Our results show that the transfer of NK cells is a possible strategic option to treat B-cell lymphoma,” Dr Mocikat said. “According to our findings, this therapeutic approach can be optimized when transferred NK cells are already activated in vitro prior to their injection, thus bypassing the missing activation potential in the tumor microenvironment. An additional injection of IFN-γ or of antibodies against IL-10 could further support the immune activity.”
Image by Joshua Strokes
Researchers say they have determined how lymphoma cells evade natural killer (NK) cells, and this discovery has revealed potential solutions to the problem.
The team found that NK-cell activation and a second, “triggering” event are both necessary for NK cells to exhibit cytotoxicity in the presence of B-cell lymphoma.
Previous research demonstrated this 2-step process in vitro. Now, researchers have shown that it occurs in vivo.
Dr Ralph Mocikat, of Helmholtz Zentrum München in Munich, Germany, and his colleagues described this research in the European Journal of Immunology.
The team conducted experiments using transplantable tumors, a λ-myc-transgenic model of endogenously arising lymphoma that mimics human Burkitt lymphoma, and mice deficient in the NK group 2 D (NKG2D) receptor.
The experiments showed that NK cells could eliminate lymphoma cells after receiving 2 signals. The first was NK-cell activation, which gave rise to IFN-γ expression.
The researchers found that NK cells could be activated in the presence of MHC class Ilow tumor cells or by injecting bone marrow-derived dendritic cells. Previous research had shown that interleukin 2 (IL-2) and IL-15 could activate NK cells.
The second step involved the NKG2D receptor and its ligands. NKG2D ligands are located on the surface of tumor cells and bind to NK cells. The researchers found that, if these ligands are down-regulated, the NK cells cannot carry out cytotoxic activity.
However, the team found they could increase NKG2D ligand levels. They introduced bortezomib to the tumor cell line 291 and saw a roughly 4-fold increase in NKG2D ligand levels.
“Our results show that the transfer of NK cells is a possible strategic option to treat B-cell lymphoma,” Dr Mocikat said. “According to our findings, this therapeutic approach can be optimized when transferred NK cells are already activated in vitro prior to their injection, thus bypassing the missing activation potential in the tumor microenvironment. An additional injection of IFN-γ or of antibodies against IL-10 could further support the immune activity.”
Early progression predicts overall survival in FL
Photo by Rhoda Baer
The goal for many cancer patients is to reach the 5-year mark without progression, but a new study suggests 2 years might be a more appropriate goal for patients with follicular lymphoma (FL).
Previous research indicated that about 20% of FL patients relapse within 2 years of treatment.
Now, researchers have found these patients have a significantly worse 5-year survival rate than patients who make it past the 2-year mark without progressing.
Carla Casulo, MD, of the University of Rochester in New York, and her colleagues recounted these findings in the Journal of Clinical Oncology.
The team analyzed data from 588 patients with stage 2-4 FL who received first-line therapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).
These patients could be separated into 2 groups: those with disease progression within 2 years of diagnosis (19%, n=110) and those who did not progress within the 2-year period (71%, n=420).
Eight percent of patients (n=46) were lost to follow-up, and 2% (n=12) died of causes other than progression within the 2-year period.
At 2 years, the overall survival (OS) rate was 68% in the early progression group and 97% in the group that did not progress. At 5 years, OS rates were 50% and 90%, respectively.
In unadjusted Cox regression analysis, early progression was associated with lower OS (hazard ratio[HR]=7.17). The same was true after the researchers adjusted for FLIPI score (HR=6.44).
The team observed similar results in a validation cohort of 147 FL patients who received first-line R-CHOP. At 2 years, the OS rate was 64% in the early progression group and 98% in the group that did not progress. At 5 years, OS rates were 34% and 94%, respectively.
Again, in an unadjusted analysis, early progression was associated with lower OS (HR=20.0). And this trend was maintained after the researchers adjusted for FLIPI score (HR=19.8).
