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RIT can improve transplant outcomes in NHL, CLL
GRAPEVINE, TEXAS—Administering radioimmunotherapy (RIT) prior to non-myeloablative allogeneic transplant (NMAT) can improve survival in patients with persistent disease, according to a speaker at the 2014 BMT Tandem Meetings.
Ryan Cassaday, MD, of the University of Washington in Seattle, noted that RIT-augmented NMAT can produce long-term remissions in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL) or chronic lymphocytic leukemia (CLL).
But outcomes for patients with persistent disease are “underdescribed.”
So he and his colleagues set out to describe outcomes of NMAT for patients with persistent indolent B-NHL or CLL and estimate the impact of RIT in these patients.
Treatment details
The researchers retrospectively analyzed data from 89 patients who underwent NMAT from December 1998 to April 2009 and were followed until September 2013. Eighteen of the patients had received RIT as part of a prospective study (AK Gopal et al, Blood 2011).
The remaining 71 patients did not receive RIT but met eligibility criteria for that study. Specifically, they had a CD20+ B-cell malignancy, an HLA-matched peripheral blood stem cell donor, and persistent disease at NMAT. These control subjects received fludarabine (30 mg/m2 on days -7, -6, and -5) and 2 Gy of total body irradiation prior to NMAT.
Patients in the RIT group received the same treatment following RIT. On day -21, they received 250 mg/m2 of rituximab before an imaging dose of 111In-ibritumomab tiuxetan. And on day -14, they received 250 mg/m2 of rituximab and 0.4 mCi/kg of 90Y-ibritumomab tiuxetan.
Patient characteristics
In the RIT group, 10 patients had CLL/small lymphocytic lymphoma (SLL), 6 had follicular lymphoma (FL), 1 had marginal zone lymphoma (MZL), and 1 had hairy cell leukemia. As for controls, 52 had CLL/SLL, 18 had FL, and 1 had MZL.
“The majority of patients were male [74%] and a relatively young age, given the diseases being treated [median of 56 years],” Dr Cassaday said. “The majority of patients had previously received rituximab [88%], and patients were heavily pretreated [median of 4 prior therapies, range 1-12].”
There were no significant differences between the 2 treatment groups with regard to the aforementioned characteristics. However, there were some “striking differences” between the 2 groups, Dr Cassaday said, including characteristics that portend worse prognosis.
Specifically, RIT-treated patients had more bulky disease (> 5 cm) than controls (61% vs 15%, P<0.001) and more chemoresistant disease (81% vs 39%, P=0.003). And RIT patients were more likely to have HCT comorbidity index scores of 3 or higher (72% vs 37%, P=0.006), as well as pre-NMAT platelet counts less than 25k/μL (33% vs 7%, P=0.002).
RIT improves PFS, OS
The researchers conducted a multivariate analysis including the factors that differed significantly between the 2 treatment groups. And they found that only RIT was significantly associated with both progression-free survival (PFS) and overall survival (OS).
When calculating survival curves, the researchers adjusted for the imbalance in covariates between the treatment groups.
“[The adjusted survival rate] is essentially what one might expect had the RIT group had similar baseline characteristics as the control group,” Dr Cassaday explained.
Control subjects had a 3-year OS of 55%. For the RIT-treated patients, the unadjusted 3-year OS was 78% (P=0.20), and the adjusted OS was 87% (P=0.008).
The 3-year PFS was 44% for controls. For the RIT group, the unadjusted 3-year PFS was 56% (P=0.36), and the adjusted PFS was 71% (P=0.02).
The researchers also found that RIT did not increase the rate of non-relapse mortality. The unadjusted hazard ratio was 0.5 (P=0.32), and the adjusted hazard ratio was 0.4 (P=0.18).
“This analysis does have some limitations,” Dr Cassaday conceded. “Clearly, it does not replace the strength of evidence that would come from a randomized, controlled trial. And the relatively small sample size does limit our ability to look at a lot of different subgroups.”
In addition, the findings may not apply to other non-myeloablative regimens. And, due to the time frame of the study, the researchers could not account for the potential impact of newer agents.
Nevertheless, Dr Cassaday said the data suggest that RIT can improve the outcome of NMAT in patients with persistent indolent B-NHL or CLL. And a prospective, randomized study evaluating this approach is warranted.
Dr Cassaday presented this research at the 2014 BMT Tandem Meetings as abstract 75. Information in the abstract differs from that presented. 
GRAPEVINE, TEXAS—Administering radioimmunotherapy (RIT) prior to non-myeloablative allogeneic transplant (NMAT) can improve survival in patients with persistent disease, according to a speaker at the 2014 BMT Tandem Meetings.
Ryan Cassaday, MD, of the University of Washington in Seattle, noted that RIT-augmented NMAT can produce long-term remissions in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL) or chronic lymphocytic leukemia (CLL).
But outcomes for patients with persistent disease are “underdescribed.”
So he and his colleagues set out to describe outcomes of NMAT for patients with persistent indolent B-NHL or CLL and estimate the impact of RIT in these patients.
Treatment details
The researchers retrospectively analyzed data from 89 patients who underwent NMAT from December 1998 to April 2009 and were followed until September 2013. Eighteen of the patients had received RIT as part of a prospective study (AK Gopal et al, Blood 2011).
The remaining 71 patients did not receive RIT but met eligibility criteria for that study. Specifically, they had a CD20+ B-cell malignancy, an HLA-matched peripheral blood stem cell donor, and persistent disease at NMAT. These control subjects received fludarabine (30 mg/m2 on days -7, -6, and -5) and 2 Gy of total body irradiation prior to NMAT.
Patients in the RIT group received the same treatment following RIT. On day -21, they received 250 mg/m2 of rituximab before an imaging dose of 111In-ibritumomab tiuxetan. And on day -14, they received 250 mg/m2 of rituximab and 0.4 mCi/kg of 90Y-ibritumomab tiuxetan.
Patient characteristics
In the RIT group, 10 patients had CLL/small lymphocytic lymphoma (SLL), 6 had follicular lymphoma (FL), 1 had marginal zone lymphoma (MZL), and 1 had hairy cell leukemia. As for controls, 52 had CLL/SLL, 18 had FL, and 1 had MZL.
“The majority of patients were male [74%] and a relatively young age, given the diseases being treated [median of 56 years],” Dr Cassaday said. “The majority of patients had previously received rituximab [88%], and patients were heavily pretreated [median of 4 prior therapies, range 1-12].”
There were no significant differences between the 2 treatment groups with regard to the aforementioned characteristics. However, there were some “striking differences” between the 2 groups, Dr Cassaday said, including characteristics that portend worse prognosis.
Specifically, RIT-treated patients had more bulky disease (> 5 cm) than controls (61% vs 15%, P<0.001) and more chemoresistant disease (81% vs 39%, P=0.003). And RIT patients were more likely to have HCT comorbidity index scores of 3 or higher (72% vs 37%, P=0.006), as well as pre-NMAT platelet counts less than 25k/μL (33% vs 7%, P=0.002).
RIT improves PFS, OS
The researchers conducted a multivariate analysis including the factors that differed significantly between the 2 treatment groups. And they found that only RIT was significantly associated with both progression-free survival (PFS) and overall survival (OS).
When calculating survival curves, the researchers adjusted for the imbalance in covariates between the treatment groups.
“[The adjusted survival rate] is essentially what one might expect had the RIT group had similar baseline characteristics as the control group,” Dr Cassaday explained.
Control subjects had a 3-year OS of 55%. For the RIT-treated patients, the unadjusted 3-year OS was 78% (P=0.20), and the adjusted OS was 87% (P=0.008).
The 3-year PFS was 44% for controls. For the RIT group, the unadjusted 3-year PFS was 56% (P=0.36), and the adjusted PFS was 71% (P=0.02).
The researchers also found that RIT did not increase the rate of non-relapse mortality. The unadjusted hazard ratio was 0.5 (P=0.32), and the adjusted hazard ratio was 0.4 (P=0.18).
“This analysis does have some limitations,” Dr Cassaday conceded. “Clearly, it does not replace the strength of evidence that would come from a randomized, controlled trial. And the relatively small sample size does limit our ability to look at a lot of different subgroups.”
In addition, the findings may not apply to other non-myeloablative regimens. And, due to the time frame of the study, the researchers could not account for the potential impact of newer agents.
Nevertheless, Dr Cassaday said the data suggest that RIT can improve the outcome of NMAT in patients with persistent indolent B-NHL or CLL. And a prospective, randomized study evaluating this approach is warranted.
Dr Cassaday presented this research at the 2014 BMT Tandem Meetings as abstract 75. Information in the abstract differs from that presented.
GRAPEVINE, TEXAS—Administering radioimmunotherapy (RIT) prior to non-myeloablative allogeneic transplant (NMAT) can improve survival in patients with persistent disease, according to a speaker at the 2014 BMT Tandem Meetings.
Ryan Cassaday, MD, of the University of Washington in Seattle, noted that RIT-augmented NMAT can produce long-term remissions in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL) or chronic lymphocytic leukemia (CLL).
But outcomes for patients with persistent disease are “underdescribed.”
So he and his colleagues set out to describe outcomes of NMAT for patients with persistent indolent B-NHL or CLL and estimate the impact of RIT in these patients.
Treatment details
The researchers retrospectively analyzed data from 89 patients who underwent NMAT from December 1998 to April 2009 and were followed until September 2013. Eighteen of the patients had received RIT as part of a prospective study (AK Gopal et al, Blood 2011).
The remaining 71 patients did not receive RIT but met eligibility criteria for that study. Specifically, they had a CD20+ B-cell malignancy, an HLA-matched peripheral blood stem cell donor, and persistent disease at NMAT. These control subjects received fludarabine (30 mg/m2 on days -7, -6, and -5) and 2 Gy of total body irradiation prior to NMAT.
