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ADAR1 linked to MM pathogenesis, outcomes
Overly zealous editing of messenger RNA in multiple myeloma (MM) cells contributes to MM pathogenesis and is associated with poor outcomes after certain treatments, investigators contend.
The team found evidence to suggest that overexpression of the RNA editing enzyme ADAR1 leads to hyperediting of the MM transcriptome that appears related to a drug-resistant disease phenotype and worse prognosis.
Phaik Ju Teoh, PhD, of the Cancer Science Institute of Singapore, and colleagues reported these findings in Blood.
The investigators implicate aberrant editing of adenosine (A) to inosine (I) in malignant plasma cells and its effects on NEIL1, a gene that encodes proteins involved in base-excision repair of DNA, as important mechanisms in MM pathogenesis.
A to I editing is the most prevalent form of RNA editing in humans, and aberrant editing mediated by ADAR1 has recently been linked to the development of several cancer types, the investigators noted.
To see whether this process may also be involved in MM, the investigators examined whole blood or bone marrow samples from healthy volunteers and MM patients.
The team found that ADAR1 was overexpressed in MM cells compared to nonmalignant plasma cells.
Furthermore, ADAR1 was expressed at higher levels in patients with newly diagnosed or relapsed MM compared to patients who had smoldering myeloma or monoclonal gammopathy of undetermined significance.
Response to treatment
The investigators also assessed ADAR1 expression in relation to MM patients’ responsiveness to treatment using data from the CoMMpass study.
The team found that patients with poor responses (stable or progressive disease) to bortezomib-based and immunomodulatory-based therapies had high ADAR1 mRNA.
There was no correlation between ADAR1 and responsiveness to carfilzomib-based treatments, but the investigators said this may be because of the relatively lower number of patients who received carfilzomib in this study.
The investigators also found that bortezomib was more effective in inhibiting the growth of MM cells with low ADAR1, and bortezomib-treated cells showed downregulation of ADAR1 expression in a dose- and time-dependent manner.
ADAR1-mediated editing
The investigators determined that ADAR1 directly regulates hyperediting of the MM transcriptome. This was evidenced by a significant increase in A to guanosine (G) editing in newly diagnosed and relapsed MM samples, compared with normal plasma cells.
The team confirmed this finding by observing the effects of ADAR1 levels on editing events across the transcriptome.
The investigators followed this observation with experiments to see whether ADAR1-mediated editing contributes to oncogenesis in MM cells. The MM growth rate slowed when the team silenced ADAR1, and introducing wild-type ADAR1 into cells promoted growth and proliferation.
The investigators also identified NEIL1 as an important ADAR1 editing target in MM. The editing compromised NEIL1’s ability to accurately repair DNA damage.
This study was supported by the National Research Foundation Singapore, the Singapore Ministry of Education, and the National University of Singapore. The investigators reported no competing financial interests.
Overly zealous editing of messenger RNA in multiple myeloma (MM) cells contributes to MM pathogenesis and is associated with poor outcomes after certain treatments, investigators contend.
The team found evidence to suggest that overexpression of the RNA editing enzyme ADAR1 leads to hyperediting of the MM transcriptome that appears related to a drug-resistant disease phenotype and worse prognosis.
Phaik Ju Teoh, PhD, of the Cancer Science Institute of Singapore, and colleagues reported these findings in Blood.
The investigators implicate aberrant editing of adenosine (A) to inosine (I) in malignant plasma cells and its effects on NEIL1, a gene that encodes proteins involved in base-excision repair of DNA, as important mechanisms in MM pathogenesis.
A to I editing is the most prevalent form of RNA editing in humans, and aberrant editing mediated by ADAR1 has recently been linked to the development of several cancer types, the investigators noted.
To see whether this process may also be involved in MM, the investigators examined whole blood or bone marrow samples from healthy volunteers and MM patients.
The team found that ADAR1 was overexpressed in MM cells compared to nonmalignant plasma cells.
