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Making sense of the expanded myeloma treatment landscape
ORLANDO – The moment the Food and Drug Administration approved daratumumab, ixazomib, and elotuzumab in rapid-fire succession over 15 days in November 2015, Dr. S. Vincent Rajkumar’s phone started ringing.
As with other multiple myeloma experts, three common questions kept cropping up:
• For previously untreated patients, should we add bortezomib to lenalidomide plus dexamethasone (Rd) based on the S0777 results?
• For previously treated patients, should we add ixazomib or elotuzumab to Rd?
• Should we add daratumumab to frontline therapy right out of the box?
Daratumumab (Darzalex), ixazomib (Ninlaro), and elotuzumab (Empliciti) are welcome additions to the armamentarium, but the problem with this plethora of riches is that numerous treatments already exist for frontline multiple myeloma, observed Dr. Rajkumar, professor of medicine at the Mayo Clinic in Rochester, Minn.
In fact, the National Comprehensive Cancer Network guidelines list 22 possible newly diagnosed myeloma regimens that can be potentially recommended for patients.
“This definitely leads to confusion in the community. And this was the result of the fact that we didn’t have a single, good randomized trial with a survival benefit of a modern therapy against another modern therapy,” Dr. Rajkumar said at the annual meeting of the American Society of Hematology during a joint FDA/ASH symposium on the three newly approved agents.
This quandary was solved at ASH with phase III randomized data from the Southwest Oncology Group S0777 study showing a significant overall survival advantage with a triplet of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) followed by continuous Rd maintenance compared with Rd alone and ongoing maintenance in untreated patients who did not intend to receive stem cell transplant, he said.
Median overall survival was 75 months for the triplet vs. 64 months for the Rd doublet (hazard ratio, 0.709; two-sided log-rank P = .0250), and median PFS 43 months vs. 30 months (HR, 0.712; one-sided P = .0018), study author Dr. Brian Durie, of Cedars-Sinai Comprehensive Cancer Center in Los Angeles, reported (Abstract 25).
The VRd triplet is already in use in the United States, but based on the S0777 results, many groups, including the Mayo Clinic, have changed treatment guidelines and now “prefer bortezomib, len-dex for frontline therapy, not just in transplant candidates, but also in non-transplant candidates,” Dr. Rajkumar said.
In countries where VRd is not possible, bortezomib, thalidomide, and dexamethasone (VTd) is a second option.
Rd is an appropriate therapy for non-transplant candidates who are frail or aged 75 years or older, he said, adding that there is no need to add bortezomib for patients already on Rd and doing well.
“If your patient is doing well on a doublet, leave them alone,” Dr. Rajkumar advised.
Similarly, for patients with relapsed myeloma who are doing well on Rd, there isn’t “an urgent need” to add ixazomib or elotuzumab, but rather, he said, “We can reserve those for when the patient progresses.”
Ixazomib is approved in combination with Rd after at least one prior therapy, but the oral proteasome inhibitor may have a role in the frontline treatment of standard-risk patients. It is a very simple regimen, just three pills a month, and “the side effect profile is outstanding; virtually difficult to tell who’s taking placebo and who’s taking drug,” Dr. Rajkumar observed.
In addition, some patients may not have access to bortezomib because of insurance reasons or can’t drive to the clinic once a week to get the shot, while others may be too frail to get an intravenous or subcutaneous shot or may have neuropathy.
“For whatever reason, I think it is reasonable to keep in mind that we may have a situation where we can use ixazomib/len-dex in clinical practice if the patient’s best interests so dictate,” he said.
For high-risk patients (deletion 17p or translocations t(4;14), t(14;16), t(14;20), VRd or VTd are obvious upfront choices. Based on four phase II trials and the ASPIRE results in the relapsed and refractory setting, however, the Mayo Clinic has already decided that the recently approved second-generation proteasome inhibitor carfilzomib (Kyprolis) plus Rd is also worth considering.
Adding a monoclonal antibody such as elotuzumab or daratumumab to a VRd triplet or ixazomib, lenalidomide, and dexamethasone (IRd) triplet may be another way to improve outcomes in high-risk patients, who still die with a median overall survival of 3 years, Dr. Rajkumar said. This strategy is already being used in the ongoing SWOG S1211 study.
For maintenance therapy after VRd or VTd and autologous stem cell transplant, he recommended lenalidomide for standard-risk patients and bortezomib-based maintenance for high-risk patients, but said ixazomib-based maintenance with the addition of monoclonal antibodies may also have a role in high-risk patients.
What may be more important going forward is how these three drugs will be used in clinical trials, Dr. Rajkumar observed.
“We’d rather put all patients on clinical trials than any of the recommendations I made,” he said. “The problem is that clinical trials have to be appropriately designed.”
Several phase III trials are already ongoing comparing a doublet versus a triplet (IRd vs. Rd, elotuzumab-Rd vs. Rd, and daratumumab-Rd vs. Rd) in the frontline setting, so the key question for future trials is which triplet: VRd, KRd, elotuzumab-Rd, or daratumumab-Rd, and to what endpoint.
Progression-free survival can remain a primary endpoint for comparing two triplets in the frontline, but PFS alone is not enough in the maintenance setting and investigators should look to other primary endpoints such as PFS2, PFS1 vs. PFS2, overall survival with a higher type 1 error than currently used, or PFS plus validated patient-reported or quality of life outcomes, Dr. Rajkumar said.
Relapsed/refractory disease
Speaking on how the three new agents fit into the relapsed or refractory space,Dr. Paul Richardson, of Dana-Farber Cancer Institute, Boston, said three-drug platforms are emerging as a standard of care for relapsed or refractory disease after studies have shown time and time again they are better than doublets.
He highlighted phase III data reported at ASH by Dr. Philippe Moreau from TOURMALINE-MM1 (Abstract 727) showing a 35% improvement in PFS with weekly oral ixazomib plus lenalidomide-dexamethasone vs. Rd alone in relapsed and/or refractory multiple myeloma.
This translated into a median 6-month gain in PFS compared with an almost 9-month PFS benefit seen in ASPIRE with carfilzomib plus Rd, but cross-trial comparisons should be approached with some caution and both hazard ratios were very robust, he said. In addition, as previously observed, ixazomib is remarkably well tolerated.
“I think ixazomib, particularly in older patients and particularly in patients with high-risk disease, will be very useful in the context of the three-drug or even greater combinations. So there’s a strong rationale for its use,” Dr. Richardson said.
He went on to say that elotuzumab has shown remarkable anti-myeloma activity in the relapsed and refractory setting, improving both the overall response rate and PFS when used in combination with Ld vs. Ld alone in the ELOQUENT-2 trial. Updated results from ELOQUENT-2 were presented at the ASH meeting (Abstract 28).
A PFS benefit was also seen when elotuzumab was added to bortezomib and dexamethasone, with a 24% reduction in the risk of disease progression or death reported in a study presented at ASH by myeloma expert Dr. Antonio Palumbo (Abstract 510).
“My point in showing this is that when you think of elotuzumab being used with lenalidomide and dexamethasone in relapse, many of our patients are actually on them as maintenance when it occurs, therefore elotuzumab may have a role in combination, for example, with proteasome inhibitors in this same setting,” Dr. Richardson said.
Several pomalidomide-based triple therapy combinations have been evaluated in advanced relapsed or refractory myeloma, with a phase II study (Abstract 506) reported that morning at ASH showing the third-generation immunomodulatory drug (IMiD) pomalidomide induced responses in 60% of heavily pretreated patients when partnered with pembrolizumab and dexamethasone.
Combination strategies with daratumumab are also very provocative, particularly in the context of IMiDs, he noted. A phase Ib study reported in the same early morning session by Dr. Ajai Chari (Abstract 508) had a “very encouraging” overall response rate of 71% with daratumumab plus pomalidomide and dexamethasone in heavily pretreated patients, including 43% very good partial responses or better, and an overall response rate of 67% among double-refractory patients.
“Daratumumab and elotuzumab, in my view, as first-in-class monoclonal antibodies, are paradigm-changing agents,” Dr. Richardson concluded. “They provide us with this mutation-driven ability to overdrive the impact of those mutations and the important point is that they prescribe an entirely non-crossresistant strategy that can be easily added to existing platforms of drugs.”
Dr. Rajkumar reported discussion of off-label drug use for elotuzumab, daratumumab, ixazomib, and carfilzomib in untreated myeloma, maintenance, and early relapse. Dr. Richardson reported membership on a board of directors or advisory committee for Millennium Takeda, Celgene, Janssen, Bristol-Myers Squibb, and Novartis, and research funding from Millennium Takeda and Celgene.
ORLANDO – The moment the Food and Drug Administration approved daratumumab, ixazomib, and elotuzumab in rapid-fire succession over 15 days in November 2015, Dr. S. Vincent Rajkumar’s phone started ringing.
As with other multiple myeloma experts, three common questions kept cropping up:
• For previously untreated patients, should we add bortezomib to lenalidomide plus dexamethasone (Rd) based on the S0777 results?
• For previously treated patients, should we add ixazomib or elotuzumab to Rd?
• Should we add daratumumab to frontline therapy right out of the box?
Daratumumab (Darzalex), ixazomib (Ninlaro), and elotuzumab (Empliciti) are welcome additions to the armamentarium, but the problem with this plethora of riches is that numerous treatments already exist for frontline multiple myeloma, observed Dr. Rajkumar, professor of medicine at the Mayo Clinic in Rochester, Minn.
In fact, the National Comprehensive Cancer Network guidelines list 22 possible newly diagnosed myeloma regimens that can be potentially recommended for patients.
“This definitely leads to confusion in the community. And this was the result of the fact that we didn’t have a single, good randomized trial with a survival benefit of a modern therapy against another modern therapy,” Dr. Rajkumar said at the annual meeting of the American Society of Hematology during a joint FDA/ASH symposium on the three newly approved agents.
This quandary was solved at ASH with phase III randomized data from the Southwest Oncology Group S0777 study showing a significant overall survival advantage with a triplet of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) followed by continuous Rd maintenance compared with Rd alone and ongoing maintenance in untreated patients who did not intend to receive stem cell transplant, he said.
Median overall survival was 75 months for the triplet vs. 64 months for the Rd doublet (hazard ratio, 0.709; two-sided log-rank P = .0250), and median PFS 43 months vs. 30 months (HR, 0.712; one-sided P = .0018), study author Dr. Brian Durie, of Cedars-Sinai Comprehensive Cancer Center in Los Angeles, reported (Abstract 25).
The VRd triplet is already in use in the United States, but based on the S0777 results, many groups, including the Mayo Clinic, have changed treatment guidelines and now “prefer bortezomib, len-dex for frontline therapy, not just in transplant candidates, but also in non-transplant candidates,” Dr. Rajkumar said.
In countries where VRd is not possible, bortezomib, thalidomide, and dexamethasone (VTd) is a second option.
Rd is an appropriate therapy for non-transplant candidates who are frail or aged 75 years or older, he said, adding that there is no need to add bortezomib for patients already on Rd and doing well.
“If your patient is doing well on a doublet, leave them alone,” Dr. Rajkumar advised.
Similarly, for patients with relapsed myeloma who are doing well on Rd, there isn’t “an urgent need” to add ixazomib or elotuzumab, but rather, he said, “We can reserve those for when the patient progresses.”
Ixazomib is approved in combination with Rd after at least one prior therapy, but the oral proteasome inhibitor may have a role in the frontline treatment of standard-risk patients. It is a very simple regimen, just three pills a month, and “the side effect profile is outstanding; virtually difficult to tell who’s taking placebo and who’s taking drug,” Dr. Rajkumar observed.