Patients in the RIT group received the same treatment following RIT. On day -21, they received 250 mg/m2 of rituximab before an imaging dose of 111In-ibritumomab tiuxetan. And on day -14, they received 250 mg/m2 of rituximab and 0.4 mCi/kg of 90Y-ibritumomab tiuxetan.
Patient characteristics
In the RIT group, 10 patients had CLL/small lymphocytic lymphoma (SLL), 6 had follicular lymphoma (FL), 1 had marginal zone lymphoma (MZL), and 1 had hairy cell leukemia. As for controls, 52 had CLL/SLL, 18 had FL, and 1 had MZL.
“The majority of patients were male [74%] and a relatively young age, given the diseases being treated [median of 56 years],” Dr Cassaday said. “The majority of patients had previously received rituximab [88%], and patients were heavily pretreated [median of 4 prior therapies, range 1-12].”
There were no significant differences between the 2 treatment groups with regard to the aforementioned characteristics. However, there were some “striking differences” between the 2 groups, Dr Cassaday said, including characteristics that portend worse prognosis.
Specifically, RIT-treated patients had more bulky disease (> 5 cm) than controls (61% vs 15%, P<0.001) and more chemoresistant disease (81% vs 39%, P=0.003). And RIT patients were more likely to have HCT comorbidity index scores of 3 or higher (72% vs 37%, P=0.006), as well as pre-NMAT platelet counts less than 25k/μL (33% vs 7%, P=0.002).
RIT improves PFS, OS
The researchers conducted a multivariate analysis including the factors that differed significantly between the 2 treatment groups. And they found that only RIT was significantly associated with both progression-free survival (PFS) and overall survival (OS).
When calculating survival curves, the researchers adjusted for the imbalance in covariates between the treatment groups.
“[The adjusted survival rate] is essentially what one might expect had the RIT group had similar baseline characteristics as the control group,” Dr Cassaday explained.
Control subjects had a 3-year OS of 55%. For the RIT-treated patients, the unadjusted 3-year OS was 78% (P=0.20), and the adjusted OS was 87% (P=0.008).
The 3-year PFS was 44% for controls. For the RIT group, the unadjusted 3-year PFS was 56% (P=0.36), and the adjusted PFS was 71% (P=0.02).
The researchers also found that RIT did not increase the rate of non-relapse mortality. The unadjusted hazard ratio was 0.5 (P=0.32), and the adjusted hazard ratio was 0.4 (P=0.18).
“This analysis does have some limitations,” Dr Cassaday conceded. “Clearly, it does not replace the strength of evidence that would come from a randomized, controlled trial. And the relatively small sample size does limit our ability to look at a lot of different subgroups.”
In addition, the findings may not apply to other non-myeloablative regimens. And, due to the time frame of the study, the researchers could not account for the potential impact of newer agents.
Nevertheless, Dr Cassaday said the data suggest that RIT can improve the outcome of NMAT in patients with persistent indolent B-NHL or CLL. And a prospective, randomized study evaluating this approach is warranted.
Dr Cassaday presented this research at the 2014 BMT Tandem Meetings as abstract 75. Information in the abstract differs from that presented.
England’s Cancer Drugs Fund raises concerns
Credit: Rhoda Baer
Cancer patients in England are more likely to receive prescriptions for expensive drugs than patients in Wales, according to a study published in the British Journal of Cancer.
The research suggests this disparity is associated with the Cancer Drugs Fund (CDF), money set aside by the English government to pay for drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the National Health Service (NHS).
The governments of Wales, Scotland, and Northern Ireland do not have access to the CDF or have similar programs of their own.
“There’s been much debate surrounding the Cancer Drugs Fund,” said study author Charlotte Chamberlain, MBBS, of the University of Bristol in the UK.
“The vast majority of Cancer Drugs Fund drugs do not cure the cancer but may extend life or improve symptoms in some people. The high cost of these drugs means that the NHS cannot afford other treatments, and, therefore, critics argue that public money is being spent inefficiently.”
To assess the impact of the CDF, Dr Chamberlain and her colleagues analyzed data from hospital pharmacies in England and Wales from August 2007 to December 2012. (The CDF was established in 2010, and the researchers wanted to capture data from before and after its introduction.)
The team evaluated 15 drugs that represent different categories of NICE approval—recommended, not recommended, and not yet appraised.
The results showed that, after the CDF was established, drugs recommended by NICE were not prescribed any more in England than in Wales.
However, drugs that were rejected by NICE because they were not cost-effective were prescribed up to 7 times more often in England than in Wales. For example, in the year before the CDF was introduced, prescription rates of imatinib (which is not recommended by NICE) were substantially higher in England than in Wales.
Immediately before the introduction of the CDF, following the first NICE rejection, imatinib prescribing declined in both countries. But it declined more slowly in England than in Wales, despite 2 additional NICE rejections. Regression analysis showed evidence of an association between the CDF and increased prescribing in England compared to Wales (P<0.001).
The research also revealed surprising information regarding the 3 most recently launched drugs—bendamustine, pazopanib, and abiraterone, which were awaiting NICE appraisal when the CDF was established but have since been approved.
These drugs were prescribed less often in England than in Wales. For instance, prescription rates of bendamustine were 25% lower in England.
This finding suggests that physicians in England have been slower to adopt newer drugs that are cost-effective, the researchers said.
“Our research has highlighted that the CDF has created an inequality between cancer sufferers in England and those in Wales,” Dr Chamberlain noted. “This raises ethical, moral, financial, and policy concerns.”
Credit: Rhoda Baer
Cancer patients in England are more likely to receive prescriptions for expensive drugs than patients in Wales, according to a study published in the British Journal of Cancer.
The research suggests this disparity is associated with the Cancer Drugs Fund (CDF), money set aside by the English government to pay for drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the National Health Service (NHS).
The governments of Wales, Scotland, and Northern Ireland do not have access to the CDF or have similar programs of their own.
“There’s been much debate surrounding the Cancer Drugs Fund,” said study author Charlotte Chamberlain, MBBS, of the University of Bristol in the UK.
“The vast majority of Cancer Drugs Fund drugs do not cure the cancer but may extend life or improve symptoms in some people. The high cost of these drugs means that the NHS cannot afford other treatments, and, therefore, critics argue that public money is being spent inefficiently.”
To assess the impact of the CDF, Dr Chamberlain and her colleagues analyzed data from hospital pharmacies in England and Wales from August 2007 to December 2012. (The CDF was established in 2010, and the researchers wanted to capture data from before and after its introduction.)
The team evaluated 15 drugs that represent different categories of NICE approval—recommended, not recommended, and not yet appraised.
The results showed that, after the CDF was established, drugs recommended by NICE were not prescribed any more in England than in Wales.
However, drugs that were rejected by NICE because they were not cost-effective were prescribed up to 7 times more often in England than in Wales. For example, in the year before the CDF was introduced, prescription rates of imatinib (which is not recommended by NICE) were substantially higher in England than in Wales.
Immediately before the introduction of the CDF, following the first NICE rejection, imatinib prescribing declined in both countries. But it declined more slowly in England than in Wales, despite 2 additional NICE rejections. Regression analysis showed evidence of an association between the CDF and increased prescribing in England compared to Wales (P<0.001).
The research also revealed surprising information regarding the 3 most recently launched drugs—bendamustine, pazopanib, and abiraterone, which were awaiting NICE appraisal when the CDF was established but have since been approved.
These drugs were prescribed less often in England than in Wales. For instance, prescription rates of bendamustine were 25% lower in England.
This finding suggests that physicians in England have been slower to adopt newer drugs that are cost-effective, the researchers said.
“Our research has highlighted that the CDF has created an inequality between cancer sufferers in England and those in Wales,” Dr Chamberlain noted. “This raises ethical, moral, financial, and policy concerns.”
Credit: Rhoda Baer
Cancer patients in England are more likely to receive prescriptions for expensive drugs than patients in Wales, according to a study published in the British Journal of Cancer.
The research suggests this disparity is associated with the Cancer Drugs Fund (CDF), money set aside by the English government to pay for drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the National Health Service (NHS).
The governments of Wales, Scotland, and Northern Ireland do not have access to the CDF or have similar programs of their own.
“There’s been much debate surrounding the Cancer Drugs Fund,” said study author Charlotte Chamberlain, MBBS, of the University of Bristol in the UK.
“The vast majority of Cancer Drugs Fund drugs do not cure the cancer but may extend life or improve symptoms in some people. The high cost of these drugs means that the NHS cannot afford other treatments, and, therefore, critics argue that public money is being spent inefficiently.”
To assess the impact of the CDF, Dr Chamberlain and her colleagues analyzed data from hospital pharmacies in England and Wales from August 2007 to December 2012. (The CDF was established in 2010, and the researchers wanted to capture data from before and after its introduction.)
The team evaluated 15 drugs that represent different categories of NICE approval—recommended, not recommended, and not yet appraised.
The results showed that, after the CDF was established, drugs recommended by NICE were not prescribed any more in England than in Wales.
However, drugs that were rejected by NICE because they were not cost-effective were prescribed up to 7 times more often in England than in Wales. For example, in the year before the CDF was introduced, prescription rates of imatinib (which is not recommended by NICE) were substantially higher in England than in Wales.
Immediately before the introduction of the CDF, following the first NICE rejection, imatinib prescribing declined in both countries. But it declined more slowly in England than in Wales, despite 2 additional NICE rejections. Regression analysis showed evidence of an association between the CDF and increased prescribing in England compared to Wales (P<0.001).
The research also revealed surprising information regarding the 3 most recently launched drugs—bendamustine, pazopanib, and abiraterone, which were awaiting NICE appraisal when the CDF was established but have since been approved.
These drugs were prescribed less often in England than in Wales. For instance, prescription rates of bendamustine were 25% lower in England.
This finding suggests that physicians in England have been slower to adopt newer drugs that are cost-effective, the researchers said.