The researchers also found that, for patients in the early progression group, clinical factors that were predictive of inferior OS were age, ECOG performance score, nodal sites, and disease stage. For the group that did not progress within 2 years, clinical factors that were predictive of OS were age and extranodal sites.
In a Cox regression analysis that encompassed these factors and early progression, only early progression, age, and ECOG performance scores remained significantly predictive of OS.
“[W]e have confirmed that all relapsed patients are not equal and therefore should not be approached the same at diagnosis, nor at the time of relapse, in terms of therapies,” Dr Casulo said.
“It will be critical to predict who is most likely to relapse early. We believe that targeted sequencing or gene-expression profiling will be important to understanding how to improve the outcomes of this group.”
Photo by Rhoda Baer
The goal for many cancer patients is to reach the 5-year mark without progression, but a new study suggests 2 years might be a more appropriate goal for patients with follicular lymphoma (FL).
Previous research indicated that about 20% of FL patients relapse within 2 years of treatment.
Now, researchers have found these patients have a significantly worse 5-year survival rate than patients who make it past the 2-year mark without progressing.
Carla Casulo, MD, of the University of Rochester in New York, and her colleagues recounted these findings in the Journal of Clinical Oncology.
The team analyzed data from 588 patients with stage 2-4 FL who received first-line therapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).
These patients could be separated into 2 groups: those with disease progression within 2 years of diagnosis (19%, n=110) and those who did not progress within the 2-year period (71%, n=420).
Eight percent of patients (n=46) were lost to follow-up, and 2% (n=12) died of causes other than progression within the 2-year period.
At 2 years, the overall survival (OS) rate was 68% in the early progression group and 97% in the group that did not progress. At 5 years, OS rates were 50% and 90%, respectively.
In unadjusted Cox regression analysis, early progression was associated with lower OS (hazard ratio[HR]=7.17). The same was true after the researchers adjusted for FLIPI score (HR=6.44).
The team observed similar results in a validation cohort of 147 FL patients who received first-line R-CHOP. At 2 years, the OS rate was 64% in the early progression group and 98% in the group that did not progress. At 5 years, OS rates were 34% and 94%, respectively.
Again, in an unadjusted analysis, early progression was associated with lower OS (HR=20.0). And this trend was maintained after the researchers adjusted for FLIPI score (HR=19.8).
The researchers also found that, for patients in the early progression group, clinical factors that were predictive of inferior OS were age, ECOG performance score, nodal sites, and disease stage. For the group that did not progress within 2 years, clinical factors that were predictive of OS were age and extranodal sites.
In a Cox regression analysis that encompassed these factors and early progression, only early progression, age, and ECOG performance scores remained significantly predictive of OS.
“[W]e have confirmed that all relapsed patients are not equal and therefore should not be approached the same at diagnosis, nor at the time of relapse, in terms of therapies,” Dr Casulo said.
“It will be critical to predict who is most likely to relapse early. We believe that targeted sequencing or gene-expression profiling will be important to understanding how to improve the outcomes of this group.”
Photo by Rhoda Baer
The goal for many cancer patients is to reach the 5-year mark without progression, but a new study suggests 2 years might be a more appropriate goal for patients with follicular lymphoma (FL).
Previous research indicated that about 20% of FL patients relapse within 2 years of treatment.
Now, researchers have found these patients have a significantly worse 5-year survival rate than patients who make it past the 2-year mark without progressing.
Carla Casulo, MD, of the University of Rochester in New York, and her colleagues recounted these findings in the Journal of Clinical Oncology.
The team analyzed data from 588 patients with stage 2-4 FL who received first-line therapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).
These patients could be separated into 2 groups: those with disease progression within 2 years of diagnosis (19%, n=110) and those who did not progress within the 2-year period (71%, n=420).
Eight percent of patients (n=46) were lost to follow-up, and 2% (n=12) died of causes other than progression within the 2-year period.
At 2 years, the overall survival (OS) rate was 68% in the early progression group and 97% in the group that did not progress. At 5 years, OS rates were 50% and 90%, respectively.