In addition, some patients may not have access to bortezomib because of insurance reasons or can’t drive to the clinic once a week to get the shot, while others may be too frail to get an intravenous or subcutaneous shot or may have neuropathy.
“For whatever reason, I think it is reasonable to keep in mind that we may have a situation where we can use ixazomib/len-dex in clinical practice if the patient’s best interests so dictate,” he said.
For high-risk patients (deletion 17p or translocations t(4;14), t(14;16), t(14;20), VRd or VTd are obvious upfront choices. Based on four phase II trials and the ASPIRE results in the relapsed and refractory setting, however, the Mayo Clinic has already decided that the recently approved second-generation proteasome inhibitor carfilzomib (Kyprolis) plus Rd is also worth considering.
Adding a monoclonal antibody such as elotuzumab or daratumumab to a VRd triplet or ixazomib, lenalidomide, and dexamethasone (IRd) triplet may be another way to improve outcomes in high-risk patients, who still die with a median overall survival of 3 years, Dr. Rajkumar said. This strategy is already being used in the ongoing SWOG S1211 study.
For maintenance therapy after VRd or VTd and autologous stem cell transplant, he recommended lenalidomide for standard-risk patients and bortezomib-based maintenance for high-risk patients, but said ixazomib-based maintenance with the addition of monoclonal antibodies may also have a role in high-risk patients.
What may be more important going forward is how these three drugs will be used in clinical trials, Dr. Rajkumar observed.
“We’d rather put all patients on clinical trials than any of the recommendations I made,” he said. “The problem is that clinical trials have to be appropriately designed.”
Several phase III trials are already ongoing comparing a doublet versus a triplet (IRd vs. Rd, elotuzumab-Rd vs. Rd, and daratumumab-Rd vs. Rd) in the frontline setting, so the key question for future trials is which triplet: VRd, KRd, elotuzumab-Rd, or daratumumab-Rd, and to what endpoint.
Progression-free survival can remain a primary endpoint for comparing two triplets in the frontline, but PFS alone is not enough in the maintenance setting and investigators should look to other primary endpoints such as PFS2, PFS1 vs. PFS2, overall survival with a higher type 1 error than currently used, or PFS plus validated patient-reported or quality of life outcomes, Dr. Rajkumar said.
Relapsed/refractory disease
Speaking on how the three new agents fit into the relapsed or refractory space,Dr. Paul Richardson, of Dana-Farber Cancer Institute, Boston, said three-drug platforms are emerging as a standard of care for relapsed or refractory disease after studies have shown time and time again they are better than doublets.
He highlighted phase III data reported at ASH by Dr. Philippe Moreau from TOURMALINE-MM1 (Abstract 727) showing a 35% improvement in PFS with weekly oral ixazomib plus lenalidomide-dexamethasone vs. Rd alone in relapsed and/or refractory multiple myeloma.
This translated into a median 6-month gain in PFS compared with an almost 9-month PFS benefit seen in ASPIRE with carfilzomib plus Rd, but cross-trial comparisons should be approached with some caution and both hazard ratios were very robust, he said. In addition, as previously observed, ixazomib is remarkably well tolerated.
“I think ixazomib, particularly in older patients and particularly in patients with high-risk disease, will be very useful in the context of the three-drug or even greater combinations. So there’s a strong rationale for its use,” Dr. Richardson said.
He went on to say that elotuzumab has shown remarkable anti-myeloma activity in the relapsed and refractory setting, improving both the overall response rate and PFS when used in combination with Ld vs. Ld alone in the ELOQUENT-2 trial. Updated results from ELOQUENT-2 were presented at the ASH meeting (Abstract 28).
A PFS benefit was also seen when elotuzumab was added to bortezomib and dexamethasone, with a 24% reduction in the risk of disease progression or death reported in a study presented at ASH by myeloma expert Dr. Antonio Palumbo (Abstract 510).
“My point in showing this is that when you think of elotuzumab being used with lenalidomide and dexamethasone in relapse, many of our patients are actually on them as maintenance when it occurs, therefore elotuzumab may have a role in combination, for example, with proteasome inhibitors in this same setting,” Dr. Richardson said.
Several pomalidomide-based triple therapy combinations have been evaluated in advanced relapsed or refractory myeloma, with a phase II study (Abstract 506) reported that morning at ASH showing the third-generation immunomodulatory drug (IMiD) pomalidomide induced responses in 60% of heavily pretreated patients when partnered with pembrolizumab and dexamethasone.
Combination strategies with daratumumab are also very provocative, particularly in the context of IMiDs, he noted. A phase Ib study reported in the same early morning session by Dr. Ajai Chari (Abstract 508) had a “very encouraging” overall response rate of 71% with daratumumab plus pomalidomide and dexamethasone in heavily pretreated patients, including 43% very good partial responses or better, and an overall response rate of 67% among double-refractory patients.
“Daratumumab and elotuzumab, in my view, as first-in-class monoclonal antibodies, are paradigm-changing agents,” Dr. Richardson concluded. “They provide us with this mutation-driven ability to overdrive the impact of those mutations and the important point is that they prescribe an entirely non-crossresistant strategy that can be easily added to existing platforms of drugs.”
Dr. Rajkumar reported discussion of off-label drug use for elotuzumab, daratumumab, ixazomib, and carfilzomib in untreated myeloma, maintenance, and early relapse. Dr. Richardson reported membership on a board of directors or advisory committee for Millennium Takeda, Celgene, Janssen, Bristol-Myers Squibb, and Novartis, and research funding from Millennium Takeda and Celgene.
ORLANDO – The moment the Food and Drug Administration approved daratumumab, ixazomib, and elotuzumab in rapid-fire succession over 15 days in November 2015, Dr. S. Vincent Rajkumar’s phone started ringing.
As with other multiple myeloma experts, three common questions kept cropping up:
• For previously untreated patients, should we add bortezomib to lenalidomide plus dexamethasone (Rd) based on the S0777 results?
• For previously treated patients, should we add ixazomib or elotuzumab to Rd?
• Should we add daratumumab to frontline therapy right out of the box?
Daratumumab (Darzalex), ixazomib (Ninlaro), and elotuzumab (Empliciti) are welcome additions to the armamentarium, but the problem with this plethora of riches is that numerous treatments already exist for frontline multiple myeloma, observed Dr. Rajkumar, professor of medicine at the Mayo Clinic in Rochester, Minn.
In fact, the National Comprehensive Cancer Network guidelines list 22 possible newly diagnosed myeloma regimens that can be potentially recommended for patients.
“This definitely leads to confusion in the community. And this was the result of the fact that we didn’t have a single, good randomized trial with a survival benefit of a modern therapy against another modern therapy,” Dr. Rajkumar said at the annual meeting of the American Society of Hematology during a joint FDA/ASH symposium on the three newly approved agents.
This quandary was solved at ASH with phase III randomized data from the Southwest Oncology Group S0777 study showing a significant overall survival advantage with a triplet of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) followed by continuous Rd maintenance compared with Rd alone and ongoing maintenance in untreated patients who did not intend to receive stem cell transplant, he said.
Median overall survival was 75 months for the triplet vs. 64 months for the Rd doublet (hazard ratio, 0.709; two-sided log-rank P = .0250), and median PFS 43 months vs. 30 months (HR, 0.712; one-sided P = .0018), study author Dr. Brian Durie, of Cedars-Sinai Comprehensive Cancer Center in Los Angeles, reported (Abstract 25).
The VRd triplet is already in use in the United States, but based on the S0777 results, many groups, including the Mayo Clinic, have changed treatment guidelines and now “prefer bortezomib, len-dex for frontline therapy, not just in transplant candidates, but also in non-transplant candidates,” Dr. Rajkumar said.
In countries where VRd is not possible, bortezomib, thalidomide, and dexamethasone (VTd) is a second option.
Rd is an appropriate therapy for non-transplant candidates who are frail or aged 75 years or older, he said, adding that there is no need to add bortezomib for patients already on Rd and doing well.
“If your patient is doing well on a doublet, leave them alone,” Dr. Rajkumar advised.
Similarly, for patients with relapsed myeloma who are doing well on Rd, there isn’t “an urgent need” to add ixazomib or elotuzumab, but rather, he said, “We can reserve those for when the patient progresses.”
Ixazomib is approved in combination with Rd after at least one prior therapy, but the oral proteasome inhibitor may have a role in the frontline treatment of standard-risk patients. It is a very simple regimen, just three pills a month, and “the side effect profile is outstanding; virtually difficult to tell who’s taking placebo and who’s taking drug,” Dr. Rajkumar observed.
In addition, some patients may not have access to bortezomib because of insurance reasons or can’t drive to the clinic once a week to get the shot, while others may be too frail to get an intravenous or subcutaneous shot or may have neuropathy.
“For whatever reason, I think it is reasonable to keep in mind that we may have a situation where we can use ixazomib/len-dex in clinical practice if the patient’s best interests so dictate,” he said.
For high-risk patients (deletion 17p or translocations t(4;14), t(14;16), t(14;20), VRd or VTd are obvious upfront choices. Based on four phase II trials and the ASPIRE results in the relapsed and refractory setting, however, the Mayo Clinic has already decided that the recently approved second-generation proteasome inhibitor carfilzomib (Kyprolis) plus Rd is also worth considering.
Adding a monoclonal antibody such as elotuzumab or daratumumab to a VRd triplet or ixazomib, lenalidomide, and dexamethasone (IRd) triplet may be another way to improve outcomes in high-risk patients, who still die with a median overall survival of 3 years, Dr. Rajkumar said. This strategy is already being used in the ongoing SWOG S1211 study.
For maintenance therapy after VRd or VTd and autologous stem cell transplant, he recommended lenalidomide for standard-risk patients and bortezomib-based maintenance for high-risk patients, but said ixazomib-based maintenance with the addition of monoclonal antibodies may also have a role in high-risk patients.
What may be more important going forward is how these three drugs will be used in clinical trials, Dr. Rajkumar observed.
“We’d rather put all patients on clinical trials than any of the recommendations I made,” he said. “The problem is that clinical trials have to be appropriately designed.”
Several phase III trials are already ongoing comparing a doublet versus a triplet (IRd vs. Rd, elotuzumab-Rd vs. Rd, and daratumumab-Rd vs. Rd) in the frontline setting, so the key question for future trials is which triplet: VRd, KRd, elotuzumab-Rd, or daratumumab-Rd, and to what endpoint.
Progression-free survival can remain a primary endpoint for comparing two triplets in the frontline, but PFS alone is not enough in the maintenance setting and investigators should look to other primary endpoints such as PFS2, PFS1 vs. PFS2, overall survival with a higher type 1 error than currently used, or PFS plus validated patient-reported or quality of life outcomes, Dr. Rajkumar said.
Relapsed/refractory disease
Speaking on how the three new agents fit into the relapsed or refractory space,Dr. Paul Richardson, of Dana-Farber Cancer Institute, Boston, said three-drug platforms are emerging as a standard of care for relapsed or refractory disease after studies have shown time and time again they are better than doublets.
He highlighted phase III data reported at ASH by Dr. Philippe Moreau from TOURMALINE-MM1 (Abstract 727) showing a 35% improvement in PFS with weekly oral ixazomib plus lenalidomide-dexamethasone vs. Rd alone in relapsed and/or refractory multiple myeloma.
This translated into a median 6-month gain in PFS compared with an almost 9-month PFS benefit seen in ASPIRE with carfilzomib plus Rd, but cross-trial comparisons should be approached with some caution and both hazard ratios were very robust, he said. In addition, as previously observed, ixazomib is remarkably well tolerated.
“I think ixazomib, particularly in older patients and particularly in patients with high-risk disease, will be very useful in the context of the three-drug or even greater combinations. So there’s a strong rationale for its use,” Dr. Richardson said.