“Our research has highlighted that the CDF has created an inequality between cancer sufferers in England and those in Wales,” Dr Chamberlain noted. “This raises ethical, moral, financial, and policy concerns.”
Nanoparticle therapy active in B-cell malignancies
An experimental nanoparticle therapy has shown preclinical activity against a range of B-cell malignancies, researchers have reported.
The therapy, SNS01-T, inhibited tumor growth and improved survival in mouse models of multiple myeloma, mantle cell lymphoma, and diffuse large B-cell lymphoma.
The treatment exhibited single-agent activity in these mice but also demonstrated synergy with lenalidomide and bortezomib.
Sarah Francis, PhD, of the University of Waterloo in Ontario, Canada, and her colleagues conducted this research and recounted the results in Molecular Therapy.
SNS01-T consists of 3 components: small interfering RNA targeting the native eukaryotic translation initiation factor 5A (eIF5A), plasmids expressing a pro-apoptotic mutant of elF5A under the control of a B-cell specific promoter, and a synthetic cationic polymer polyethylenimine, which serves as the delivery vehicle.
The small interfering RNA component of SNS01-T suppresses elF5A expression, thereby interfering with translation of eIF5A and reducing levels of hypusinated elF5A in cancer cells. This inhibits activation of NF-kB and induces apoptosis.
The B-cell specific plasmid component of SNS01-T expresses an arginine substituted form of eIF5A—eIF5AK50R—that cannot be hypusinated, which leads to selective induction of apoptosis in B cells.
Dr Francis and her colleagues found that SNS01-T is preferentially taken up by malignant B cells. In myeloma cells, uptake of SNS01-T was up to 5-fold higher than uptake by normal, naïve B cells.
Uptake into myeloma cells induced 45% cell death within 24 hours, but there was almost no measureable death of normal, naïve B cells.
SNS01-T also prompted dose-dependent inhibition of tumor growth in mouse models of multiple myeloma, mantle cell lymphoma, and diffuse large B-cell lymphoma, with up to 90% inhibition at the highest doses.
When administered at doses of 0.18 mg/kg or more, SNS01-T significantly extended the life span of treated mice. The researchers observed a reduction in the pro-survival form of the eIF5A protein in tumor tissue, which was consistent with drug activity.
SNS01-T also demonstrated synergy with bortezomib and lenalidomide. Mice that received SNS01-T and lenalidomide in combination had a 100% survival rate, compared to 60% for mice that received SNS01-T alone and 20% for mice that received lenalidomide alone.
A single 6-week cycle of SNS01-T and lenalidomide eradicated tumors in 67% of mice, and there was no regrowth after an additional 8 weeks without further treatment.
Similarly, combination SNS01-T and bortezomib inhibited tumor growth by 89%, compared to 59% for SNS01-T alone and 39% for bortezomib alone.
This research was supported by Senesco Technologies, Inc., the company developing SNS01-T.
An experimental nanoparticle therapy has shown preclinical activity against a range of B-cell malignancies, researchers have reported.
The therapy, SNS01-T, inhibited tumor growth and improved survival in mouse models of multiple myeloma, mantle cell lymphoma, and diffuse large B-cell lymphoma.
The treatment exhibited single-agent activity in these mice but also demonstrated synergy with lenalidomide and bortezomib.
Sarah Francis, PhD, of the University of Waterloo in Ontario, Canada, and her colleagues conducted this research and recounted the results in Molecular Therapy.
SNS01-T consists of 3 components: small interfering RNA targeting the native eukaryotic translation initiation factor 5A (eIF5A), plasmids expressing a pro-apoptotic mutant of elF5A under the control of a B-cell specific promoter, and a synthetic cationic polymer polyethylenimine, which serves as the delivery vehicle.
The small interfering RNA component of SNS01-T suppresses elF5A expression, thereby interfering with translation of eIF5A and reducing levels of hypusinated elF5A in cancer cells. This inhibits activation of NF-kB and induces apoptosis.
The B-cell specific plasmid component of SNS01-T expresses an arginine substituted form of eIF5A—eIF5AK50R—that cannot be hypusinated, which leads to selective induction of apoptosis in B cells.
Dr Francis and her colleagues found that SNS01-T is preferentially taken up by malignant B cells. In myeloma cells, uptake of SNS01-T was up to 5-fold higher than uptake by normal, naïve B cells.
Uptake into myeloma cells induced 45% cell death within 24 hours, but there was almost no measureable death of normal, naïve B cells.
SNS01-T also prompted dose-dependent inhibition of tumor growth in mouse models of multiple myeloma, mantle cell lymphoma, and diffuse large B-cell lymphoma, with up to 90% inhibition at the highest doses.
When administered at doses of 0.18 mg/kg or more, SNS01-T significantly extended the life span of treated mice. The researchers observed a reduction in the pro-survival form of the eIF5A protein in tumor tissue, which was consistent with drug activity.
SNS01-T also demonstrated synergy with bortezomib and lenalidomide. Mice that received SNS01-T and lenalidomide in combination had a 100% survival rate, compared to 60% for mice that received SNS01-T alone and 20% for mice that received lenalidomide alone.
A single 6-week cycle of SNS01-T and lenalidomide eradicated tumors in 67% of mice, and there was no regrowth after an additional 8 weeks without further treatment.
Similarly, combination SNS01-T and bortezomib inhibited tumor growth by 89%, compared to 59% for SNS01-T alone and 39% for bortezomib alone.
This research was supported by Senesco Technologies, Inc., the company developing SNS01-T.
An experimental nanoparticle therapy has shown preclinical activity against a range of B-cell malignancies, researchers have reported.
The therapy, SNS01-T, inhibited tumor growth and improved survival in mouse models of multiple myeloma, mantle cell lymphoma, and diffuse large B-cell lymphoma.
The treatment exhibited single-agent activity in these mice but also demonstrated synergy with lenalidomide and bortezomib.
Sarah Francis, PhD, of the University of Waterloo in Ontario, Canada, and her colleagues conducted this research and recounted the results in Molecular Therapy.
SNS01-T consists of 3 components: small interfering RNA targeting the native eukaryotic translation initiation factor 5A (eIF5A), plasmids expressing a pro-apoptotic mutant of elF5A under the control of a B-cell specific promoter, and a synthetic cationic polymer polyethylenimine, which serves as the delivery vehicle.
The small interfering RNA component of SNS01-T suppresses elF5A expression, thereby interfering with translation of eIF5A and reducing levels of hypusinated elF5A in cancer cells. This inhibits activation of NF-kB and induces apoptosis.
The B-cell specific plasmid component of SNS01-T expresses an arginine substituted form of eIF5A—eIF5AK50R—that cannot be hypusinated, which leads to selective induction of apoptosis in B cells.
Dr Francis and her colleagues found that SNS01-T is preferentially taken up by malignant B cells. In myeloma cells, uptake of SNS01-T was up to 5-fold higher than uptake by normal, naïve B cells.
Uptake into myeloma cells induced 45% cell death within 24 hours, but there was almost no measureable death of normal, naïve B cells.
SNS01-T also prompted dose-dependent inhibition of tumor growth in mouse models of multiple myeloma, mantle cell lymphoma, and diffuse large B-cell lymphoma, with up to 90% inhibition at the highest doses.
When administered at doses of 0.18 mg/kg or more, SNS01-T significantly extended the life span of treated mice. The researchers observed a reduction in the pro-survival form of the eIF5A protein in tumor tissue, which was consistent with drug activity.
SNS01-T also demonstrated synergy with bortezomib and lenalidomide. Mice that received SNS01-T and lenalidomide in combination had a 100% survival rate, compared to 60% for mice that received SNS01-T alone and 20% for mice that received lenalidomide alone.
A single 6-week cycle of SNS01-T and lenalidomide eradicated tumors in 67% of mice, and there was no regrowth after an additional 8 weeks without further treatment.
Similarly, combination SNS01-T and bortezomib inhibited tumor growth by 89%, compared to 59% for SNS01-T alone and 39% for bortezomib alone.
This research was supported by Senesco Technologies, Inc., the company developing SNS01-T.
Palliative chemo can have undesired outcomes
Credit: Rhoda Baer
Palliative chemotherapy can negatively impact the end of life for terminally ill cancer patients, according to a paper published in BMJ.
Investigators found that patients who received palliative chemotherapy in their last months of life had an increased risk of requiring intensive medical care, such as resuscitation, and dying in a place they did not choose, such as an intensive care unit.
The researchers therefore suggested that end-of-life discussions may be particularly important for patients who want to receive palliative chemotherapy.
“The results highlight the need for more effective communication by doctors of terminal prognoses and the likely outcomes of chemotherapy for these patients,” said study author Holly Prigerson, PhD, of Weill Cornell Medical College in New York.
“For patients to make informed choices about their care, they need to know if they are incurable and understand what their life expectancy is, that palliative chemotherapy is not intended to cure them, that it may not appreciably prolong their life, and that it may result in the receipt of very aggressive, life-prolonging care at the expense of their quality of life.”
Data have suggested that between 20% and 50% of patients with incurable cancers undergo palliative chemotherapy within 30 days of death. But it has not been clear whether the use of chemotherapy in a patient’s last months is associated with the need for intensive medical care in the last week of life or with the patient’s death.
So Dr Prigerson and her colleagues decided to study the use of palliative chemotherapy in patients with 6 or fewer months to live. The researchers used data from “Coping with Cancer,” a 6-year study of 386 terminally ill patients.
The patients were interviewed around the time of their decision regarding palliative chemotherapy. In the month after each patient died, caregivers were asked to rate their loved ones’ care, quality of life, and place of death as being where the patient would have wanted to die. The investigators then reviewed patients’ medical charts to determine the type of care they actually received in their last week.
Effects of palliative chemo
In all, 56% of patients opted to receive palliative chemotherapy. They were more likely to be younger, married, and better educated than patients not on the treatment.