In unadjusted Cox regression analysis, early progression was associated with lower OS (hazard ratio[HR]=7.17). The same was true after the researchers adjusted for FLIPI score (HR=6.44).
The team observed similar results in a validation cohort of 147 FL patients who received first-line R-CHOP. At 2 years, the OS rate was 64% in the early progression group and 98% in the group that did not progress. At 5 years, OS rates were 34% and 94%, respectively.
Again, in an unadjusted analysis, early progression was associated with lower OS (HR=20.0). And this trend was maintained after the researchers adjusted for FLIPI score (HR=19.8).
The researchers also found that, for patients in the early progression group, clinical factors that were predictive of inferior OS were age, ECOG performance score, nodal sites, and disease stage. For the group that did not progress within 2 years, clinical factors that were predictive of OS were age and extranodal sites.
In a Cox regression analysis that encompassed these factors and early progression, only early progression, age, and ECOG performance scores remained significantly predictive of OS.
“[W]e have confirmed that all relapsed patients are not equal and therefore should not be approached the same at diagnosis, nor at the time of relapse, in terms of therapies,” Dr Casulo said.
“It will be critical to predict who is most likely to relapse early. We believe that targeted sequencing or gene-expression profiling will be important to understanding how to improve the outcomes of this group.”
Novel mAb targeting CD70 shows activity in TCL
Photo by Linda Bartlett
LUGANO—The defucosylated monoclonal antibody (mAb) ARGX-110, which is active against CD70-bearing tumor cells and CD70-dependent stimulation of regulatory T cells, has shown activity in relapsed/refractory T-cell lymphoma (TCL), according to investigators.
Of the 8 TCL patients enrolled in a phase 1 trial of ARGX-110, 3 had a biological response to the mAb.
In this dose-escalation trial, the maximum tolerated dose of ARGX-110 was not reached.
Marie Maerevoet, MD, of the Institut Jules Bordet in Brussels, Belgium, presented results from the lymphoma cohort of this trial at the 13th International Congress on Malignant Lymphoma (abstract 040*). The study was sponsored by arGEN-X, the company developing ARGX-110.
Dr Maerevoet pointed out that more than half the tumor cells in 71% of patients with cutaneous T-cell lymphoma (CTCL) and 22% with peripheral T-cell lymphoma (PTCL) are CD70-positive. CD70 signaling occurs via CD27, and CD27 shedding is a biomarker for an active pathway.
Since ARGX-110 has an affinity for CD70, inhibits CD27 signaling, and mediates the lysis of TCL in Sézary syndrome (SS), mycosis fungoides, and anaplastic large cell lymphoma (ALCL) cell lines, researchers decided to investigate the safety and clinical pharmacology of ARGX-110 monotherapy in metastatic, relapsed or refractory, solid tumors and hematologic malignancies.
Patients’ tumors had to express CD70 by immunohistochemistry, defined as more than 10% tumor cells of 2+ or 3+ intensity.
The primary endpoint was to determine the maximum tolerated dose. Secondary endpoints were pharmacology, immunogenicity, and efficacy signals.
Patient demographics
Between February 2013 and April 2015, investigators assigned 63 patients to receive ARGX-110 at doses ranging from 0.1 to 10 mg/kg intravenously once every 3 weeks until disease progression or withdrawal due to toxicity. Patients were pre-medicated with corticoid regimens.
Eighteen patients had lymphoid malignancies—8 with B-cell lymphomas, 8 with TCL, and 2 with Hodgkin lymphoma.
The TCL cohort consisted of 1 patient with SS, 1 with transformed SS, 1 with T-helper CTCL, 2 with angioimmunoblastic T-cell lymphoma (AITL), 2 with PTCL not otherwise specified (NOS), and 1 with ALCL.
Patients were a median age of 62 (range, 55–78), had a median of 4 prior treatment regimens (range, 2–6), and received a median of 2 cycles of ARGX-110 (range, 1–6).