He went on to say that elotuzumab has shown remarkable anti-myeloma activity in the relapsed and refractory setting, improving both the overall response rate and PFS when used in combination with Ld vs. Ld alone in the ELOQUENT-2 trial. Updated results from ELOQUENT-2 were presented at the ASH meeting (Abstract 28).
A PFS benefit was also seen when elotuzumab was added to bortezomib and dexamethasone, with a 24% reduction in the risk of disease progression or death reported in a study presented at ASH by myeloma expert Dr. Antonio Palumbo (Abstract 510).
“My point in showing this is that when you think of elotuzumab being used with lenalidomide and dexamethasone in relapse, many of our patients are actually on them as maintenance when it occurs, therefore elotuzumab may have a role in combination, for example, with proteasome inhibitors in this same setting,” Dr. Richardson said.
Several pomalidomide-based triple therapy combinations have been evaluated in advanced relapsed or refractory myeloma, with a phase II study (Abstract 506) reported that morning at ASH showing the third-generation immunomodulatory drug (IMiD) pomalidomide induced responses in 60% of heavily pretreated patients when partnered with pembrolizumab and dexamethasone.
Combination strategies with daratumumab are also very provocative, particularly in the context of IMiDs, he noted. A phase Ib study reported in the same early morning session by Dr. Ajai Chari (Abstract 508) had a “very encouraging” overall response rate of 71% with daratumumab plus pomalidomide and dexamethasone in heavily pretreated patients, including 43% very good partial responses or better, and an overall response rate of 67% among double-refractory patients.
“Daratumumab and elotuzumab, in my view, as first-in-class monoclonal antibodies, are paradigm-changing agents,” Dr. Richardson concluded. “They provide us with this mutation-driven ability to overdrive the impact of those mutations and the important point is that they prescribe an entirely non-crossresistant strategy that can be easily added to existing platforms of drugs.”
Dr. Rajkumar reported discussion of off-label drug use for elotuzumab, daratumumab, ixazomib, and carfilzomib in untreated myeloma, maintenance, and early relapse. Dr. Richardson reported membership on a board of directors or advisory committee for Millennium Takeda, Celgene, Janssen, Bristol-Myers Squibb, and Novartis, and research funding from Millennium Takeda and Celgene.
EXPERT ANALYSIS FROM ASH 2015
Drug gets priority review as CLL treatment
Image by Mary Ann Thompson
Despite previous safety concerns, the US Food and Drug Administration (FDA) has granted priority review for the BCL-2 inhibitor venetoclax.
The FDA is reviewing the drug as a potential treatment for patients with chronic lymphocytic leukemia (CLL), including those with 17p deletion, who have received at least 1 prior therapy.
A priority review designation is granted to drugs thought to have the potential to provide significant improvements in the treatment, prevention, or diagnosis of a disease.
The designation means the FDA’s goal is to take action on a drug application within 6 months, compared to 10 months under standard review.
Venetoclax has proven active against CLL and other hematologic malignancies, but it is known to induce tumor lysis syndrome (TLS). In fact, TLS-related deaths temporarily halted enrollment in trials of venetoclax. But researchers discovered ways to reduce the risk of TLS, and the trials continued.
Venetoclax received breakthrough therapy designation from the FDA last year for the treatment of patients with relapsed or refractory CLL and 17p deletion. This designation is designed to expedite the development and review of medicines intended to treat serious or life-threatening diseases.
The new drug application for venetoclax is based, in part, on data from the phase 2 M13-982 study, which were just presented at the 2015 ASH Annual Meeting.
Phase 2 trial
M13-982 is an open-label, single-arm, multicenter study in which researchers are evaluating the efficacy and safety of venetoclax in patients with relapsed, refractory, or previously untreated CLL with 17p deletion.
The study included 107 patients with relapsed or refractory disease, and all but 1 had 17p deletion. An additional 50 patients with relapsed, refractory, or previously untreated disease have been enrolled in the safety expansion cohort.
The primary endpoint of the study is overall response rate as determined by an independent review committee, and secondary endpoints include complete response, partial response, duration of response, progression-free survival, and overall survival. The level of minimal residual disease (MRD) in peripheral blood and/or bone marrow was assessed in a subset of patients.
The study met its primary endpoint, with an overall response rate of 79.4% among the 107 patients with relapsed or refractory disease. In addition, 7.5% of patients achieved a complete response, with or without complete recovery of blood counts in the bone marrow.
Forty-five patients had an assessment for MRD in the blood. Of these, 18 patients achieved MRD-negativity. Ten of these 18 patients also had bone marrow assessments, and 6 were MRD-negative.
At 1 year, 84.7% of all responses and 94.4% of MRD-negative responses were maintained. The 1-year progression-free survival and overall survival rates were 72% and 86.7%, respectively.
The most common serious adverse events were pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%). The most common grade 3-4 adverse events were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%).
Laboratory TLS was reported in 5 patients. None had clinical consequences.
Venetoclax is under development by AbbVie and Genentech/Roche. 
Image by Mary Ann Thompson
Despite previous safety concerns, the US Food and Drug Administration (FDA) has granted priority review for the BCL-2 inhibitor venetoclax.
The FDA is reviewing the drug as a potential treatment for patients with chronic lymphocytic leukemia (CLL), including those with 17p deletion, who have received at least 1 prior therapy.
A priority review designation is granted to drugs thought to have the potential to provide significant improvements in the treatment, prevention, or diagnosis of a disease.
The designation means the FDA’s goal is to take action on a drug application within 6 months, compared to 10 months under standard review.
Venetoclax has proven active against CLL and other hematologic malignancies, but it is known to induce tumor lysis syndrome (TLS). In fact, TLS-related deaths temporarily halted enrollment in trials of venetoclax. But researchers discovered ways to reduce the risk of TLS, and the trials continued.
Venetoclax received breakthrough therapy designation from the FDA last year for the treatment of patients with relapsed or refractory CLL and 17p deletion. This designation is designed to expedite the development and review of medicines intended to treat serious or life-threatening diseases.
The new drug application for venetoclax is based, in part, on data from the phase 2 M13-982 study, which were just presented at the 2015 ASH Annual Meeting.
Phase 2 trial
M13-982 is an open-label, single-arm, multicenter study in which researchers are evaluating the efficacy and safety of venetoclax in patients with relapsed, refractory, or previously untreated CLL with 17p deletion.
The study included 107 patients with relapsed or refractory disease, and all but 1 had 17p deletion. An additional 50 patients with relapsed, refractory, or previously untreated disease have been enrolled in the safety expansion cohort.
The primary endpoint of the study is overall response rate as determined by an independent review committee, and secondary endpoints include complete response, partial response, duration of response, progression-free survival, and overall survival. The level of minimal residual disease (MRD) in peripheral blood and/or bone marrow was assessed in a subset of patients.
The study met its primary endpoint, with an overall response rate of 79.4% among the 107 patients with relapsed or refractory disease. In addition, 7.5% of patients achieved a complete response, with or without complete recovery of blood counts in the bone marrow.
Forty-five patients had an assessment for MRD in the blood. Of these, 18 patients achieved MRD-negativity. Ten of these 18 patients also had bone marrow assessments, and 6 were MRD-negative.
At 1 year, 84.7% of all responses and 94.4% of MRD-negative responses were maintained. The 1-year progression-free survival and overall survival rates were 72% and 86.7%, respectively.
The most common serious adverse events were pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%). The most common grade 3-4 adverse events were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%).
Laboratory TLS was reported in 5 patients. None had clinical consequences.
Venetoclax is under development by AbbVie and Genentech/Roche.
Image by Mary Ann Thompson
Despite previous safety concerns, the US Food and Drug Administration (FDA) has granted priority review for the BCL-2 inhibitor venetoclax.
The FDA is reviewing the drug as a potential treatment for patients with chronic lymphocytic leukemia (CLL), including those with 17p deletion, who have received at least 1 prior therapy.
A priority review designation is granted to drugs thought to have the potential to provide significant improvements in the treatment, prevention, or diagnosis of a disease.
The designation means the FDA’s goal is to take action on a drug application within 6 months, compared to 10 months under standard review.
Venetoclax has proven active against CLL and other hematologic malignancies, but it is known to induce tumor lysis syndrome (TLS). In fact, TLS-related deaths temporarily halted enrollment in trials of venetoclax. But researchers discovered ways to reduce the risk of TLS, and the trials continued.
Venetoclax received breakthrough therapy designation from the FDA last year for the treatment of patients with relapsed or refractory CLL and 17p deletion. This designation is designed to expedite the development and review of medicines intended to treat serious or life-threatening diseases.
The new drug application for venetoclax is based, in part, on data from the phase 2 M13-982 study, which were just presented at the 2015 ASH Annual Meeting.
Phase 2 trial
M13-982 is an open-label, single-arm, multicenter study in which researchers are evaluating the efficacy and safety of venetoclax in patients with relapsed, refractory, or previously untreated CLL with 17p deletion.
The study included 107 patients with relapsed or refractory disease, and all but 1 had 17p deletion. An additional 50 patients with relapsed, refractory, or previously untreated disease have been enrolled in the safety expansion cohort.
The primary endpoint of the study is overall response rate as determined by an independent review committee, and secondary endpoints include complete response, partial response, duration of response, progression-free survival, and overall survival. The level of minimal residual disease (MRD) in peripheral blood and/or bone marrow was assessed in a subset of patients.
The study met its primary endpoint, with an overall response rate of 79.4% among the 107 patients with relapsed or refractory disease. In addition, 7.5% of patients achieved a complete response, with or without complete recovery of blood counts in the bone marrow.
Forty-five patients had an assessment for MRD in the blood. Of these, 18 patients achieved MRD-negativity. Ten of these 18 patients also had bone marrow assessments, and 6 were MRD-negative.
At 1 year, 84.7% of all responses and 94.4% of MRD-negative responses were maintained. The 1-year progression-free survival and overall survival rates were 72% and 86.7%, respectively.
The most common serious adverse events were pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%). The most common grade 3-4 adverse events were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%).
Laboratory TLS was reported in 5 patients. None had clinical consequences.
Venetoclax is under development by AbbVie and Genentech/Roche.
Hodgkin lymphoma going untreated in patients with HIV
cultured lymphocyte
Image courtesy of the CDC
Patients with HIV-associated Hodgkin lymphoma may not be getting potentially curative treatment, according to a study published in the journal AIDS.
The study showed that 16% of HIV-positive patients did not receive treatment for their lymphoma, compared to 9% of Hodgkin lymphoma patients who were HIV-negative.
“Hodgkin lymphoma is generally believed to be highly curable,” said study author Adam Olszewski, MD, of Brown University in Providence, Rhode Island.
“We have an expectation to cure over 90% of early stage patients and even 70% to 80% of quite advanced cases.”
It hasn’t been clear whether HIV-positive patients with Hodgkin lymphoma survive the cancer as well as people who are HIV-negative. While some small studies, particularly in Europe, have shown that HIV status makes no difference to survival, observations in the US population suggest that being HIV-positive makes survival less likely.
The new study, which is the largest of its kind to date, may reconcile that conflict. It suggests that, in the US, the reason people with HIV seem to fare worse with the cancer is because they are less likely to be treated for it.
The study included 2090 cases of HIV-associated Hodgkin lymphoma recorded in the National Cancer Data Base between 2004 and 2012, as well as 41,846 cases of Hodgkin lymphoma in patients who were HIV-negative.
The unadjusted 5-year overall survival was 66% for HIV-positive patients and 80% for the HIV-negative population.