Patients on chemotherapy also had better performance status, overall quality of life, physical functioning, and psychological well-being at study enrollment.
However, patients who received palliative chemotherapy had a greater risk of requiring cardiopulmonary resuscitation and/or mechanical ventilation (14% vs 2%), and they were more likely to need a feeding tube (11% vs 5%) in their last weeks of life.
Patients on chemotherapy had a greater risk of being admitted to an intensive care unit (14% vs 8%) and of having a late hospice referral (54% vs 37%).
They were also less likely to die where they wanted to (65% vs 80%). They had a greater risk of dying in an intensive care unit (11% vs 2%) and were less likely than their peers to die at home (47% vs 66%).
“It’s hard to see in these data much of a silver lining to palliative chemotherapy for patients in the terminal stage of their cancer,” Dr Prigerson said. “Until now, there hasn’t been evidence of harmful effects of palliative chemotherapy in the last few months of life.”
“This study is a first step in providing evidence that specifically demonstrates what negative outcomes may result. Additional studies are needed to confirm these troubling findings.”
Explaining the negative effects
Dr Prigerson said the harmful effects of palliative chemotherapy may be a result of misunderstanding, a lack of communication, and denial. Patients may not comprehend the purpose and likely consequences of palliative chemotherapy, and they may not fully acknowledge their own prognoses.
In the study, patients receiving palliative chemotherapy were less likely than their peers to talk to their oncologists about end-of-life care (37% vs 48%), to complete Do-Not-Resuscitate orders (36% vs 49%), or to acknowledge that they were terminally ill (35% vs 47%).
“Our finding that patients with terminal cancers were at higher risk of receiving intensive end-of-life care if they were treated with palliative chemotherapy months earlier underscores the importance of oncologists asking patients about their end-of-life wishes,” said Alexi Wright, MD, of the Dana-Farber Cancer Institute in Boston.
“We often wait until patients stop chemotherapy before asking them about where and how they want to die, but this study shows we need to ask patients about their preferences while they are receiving chemotherapy to ensure they receive the kind of care they want near death.”
Moving forward
The investigators stressed that the study results do not suggest patients should be denied palliative chemotherapy.
“The vast majority of patients in this study wanted palliative chemotherapy if it might increase their survival by as little as a week,” Dr Wright said. “This study is a step towards understanding some of the human costs and benefits of palliative chemotherapy.”
The researchers said additional studies should examine whether patients who are aware that chemotherapy is not intended to cure them still want to receive the treatment, confirm the negative outcomes of palliative chemotherapy, and determine if end-of-life discussions promote more informed decision-making and receipt of value-consistent care.
In a related editorial, Mike Rabow, MD, of the University of California, San Francisco, noted that although most patients with metastatic cancer choose to receive chemotherapy, evidence suggests most do not understand its intent.
He said Dr Prigerson’s study suggests the need to “better identify patients who are likely to benefit from chemotherapy near the end of life.” And he encouraged oncologists to discuss with patients the broader implications of chemotherapy when making decisions about treatment.
Credit: Rhoda Baer
Palliative chemotherapy can negatively impact the end of life for terminally ill cancer patients, according to a paper published in BMJ.
Investigators found that patients who received palliative chemotherapy in their last months of life had an increased risk of requiring intensive medical care, such as resuscitation, and dying in a place they did not choose, such as an intensive care unit.
The researchers therefore suggested that end-of-life discussions may be particularly important for patients who want to receive palliative chemotherapy.
“The results highlight the need for more effective communication by doctors of terminal prognoses and the likely outcomes of chemotherapy for these patients,” said study author Holly Prigerson, PhD, of Weill Cornell Medical College in New York.
“For patients to make informed choices about their care, they need to know if they are incurable and understand what their life expectancy is, that palliative chemotherapy is not intended to cure them, that it may not appreciably prolong their life, and that it may result in the receipt of very aggressive, life-prolonging care at the expense of their quality of life.”
Data have suggested that between 20% and 50% of patients with incurable cancers undergo palliative chemotherapy within 30 days of death. But it has not been clear whether the use of chemotherapy in a patient’s last months is associated with the need for intensive medical care in the last week of life or with the patient’s death.
So Dr Prigerson and her colleagues decided to study the use of palliative chemotherapy in patients with 6 or fewer months to live. The researchers used data from “Coping with Cancer,” a 6-year study of 386 terminally ill patients.
The patients were interviewed around the time of their decision regarding palliative chemotherapy. In the month after each patient died, caregivers were asked to rate their loved ones’ care, quality of life, and place of death as being where the patient would have wanted to die. The investigators then reviewed patients’ medical charts to determine the type of care they actually received in their last week.
Effects of palliative chemo
In all, 56% of patients opted to receive palliative chemotherapy. They were more likely to be younger, married, and better educated than patients not on the treatment.
Patients on chemotherapy also had better performance status, overall quality of life, physical functioning, and psychological well-being at study enrollment.
However, patients who received palliative chemotherapy had a greater risk of requiring cardiopulmonary resuscitation and/or mechanical ventilation (14% vs 2%), and they were more likely to need a feeding tube (11% vs 5%) in their last weeks of life.
Patients on chemotherapy had a greater risk of being admitted to an intensive care unit (14% vs 8%) and of having a late hospice referral (54% vs 37%).
They were also less likely to die where they wanted to (65% vs 80%). They had a greater risk of dying in an intensive care unit (11% vs 2%) and were less likely than their peers to die at home (47% vs 66%).
“It’s hard to see in these data much of a silver lining to palliative chemotherapy for patients in the terminal stage of their cancer,” Dr Prigerson said. “Until now, there hasn’t been evidence of harmful effects of palliative chemotherapy in the last few months of life.”
“This study is a first step in providing evidence that specifically demonstrates what negative outcomes may result. Additional studies are needed to confirm these troubling findings.”
Explaining the negative effects
Dr Prigerson said the harmful effects of palliative chemotherapy may be a result of misunderstanding, a lack of communication, and denial. Patients may not comprehend the purpose and likely consequences of palliative chemotherapy, and they may not fully acknowledge their own prognoses.
In the study, patients receiving palliative chemotherapy were less likely than their peers to talk to their oncologists about end-of-life care (37% vs 48%), to complete Do-Not-Resuscitate orders (36% vs 49%), or to acknowledge that they were terminally ill (35% vs 47%).
“Our finding that patients with terminal cancers were at higher risk of receiving intensive end-of-life care if they were treated with palliative chemotherapy months earlier underscores the importance of oncologists asking patients about their end-of-life wishes,” said Alexi Wright, MD, of the Dana-Farber Cancer Institute in Boston.
“We often wait until patients stop chemotherapy before asking them about where and how they want to die, but this study shows we need to ask patients about their preferences while they are receiving chemotherapy to ensure they receive the kind of care they want near death.”
Moving forward
The investigators stressed that the study results do not suggest patients should be denied palliative chemotherapy.
“The vast majority of patients in this study wanted palliative chemotherapy if it might increase their survival by as little as a week,” Dr Wright said. “This study is a step towards understanding some of the human costs and benefits of palliative chemotherapy.”
The researchers said additional studies should examine whether patients who are aware that chemotherapy is not intended to cure them still want to receive the treatment, confirm the negative outcomes of palliative chemotherapy, and determine if end-of-life discussions promote more informed decision-making and receipt of value-consistent care.
In a related editorial, Mike Rabow, MD, of the University of California, San Francisco, noted that although most patients with metastatic cancer choose to receive chemotherapy, evidence suggests most do not understand its intent.
He said Dr Prigerson’s study suggests the need to “better identify patients who are likely to benefit from chemotherapy near the end of life.” And he encouraged oncologists to discuss with patients the broader implications of chemotherapy when making decisions about treatment.
Credit: Rhoda Baer
Palliative chemotherapy can negatively impact the end of life for terminally ill cancer patients, according to a paper published in BMJ.
Investigators found that patients who received palliative chemotherapy in their last months of life had an increased risk of requiring intensive medical care, such as resuscitation, and dying in a place they did not choose, such as an intensive care unit.
The researchers therefore suggested that end-of-life discussions may be particularly important for patients who want to receive palliative chemotherapy.
“The results highlight the need for more effective communication by doctors of terminal prognoses and the likely outcomes of chemotherapy for these patients,” said study author Holly Prigerson, PhD, of Weill Cornell Medical College in New York.
“For patients to make informed choices about their care, they need to know if they are incurable and understand what their life expectancy is, that palliative chemotherapy is not intended to cure them, that it may not appreciably prolong their life, and that it may result in the receipt of very aggressive, life-prolonging care at the expense of their quality of life.”
Data have suggested that between 20% and 50% of patients with incurable cancers undergo palliative chemotherapy within 30 days of death. But it has not been clear whether the use of chemotherapy in a patient’s last months is associated with the need for intensive medical care in the last week of life or with the patient’s death.
So Dr Prigerson and her colleagues decided to study the use of palliative chemotherapy in patients with 6 or fewer months to live. The researchers used data from “Coping with Cancer,” a 6-year study of 386 terminally ill patients.
The patients were interviewed around the time of their decision regarding palliative chemotherapy. In the month after each patient died, caregivers were asked to rate their loved ones’ care, quality of life, and place of death as being where the patient would have wanted to die. The investigators then reviewed patients’ medical charts to determine the type of care they actually received in their last week.
Effects of palliative chemo
In all, 56% of patients opted to receive palliative chemotherapy. They were more likely to be younger, married, and better educated than patients not on the treatment.
Patients on chemotherapy also had better performance status, overall quality of life, physical functioning, and psychological well-being at study enrollment.
However, patients who received palliative chemotherapy had a greater risk of requiring cardiopulmonary resuscitation and/or mechanical ventilation (14% vs 2%), and they were more likely to need a feeding tube (11% vs 5%) in their last weeks of life.