Dr Maerevoet noted that most lymphoma patients received a dose of 5 mg/kg every 3 weeks.
Safety
In the entire lymphoma cohort of 18 patients, 4 patients (22%) experienced a grade 1 or 2 infusion-related reaction. Three patients (18%) developed grade 3 sepsis—1 with Waldenstrom’s macroglobulinemia, 1 with AITL, and 1 with PTCL-NOS.
Two patients (11%) had hematologic toxicity consisting of a grade 3 decrease in hemoglobin and absolute neutrophil count, which was considered not related to treatment with ARGX-110.
“The maximum tolerated dose was not reached,” Dr Maerevoet said. “We didn’t observe auto-immune adverse events or impact on serum IgG or IgM.”
Efficacy outcomes
The main reason for withdrawal was progressive disease, which occurred in 14 lymphoma patients.
Two patients—1 with Waldenstrom’s macroglobulinemia and 1 with AITL—withdrew due to adverse events of sepsis (catheter infection, pneumonia), 1 patient with SS withdrew for social reasons, and 1 patient with follicular T-cell lymphoma (currently classified as PTCL-NOS) remains on study.
Dr Maerevoet described the 3 TCL patients who had a biologic response to ARGX-110. One patient with SS had a hematologic complete remission after 6 cycles at the 0.1 mg/kg dose.
Another patient with transformed SS experienced a depletion of circulating clones after 2 cycles of the 10 mg/kg dose. However, the patient ultimately died of progressive disease.
A third patient had resolution of autoimmune hemolytic anemia. This 61-year-old male with AITL achieved a partial response with normalization of LDH levels and an increase in hemoglobin to 7.9 g/dL without transfusion support after 2 doses of ARGX-110 at 5 mg/kg.
The patient became Coombs-negative and had a 16% reduction in tumor size by CT scan. However, the patient subsequently died of pneumonia.
The investigators also observed clinical activity in the peripheral blood, lymph nodes, and skin of 2 additional patients.
The biological activity of ARGX-110 as demonstrated by these TCL patients, in addition to the safety and tolerability of this mAb, led the team to conclude that further clinical investigation of ARGX-110 in TCL is warranted.
*Information in the abstract differs from that presented at the meeting.
Photo by Linda Bartlett
LUGANO—The defucosylated monoclonal antibody (mAb) ARGX-110, which is active against CD70-bearing tumor cells and CD70-dependent stimulation of regulatory T cells, has shown activity in relapsed/refractory T-cell lymphoma (TCL), according to investigators.
Of the 8 TCL patients enrolled in a phase 1 trial of ARGX-110, 3 had a biological response to the mAb.
In this dose-escalation trial, the maximum tolerated dose of ARGX-110 was not reached.
Marie Maerevoet, MD, of the Institut Jules Bordet in Brussels, Belgium, presented results from the lymphoma cohort of this trial at the 13th International Congress on Malignant Lymphoma (abstract 040*). The study was sponsored by arGEN-X, the company developing ARGX-110.
Dr Maerevoet pointed out that more than half the tumor cells in 71% of patients with cutaneous T-cell lymphoma (CTCL) and 22% with peripheral T-cell lymphoma (PTCL) are CD70-positive. CD70 signaling occurs via CD27, and CD27 shedding is a biomarker for an active pathway.
Since ARGX-110 has an affinity for CD70, inhibits CD27 signaling, and mediates the lysis of TCL in Sézary syndrome (SS), mycosis fungoides, and anaplastic large cell lymphoma (ALCL) cell lines, researchers decided to investigate the safety and clinical pharmacology of ARGX-110 monotherapy in metastatic, relapsed or refractory, solid tumors and hematologic malignancies.
Patients’ tumors had to express CD70 by immunohistochemistry, defined as more than 10% tumor cells of 2+ or 3+ intensity.
The primary endpoint was to determine the maximum tolerated dose. Secondary endpoints were pharmacology, immunogenicity, and efficacy signals.