Among the HIV-positive patients, 81% received chemotherapy (12% in combination with radiation), 13% received any radiation therapy, and 16% received no treatment for their lymphoma. The corresponding numbers for HIV-negative patients were 87%, 31%, and 9%, respectively (P<0.00001 for all comparisons).
The researchers assessed patient- and disease-related factors associated with the risk of not receiving chemotherapy in the HIV-positive population.
And they found the risk was significantly higher for patients who were older than 40, male, “nonwhite” (black, Hispanic, or Asian/”other”), did not have health insurance, lived in areas with the lowest median income, and had early stage Hodgkin lymphoma or an undetermined histology.
Dr Olszewski said the lack of treatment among HIV-positive patients could be due to a lingering assumption that they won’t tolerate the treatment well. Or some patients may be declining treatment, either for HIV (thereby making them seem more vulnerable) or for the lymphoma itself.
He noted, however, that lymphoma treatment can be effective for and tolerated by HIV-positive patients, especially when the lymphoma subtype is known.
Among the patients who received chemotherapy in this study, there was no significant difference in the hazard of death between HIV-positive and HIV-negative patients who had one of the defined classical histologic subtypes: nodular sclerosis, mixed cellularity, lymphocyte-rich, or lymphocyte-depleted Hodgkin lymphoma. However, mortality was significantly higher for HIV-positive patients with an undetermined histologic subtype.
cultured lymphocyte
Image courtesy of the CDC
Patients with HIV-associated Hodgkin lymphoma may not be getting potentially curative treatment, according to a study published in the journal AIDS.
The study showed that 16% of HIV-positive patients did not receive treatment for their lymphoma, compared to 9% of Hodgkin lymphoma patients who were HIV-negative.
“Hodgkin lymphoma is generally believed to be highly curable,” said study author Adam Olszewski, MD, of Brown University in Providence, Rhode Island.
“We have an expectation to cure over 90% of early stage patients and even 70% to 80% of quite advanced cases.”
It hasn’t been clear whether HIV-positive patients with Hodgkin lymphoma survive the cancer as well as people who are HIV-negative. While some small studies, particularly in Europe, have shown that HIV status makes no difference to survival, observations in the US population suggest that being HIV-positive makes survival less likely.
The new study, which is the largest of its kind to date, may reconcile that conflict. It suggests that, in the US, the reason people with HIV seem to fare worse with the cancer is because they are less likely to be treated for it.
The study included 2090 cases of HIV-associated Hodgkin lymphoma recorded in the National Cancer Data Base between 2004 and 2012, as well as 41,846 cases of Hodgkin lymphoma in patients who were HIV-negative.
The unadjusted 5-year overall survival was 66% for HIV-positive patients and 80% for the HIV-negative population.
Among the HIV-positive patients, 81% received chemotherapy (12% in combination with radiation), 13% received any radiation therapy, and 16% received no treatment for their lymphoma. The corresponding numbers for HIV-negative patients were 87%, 31%, and 9%, respectively (P<0.00001 for all comparisons).
The researchers assessed patient- and disease-related factors associated with the risk of not receiving chemotherapy in the HIV-positive population.
And they found the risk was significantly higher for patients who were older than 40, male, “nonwhite” (black, Hispanic, or Asian/”other”), did not have health insurance, lived in areas with the lowest median income, and had early stage Hodgkin lymphoma or an undetermined histology.
Dr Olszewski said the lack of treatment among HIV-positive patients could be due to a lingering assumption that they won’t tolerate the treatment well. Or some patients may be declining treatment, either for HIV (thereby making them seem more vulnerable) or for the lymphoma itself.
He noted, however, that lymphoma treatment can be effective for and tolerated by HIV-positive patients, especially when the lymphoma subtype is known.
Among the patients who received chemotherapy in this study, there was no significant difference in the hazard of death between HIV-positive and HIV-negative patients who had one of the defined classical histologic subtypes: nodular sclerosis, mixed cellularity, lymphocyte-rich, or lymphocyte-depleted Hodgkin lymphoma. However, mortality was significantly higher for HIV-positive patients with an undetermined histologic subtype.
cultured lymphocyte
Image courtesy of the CDC
Patients with HIV-associated Hodgkin lymphoma may not be getting potentially curative treatment, according to a study published in the journal AIDS.
The study showed that 16% of HIV-positive patients did not receive treatment for their lymphoma, compared to 9% of Hodgkin lymphoma patients who were HIV-negative.
“Hodgkin lymphoma is generally believed to be highly curable,” said study author Adam Olszewski, MD, of Brown University in Providence, Rhode Island.
“We have an expectation to cure over 90% of early stage patients and even 70% to 80% of quite advanced cases.”
It hasn’t been clear whether HIV-positive patients with Hodgkin lymphoma survive the cancer as well as people who are HIV-negative. While some small studies, particularly in Europe, have shown that HIV status makes no difference to survival, observations in the US population suggest that being HIV-positive makes survival less likely.
The new study, which is the largest of its kind to date, may reconcile that conflict. It suggests that, in the US, the reason people with HIV seem to fare worse with the cancer is because they are less likely to be treated for it.
The study included 2090 cases of HIV-associated Hodgkin lymphoma recorded in the National Cancer Data Base between 2004 and 2012, as well as 41,846 cases of Hodgkin lymphoma in patients who were HIV-negative.
The unadjusted 5-year overall survival was 66% for HIV-positive patients and 80% for the HIV-negative population.
Among the HIV-positive patients, 81% received chemotherapy (12% in combination with radiation), 13% received any radiation therapy, and 16% received no treatment for their lymphoma. The corresponding numbers for HIV-negative patients were 87%, 31%, and 9%, respectively (P<0.00001 for all comparisons).
The researchers assessed patient- and disease-related factors associated with the risk of not receiving chemotherapy in the HIV-positive population.
And they found the risk was significantly higher for patients who were older than 40, male, “nonwhite” (black, Hispanic, or Asian/”other”), did not have health insurance, lived in areas with the lowest median income, and had early stage Hodgkin lymphoma or an undetermined histology.
Dr Olszewski said the lack of treatment among HIV-positive patients could be due to a lingering assumption that they won’t tolerate the treatment well. Or some patients may be declining treatment, either for HIV (thereby making them seem more vulnerable) or for the lymphoma itself.
He noted, however, that lymphoma treatment can be effective for and tolerated by HIV-positive patients, especially when the lymphoma subtype is known.
Among the patients who received chemotherapy in this study, there was no significant difference in the hazard of death between HIV-positive and HIV-negative patients who had one of the defined classical histologic subtypes: nodular sclerosis, mixed cellularity, lymphocyte-rich, or lymphocyte-depleted Hodgkin lymphoma. However, mortality was significantly higher for HIV-positive patients with an undetermined histologic subtype.
Daratumumab clinically active, well tolerated in heavily treated multiple myeloma
In patients with multiple myeloma who were treated with at least three prior therapies (median five), daratumumab demonstrated substantial clinical activity and was well tolerated, investigators reported in the Lancet.
Overall response rates were observed in 31 of 106 people (ORR 29.2%; 95% confidence interval, 20.8-38.9), stringent complete responses in 3, and very good partial responses in 10 people. In total, 87 patients (82%) had received more than three lines of therapy: all patients had been treated previously with proteasome inhibitors and immunomodulatory drugs, and dexamethasone. In addition, 103 (97%) were refractory to the last line of therapy before study enrollment, and 95% were refractory to the most recent proteasome inhibitors and immunomodulatory drugs.
“Resistance to any previous therapy had no effect on the activity of daratumumab, lending support to a novel mechanism of action, but these findings need to be confirmed in larger studies,” wrote Dr. Sagar Lonial, executive vice chair of the department of hematology medical oncology, Emory University, Atlanta, and colleagues (Lancet. 2016 Jan 7. doi: 10.1016/S0140-6736[15]01120-4).
Daratumumab was well tolerated. The most common hematologic treatment-emergent adverse events of any grade were anemia (33%), thrombocytopenia (25%), and neutropenia (23%). The overall favorable safety profile makes it a promising candidate for combination regimens, and the monoclonal IgG1 antibody has shown early activity in combination with lenalidomide and dexamethasone, according to the researchers.
The open-label, multicenter, phase II trial included 106 patients who received daratumumab 16 mg/kg. The median time since initial diagnosis was 4.8 years (1.1-23.8 years), median number of previous therapies was 5 (2-14), and 80% of patients had received autologous stem cell transplantation.
In patients with multiple myeloma who were treated with at least three prior therapies (median five), daratumumab demonstrated substantial clinical activity and was well tolerated, investigators reported in the Lancet.
Overall response rates were observed in 31 of 106 people (ORR 29.2%; 95% confidence interval, 20.8-38.9), stringent complete responses in 3, and very good partial responses in 10 people. In total, 87 patients (82%) had received more than three lines of therapy: all patients had been treated previously with proteasome inhibitors and immunomodulatory drugs, and dexamethasone. In addition, 103 (97%) were refractory to the last line of therapy before study enrollment, and 95% were refractory to the most recent proteasome inhibitors and immunomodulatory drugs.
“Resistance to any previous therapy had no effect on the activity of daratumumab, lending support to a novel mechanism of action, but these findings need to be confirmed in larger studies,” wrote Dr. Sagar Lonial, executive vice chair of the department of hematology medical oncology, Emory University, Atlanta, and colleagues (Lancet. 2016 Jan 7. doi: 10.1016/S0140-6736[15]01120-4).
Daratumumab was well tolerated. The most common hematologic treatment-emergent adverse events of any grade were anemia (33%), thrombocytopenia (25%), and neutropenia (23%). The overall favorable safety profile makes it a promising candidate for combination regimens, and the monoclonal IgG1 antibody has shown early activity in combination with lenalidomide and dexamethasone, according to the researchers.
The open-label, multicenter, phase II trial included 106 patients who received daratumumab 16 mg/kg. The median time since initial diagnosis was 4.8 years (1.1-23.8 years), median number of previous therapies was 5 (2-14), and 80% of patients had received autologous stem cell transplantation.
In patients with multiple myeloma who were treated with at least three prior therapies (median five), daratumumab demonstrated substantial clinical activity and was well tolerated, investigators reported in the Lancet.
Overall response rates were observed in 31 of 106 people (ORR 29.2%; 95% confidence interval, 20.8-38.9), stringent complete responses in 3, and very good partial responses in 10 people. In total, 87 patients (82%) had received more than three lines of therapy: all patients had been treated previously with proteasome inhibitors and immunomodulatory drugs, and dexamethasone. In addition, 103 (97%) were refractory to the last line of therapy before study enrollment, and 95% were refractory to the most recent proteasome inhibitors and immunomodulatory drugs.
“Resistance to any previous therapy had no effect on the activity of daratumumab, lending support to a novel mechanism of action, but these findings need to be confirmed in larger studies,” wrote Dr. Sagar Lonial, executive vice chair of the department of hematology medical oncology, Emory University, Atlanta, and colleagues (Lancet. 2016 Jan 7. doi: 10.1016/S0140-6736[15]01120-4).
Daratumumab was well tolerated. The most common hematologic treatment-emergent adverse events of any grade were anemia (33%), thrombocytopenia (25%), and neutropenia (23%). The overall favorable safety profile makes it a promising candidate for combination regimens, and the monoclonal IgG1 antibody has shown early activity in combination with lenalidomide and dexamethasone, according to the researchers.
The open-label, multicenter, phase II trial included 106 patients who received daratumumab 16 mg/kg. The median time since initial diagnosis was 4.8 years (1.1-23.8 years), median number of previous therapies was 5 (2-14), and 80% of patients had received autologous stem cell transplantation.
FROM THE LANCET
Key clinical point: Daratumumab monotherapy was clinically active and well tolerated in patients with multiple myeloma who were treated with at least three prior therapies.