Patients on chemotherapy had a greater risk of being admitted to an intensive care unit (14% vs 8%) and of having a late hospice referral (54% vs 37%).
They were also less likely to die where they wanted to (65% vs 80%). They had a greater risk of dying in an intensive care unit (11% vs 2%) and were less likely than their peers to die at home (47% vs 66%).
“It’s hard to see in these data much of a silver lining to palliative chemotherapy for patients in the terminal stage of their cancer,” Dr Prigerson said. “Until now, there hasn’t been evidence of harmful effects of palliative chemotherapy in the last few months of life.”
“This study is a first step in providing evidence that specifically demonstrates what negative outcomes may result. Additional studies are needed to confirm these troubling findings.”
Explaining the negative effects
Dr Prigerson said the harmful effects of palliative chemotherapy may be a result of misunderstanding, a lack of communication, and denial. Patients may not comprehend the purpose and likely consequences of palliative chemotherapy, and they may not fully acknowledge their own prognoses.
In the study, patients receiving palliative chemotherapy were less likely than their peers to talk to their oncologists about end-of-life care (37% vs 48%), to complete Do-Not-Resuscitate orders (36% vs 49%), or to acknowledge that they were terminally ill (35% vs 47%).
“Our finding that patients with terminal cancers were at higher risk of receiving intensive end-of-life care if they were treated with palliative chemotherapy months earlier underscores the importance of oncologists asking patients about their end-of-life wishes,” said Alexi Wright, MD, of the Dana-Farber Cancer Institute in Boston.
“We often wait until patients stop chemotherapy before asking them about where and how they want to die, but this study shows we need to ask patients about their preferences while they are receiving chemotherapy to ensure they receive the kind of care they want near death.”
Moving forward
The investigators stressed that the study results do not suggest patients should be denied palliative chemotherapy.
“The vast majority of patients in this study wanted palliative chemotherapy if it might increase their survival by as little as a week,” Dr Wright said. “This study is a step towards understanding some of the human costs and benefits of palliative chemotherapy.”
The researchers said additional studies should examine whether patients who are aware that chemotherapy is not intended to cure them still want to receive the treatment, confirm the negative outcomes of palliative chemotherapy, and determine if end-of-life discussions promote more informed decision-making and receipt of value-consistent care.
In a related editorial, Mike Rabow, MD, of the University of California, San Francisco, noted that although most patients with metastatic cancer choose to receive chemotherapy, evidence suggests most do not understand its intent.
He said Dr Prigerson’s study suggests the need to “better identify patients who are likely to benefit from chemotherapy near the end of life.” And he encouraged oncologists to discuss with patients the broader implications of chemotherapy when making decisions about treatment.
Neutropenia prophylaxis, incidence increase with age
Credit: Volker Brinkmann
New research suggests that older non-Hodgkin lymphoma patients are more likely than their younger counterparts to receive prophylaxis for neutropenia, but the older patients still have a higher incidence of severe neutropenia.
Most of the patients studied had received granulocyte colony-stimulating factor (G-CSF) as neutropenia prophylaxis, but more than half of patients in each age group developed grade 3/4 neutropenia.
And although patients aged 65 and older were more likely to receive G-CSF, they had a higher incidence of grade 3/4 neutropenia than patients who were younger than 65.
Lee S. Schwartzberg, MD, of The West Clinic in Memphis, Tennessee, and his colleagues reported these findings in Supportive Care in Cancer.
The researchers conducted a review of 1579 patients with non-Hodgkin lymphoma. Nearly 46% of patients were 65 years of age or older, and 54.1% were younger than 65.
Most patients had received treatment with R-CHOP every 3 weeks. And the dose levels were about the same in both groups of patients. The mean relative dose intensity was 80.4% among younger patients and 73.9% among the older patients.
The incidence of treatment delays was similar between the 2 groups—24.6% among the older patients and 26.5% among the younger patients.
But older patients were more likely to experience dose reductions—24.9% compared to 9.6% of younger patients.
A majority of all patients—86.9%—received G-CSF, but older patients were more likely to receive it upfront.
Among the older patients, 80.1% received G-CSF as primary prophylaxis, 11.6% received it as secondary prophylaxis, and 8.3% received it as treatment.
Among the younger patients, 71.9% received G-CSF as primary prophylaxis, 17.4% received it as secondary prophylaxis, and 10.7% received it as treatment.
The incidence of grade 3/4 neutropenia was 52.3% for the younger patients and 63.2% for the older patients.
Credit: Volker Brinkmann
New research suggests that older non-Hodgkin lymphoma patients are more likely than their younger counterparts to receive prophylaxis for neutropenia, but the older patients still have a higher incidence of severe neutropenia.
Most of the patients studied had received granulocyte colony-stimulating factor (G-CSF) as neutropenia prophylaxis, but more than half of patients in each age group developed grade 3/4 neutropenia.
And although patients aged 65 and older were more likely to receive G-CSF, they had a higher incidence of grade 3/4 neutropenia than patients who were younger than 65.
Lee S. Schwartzberg, MD, of The West Clinic in Memphis, Tennessee, and his colleagues reported these findings in Supportive Care in Cancer.
The researchers conducted a review of 1579 patients with non-Hodgkin lymphoma. Nearly 46% of patients were 65 years of age or older, and 54.1% were younger than 65.
Most patients had received treatment with R-CHOP every 3 weeks. And the dose levels were about the same in both groups of patients. The mean relative dose intensity was 80.4% among younger patients and 73.9% among the older patients.
The incidence of treatment delays was similar between the 2 groups—24.6% among the older patients and 26.5% among the younger patients.
But older patients were more likely to experience dose reductions—24.9% compared to 9.6% of younger patients.
A majority of all patients—86.9%—received G-CSF, but older patients were more likely to receive it upfront.
Among the older patients, 80.1% received G-CSF as primary prophylaxis, 11.6% received it as secondary prophylaxis, and 8.3% received it as treatment.
Among the younger patients, 71.9% received G-CSF as primary prophylaxis, 17.4% received it as secondary prophylaxis, and 10.7% received it as treatment.
The incidence of grade 3/4 neutropenia was 52.3% for the younger patients and 63.2% for the older patients.
Credit: Volker Brinkmann
New research suggests that older non-Hodgkin lymphoma patients are more likely than their younger counterparts to receive prophylaxis for neutropenia, but the older patients still have a higher incidence of severe neutropenia.
Most of the patients studied had received granulocyte colony-stimulating factor (G-CSF) as neutropenia prophylaxis, but more than half of patients in each age group developed grade 3/4 neutropenia.
And although patients aged 65 and older were more likely to receive G-CSF, they had a higher incidence of grade 3/4 neutropenia than patients who were younger than 65.
Lee S. Schwartzberg, MD, of The West Clinic in Memphis, Tennessee, and his colleagues reported these findings in Supportive Care in Cancer.
The researchers conducted a review of 1579 patients with non-Hodgkin lymphoma. Nearly 46% of patients were 65 years of age or older, and 54.1% were younger than 65.
Most patients had received treatment with R-CHOP every 3 weeks. And the dose levels were about the same in both groups of patients. The mean relative dose intensity was 80.4% among younger patients and 73.9% among the older patients.
The incidence of treatment delays was similar between the 2 groups—24.6% among the older patients and 26.5% among the younger patients.
But older patients were more likely to experience dose reductions—24.9% compared to 9.6% of younger patients.
A majority of all patients—86.9%—received G-CSF, but older patients were more likely to receive it upfront.
Among the older patients, 80.1% received G-CSF as primary prophylaxis, 11.6% received it as secondary prophylaxis, and 8.3% received it as treatment.
Among the younger patients, 71.9% received G-CSF as primary prophylaxis, 17.4% received it as secondary prophylaxis, and 10.7% received it as treatment.
The incidence of grade 3/4 neutropenia was 52.3% for the younger patients and 63.2% for the older patients.
Drug could enhance effects of chemo
Credit: Rhoda Baer
The drug spironolactone could improve the efficacy of platinum-based chemotherapy by preventing tumor cell repair, according to research published in Chemistry & Biology.
The researchers knew that platinum-based chemotherapy drugs bind to cellular DNA to induce damage.
So they theorized that blocking DNA repair mechanisms would help potentiate chemotherapy by reducing cancer cells’ resistance to treatment.
The team focused their efforts on inhibiting nucleotide excision repair (NER), in which a damaged DNA fragment is replaced with an intact fragment.
Frédéric Coin, PhD, of the Institute of Genetics and Molecular and Cellular Biology in Illkirch, France, and his colleagues screened more than 1200 drugs looking for one that would inhibit NER activity.
And they found that spironolactone—a drug already used to treat fluid retention, high blood pressure, and other conditions—affects NER activity.
Specifically, the team found that, when combined with platinum derivatives, spironolactone significantly increased cytotoxicity in ovarian and colon cancer cells.
As platinum-based chemotherapy is used to treat a range of cancers, similar results might occur in other malignancies as well.
The researchers also noted that, because spironolactone is already in use for other purposes, it doesn’t require a new application for marketing authorization. And its side effects are already known.
The team said this suggests that protocols testing spironolactone in combination with platinum-based chemotherapy could be organized rather quickly.
Credit: Rhoda Baer
The drug spironolactone could improve the efficacy of platinum-based chemotherapy by preventing tumor cell repair, according to research published in Chemistry & Biology.
The researchers knew that platinum-based chemotherapy drugs bind to cellular DNA to induce damage.
So they theorized that blocking DNA repair mechanisms would help potentiate chemotherapy by reducing cancer cells’ resistance to treatment.
The team focused their efforts on inhibiting nucleotide excision repair (NER), in which a damaged DNA fragment is replaced with an intact fragment.
Frédéric Coin, PhD, of the Institute of Genetics and Molecular and Cellular Biology in Illkirch, France, and his colleagues screened more than 1200 drugs looking for one that would inhibit NER activity.