Patient demographics
Between February 2013 and April 2015, investigators assigned 63 patients to receive ARGX-110 at doses ranging from 0.1 to 10 mg/kg intravenously once every 3 weeks until disease progression or withdrawal due to toxicity. Patients were pre-medicated with corticoid regimens.
Eighteen patients had lymphoid malignancies—8 with B-cell lymphomas, 8 with TCL, and 2 with Hodgkin lymphoma.
The TCL cohort consisted of 1 patient with SS, 1 with transformed SS, 1 with T-helper CTCL, 2 with angioimmunoblastic T-cell lymphoma (AITL), 2 with PTCL not otherwise specified (NOS), and 1 with ALCL.
Patients were a median age of 62 (range, 55–78), had a median of 4 prior treatment regimens (range, 2–6), and received a median of 2 cycles of ARGX-110 (range, 1–6).
Dr Maerevoet noted that most lymphoma patients received a dose of 5 mg/kg every 3 weeks.
Safety
In the entire lymphoma cohort of 18 patients, 4 patients (22%) experienced a grade 1 or 2 infusion-related reaction. Three patients (18%) developed grade 3 sepsis—1 with Waldenstrom’s macroglobulinemia, 1 with AITL, and 1 with PTCL-NOS.
Two patients (11%) had hematologic toxicity consisting of a grade 3 decrease in hemoglobin and absolute neutrophil count, which was considered not related to treatment with ARGX-110.
“The maximum tolerated dose was not reached,” Dr Maerevoet said. “We didn’t observe auto-immune adverse events or impact on serum IgG or IgM.”
Efficacy outcomes
The main reason for withdrawal was progressive disease, which occurred in 14 lymphoma patients.
Two patients—1 with Waldenstrom’s macroglobulinemia and 1 with AITL—withdrew due to adverse events of sepsis (catheter infection, pneumonia), 1 patient with SS withdrew for social reasons, and 1 patient with follicular T-cell lymphoma (currently classified as PTCL-NOS) remains on study.
Dr Maerevoet described the 3 TCL patients who had a biologic response to ARGX-110. One patient with SS had a hematologic complete remission after 6 cycles at the 0.1 mg/kg dose.
Another patient with transformed SS experienced a depletion of circulating clones after 2 cycles of the 10 mg/kg dose. However, the patient ultimately died of progressive disease.
A third patient had resolution of autoimmune hemolytic anemia. This 61-year-old male with AITL achieved a partial response with normalization of LDH levels and an increase in hemoglobin to 7.9 g/dL without transfusion support after 2 doses of ARGX-110 at 5 mg/kg.
The patient became Coombs-negative and had a 16% reduction in tumor size by CT scan. However, the patient subsequently died of pneumonia.
The investigators also observed clinical activity in the peripheral blood, lymph nodes, and skin of 2 additional patients.
The biological activity of ARGX-110 as demonstrated by these TCL patients, in addition to the safety and tolerability of this mAb, led the team to conclude that further clinical investigation of ARGX-110 in TCL is warranted.
*Information in the abstract differs from that presented at the meeting.
Photo by Linda Bartlett
LUGANO—The defucosylated monoclonal antibody (mAb) ARGX-110, which is active against CD70-bearing tumor cells and CD70-dependent stimulation of regulatory T cells, has shown activity in relapsed/refractory T-cell lymphoma (TCL), according to investigators.
Of the 8 TCL patients enrolled in a phase 1 trial of ARGX-110, 3 had a biological response to the mAb.
In this dose-escalation trial, the maximum tolerated dose of ARGX-110 was not reached.
Marie Maerevoet, MD, of the Institut Jules Bordet in Brussels, Belgium, presented results from the lymphoma cohort of this trial at the 13th International Congress on Malignant Lymphoma (abstract 040*). The study was sponsored by arGEN-X, the company developing ARGX-110.