Major finding: In the 16 mg/kg group, 31 of 106 patients achieved an overall response rate (ORR 29.2%; 95% confidence interval, 20.8-38.9); 3 achieved a stringent complete response; 10 achieved a very good partial response.
Data source: The open-label, multicenter, phase II trial included 106 patients who received daratumumab 16 mg/kg.
Disclosures: Janssen Research & Development contributed to the design of the study. Dr. Lonial reported ties Bristol-Myers Squibb, Celgene, Janssen, Millennium, Novartis, and Onyx. Several of his coauthors reported ties to industry.
Increasing eligibility for engineered T-cell therapy
Image courtesy of NIAID
A new study suggests that having a certain type of cancer or receiving certain chemotherapeutic agents
can affect T-cell function and make patients ineligible for engineered T-cell therapy.
However, researchers found that proper timing of T-cell collection can increase the number of patients eiligible for the therapy.
And the team developed a culture technique that can boost T cells’ fitness for expansion, which can increase eligibility as well.
Nathan Singh, MD, of the University of Pennsylvania in Philadelphia, and his colleagues described this work in Science Translational Medicine.
The researchers set out to determine why some patients’ T cells fail to multiply in culture. The team studied T cells from children with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) who were undergoing chemotherapy. (NHL subtypes included Burkitt lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, primary lymphoma of bone, and follicular lymphoma.)
The researchers found that T cells from patients with ALL expanded better in culture than those from patients with NHL.
The team said a threshold of greater than 5-fold expansion during test expansion was associated with a high likelihood of successful clinical expansion.
Nearly 80% of patients with ALL met this threshold at diagnosis, but the rate declined over the course of therapy, falling to about 40% during maintenance therapy.
About 25% of NHL patients met the threshold at diagnosis, but few samples demonstrated any expansion after therapy began (12.5% of samples at all remaining time points tested).
The researchers said the difference in the proportion of ALL and NHL samples that met the expansion threshold was significant at all time points tested.
Analysis revealed that ALL patients had higher numbers of naïve T cells and stem central memory T cells, T cell subtypes known to be highly potent and proliferative with an enhanced capacity for self-renewal.
The researchers also found that certain chemotherapy drugs—namely, cyclophosphamide and cytarabine—selectively depleted early lineage T cells.
Fortunately, the team discovered that poor expansion can be rescued by exposing T cells to signaling molecules that stimulate T-cell activity. Culture with IL-7 and IL-15 boosted the expansion capacity of T cells from patients with NHL and those with ALL.
The researchers therefore concluded that using this culture technique or collecting T cells prior to chemotherapy can increase the number of patients eligible for engineered T-cell therapy.
Image courtesy of NIAID
A new study suggests that having a certain type of cancer or receiving certain chemotherapeutic agents
can affect T-cell function and make patients ineligible for engineered T-cell therapy.
However, researchers found that proper timing of T-cell collection can increase the number of patients eiligible for the therapy.
And the team developed a culture technique that can boost T cells’ fitness for expansion, which can increase eligibility as well.
Nathan Singh, MD, of the University of Pennsylvania in Philadelphia, and his colleagues described this work in Science Translational Medicine.
The researchers set out to determine why some patients’ T cells fail to multiply in culture. The team studied T cells from children with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) who were undergoing chemotherapy. (NHL subtypes included Burkitt lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, primary lymphoma of bone, and follicular lymphoma.)
The researchers found that T cells from patients with ALL expanded better in culture than those from patients with NHL.
The team said a threshold of greater than 5-fold expansion during test expansion was associated with a high likelihood of successful clinical expansion.
Nearly 80% of patients with ALL met this threshold at diagnosis, but the rate declined over the course of therapy, falling to about 40% during maintenance therapy.
About 25% of NHL patients met the threshold at diagnosis, but few samples demonstrated any expansion after therapy began (12.5% of samples at all remaining time points tested).
The researchers said the difference in the proportion of ALL and NHL samples that met the expansion threshold was significant at all time points tested.
Analysis revealed that ALL patients had higher numbers of naïve T cells and stem central memory T cells, T cell subtypes known to be highly potent and proliferative with an enhanced capacity for self-renewal.
The researchers also found that certain chemotherapy drugs—namely, cyclophosphamide and cytarabine—selectively depleted early lineage T cells.
Fortunately, the team discovered that poor expansion can be rescued by exposing T cells to signaling molecules that stimulate T-cell activity. Culture with IL-7 and IL-15 boosted the expansion capacity of T cells from patients with NHL and those with ALL.
The researchers therefore concluded that using this culture technique or collecting T cells prior to chemotherapy can increase the number of patients eligible for engineered T-cell therapy.
Image courtesy of NIAID
A new study suggests that having a certain type of cancer or receiving certain chemotherapeutic agents
can affect T-cell function and make patients ineligible for engineered T-cell therapy.
However, researchers found that proper timing of T-cell collection can increase the number of patients eiligible for the therapy.
And the team developed a culture technique that can boost T cells’ fitness for expansion, which can increase eligibility as well.
Nathan Singh, MD, of the University of Pennsylvania in Philadelphia, and his colleagues described this work in Science Translational Medicine.
The researchers set out to determine why some patients’ T cells fail to multiply in culture. The team studied T cells from children with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) who were undergoing chemotherapy. (NHL subtypes included Burkitt lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, primary lymphoma of bone, and follicular lymphoma.)
The researchers found that T cells from patients with ALL expanded better in culture than those from patients with NHL.
The team said a threshold of greater than 5-fold expansion during test expansion was associated with a high likelihood of successful clinical expansion.
Nearly 80% of patients with ALL met this threshold at diagnosis, but the rate declined over the course of therapy, falling to about 40% during maintenance therapy.
About 25% of NHL patients met the threshold at diagnosis, but few samples demonstrated any expansion after therapy began (12.5% of samples at all remaining time points tested).
The researchers said the difference in the proportion of ALL and NHL samples that met the expansion threshold was significant at all time points tested.
Analysis revealed that ALL patients had higher numbers of naïve T cells and stem central memory T cells, T cell subtypes known to be highly potent and proliferative with an enhanced capacity for self-renewal.
The researchers also found that certain chemotherapy drugs—namely, cyclophosphamide and cytarabine—selectively depleted early lineage T cells.
Fortunately, the team discovered that poor expansion can be rescued by exposing T cells to signaling molecules that stimulate T-cell activity. Culture with IL-7 and IL-15 boosted the expansion capacity of T cells from patients with NHL and those with ALL.
The researchers therefore concluded that using this culture technique or collecting T cells prior to chemotherapy can increase the number of patients eligible for engineered T-cell therapy.
US cancer stats: The good and the bad
patient and her father
Photo by Rhoda Baer
The American Cancer Society’s 2016 report on cancer in the US suggests that, in recent years, overall trends in cancer incidence have remained stable for women and declined for men.
However, the rates of certain malignancies are on the rise. This includes some leukemia subtypes for men and women, as well as myeloma for men.
Leukemia is the leading cause of cancer death for men ages 20 to 39, but leukemia is no longer the leading cause of cancer death among children and adolescents (of both genders).
These and other data are included in the report, which is published in CA: A Cancer Journal for Clinicians.
The report estimates there will be 1,685,210 new cancer cases and 595,690 cancer deaths in the US in 2016. This includes 81,080 new lymphoma cases and 21,270 lymphoma deaths, 60,140 new leukemia cases and 24,400 leukemia deaths, and 30,330 new myeloma cases and 12,650 myeloma deaths.
Cancer incidence over time
The report suggests the overall cancer incidence for women has been stable from 1998 to 2012. But the incidence for men has declined by 3.1% per year from 2009 to 2012, with one-half of the drop in men due to recent rapid declines in prostate cancer diagnoses as prostate-specific antigen testing decreases.
Incidence rates increased from 2003 to 2012 among both men and women for some leukemia subtypes and for cancers of the tongue, tonsil, small intestine, liver, pancreas, kidney, renal pelvis, and thyroid.
Incidence rates increased in men for melanoma, myeloma, and cancers of the breast, testis, and oropharynx. Among women, incidence rates increased for cancers of the anus, vulva, and uterine corpus.
Cancer deaths
The rate of cancer deaths in the US has dropped 23% from its peak in 1991 to 2012. The incidence of cancer death was 215.1 per 100,000 in 1991 and 166.4 per 100,000 in 2012.
The decline is larger in men (28% since 1990) than in women (19% since 1991). Over the past decade of data, the rate dropped by 1.8% per year in men and 1.4% per year in women.
The decline in cancer death rates over the past 2 decades is driven by continued decreases in death rates for the 4 major cancer sites: lung, breast, prostate, and colon/rectum.
Breast cancer is the leading cause of cancer death in women ages 20 to 59, while lung cancer is the leading cause of cancer death in women 60 and older.
Among men, leukemia is the leading cause of cancer death for those ages 20 to 39, whereas lung cancer ranks first among men 40 and older.
Among children and adolescents (0-19), brain cancer has surpassed leukemia as the leading cause of cancer death, a result of more rapid therapeutic advances against leukemia.
The report also features an analysis of leading causes of death by state. It shows that, even as cancer remains the second leading cause of death nationwide, steep drops in deaths from heart disease have made cancer the leading cause of death in 21 states: Alaska, Arizona, Colorado, Delaware, Florida, Georgia, Idaho, Kansas, Maine, Massachusetts, Minnesota, Montana, Nebraska, New Hampshire, New Mexico, North Carolina, Oregon, South Carolina, Vermont, Virginia, and Washington.
In addition, cancer is the leading cause of death among adults ages 40 to 79 and among both Hispanics and Asian/Pacific Islanders, who together make up one-quarter of the US population.
Heart disease remains the top cause of death overall in the US. In 2012, there were 599,711 (24%) deaths from heart disease, compared to 582,623 (23%) deaths from cancer.
“We’re gratified to see cancer death rates continuing to drop,” said Otis W. Brawley, MD, chief medical officer of the American Cancer Society.
“But the fact that cancer is nonetheless becoming the top cause of death in many populations is a strong reminder that the fight is not over.”
patient and her father
Photo by Rhoda Baer
The American Cancer Society’s 2016 report on cancer in the US suggests that, in recent years, overall trends in cancer incidence have remained stable for women and declined for men.
However, the rates of certain malignancies are on the rise. This includes some leukemia subtypes for men and women, as well as myeloma for men.
Leukemia is the leading cause of cancer death for men ages 20 to 39, but leukemia is no longer the leading cause of cancer death among children and adolescents (of both genders).
These and other data are included in the report, which is published in CA: A Cancer Journal for Clinicians.
The report estimates there will be 1,685,210 new cancer cases and 595,690 cancer deaths in the US in 2016. This includes 81,080 new lymphoma cases and 21,270 lymphoma deaths, 60,140 new leukemia cases and 24,400 leukemia deaths, and 30,330 new myeloma cases and 12,650 myeloma deaths.
Cancer incidence over time
The report suggests the overall cancer incidence for women has been stable from 1998 to 2012. But the incidence for men has declined by 3.1% per year from 2009 to 2012, with one-half of the drop in men due to recent rapid declines in prostate cancer diagnoses as prostate-specific antigen testing decreases.
Incidence rates increased from 2003 to 2012 among both men and women for some leukemia subtypes and for cancers of the tongue, tonsil, small intestine, liver, pancreas, kidney, renal pelvis, and thyroid.
Incidence rates increased in men for melanoma, myeloma, and cancers of the breast, testis, and oropharynx. Among women, incidence rates increased for cancers of the anus, vulva, and uterine corpus.