Furthermore, ADAR1 was expressed at higher levels in patients with newly diagnosed or relapsed MM compared to patients who had smoldering myeloma or monoclonal gammopathy of undetermined significance.
Response to treatment
The investigators also assessed ADAR1 expression in relation to MM patients’ responsiveness to treatment using data from the CoMMpass study.
The team found that patients with poor responses (stable or progressive disease) to bortezomib-based and immunomodulatory-based therapies had high ADAR1 mRNA.
There was no correlation between ADAR1 and responsiveness to carfilzomib-based treatments, but the investigators said this may be because of the relatively lower number of patients who received carfilzomib in this study.
The investigators also found that bortezomib was more effective in inhibiting the growth of MM cells with low ADAR1, and bortezomib-treated cells showed downregulation of ADAR1 expression in a dose- and time-dependent manner.
ADAR1-mediated editing
The investigators determined that ADAR1 directly regulates hyperediting of the MM transcriptome. This was evidenced by a significant increase in A to guanosine (G) editing in newly diagnosed and relapsed MM samples, compared with normal plasma cells.
The team confirmed this finding by observing the effects of ADAR1 levels on editing events across the transcriptome.
The investigators followed this observation with experiments to see whether ADAR1-mediated editing contributes to oncogenesis in MM cells. The MM growth rate slowed when the team silenced ADAR1, and introducing wild-type ADAR1 into cells promoted growth and proliferation.
The investigators also identified NEIL1 as an important ADAR1 editing target in MM. The editing compromised NEIL1’s ability to accurately repair DNA damage.
This study was supported by the National Research Foundation Singapore, the Singapore Ministry of Education, and the National University of Singapore. The investigators reported no competing financial interests.
Overly zealous editing of messenger RNA in multiple myeloma (MM) cells contributes to MM pathogenesis and is associated with poor outcomes after certain treatments, investigators contend.
The team found evidence to suggest that overexpression of the RNA editing enzyme ADAR1 leads to hyperediting of the MM transcriptome that appears related to a drug-resistant disease phenotype and worse prognosis.
Phaik Ju Teoh, PhD, of the Cancer Science Institute of Singapore, and colleagues reported these findings in Blood.
The investigators implicate aberrant editing of adenosine (A) to inosine (I) in malignant plasma cells and its effects on NEIL1, a gene that encodes proteins involved in base-excision repair of DNA, as important mechanisms in MM pathogenesis.
A to I editing is the most prevalent form of RNA editing in humans, and aberrant editing mediated by ADAR1 has recently been linked to the development of several cancer types, the investigators noted.
To see whether this process may also be involved in MM, the investigators examined whole blood or bone marrow samples from healthy volunteers and MM patients.
The team found that ADAR1 was overexpressed in MM cells compared to nonmalignant plasma cells.
Furthermore, ADAR1 was expressed at higher levels in patients with newly diagnosed or relapsed MM compared to patients who had smoldering myeloma or monoclonal gammopathy of undetermined significance.
Response to treatment
The investigators also assessed ADAR1 expression in relation to MM patients’ responsiveness to treatment using data from the CoMMpass study.
The team found that patients with poor responses (stable or progressive disease) to bortezomib-based and immunomodulatory-based therapies had high ADAR1 mRNA.
There was no correlation between ADAR1 and responsiveness to carfilzomib-based treatments, but the investigators said this may be because of the relatively lower number of patients who received carfilzomib in this study.
The investigators also found that bortezomib was more effective in inhibiting the growth of MM cells with low ADAR1, and bortezomib-treated cells showed downregulation of ADAR1 expression in a dose- and time-dependent manner.
ADAR1-mediated editing
The investigators determined that ADAR1 directly regulates hyperediting of the MM transcriptome. This was evidenced by a significant increase in A to guanosine (G) editing in newly diagnosed and relapsed MM samples, compared with normal plasma cells.