Dr Maerevoet pointed out that more than half the tumor cells in 71% of patients with cutaneous T-cell lymphoma (CTCL) and 22% with peripheral T-cell lymphoma (PTCL) are CD70-positive. CD70 signaling occurs via CD27, and CD27 shedding is a biomarker for an active pathway.
Since ARGX-110 has an affinity for CD70, inhibits CD27 signaling, and mediates the lysis of TCL in Sézary syndrome (SS), mycosis fungoides, and anaplastic large cell lymphoma (ALCL) cell lines, researchers decided to investigate the safety and clinical pharmacology of ARGX-110 monotherapy in metastatic, relapsed or refractory, solid tumors and hematologic malignancies.
Patients’ tumors had to express CD70 by immunohistochemistry, defined as more than 10% tumor cells of 2+ or 3+ intensity.
The primary endpoint was to determine the maximum tolerated dose. Secondary endpoints were pharmacology, immunogenicity, and efficacy signals.
Patient demographics
Between February 2013 and April 2015, investigators assigned 63 patients to receive ARGX-110 at doses ranging from 0.1 to 10 mg/kg intravenously once every 3 weeks until disease progression or withdrawal due to toxicity. Patients were pre-medicated with corticoid regimens.
Eighteen patients had lymphoid malignancies—8 with B-cell lymphomas, 8 with TCL, and 2 with Hodgkin lymphoma.
The TCL cohort consisted of 1 patient with SS, 1 with transformed SS, 1 with T-helper CTCL, 2 with angioimmunoblastic T-cell lymphoma (AITL), 2 with PTCL not otherwise specified (NOS), and 1 with ALCL.
Patients were a median age of 62 (range, 55–78), had a median of 4 prior treatment regimens (range, 2–6), and received a median of 2 cycles of ARGX-110 (range, 1–6).
Dr Maerevoet noted that most lymphoma patients received a dose of 5 mg/kg every 3 weeks.
Safety
In the entire lymphoma cohort of 18 patients, 4 patients (22%) experienced a grade 1 or 2 infusion-related reaction. Three patients (18%) developed grade 3 sepsis—1 with Waldenstrom’s macroglobulinemia, 1 with AITL, and 1 with PTCL-NOS.
Two patients (11%) had hematologic toxicity consisting of a grade 3 decrease in hemoglobin and absolute neutrophil count, which was considered not related to treatment with ARGX-110.
“The maximum tolerated dose was not reached,” Dr Maerevoet said. “We didn’t observe auto-immune adverse events or impact on serum IgG or IgM.”
Efficacy outcomes
The main reason for withdrawal was progressive disease, which occurred in 14 lymphoma patients.
Two patients—1 with Waldenstrom’s macroglobulinemia and 1 with AITL—withdrew due to adverse events of sepsis (catheter infection, pneumonia), 1 patient with SS withdrew for social reasons, and 1 patient with follicular T-cell lymphoma (currently classified as PTCL-NOS) remains on study.
Dr Maerevoet described the 3 TCL patients who had a biologic response to ARGX-110. One patient with SS had a hematologic complete remission after 6 cycles at the 0.1 mg/kg dose.
Another patient with transformed SS experienced a depletion of circulating clones after 2 cycles of the 10 mg/kg dose. However, the patient ultimately died of progressive disease.
A third patient had resolution of autoimmune hemolytic anemia. This 61-year-old male with AITL achieved a partial response with normalization of LDH levels and an increase in hemoglobin to 7.9 g/dL without transfusion support after 2 doses of ARGX-110 at 5 mg/kg.
The patient became Coombs-negative and had a 16% reduction in tumor size by CT scan. However, the patient subsequently died of pneumonia.
The investigators also observed clinical activity in the peripheral blood, lymph nodes, and skin of 2 additional patients.
The biological activity of ARGX-110 as demonstrated by these TCL patients, in addition to the safety and tolerability of this mAb, led the team to conclude that further clinical investigation of ARGX-110 in TCL is warranted.
*Information in the abstract differs from that presented at the meeting.