And they found that spironolactone—a drug already used to treat fluid retention, high blood pressure, and other conditions—affects NER activity.
Specifically, the team found that, when combined with platinum derivatives, spironolactone significantly increased cytotoxicity in ovarian and colon cancer cells.
As platinum-based chemotherapy is used to treat a range of cancers, similar results might occur in other malignancies as well.
The researchers also noted that, because spironolactone is already in use for other purposes, it doesn’t require a new application for marketing authorization. And its side effects are already known.
The team said this suggests that protocols testing spironolactone in combination with platinum-based chemotherapy could be organized rather quickly.
Credit: Rhoda Baer
The drug spironolactone could improve the efficacy of platinum-based chemotherapy by preventing tumor cell repair, according to research published in Chemistry & Biology.
The researchers knew that platinum-based chemotherapy drugs bind to cellular DNA to induce damage.
So they theorized that blocking DNA repair mechanisms would help potentiate chemotherapy by reducing cancer cells’ resistance to treatment.
The team focused their efforts on inhibiting nucleotide excision repair (NER), in which a damaged DNA fragment is replaced with an intact fragment.
Frédéric Coin, PhD, of the Institute of Genetics and Molecular and Cellular Biology in Illkirch, France, and his colleagues screened more than 1200 drugs looking for one that would inhibit NER activity.
And they found that spironolactone—a drug already used to treat fluid retention, high blood pressure, and other conditions—affects NER activity.
Specifically, the team found that, when combined with platinum derivatives, spironolactone significantly increased cytotoxicity in ovarian and colon cancer cells.
As platinum-based chemotherapy is used to treat a range of cancers, similar results might occur in other malignancies as well.
The researchers also noted that, because spironolactone is already in use for other purposes, it doesn’t require a new application for marketing authorization. And its side effects are already known.
The team said this suggests that protocols testing spironolactone in combination with platinum-based chemotherapy could be organized rather quickly.
Study reveals potential target for mucositis, GVHD prevention
Results of preclinical research point to a possible way of preventing mucositis, graft-vs-host disease, and other disorders associated with epithelial permeability.
Investigators created a mouse model of mucositis and discovered that interleukin-1 (IL-1) beta, a protein secreted by the stressed mucosa, played an important role in the condition.
But inhibiting IL-1 beta alleviated mucositis. So the researchers speculated that targeting IL-1 beta might prevent mucositis in humans.
Naama Kanarek, a doctoral student at Hebrew University Hadassah Medical School in Jerusalem, and her colleagues described this research in PNAS.
The investigators began by generating a mouse model deficient in a gene encoding the enzyme beta-TrCP. They chose this enzyme because it’s a major regulator of inflammatory cascades.
The team found that beta-TrCP deletion in the gut caused mucosal DNA damage in the mice, mimicking the effects of chemotherapy and irradiation. Similar to human patients, a severe mucositis reaction occurred in mice that were genetically engineered to be beta-TrCP-deficient.
Tracing the pathological basis of the mouse mucositis revealed that the source of the problem was IL-1 beta. IL-1 beta opened the gut lining, allowing gut bacteria to penetrate and destroy the gut interior.
To confirm this finding, the researchers treated mice with an antibody neutralizing IL-1 beta prior to deleting beta-TrCP. They found this prevented the onset of mucositis.
Therefore, the team has proposed that IL-1 receptor agonists should be tested as mucositis prophylaxis in humans. An example is anakinra (Kineret), which is used to treat chronic inflammatory conditions, such as rheumatoid arthritis and Crohn’s disease.
The investigators believe such treatments might also be used to prevent graft-vs-host disease, burn injuries, head and neck trauma, and other disorders associated with
epithelial permeability.
Results of preclinical research point to a possible way of preventing mucositis, graft-vs-host disease, and other disorders associated with epithelial permeability.
Investigators created a mouse model of mucositis and discovered that interleukin-1 (IL-1) beta, a protein secreted by the stressed mucosa, played an important role in the condition.
But inhibiting IL-1 beta alleviated mucositis. So the researchers speculated that targeting IL-1 beta might prevent mucositis in humans.
Naama Kanarek, a doctoral student at Hebrew University Hadassah Medical School in Jerusalem, and her colleagues described this research in PNAS.
The investigators began by generating a mouse model deficient in a gene encoding the enzyme beta-TrCP. They chose this enzyme because it’s a major regulator of inflammatory cascades.
The team found that beta-TrCP deletion in the gut caused mucosal DNA damage in the mice, mimicking the effects of chemotherapy and irradiation. Similar to human patients, a severe mucositis reaction occurred in mice that were genetically engineered to be beta-TrCP-deficient.
Tracing the pathological basis of the mouse mucositis revealed that the source of the problem was IL-1 beta. IL-1 beta opened the gut lining, allowing gut bacteria to penetrate and destroy the gut interior.
To confirm this finding, the researchers treated mice with an antibody neutralizing IL-1 beta prior to deleting beta-TrCP. They found this prevented the onset of mucositis.
Therefore, the team has proposed that IL-1 receptor agonists should be tested as mucositis prophylaxis in humans. An example is anakinra (Kineret), which is used to treat chronic inflammatory conditions, such as rheumatoid arthritis and Crohn’s disease.
The investigators believe such treatments might also be used to prevent graft-vs-host disease, burn injuries, head and neck trauma, and other disorders associated with
epithelial permeability.
Results of preclinical research point to a possible way of preventing mucositis, graft-vs-host disease, and other disorders associated with epithelial permeability.
Investigators created a mouse model of mucositis and discovered that interleukin-1 (IL-1) beta, a protein secreted by the stressed mucosa, played an important role in the condition.
But inhibiting IL-1 beta alleviated mucositis. So the researchers speculated that targeting IL-1 beta might prevent mucositis in humans.
Naama Kanarek, a doctoral student at Hebrew University Hadassah Medical School in Jerusalem, and her colleagues described this research in PNAS.
The investigators began by generating a mouse model deficient in a gene encoding the enzyme beta-TrCP. They chose this enzyme because it’s a major regulator of inflammatory cascades.
The team found that beta-TrCP deletion in the gut caused mucosal DNA damage in the mice, mimicking the effects of chemotherapy and irradiation. Similar to human patients, a severe mucositis reaction occurred in mice that were genetically engineered to be beta-TrCP-deficient.
Tracing the pathological basis of the mouse mucositis revealed that the source of the problem was IL-1 beta. IL-1 beta opened the gut lining, allowing gut bacteria to penetrate and destroy the gut interior.
To confirm this finding, the researchers treated mice with an antibody neutralizing IL-1 beta prior to deleting beta-TrCP. They found this prevented the onset of mucositis.
Therefore, the team has proposed that IL-1 receptor agonists should be tested as mucositis prophylaxis in humans. An example is anakinra (Kineret), which is used to treat chronic inflammatory conditions, such as rheumatoid arthritis and Crohn’s disease.
The investigators believe such treatments might also be used to prevent graft-vs-host disease, burn injuries, head and neck trauma, and other disorders associated with
epithelial permeability.
How Bcl-2 helps cancer cells survive treatment
Researchers believe they’ve discovered how the Bcl-2 protein helps leukemia and lymphoma cells survive anticancer treatment.
The team found that Bcl-2 alters the level of calcium ions in cancer cells, and this promotes the cells’ survival.
The group thinks these findings, published in PNAS, could help spur the development of drugs that effectively inhibit Bcl-2 and produce better outcomes for cancer patients.
“Since 1993, our team has been conducting research on key mechanisms by which the protein Bcl-2 keeps cancer cells alive,” said study author Clark W. Distelhorst, MD, of Case Western Reserve School of Medicine in Cleveland, Ohio.
“Now, for the first time, we have evidence of how Bcl-2 is promoting abnormally long survival of the cancer cells by regulating calcium levels within cells, and [we] will use the discovery and data to deliver therapies designed to attack the Bcl-2 protein and inhibit its impact.”
More than a decade ago, researchers in Dr Distelhorst’s lab discovered that Bcl-2 binds to the inositol 1,4,5-trisphosphate receptor (InsP3R) channel and regulates the release of calcium ions.
In the current study, the team found that when Bcl-2 binds to the InsP3R channel, it initiates a complex feedback mechanism that blocks the release of calcium ions intended to induce cell death. Instead of dying, the cancer cells continue to proliferate.
Specifically, the researchers discovered that Bcl-2 interacts with the Ca2+-activated protein phosphatase calcineurin (CaN) and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), a CaN-regulated inhibitor of protein phosphatase 1.
Bcl-2 docks DARPP-32 and CaN on the InsP3R, creating a negative feedback loop that responds to InsP3R-mediated Ca2+ release by inhibiting InsP3R phosphorylation at Ser1755. And this prevents the excessive Ca2+ elevation that induces cell death.
The team theorized that cancer cells overexpressing Bcl-2 may exploit this mechanism to prevent apoptosis. And experiments in chronic lymphocytic leukemia cells appeared to confirm this theory.
The researchers treated the cells with the peptide TAT-IDPDD/AA, which inhibits Bcl-2–InsP3R interaction. This increased P-Ser1755 InsP3R-1 levels and elevated Ca2+, which induced apoptosis.
“We have recognized for decades that cancer cells grow and forget to die,” said Stanton Gerson, MD, director of the Case Comprehensive Cancer Center, who was not involved in this study.
“[N]ow, we understand why. I predict that this work will focus the discovery of new drugs against the Bcl-2-calcium-flow system.”
Researchers believe they’ve discovered how the Bcl-2 protein helps leukemia and lymphoma cells survive anticancer treatment.
The team found that Bcl-2 alters the level of calcium ions in cancer cells, and this promotes the cells’ survival.
The group thinks these findings, published in PNAS, could help spur the development of drugs that effectively inhibit Bcl-2 and produce better outcomes for cancer patients.