The team confirmed this finding by observing the effects of ADAR1 levels on editing events across the transcriptome.
The investigators followed this observation with experiments to see whether ADAR1-mediated editing contributes to oncogenesis in MM cells. The MM growth rate slowed when the team silenced ADAR1, and introducing wild-type ADAR1 into cells promoted growth and proliferation.
The investigators also identified NEIL1 as an important ADAR1 editing target in MM. The editing compromised NEIL1’s ability to accurately repair DNA damage.
This study was supported by the National Research Foundation Singapore, the Singapore Ministry of Education, and the National University of Singapore. The investigators reported no competing financial interests.
Financial burden of blood cancers in the U.S.
An analysis of more than 2,000 U.S. patients with blood cancers revealed an average healthcare cost of almost $157,000 in the first year after diagnosis.
Costs were highest for acute leukemia patients—almost triple the average for all blood cancers.
Out-of-pocket (OOP) costs were initially highest for acute leukemia patients. However, over time, OOP costs became highest for patients with multiple myeloma.
These results are included in a report commissioned by the Leukemia & Lymphoma Society and prepared by the actuarial firm Milliman.
The report is based on data from the Truven Health MarketScan commercial claims databases.
The cost figures are drawn from data for 2,332 patients, ages 18 to 64, who were diagnosed with blood cancer in 2014 and followed through 2016. This includes the following:
- 1,468 patients with lymphoma
- 286 with chronic leukemia
- 282 with multiple myeloma
- 148 with acute leukemia
- 148 with bone marrow disorders (myelodysplastic syndromes).
The average allowed spending—the amount paid by the payer and patient combined—in the first 12 months after diagnosis was:
- $156,845 overall
- $463,414 for acute leukemia
- $213,879 for multiple myeloma
- $133,744 for bone marrow disorders
- $130,545 for lymphoma
- $88,913 for chronic leukemia.
Differences in OOP costs were smaller, although OOP spending was 32% higher for acute leukemia patients than the overall average.
Average OOP costs—which include coinsurance, copay, and deductible—in the first 12 months after diagnosis were:
- $3,877 overall
- $5,147 for acute leukemia
- $4,849 for multiple myeloma
- $3,695 for lymphoma
- $3,480 for chronic leukemia
- $3,336 for bone marrow disorders.
Although OOP costs were initially highest for acute leukemia patients, over time, costs for multiple myeloma patients became the highest.
The average OOP costs in the month of diagnosis were $1,637 for acute leukemia patients and $1,210 for multiple myeloma patients.
The total accumulated OOP costs 3 years after diagnosis were $8,797 for acute leukemia and $9,127 for multiple myeloma. For the other blood cancers, the average 3-year accumulated OOP costs were under $7,800.
The Leukemia & Lymphoma Society received support from Pfizer, Genentech, and Amgen for this work.
An analysis of more than 2,000 U.S. patients with blood cancers revealed an average healthcare cost of almost $157,000 in the first year after diagnosis.
Costs were highest for acute leukemia patients—almost triple the average for all blood cancers.
Out-of-pocket (OOP) costs were initially highest for acute leukemia patients. However, over time, OOP costs became highest for patients with multiple myeloma.
These results are included in a report commissioned by the Leukemia & Lymphoma Society and prepared by the actuarial firm Milliman.
The report is based on data from the Truven Health MarketScan commercial claims databases.
The cost figures are drawn from data for 2,332 patients, ages 18 to 64, who were diagnosed with blood cancer in 2014 and followed through 2016. This includes the following:
- 1,468 patients with lymphoma
- 286 with chronic leukemia
- 282 with multiple myeloma
- 148 with acute leukemia
- 148 with bone marrow disorders (myelodysplastic syndromes).
The average allowed spending—the amount paid by the payer and patient combined—in the first 12 months after diagnosis was:
- $156,845 overall
- $463,414 for acute leukemia
- $213,879 for multiple myeloma
- $133,744 for bone marrow disorders
- $130,545 for lymphoma
- $88,913 for chronic leukemia.