Cancer deaths
The rate of cancer deaths in the US has dropped 23% from its peak in 1991 to 2012. The incidence of cancer death was 215.1 per 100,000 in 1991 and 166.4 per 100,000 in 2012.
The decline is larger in men (28% since 1990) than in women (19% since 1991). Over the past decade of data, the rate dropped by 1.8% per year in men and 1.4% per year in women.
The decline in cancer death rates over the past 2 decades is driven by continued decreases in death rates for the 4 major cancer sites: lung, breast, prostate, and colon/rectum.
Breast cancer is the leading cause of cancer death in women ages 20 to 59, while lung cancer is the leading cause of cancer death in women 60 and older.
Among men, leukemia is the leading cause of cancer death for those ages 20 to 39, whereas lung cancer ranks first among men 40 and older.
Among children and adolescents (0-19), brain cancer has surpassed leukemia as the leading cause of cancer death, a result of more rapid therapeutic advances against leukemia.
The report also features an analysis of leading causes of death by state. It shows that, even as cancer remains the second leading cause of death nationwide, steep drops in deaths from heart disease have made cancer the leading cause of death in 21 states: Alaska, Arizona, Colorado, Delaware, Florida, Georgia, Idaho, Kansas, Maine, Massachusetts, Minnesota, Montana, Nebraska, New Hampshire, New Mexico, North Carolina, Oregon, South Carolina, Vermont, Virginia, and Washington.
In addition, cancer is the leading cause of death among adults ages 40 to 79 and among both Hispanics and Asian/Pacific Islanders, who together make up one-quarter of the US population.
Heart disease remains the top cause of death overall in the US. In 2012, there were 599,711 (24%) deaths from heart disease, compared to 582,623 (23%) deaths from cancer.
“We’re gratified to see cancer death rates continuing to drop,” said Otis W. Brawley, MD, chief medical officer of the American Cancer Society.
“But the fact that cancer is nonetheless becoming the top cause of death in many populations is a strong reminder that the fight is not over.”
patient and her father
Photo by Rhoda Baer
The American Cancer Society’s 2016 report on cancer in the US suggests that, in recent years, overall trends in cancer incidence have remained stable for women and declined for men.
However, the rates of certain malignancies are on the rise. This includes some leukemia subtypes for men and women, as well as myeloma for men.
Leukemia is the leading cause of cancer death for men ages 20 to 39, but leukemia is no longer the leading cause of cancer death among children and adolescents (of both genders).
These and other data are included in the report, which is published in CA: A Cancer Journal for Clinicians.
The report estimates there will be 1,685,210 new cancer cases and 595,690 cancer deaths in the US in 2016. This includes 81,080 new lymphoma cases and 21,270 lymphoma deaths, 60,140 new leukemia cases and 24,400 leukemia deaths, and 30,330 new myeloma cases and 12,650 myeloma deaths.
Cancer incidence over time
The report suggests the overall cancer incidence for women has been stable from 1998 to 2012. But the incidence for men has declined by 3.1% per year from 2009 to 2012, with one-half of the drop in men due to recent rapid declines in prostate cancer diagnoses as prostate-specific antigen testing decreases.
Incidence rates increased from 2003 to 2012 among both men and women for some leukemia subtypes and for cancers of the tongue, tonsil, small intestine, liver, pancreas, kidney, renal pelvis, and thyroid.
Incidence rates increased in men for melanoma, myeloma, and cancers of the breast, testis, and oropharynx. Among women, incidence rates increased for cancers of the anus, vulva, and uterine corpus.
Cancer deaths
The rate of cancer deaths in the US has dropped 23% from its peak in 1991 to 2012. The incidence of cancer death was 215.1 per 100,000 in 1991 and 166.4 per 100,000 in 2012.
The decline is larger in men (28% since 1990) than in women (19% since 1991). Over the past decade of data, the rate dropped by 1.8% per year in men and 1.4% per year in women.
The decline in cancer death rates over the past 2 decades is driven by continued decreases in death rates for the 4 major cancer sites: lung, breast, prostate, and colon/rectum.
Breast cancer is the leading cause of cancer death in women ages 20 to 59, while lung cancer is the leading cause of cancer death in women 60 and older.
Among men, leukemia is the leading cause of cancer death for those ages 20 to 39, whereas lung cancer ranks first among men 40 and older.
Among children and adolescents (0-19), brain cancer has surpassed leukemia as the leading cause of cancer death, a result of more rapid therapeutic advances against leukemia.
The report also features an analysis of leading causes of death by state. It shows that, even as cancer remains the second leading cause of death nationwide, steep drops in deaths from heart disease have made cancer the leading cause of death in 21 states: Alaska, Arizona, Colorado, Delaware, Florida, Georgia, Idaho, Kansas, Maine, Massachusetts, Minnesota, Montana, Nebraska, New Hampshire, New Mexico, North Carolina, Oregon, South Carolina, Vermont, Virginia, and Washington.
In addition, cancer is the leading cause of death among adults ages 40 to 79 and among both Hispanics and Asian/Pacific Islanders, who together make up one-quarter of the US population.
Heart disease remains the top cause of death overall in the US. In 2012, there were 599,711 (24%) deaths from heart disease, compared to 582,623 (23%) deaths from cancer.
“We’re gratified to see cancer death rates continuing to drop,” said Otis W. Brawley, MD, chief medical officer of the American Cancer Society.
“But the fact that cancer is nonetheless becoming the top cause of death in many populations is a strong reminder that the fight is not over.”
How microbes drive progression of CTCL
New research indicates that toxins in Staphylococcus bacteria help malignant cells gain control over healthy cells in patients with cutaneous T-cell lymphoma (CTCL).
Investigators found that staphylococcal enterotoxin-A (SEA) induces STAT3 activation and IL-17 expression in malignant T cells via engagement of non-malignant CD4 T cells.
As STAT3 activation has been implicated in CTCL pathogenesis, the discovery suggests bacterial toxins play a key role in activating an oncogenic pathway in CTCL.
“We have gained important insight into the processes that activate cancer cells and make them grow,” said Niels Oedum, MD, of the University of Copenhagen in Denmark.
“[CTCL] patients’ frequent bacterial infections might not be a mere side effect of the disease. On the contrary, toxins in the bacteria actually ‘benefit’ cancer cells. Our next step is examining whether combatting infections can slow down the growth of cancer cells and thus stop the disease.”
Dr Oedum and his colleagues described their research in Blood.
The investigators knew that, in CTCL, CD4 T cells become malignant and turn parasitic on the rest of the immune system. In addition to using healthy cells to do their work for them, the malignant cells slowly destroy the skin’s immune defense mechanism.
The team’s new discoveries indicate that bacterial toxins in some patients enable malignant cells to send off signals that obstruct and change the immune defense mechanism, which would otherwise fight the malignant cells. What was believed to be an overly active immune defense mechanism could, in other words, turn out to be a malignant infection brought on by bacteria, which only worsens the disease.
Dr Oedum and his colleagues found that SEA-positive bacteria isolatated from the skin of CTCL patients stimulated activation of STAT3 and upregulation of IL-17 in malignant and non-malignant T cells.
Malignant T cells expressing an SEA non-responsive T-cell receptor V beta chain did not respond to SEA when cultured alone but exhibited STAT3 activation and IL-17 expression in co-cultures with SEA-responsive, non-malignant T cells.
The investigators found evidence to suggest the response is induced via IL-2Rg cytokines and a JAK3-dependent pathway in malignant T cells. The JAK3 inhibitor tofacitinib inhibited SEA-induced IL-17 production in co-cultures of malignant and non-malignant T cells.
Dr Oedum and his colleagues plan to continue their work investigating how bacteria might affect the balance between the immune defense mechanism and the disease in patients with CTCL.
In the long-term, the investigators’ aim is to understand how bacteria and their toxins can worsen CTCL, knowledge that may be used to develop new targeted treatments.
As only some of the bacteria produce toxins, the team said it will also be important to develop methods to determine which patients may benefit from treatment with antibiotics.
New research indicates that toxins in Staphylococcus bacteria help malignant cells gain control over healthy cells in patients with cutaneous T-cell lymphoma (CTCL).
Investigators found that staphylococcal enterotoxin-A (SEA) induces STAT3 activation and IL-17 expression in malignant T cells via engagement of non-malignant CD4 T cells.
As STAT3 activation has been implicated in CTCL pathogenesis, the discovery suggests bacterial toxins play a key role in activating an oncogenic pathway in CTCL.
“We have gained important insight into the processes that activate cancer cells and make them grow,” said Niels Oedum, MD, of the University of Copenhagen in Denmark.
“[CTCL] patients’ frequent bacterial infections might not be a mere side effect of the disease. On the contrary, toxins in the bacteria actually ‘benefit’ cancer cells. Our next step is examining whether combatting infections can slow down the growth of cancer cells and thus stop the disease.”
Dr Oedum and his colleagues described their research in Blood.
The investigators knew that, in CTCL, CD4 T cells become malignant and turn parasitic on the rest of the immune system. In addition to using healthy cells to do their work for them, the malignant cells slowly destroy the skin’s immune defense mechanism.
The team’s new discoveries indicate that bacterial toxins in some patients enable malignant cells to send off signals that obstruct and change the immune defense mechanism, which would otherwise fight the malignant cells. What was believed to be an overly active immune defense mechanism could, in other words, turn out to be a malignant infection brought on by bacteria, which only worsens the disease.
Dr Oedum and his colleagues found that SEA-positive bacteria isolatated from the skin of CTCL patients stimulated activation of STAT3 and upregulation of IL-17 in malignant and non-malignant T cells.
Malignant T cells expressing an SEA non-responsive T-cell receptor V beta chain did not respond to SEA when cultured alone but exhibited STAT3 activation and IL-17 expression in co-cultures with SEA-responsive, non-malignant T cells.
The investigators found evidence to suggest the response is induced via IL-2Rg cytokines and a JAK3-dependent pathway in malignant T cells. The JAK3 inhibitor tofacitinib inhibited SEA-induced IL-17 production in co-cultures of malignant and non-malignant T cells.
Dr Oedum and his colleagues plan to continue their work investigating how bacteria might affect the balance between the immune defense mechanism and the disease in patients with CTCL.
In the long-term, the investigators’ aim is to understand how bacteria and their toxins can worsen CTCL, knowledge that may be used to develop new targeted treatments.
As only some of the bacteria produce toxins, the team said it will also be important to develop methods to determine which patients may benefit from treatment with antibiotics.
New research indicates that toxins in Staphylococcus bacteria help malignant cells gain control over healthy cells in patients with cutaneous T-cell lymphoma (CTCL).
Investigators found that staphylococcal enterotoxin-A (SEA) induces STAT3 activation and IL-17 expression in malignant T cells via engagement of non-malignant CD4 T cells.
As STAT3 activation has been implicated in CTCL pathogenesis, the discovery suggests bacterial toxins play a key role in activating an oncogenic pathway in CTCL.
“We have gained important insight into the processes that activate cancer cells and make them grow,” said Niels Oedum, MD, of the University of Copenhagen in Denmark.
“[CTCL] patients’ frequent bacterial infections might not be a mere side effect of the disease. On the contrary, toxins in the bacteria actually ‘benefit’ cancer cells. Our next step is examining whether combatting infections can slow down the growth of cancer cells and thus stop the disease.”
Dr Oedum and his colleagues described their research in Blood.
The investigators knew that, in CTCL, CD4 T cells become malignant and turn parasitic on the rest of the immune system. In addition to using healthy cells to do their work for them, the malignant cells slowly destroy the skin’s immune defense mechanism.