“Since 1993, our team has been conducting research on key mechanisms by which the protein Bcl-2 keeps cancer cells alive,” said study author Clark W. Distelhorst, MD, of Case Western Reserve School of Medicine in Cleveland, Ohio.
“Now, for the first time, we have evidence of how Bcl-2 is promoting abnormally long survival of the cancer cells by regulating calcium levels within cells, and [we] will use the discovery and data to deliver therapies designed to attack the Bcl-2 protein and inhibit its impact.”
More than a decade ago, researchers in Dr Distelhorst’s lab discovered that Bcl-2 binds to the inositol 1,4,5-trisphosphate receptor (InsP3R) channel and regulates the release of calcium ions.
In the current study, the team found that when Bcl-2 binds to the InsP3R channel, it initiates a complex feedback mechanism that blocks the release of calcium ions intended to induce cell death. Instead of dying, the cancer cells continue to proliferate.
Specifically, the researchers discovered that Bcl-2 interacts with the Ca2+-activated protein phosphatase calcineurin (CaN) and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), a CaN-regulated inhibitor of protein phosphatase 1.
Bcl-2 docks DARPP-32 and CaN on the InsP3R, creating a negative feedback loop that responds to InsP3R-mediated Ca2+ release by inhibiting InsP3R phosphorylation at Ser1755. And this prevents the excessive Ca2+ elevation that induces cell death.
The team theorized that cancer cells overexpressing Bcl-2 may exploit this mechanism to prevent apoptosis. And experiments in chronic lymphocytic leukemia cells appeared to confirm this theory.
The researchers treated the cells with the peptide TAT-IDPDD/AA, which inhibits Bcl-2–InsP3R interaction. This increased P-Ser1755 InsP3R-1 levels and elevated Ca2+, which induced apoptosis.
“We have recognized for decades that cancer cells grow and forget to die,” said Stanton Gerson, MD, director of the Case Comprehensive Cancer Center, who was not involved in this study.
“[N]ow, we understand why. I predict that this work will focus the discovery of new drugs against the Bcl-2-calcium-flow system.”
Researchers believe they’ve discovered how the Bcl-2 protein helps leukemia and lymphoma cells survive anticancer treatment.
The team found that Bcl-2 alters the level of calcium ions in cancer cells, and this promotes the cells’ survival.
The group thinks these findings, published in PNAS, could help spur the development of drugs that effectively inhibit Bcl-2 and produce better outcomes for cancer patients.
“Since 1993, our team has been conducting research on key mechanisms by which the protein Bcl-2 keeps cancer cells alive,” said study author Clark W. Distelhorst, MD, of Case Western Reserve School of Medicine in Cleveland, Ohio.
“Now, for the first time, we have evidence of how Bcl-2 is promoting abnormally long survival of the cancer cells by regulating calcium levels within cells, and [we] will use the discovery and data to deliver therapies designed to attack the Bcl-2 protein and inhibit its impact.”
More than a decade ago, researchers in Dr Distelhorst’s lab discovered that Bcl-2 binds to the inositol 1,4,5-trisphosphate receptor (InsP3R) channel and regulates the release of calcium ions.
In the current study, the team found that when Bcl-2 binds to the InsP3R channel, it initiates a complex feedback mechanism that blocks the release of calcium ions intended to induce cell death. Instead of dying, the cancer cells continue to proliferate.
Specifically, the researchers discovered that Bcl-2 interacts with the Ca2+-activated protein phosphatase calcineurin (CaN) and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), a CaN-regulated inhibitor of protein phosphatase 1.
Bcl-2 docks DARPP-32 and CaN on the InsP3R, creating a negative feedback loop that responds to InsP3R-mediated Ca2+ release by inhibiting InsP3R phosphorylation at Ser1755. And this prevents the excessive Ca2+ elevation that induces cell death.
The team theorized that cancer cells overexpressing Bcl-2 may exploit this mechanism to prevent apoptosis. And experiments in chronic lymphocytic leukemia cells appeared to confirm this theory.
The researchers treated the cells with the peptide TAT-IDPDD/AA, which inhibits Bcl-2–InsP3R interaction. This increased P-Ser1755 InsP3R-1 levels and elevated Ca2+, which induced apoptosis.
“We have recognized for decades that cancer cells grow and forget to die,” said Stanton Gerson, MD, director of the Case Comprehensive Cancer Center, who was not involved in this study.
“[N]ow, we understand why. I predict that this work will focus the discovery of new drugs against the Bcl-2-calcium-flow system.”
Bridging the gap: a palliative care consultation service in a hematological malignancy–bone marrow transplant unit
Background There is often a lack of collaboration between hematological malignancy–bone marrow transplantation (HM-BMT) units and palliative care (PC) services. In this paper, we describe a quality improvement project that sought to close this gap at a tertiary care hospital in Pittsburgh, Pennsylvania, from August 2006 to May 2010.
Design and methods Through a needs assessment, didactic lectures, clinical consultation, and the informal presence of PC clinicians, the team created a palliative care service in HM-BMT unit of the Western Pennsylvania Hospital in Pittsburgh. The following data were collected for each consult: referral reason, daily pain assessments, whether or not a “goals of care” conversation took place, and hospice enrollment. Lastly, satisfaction surveys were administered.
Results During the program, 392 PC consultations were provided to 256 unique patients. Of these 256 patients, the PC clinicians documented the first goals of care conversations in 67% of patients (n = 172). Of the 278 consults referred for pain, 70% (n = 194) involved reports of unacceptable or very unacceptable pain at baseline. Sixty-six percent (n = 129) of these 194 consults involved reports of pain that was acceptable or very acceptable within 48 hours of consultation. In addition, the hospice referral rate grew from a pre-implementation rate of 5% to 41% (n = 67) of 165 patients who died during the period of program implementation. Lastly, hematological oncologists reported high levels of satisfaction with the program.
Limitations The main limitation of this project is that it was a single institution study.
Conclusion The successful integration of a PC team into a hematological malignancy unit suggests great potential for positive interdisciplinary collaboration between these two fields.
Click on the PDF icon at the top of this introduction to read the full article.
Background There is often a lack of collaboration between hematological malignancy–bone marrow transplantation (HM-BMT) units and palliative care (PC) services. In this paper, we describe a quality improvement project that sought to close this gap at a tertiary care hospital in Pittsburgh, Pennsylvania, from August 2006 to May 2010.
Design and methods Through a needs assessment, didactic lectures, clinical consultation, and the informal presence of PC clinicians, the team created a palliative care service in HM-BMT unit of the Western Pennsylvania Hospital in Pittsburgh. The following data were collected for each consult: referral reason, daily pain assessments, whether or not a “goals of care” conversation took place, and hospice enrollment. Lastly, satisfaction surveys were administered.
Results During the program, 392 PC consultations were provided to 256 unique patients. Of these 256 patients, the PC clinicians documented the first goals of care conversations in 67% of patients (n = 172). Of the 278 consults referred for pain, 70% (n = 194) involved reports of unacceptable or very unacceptable pain at baseline. Sixty-six percent (n = 129) of these 194 consults involved reports of pain that was acceptable or very acceptable within 48 hours of consultation. In addition, the hospice referral rate grew from a pre-implementation rate of 5% to 41% (n = 67) of 165 patients who died during the period of program implementation. Lastly, hematological oncologists reported high levels of satisfaction with the program.
Limitations The main limitation of this project is that it was a single institution study.
Conclusion The successful integration of a PC team into a hematological malignancy unit suggests great potential for positive interdisciplinary collaboration between these two fields.
Click on the PDF icon at the top of this introduction to read the full article.
Background There is often a lack of collaboration between hematological malignancy–bone marrow transplantation (HM-BMT) units and palliative care (PC) services. In this paper, we describe a quality improvement project that sought to close this gap at a tertiary care hospital in Pittsburgh, Pennsylvania, from August 2006 to May 2010.
Design and methods Through a needs assessment, didactic lectures, clinical consultation, and the informal presence of PC clinicians, the team created a palliative care service in HM-BMT unit of the Western Pennsylvania Hospital in Pittsburgh. The following data were collected for each consult: referral reason, daily pain assessments, whether or not a “goals of care” conversation took place, and hospice enrollment. Lastly, satisfaction surveys were administered.
Results During the program, 392 PC consultations were provided to 256 unique patients. Of these 256 patients, the PC clinicians documented the first goals of care conversations in 67% of patients (n = 172). Of the 278 consults referred for pain, 70% (n = 194) involved reports of unacceptable or very unacceptable pain at baseline. Sixty-six percent (n = 129) of these 194 consults involved reports of pain that was acceptable or very acceptable within 48 hours of consultation. In addition, the hospice referral rate grew from a pre-implementation rate of 5% to 41% (n = 67) of 165 patients who died during the period of program implementation. Lastly, hematological oncologists reported high levels of satisfaction with the program.
Limitations The main limitation of this project is that it was a single institution study.
Conclusion The successful integration of a PC team into a hematological malignancy unit suggests great potential for positive interdisciplinary collaboration between these two fields.
Click on the PDF icon at the top of this introduction to read the full article.
CAR T-cell therapy: The good and the bad
Credit: MSKCC
Several studies have shown that infusions of T cells modified with chimeric antigen receptors (CARs) can elicit complete responses in leukemia patients who have run out of treatment options.
However, the therapy also puts patients at risk of developing cytokine release syndrome (CRS).
With updated research, investigators have again shown that CAR T cells can produce complete responses in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), thereby allowing them to receive allogeneic stem cell transplant (allo-SCT).
But the researchers have also used this group of patients to define diagnostic criteria for severe CRS. And the team has discovered that measuring C-reactive protein levels can help predict the severity of CRS.
Michel Sadelain, MD, PhD, of Memorial Sloan-Kettering Cancer Center in New York, and his colleagues described these findings in Science Translational Medicine.