The team’s new discoveries indicate that bacterial toxins in some patients enable malignant cells to send off signals that obstruct and change the immune defense mechanism, which would otherwise fight the malignant cells. What was believed to be an overly active immune defense mechanism could, in other words, turn out to be a malignant infection brought on by bacteria, which only worsens the disease.
Dr Oedum and his colleagues found that SEA-positive bacteria isolatated from the skin of CTCL patients stimulated activation of STAT3 and upregulation of IL-17 in malignant and non-malignant T cells.
Malignant T cells expressing an SEA non-responsive T-cell receptor V beta chain did not respond to SEA when cultured alone but exhibited STAT3 activation and IL-17 expression in co-cultures with SEA-responsive, non-malignant T cells.
The investigators found evidence to suggest the response is induced via IL-2Rg cytokines and a JAK3-dependent pathway in malignant T cells. The JAK3 inhibitor tofacitinib inhibited SEA-induced IL-17 production in co-cultures of malignant and non-malignant T cells.
Dr Oedum and his colleagues plan to continue their work investigating how bacteria might affect the balance between the immune defense mechanism and the disease in patients with CTCL.
In the long-term, the investigators’ aim is to understand how bacteria and their toxins can worsen CTCL, knowledge that may be used to develop new targeted treatments.
As only some of the bacteria produce toxins, the team said it will also be important to develop methods to determine which patients may benefit from treatment with antibiotics.
Cardiac abnormalities among childhood cancer survivors
Photo by Bill Branson
A new study has provided additional insight into the development of cardiac abnormalities in adult survivors of childhood cancer.
Researchers analyzed more than 1800 cancer survivors who were exposed to cardiotoxic therapies as children.
The team said they found evidence of cardiac abnormalities in a substantial number of these subjects, many of whom were younger and did not exhibit symptoms of abnormalities.
Daniel A. Mulrooney, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in Annals of Internal Medicine.
The team assessed cardiac outcomes among 1853 subjects who were 18 and older and had received cancer-related cardiotoxic therapy at least 10 years earlier.
The subjects were pretty evenly split along gender lines (52.3% male), their median age at cancer diagnosis was 8 (range, 0 to 24), and their median age at evaluation was 31 (range, 18 to 60).
At evaluation, 7.4% of subjects had cardiomyopathy (newly identified in 4.7%), 3.8% had coronary artery disease (newly identified in 2.2%), 28% had valvular regurgitation or stenosis (newly identified in 24.8%), and 4.4% had conduction or rhythm abnormalities (newly identified in 1.4%). All but 5 subjects were asymptomatic.
Multivariable analysis suggested the odds of developing cardiomyopathy were significantly associated with being male (odds ratio [OR]=1.9), receiving anthracycline doses of 250 mg/m2 or greater (OR=2.7), having cardiac radiation exposure greater than 1500 cGy (OR=1.9), and having hypertension (OR=3.0).
Being younger at diagnosis was associated with higher odds of valvular disease. The ORs were 1.5 for patients who were 0 to 4 years of age at diagnosis and 1.3 for patients who were 5 to 9 at diagnosis.
Receiving higher radiation doses was associated with higher odds of valvular disease as well. But associations between radiation and valvular disease varied according to a patient’s anthracycline exposure (interaction P<0.001). The highest odds were among survivors with the highest doses of radiation exposure and any anthracycline exposure (OR=4.5).
The researchers also noted a reduction in the OR for valvular disease among obese patients (OR=0.4) and those with dyslipidemia (OR=0.7).
The team said there were not enough cases of coronary artery disease and conduction or rhythm abnormalities to support a fully adjusted multivariable model. However, it seemed these outcomes were more common with older age (≥40 years) and among patients with cardiac radiation doses of 1500 cGy or greater.
The researchers said this study revealed “considerable cardiovascular disease” in a large cohort of adult survivors of childhood cancer, which suggests a substantial future healthcare burden.
The team believes their findings could guide stratification of risk factors, screening practices, health counseling, and potential therapeutic measures aimed at changing the disease trajectory in this young adult population.
Photo by Bill Branson
A new study has provided additional insight into the development of cardiac abnormalities in adult survivors of childhood cancer.
Researchers analyzed more than 1800 cancer survivors who were exposed to cardiotoxic therapies as children.
The team said they found evidence of cardiac abnormalities in a substantial number of these subjects, many of whom were younger and did not exhibit symptoms of abnormalities.
Daniel A. Mulrooney, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in Annals of Internal Medicine.
The team assessed cardiac outcomes among 1853 subjects who were 18 and older and had received cancer-related cardiotoxic therapy at least 10 years earlier.
The subjects were pretty evenly split along gender lines (52.3% male), their median age at cancer diagnosis was 8 (range, 0 to 24), and their median age at evaluation was 31 (range, 18 to 60).
At evaluation, 7.4% of subjects had cardiomyopathy (newly identified in 4.7%), 3.8% had coronary artery disease (newly identified in 2.2%), 28% had valvular regurgitation or stenosis (newly identified in 24.8%), and 4.4% had conduction or rhythm abnormalities (newly identified in 1.4%). All but 5 subjects were asymptomatic.
Multivariable analysis suggested the odds of developing cardiomyopathy were significantly associated with being male (odds ratio [OR]=1.9), receiving anthracycline doses of 250 mg/m2 or greater (OR=2.7), having cardiac radiation exposure greater than 1500 cGy (OR=1.9), and having hypertension (OR=3.0).
Being younger at diagnosis was associated with higher odds of valvular disease. The ORs were 1.5 for patients who were 0 to 4 years of age at diagnosis and 1.3 for patients who were 5 to 9 at diagnosis.
Receiving higher radiation doses was associated with higher odds of valvular disease as well. But associations between radiation and valvular disease varied according to a patient’s anthracycline exposure (interaction P<0.001). The highest odds were among survivors with the highest doses of radiation exposure and any anthracycline exposure (OR=4.5).
The researchers also noted a reduction in the OR for valvular disease among obese patients (OR=0.4) and those with dyslipidemia (OR=0.7).
The team said there were not enough cases of coronary artery disease and conduction or rhythm abnormalities to support a fully adjusted multivariable model. However, it seemed these outcomes were more common with older age (≥40 years) and among patients with cardiac radiation doses of 1500 cGy or greater.
The researchers said this study revealed “considerable cardiovascular disease” in a large cohort of adult survivors of childhood cancer, which suggests a substantial future healthcare burden.
The team believes their findings could guide stratification of risk factors, screening practices, health counseling, and potential therapeutic measures aimed at changing the disease trajectory in this young adult population.
Photo by Bill Branson
A new study has provided additional insight into the development of cardiac abnormalities in adult survivors of childhood cancer.
Researchers analyzed more than 1800 cancer survivors who were exposed to cardiotoxic therapies as children.
The team said they found evidence of cardiac abnormalities in a substantial number of these subjects, many of whom were younger and did not exhibit symptoms of abnormalities.
Daniel A. Mulrooney, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in Annals of Internal Medicine.
The team assessed cardiac outcomes among 1853 subjects who were 18 and older and had received cancer-related cardiotoxic therapy at least 10 years earlier.
The subjects were pretty evenly split along gender lines (52.3% male), their median age at cancer diagnosis was 8 (range, 0 to 24), and their median age at evaluation was 31 (range, 18 to 60).
At evaluation, 7.4% of subjects had cardiomyopathy (newly identified in 4.7%), 3.8% had coronary artery disease (newly identified in 2.2%), 28% had valvular regurgitation or stenosis (newly identified in 24.8%), and 4.4% had conduction or rhythm abnormalities (newly identified in 1.4%). All but 5 subjects were asymptomatic.
Multivariable analysis suggested the odds of developing cardiomyopathy were significantly associated with being male (odds ratio [OR]=1.9), receiving anthracycline doses of 250 mg/m2 or greater (OR=2.7), having cardiac radiation exposure greater than 1500 cGy (OR=1.9), and having hypertension (OR=3.0).
Being younger at diagnosis was associated with higher odds of valvular disease. The ORs were 1.5 for patients who were 0 to 4 years of age at diagnosis and 1.3 for patients who were 5 to 9 at diagnosis.
Receiving higher radiation doses was associated with higher odds of valvular disease as well. But associations between radiation and valvular disease varied according to a patient’s anthracycline exposure (interaction P<0.001). The highest odds were among survivors with the highest doses of radiation exposure and any anthracycline exposure (OR=4.5).
The researchers also noted a reduction in the OR for valvular disease among obese patients (OR=0.4) and those with dyslipidemia (OR=0.7).
The team said there were not enough cases of coronary artery disease and conduction or rhythm abnormalities to support a fully adjusted multivariable model. However, it seemed these outcomes were more common with older age (≥40 years) and among patients with cardiac radiation doses of 1500 cGy or greater.
The researchers said this study revealed “considerable cardiovascular disease” in a large cohort of adult survivors of childhood cancer, which suggests a substantial future healthcare burden.
The team believes their findings could guide stratification of risk factors, screening practices, health counseling, and potential therapeutic measures aimed at changing the disease trajectory in this young adult population.
Novel delivery system could treat MCL
Researchers say they have developed a system for delivering therapy at the site of mantle cell lymphoma (MCL).
The system harnesses nanoparticles coated with “GPS” antibodies that navigate toward cancerous cells, where they offload cyclin D1-blockers in the form of small interfering RNAs (siRNAs).
Experiments showed the system can halt the proliferation of cyclin D1 in both animal models and samples from MCL patients.
Dan Peer, PhD, of Tel Aviv University in Israel, and his colleagues reported these results in PNAS.
“MCL has a genetic hallmark,” Dr Peer noted. “In 85% of cases, the characteristic that defines this aggressive and prototypic B-cell lymphoma is the heightened activity of the gene CCND1, which leads to the extreme overexpression—a 3000- to 15,000-fold increase—of cyclin D1, a protein that controls the proliferation of cells. Downregulation of cyclin D1 using siRNAs is a potential therapeutic approach to this malignancy.”
For this research, Dr Peer and his colleagues designed lipid-based nanoparticles (LNPs) coated with anti-CD38 monoclonal antibodies that were taken up by human MCL cells in the bone marrow of affected mice.
When loaded with siRNAs against cyclin D1, the targeting LNPs induced gene silencing in MCL cells and prolonged the survival of tumor-bearing mice, with no observed adverse effects.
“In MCL, cyclin D1 is the exclusive cause of the overproduction of B lymphocytes, the cells responsible for generating antibodies,” Dr Peer said. “This makes the protein a perfect target for RNA therapy by siRNAs.”
“Normal, healthy cells don’t express the gene, so therapies that destroy the gene will only attack cancer cells. The RNA interference we have developed targets the faulty cyclin D1 within the cancerous cells. And when the cells are inhibited from proliferating, they sense they are being targeted and begin to die off.”
Dr Peer and his colleagues believe this work presents new opportunities for treating MCL and other similar B-cell malignancies.
“This research makes a definite contribution to the revolution of personalized medicine, whereby you tailor the drug based on the genetic profile of patient,” Dr Peer said. “In this case, MCL is a disease with a specific genetic hallmark, so you can sequence the patient to identify the mutation(s) and design RNA blockers to be placed inside a nanovehicle.”
“While the targeting antibodies—the ‘GPS’—can be used to target many different B-cell malignancies, the drug itself is designed to silence this specific disease. However, the delivery system can be used to accommodate any disease with a genetic profile. This could be the future. We are seeing it happen before our very eyes.”
Researchers say they have developed a system for delivering therapy at the site of mantle cell lymphoma (MCL).
The system harnesses nanoparticles coated with “GPS” antibodies that navigate toward cancerous cells, where they offload cyclin D1-blockers in the form of small interfering RNAs (siRNAs).
Experiments showed the system can halt the proliferation of cyclin D1 in both animal models and samples from MCL patients.
Dan Peer, PhD, of Tel Aviv University in Israel, and his colleagues reported these results in PNAS.
“MCL has a genetic hallmark,” Dr Peer noted. “In 85% of cases, the characteristic that defines this aggressive and prototypic B-cell lymphoma is the heightened activity of the gene CCND1, which leads to the extreme overexpression—a 3000- to 15,000-fold increase—of cyclin D1, a protein that controls the proliferation of cells. Downregulation of cyclin D1 using siRNAs is a potential therapeutic approach to this malignancy.”
For this research, Dr Peer and his colleagues designed lipid-based nanoparticles (LNPs) coated with anti-CD38 monoclonal antibodies that were taken up by human MCL cells in the bone marrow of affected mice.
When loaded with siRNAs against cyclin D1, the targeting LNPs induced gene silencing in MCL cells and prolonged the survival of tumor-bearing mice, with no observed adverse effects.
“In MCL, cyclin D1 is the exclusive cause of the overproduction of B lymphocytes, the cells responsible for generating antibodies,” Dr Peer said. “This makes the protein a perfect target for RNA therapy by siRNAs.”
“Normal, healthy cells don’t express the gene, so therapies that destroy the gene will only attack cancer cells. The RNA interference we have developed targets the faulty cyclin D1 within the cancerous cells. And when the cells are inhibited from proliferating, they sense they are being targeted and begin to die off.”
Dr Peer and his colleagues believe this work presents new opportunities for treating MCL and other similar B-cell malignancies.
“This research makes a definite contribution to the revolution of personalized medicine, whereby you tailor the drug based on the genetic profile of patient,” Dr Peer said. “In this case, MCL is a disease with a specific genetic hallmark, so you can sequence the patient to identify the mutation(s) and design RNA blockers to be placed inside a nanovehicle.”
“While the targeting antibodies—the ‘GPS’—can be used to target many different B-cell malignancies, the drug itself is designed to silence this specific disease. However, the delivery system can be used to accommodate any disease with a genetic profile. This could be the future. We are seeing it happen before our very eyes.”
Researchers say they have developed a system for delivering therapy at the site of mantle cell lymphoma (MCL).
The system harnesses nanoparticles coated with “GPS” antibodies that navigate toward cancerous cells, where they offload cyclin D1-blockers in the form of small interfering RNAs (siRNAs).
Experiments showed the system can halt the proliferation of cyclin D1 in both animal models and samples from MCL patients.
Dan Peer, PhD, of Tel Aviv University in Israel, and his colleagues reported these results in PNAS.
“MCL has a genetic hallmark,” Dr Peer noted. “In 85% of cases, the characteristic that defines this aggressive and prototypic B-cell lymphoma is the heightened activity of the gene CCND1, which leads to the extreme overexpression—a 3000- to 15,000-fold increase—of cyclin D1, a protein that controls the proliferation of cells. Downregulation of cyclin D1 using siRNAs is a potential therapeutic approach to this malignancy.”
For this research, Dr Peer and his colleagues designed lipid-based nanoparticles (LNPs) coated with anti-CD38 monoclonal antibodies that were taken up by human MCL cells in the bone marrow of affected mice.
When loaded with siRNAs against cyclin D1, the targeting LNPs induced gene silencing in MCL cells and prolonged the survival of tumor-bearing mice, with no observed adverse effects.
“In MCL, cyclin D1 is the exclusive cause of the overproduction of B lymphocytes, the cells responsible for generating antibodies,” Dr Peer said. “This makes the protein a perfect target for RNA therapy by siRNAs.”
“Normal, healthy cells don’t express the gene, so therapies that destroy the gene will only attack cancer cells. The RNA interference we have developed targets the faulty cyclin D1 within the cancerous cells. And when the cells are inhibited from proliferating, they sense they are being targeted and begin to die off.”
Dr Peer and his colleagues believe this work presents new opportunities for treating MCL and other similar B-cell malignancies.
“This research makes a definite contribution to the revolution of personalized medicine, whereby you tailor the drug based on the genetic profile of patient,” Dr Peer said. “In this case, MCL is a disease with a specific genetic hallmark, so you can sequence the patient to identify the mutation(s) and design RNA blockers to be placed inside a nanovehicle.”
“While the targeting antibodies—the ‘GPS’—can be used to target many different B-cell malignancies, the drug itself is designed to silence this specific disease. However, the delivery system can be used to accommodate any disease with a genetic profile. This could be the future. We are seeing it happen before our very eyes.”
Paste may reduce radiation-induced fibrosis
woman for radiation
Photo by Rhoda Baer
A topical paste can reduce fibrosis caused by radiation therapy, according to preclinical research published in The FASEB Journal.
The study addressed a type of fibrosis called radiation dermatitis, in which radiation applied to the skin causes the buildup of fibrotic tissue and skin thickening.
To test their topical paste, researchers mimicked the development of radiation dermatitis in mice.
They exposed the mice’s skin to a single dose of 40 Gy, an amount of radiation similar to what patients undergoing anticancer radiation typically receive over 5 weeks.
Some of the irradiated animals were wild-type mice, while others were genetically engineered to lack the A2A receptor (A2AR). The researchers had previously shown that occupancy of A2AR induces collagen production.
The wild-type mice went on to receive placebo or daily treatment with ZM241385, a paste made with the research team’s patented A2AR blocker. The paste contains 2.5 milligrams of active ingredient per milliliter of 3% carboxymethyl cellulose, a gum “binder.”
A month after exposure, wild-type mice that received placebo had a nearly 2-fold increase in the amount of collagen and skin thickness. These mice also experienced epithelial hyperplasia.
On the other hand, mice treated with ZM241385 accumulated only 10% more skin-thickening collagen. ZM241385 treatment reduced the number of myofibroblasts, collagen fibrils, proliferating keratinocytes, and angiogenesis when compared to placebo. And the paste prevented epithelial hyperplasia.
Like ZM241385-treated mice, A2AR knockout mice did not have the excessive collagen production and skin thickening observed in placebo-treated wild-type mice. The knockout mice also exhibited reductions in myofibroblast content, angiogenesis, and epithelial hyperplasia.
The researchers noted that radiation-induced changes in the dermis and epidermis were accompanied by an infiltrate of T cells, which was prevented in both ZM241385-treated and A2AR knockout mice.
“Our latest study is the first to demonstrate that blocking or deleting the A2A receptor can be useful in reducing radiation-induced scarring in skin,” said study author Bruce Cronstein, MD, of New York University School of Medicine in New York, New York.
“The study also suggests that adenosine A2A receptor antagonists may have broad applications as drug therapies for preventing fibrosis and scarring, not just in the liver but also in the skin.”
If further experiments prove successful, Dr Cronstein said, clinicians treating early stage cancers with radiation could eventually prescribe an A2AR inhibitor paste to prevent fibrosis. He said his team next plans to study the mechanism underlying A2AR’s role in fibrosis.
woman for radiation
Photo by Rhoda Baer
A topical paste can reduce fibrosis caused by radiation therapy, according to preclinical research published in The FASEB Journal.
The study addressed a type of fibrosis called radiation dermatitis, in which radiation applied to the skin causes the buildup of fibrotic tissue and skin thickening.
To test their topical paste, researchers mimicked the development of radiation dermatitis in mice.
They exposed the mice’s skin to a single dose of 40 Gy, an amount of radiation similar to what patients undergoing anticancer radiation typically receive over 5 weeks.
Some of the irradiated animals were wild-type mice, while others were genetically engineered to lack the A2A receptor (A2AR). The researchers had previously shown that occupancy of A2AR induces collagen production.
The wild-type mice went on to receive placebo or daily treatment with ZM241385, a paste made with the research team’s patented A2AR blocker. The paste contains 2.5 milligrams of active ingredient per milliliter of 3% carboxymethyl cellulose, a gum “binder.”
A month after exposure, wild-type mice that received placebo had a nearly 2-fold increase in the amount of collagen and skin thickness. These mice also experienced epithelial hyperplasia.
On the other hand, mice treated with ZM241385 accumulated only 10% more skin-thickening collagen. ZM241385 treatment reduced the number of myofibroblasts, collagen fibrils, proliferating keratinocytes, and angiogenesis when compared to placebo. And the paste prevented epithelial hyperplasia.
Like ZM241385-treated mice, A2AR knockout mice did not have the excessive collagen production and skin thickening observed in placebo-treated wild-type mice. The knockout mice also exhibited reductions in myofibroblast content, angiogenesis, and epithelial hyperplasia.
The researchers noted that radiation-induced changes in the dermis and epidermis were accompanied by an infiltrate of T cells, which was prevented in both ZM241385-treated and A2AR knockout mice.
“Our latest study is the first to demonstrate that blocking or deleting the A2A receptor can be useful in reducing radiation-induced scarring in skin,” said study author Bruce Cronstein, MD, of New York University School of Medicine in New York, New York.
“The study also suggests that adenosine A2A receptor antagonists may have broad applications as drug therapies for preventing fibrosis and scarring, not just in the liver but also in the skin.”
If further experiments prove successful, Dr Cronstein said, clinicians treating early stage cancers with radiation could eventually prescribe an A2AR inhibitor paste to prevent fibrosis. He said his team next plans to study the mechanism underlying A2AR’s role in fibrosis.
woman for radiation
Photo by Rhoda Baer
A topical paste can reduce fibrosis caused by radiation therapy, according to preclinical research published in The FASEB Journal.
The study addressed a type of fibrosis called radiation dermatitis, in which radiation applied to the skin causes the buildup of fibrotic tissue and skin thickening.
To test their topical paste, researchers mimicked the development of radiation dermatitis in mice.
They exposed the mice’s skin to a single dose of 40 Gy, an amount of radiation similar to what patients undergoing anticancer radiation typically receive over 5 weeks.
Some of the irradiated animals were wild-type mice, while others were genetically engineered to lack the A2A receptor (A2AR). The researchers had previously shown that occupancy of A2AR induces collagen production.
The wild-type mice went on to receive placebo or daily treatment with ZM241385, a paste made with the research team’s patented A2AR blocker. The paste contains 2.5 milligrams of active ingredient per milliliter of 3% carboxymethyl cellulose, a gum “binder.”
A month after exposure, wild-type mice that received placebo had a nearly 2-fold increase in the amount of collagen and skin thickness. These mice also experienced epithelial hyperplasia.
On the other hand, mice treated with ZM241385 accumulated only 10% more skin-thickening collagen. ZM241385 treatment reduced the number of myofibroblasts, collagen fibrils, proliferating keratinocytes, and angiogenesis when compared to placebo. And the paste prevented epithelial hyperplasia.
Like ZM241385-treated mice, A2AR knockout mice did not have the excessive collagen production and skin thickening observed in placebo-treated wild-type mice. The knockout mice also exhibited reductions in myofibroblast content, angiogenesis, and epithelial hyperplasia.
The researchers noted that radiation-induced changes in the dermis and epidermis were accompanied by an infiltrate of T cells, which was prevented in both ZM241385-treated and A2AR knockout mice.
“Our latest study is the first to demonstrate that blocking or deleting the A2A receptor can be useful in reducing radiation-induced scarring in skin,” said study author Bruce Cronstein, MD, of New York University School of Medicine in New York, New York.
“The study also suggests that adenosine A2A receptor antagonists may have broad applications as drug therapies for preventing fibrosis and scarring, not just in the liver but also in the skin.”
If further experiments prove successful, Dr Cronstein said, clinicians treating early stage cancers with radiation could eventually prescribe an A2AR inhibitor paste to prevent fibrosis. He said his team next plans to study the mechanism underlying A2AR’s role in fibrosis.