Response, bridge to allo-SCT
Dr Sadelain and his colleagues previously reported results in 5 patients with relapsed/refractory B-ALL who received autologous T cells expressing a CD19-specific, CD28/CD3z CAR called 19-28z.
After receiving salvage chemotherapy and CAR T cells, all 5 patients were negative for minimal residual disease. And 4 of the patients went on to receive allo-SCT.
Now, the investigators have expanded upon these findings, reporting results in a total of 16 patients with relapsed/refractory B-ALL who received the 19-28z CAR T cells.
Forty-four percent of patients (n=7) had a complete response to the salvage chemotherapy, and 88% (n=14) had a complete response after CAR T-cell therapy (alghough some had incomplete count recovery). Sixty-three percent of patients (n=10) achieved a complete remission.
Of the 10 patients who were eligible for allo-SCT, 7 underwent the procedure, and all 7 remain free of relapse.
“These extraordinary results demonstrate that cell therapy is a powerful treatment for patients who have exhausted all conventional therapies,” Dr Sadelain said. “Our initial findings have held up in a larger cohort of patients, and we are already looking at new clinical studies to advance this novel therapeutic approach in fighting cancer.”
CRS diagnosis, stratification
In their analysis of 5 B-ALL patients, Dr Sadelain and his colleagues observed a correlation between cytokine elevation and tumor burden at the time of CAR T-cell administration. The team confirmed this correlation in the larger cohort of 16 patients and identified 7 cytokines whose elevation was correlated with pretreatment tumor burden and severe CRS.
Patients with CRS that required intensive medical intervention had a 75-fold increase over baseline levels in 2 of the 7 cytokines, which included IFN-γ, IL-5, IL-6, IL-10, Flt-3L, Fracktalkine, and GM-CSF. These patients also had at least 1 of the following: hypoxia, hypotension, and neurologic changes (such as delirium and seizure-like activity).
Taking these findings together, the researchers concluded that patients had severe CRS if they had persistent fevers (38°C) for more than 3 days, selected cytokine elevations, and additional clinical evidence of toxicity.
The investigators stressed that these patients should be closely monitored. Patients with severe CRS are more likely to need medical intervention than patients with mild CRS, which is characterized by low-grade fever and mild cytokine increases, or absent CRS, which is defined as no fevers and/or no significant cytokine elevations.
Finally, the researchers found that measuring C-reactive protein in serum samples could predict the severity of CRS. Only those patients who met the criteria for severe CRS had a C-reactive protein level of 20 mg/dL or higher.
Patients who had received high-dose steroids were excluded from this analysis, due to the inverse correlation between high-dose steroid treatment and serum C-reactive protein.
Incidentally, the investigators confirmed prior findings that the monoclonal antibody tocilizumab can ameliorate severe CRS as effectively as steroid treatment, without inhibiting the expansion of CAR T cells.
Credit: MSKCC
Several studies have shown that infusions of T cells modified with chimeric antigen receptors (CARs) can elicit complete responses in leukemia patients who have run out of treatment options.
However, the therapy also puts patients at risk of developing cytokine release syndrome (CRS).
With updated research, investigators have again shown that CAR T cells can produce complete responses in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), thereby allowing them to receive allogeneic stem cell transplant (allo-SCT).
But the researchers have also used this group of patients to define diagnostic criteria for severe CRS. And the team has discovered that measuring C-reactive protein levels can help predict the severity of CRS.
Michel Sadelain, MD, PhD, of Memorial Sloan-Kettering Cancer Center in New York, and his colleagues described these findings in Science Translational Medicine.
Response, bridge to allo-SCT
Dr Sadelain and his colleagues previously reported results in 5 patients with relapsed/refractory B-ALL who received autologous T cells expressing a CD19-specific, CD28/CD3z CAR called 19-28z.
After receiving salvage chemotherapy and CAR T cells, all 5 patients were negative for minimal residual disease. And 4 of the patients went on to receive allo-SCT.
Now, the investigators have expanded upon these findings, reporting results in a total of 16 patients with relapsed/refractory B-ALL who received the 19-28z CAR T cells.
Forty-four percent of patients (n=7) had a complete response to the salvage chemotherapy, and 88% (n=14) had a complete response after CAR T-cell therapy (alghough some had incomplete count recovery). Sixty-three percent of patients (n=10) achieved a complete remission.
Of the 10 patients who were eligible for allo-SCT, 7 underwent the procedure, and all 7 remain free of relapse.
“These extraordinary results demonstrate that cell therapy is a powerful treatment for patients who have exhausted all conventional therapies,” Dr Sadelain said. “Our initial findings have held up in a larger cohort of patients, and we are already looking at new clinical studies to advance this novel therapeutic approach in fighting cancer.”
CRS diagnosis, stratification
In their analysis of 5 B-ALL patients, Dr Sadelain and his colleagues observed a correlation between cytokine elevation and tumor burden at the time of CAR T-cell administration. The team confirmed this correlation in the larger cohort of 16 patients and identified 7 cytokines whose elevation was correlated with pretreatment tumor burden and severe CRS.
Patients with CRS that required intensive medical intervention had a 75-fold increase over baseline levels in 2 of the 7 cytokines, which included IFN-γ, IL-5, IL-6, IL-10, Flt-3L, Fracktalkine, and GM-CSF. These patients also had at least 1 of the following: hypoxia, hypotension, and neurologic changes (such as delirium and seizure-like activity).
Taking these findings together, the researchers concluded that patients had severe CRS if they had persistent fevers (38°C) for more than 3 days, selected cytokine elevations, and additional clinical evidence of toxicity.
The investigators stressed that these patients should be closely monitored. Patients with severe CRS are more likely to need medical intervention than patients with mild CRS, which is characterized by low-grade fever and mild cytokine increases, or absent CRS, which is defined as no fevers and/or no significant cytokine elevations.
Finally, the researchers found that measuring C-reactive protein in serum samples could predict the severity of CRS. Only those patients who met the criteria for severe CRS had a C-reactive protein level of 20 mg/dL or higher.
Patients who had received high-dose steroids were excluded from this analysis, due to the inverse correlation between high-dose steroid treatment and serum C-reactive protein.
Incidentally, the investigators confirmed prior findings that the monoclonal antibody tocilizumab can ameliorate severe CRS as effectively as steroid treatment, without inhibiting the expansion of CAR T cells.
Credit: MSKCC
Several studies have shown that infusions of T cells modified with chimeric antigen receptors (CARs) can elicit complete responses in leukemia patients who have run out of treatment options.
However, the therapy also puts patients at risk of developing cytokine release syndrome (CRS).
With updated research, investigators have again shown that CAR T cells can produce complete responses in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), thereby allowing them to receive allogeneic stem cell transplant (allo-SCT).
But the researchers have also used this group of patients to define diagnostic criteria for severe CRS. And the team has discovered that measuring C-reactive protein levels can help predict the severity of CRS.
Michel Sadelain, MD, PhD, of Memorial Sloan-Kettering Cancer Center in New York, and his colleagues described these findings in Science Translational Medicine.
Response, bridge to allo-SCT
Dr Sadelain and his colleagues previously reported results in 5 patients with relapsed/refractory B-ALL who received autologous T cells expressing a CD19-specific, CD28/CD3z CAR called 19-28z.
After receiving salvage chemotherapy and CAR T cells, all 5 patients were negative for minimal residual disease. And 4 of the patients went on to receive allo-SCT.
Now, the investigators have expanded upon these findings, reporting results in a total of 16 patients with relapsed/refractory B-ALL who received the 19-28z CAR T cells.
Forty-four percent of patients (n=7) had a complete response to the salvage chemotherapy, and 88% (n=14) had a complete response after CAR T-cell therapy (alghough some had incomplete count recovery). Sixty-three percent of patients (n=10) achieved a complete remission.
Of the 10 patients who were eligible for allo-SCT, 7 underwent the procedure, and all 7 remain free of relapse.
“These extraordinary results demonstrate that cell therapy is a powerful treatment for patients who have exhausted all conventional therapies,” Dr Sadelain said. “Our initial findings have held up in a larger cohort of patients, and we are already looking at new clinical studies to advance this novel therapeutic approach in fighting cancer.”
CRS diagnosis, stratification
In their analysis of 5 B-ALL patients, Dr Sadelain and his colleagues observed a correlation between cytokine elevation and tumor burden at the time of CAR T-cell administration. The team confirmed this correlation in the larger cohort of 16 patients and identified 7 cytokines whose elevation was correlated with pretreatment tumor burden and severe CRS.
Patients with CRS that required intensive medical intervention had a 75-fold increase over baseline levels in 2 of the 7 cytokines, which included IFN-γ, IL-5, IL-6, IL-10, Flt-3L, Fracktalkine, and GM-CSF. These patients also had at least 1 of the following: hypoxia, hypotension, and neurologic changes (such as delirium and seizure-like activity).
Taking these findings together, the researchers concluded that patients had severe CRS if they had persistent fevers (38°C) for more than 3 days, selected cytokine elevations, and additional clinical evidence of toxicity.
The investigators stressed that these patients should be closely monitored. Patients with severe CRS are more likely to need medical intervention than patients with mild CRS, which is characterized by low-grade fever and mild cytokine increases, or absent CRS, which is defined as no fevers and/or no significant cytokine elevations.
Finally, the researchers found that measuring C-reactive protein in serum samples could predict the severity of CRS. Only those patients who met the criteria for severe CRS had a C-reactive protein level of 20 mg/dL or higher.
Patients who had received high-dose steroids were excluded from this analysis, due to the inverse correlation between high-dose steroid treatment and serum C-reactive protein.
Incidentally, the investigators confirmed prior findings that the monoclonal antibody tocilizumab can ameliorate severe CRS as effectively as steroid treatment, without inhibiting the expansion of CAR T cells.