Differences in OOP costs were smaller, although OOP spending was 32% higher for acute leukemia patients than the overall average.
Average OOP costs—which include coinsurance, copay, and deductible—in the first 12 months after diagnosis were:
- $3,877 overall
- $5,147 for acute leukemia
- $4,849 for multiple myeloma
- $3,695 for lymphoma
- $3,480 for chronic leukemia
- $3,336 for bone marrow disorders.
Although OOP costs were initially highest for acute leukemia patients, over time, costs for multiple myeloma patients became the highest.
The average OOP costs in the month of diagnosis were $1,637 for acute leukemia patients and $1,210 for multiple myeloma patients.
The total accumulated OOP costs 3 years after diagnosis were $8,797 for acute leukemia and $9,127 for multiple myeloma. For the other blood cancers, the average 3-year accumulated OOP costs were under $7,800.
The Leukemia & Lymphoma Society received support from Pfizer, Genentech, and Amgen for this work.
An analysis of more than 2,000 U.S. patients with blood cancers revealed an average healthcare cost of almost $157,000 in the first year after diagnosis.
Costs were highest for acute leukemia patients—almost triple the average for all blood cancers.
Out-of-pocket (OOP) costs were initially highest for acute leukemia patients. However, over time, OOP costs became highest for patients with multiple myeloma.
These results are included in a report commissioned by the Leukemia & Lymphoma Society and prepared by the actuarial firm Milliman.
The report is based on data from the Truven Health MarketScan commercial claims databases.
The cost figures are drawn from data for 2,332 patients, ages 18 to 64, who were diagnosed with blood cancer in 2014 and followed through 2016. This includes the following:
- 1,468 patients with lymphoma
- 286 with chronic leukemia
- 282 with multiple myeloma
- 148 with acute leukemia
- 148 with bone marrow disorders (myelodysplastic syndromes).
The average allowed spending—the amount paid by the payer and patient combined—in the first 12 months after diagnosis was:
- $156,845 overall
- $463,414 for acute leukemia
- $213,879 for multiple myeloma
- $133,744 for bone marrow disorders
- $130,545 for lymphoma
- $88,913 for chronic leukemia.
Differences in OOP costs were smaller, although OOP spending was 32% higher for acute leukemia patients than the overall average.
Average OOP costs—which include coinsurance, copay, and deductible—in the first 12 months after diagnosis were:
- $3,877 overall
- $5,147 for acute leukemia
- $4,849 for multiple myeloma
- $3,695 for lymphoma
- $3,480 for chronic leukemia
- $3,336 for bone marrow disorders.
Although OOP costs were initially highest for acute leukemia patients, over time, costs for multiple myeloma patients became the highest.
The average OOP costs in the month of diagnosis were $1,637 for acute leukemia patients and $1,210 for multiple myeloma patients.
The total accumulated OOP costs 3 years after diagnosis were $8,797 for acute leukemia and $9,127 for multiple myeloma. For the other blood cancers, the average 3-year accumulated OOP costs were under $7,800.
The Leukemia & Lymphoma Society received support from Pfizer, Genentech, and Amgen for this work.
Triplet improves PFS in relapsed/refractory MM
Adding elotuzumab to pomalidomide and low-dose dexamethasone can improve progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM), according to the ELOQUENT-3 trial.
These results support the recent U.S. approval of elotuzumab, pomalidomide, and dexamethasone in adults with MM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.
Results from ELOQUENT-3 were recently published in The New England Journal of Medicine and previously presented at the 23rd Congress of the European Hematology Association in June.
The phase 2 trial included patients with refractory or relapsed and refractory MM who had received lenalidomide and a proteasome inhibitor.
The patients were randomized to receive elotuzumab plus pomalidomide and low-dose dexamethasone (EPd, n=60) or pomalidomide and low-dose dexamethasone (Pd, n=57) in 28-day cycles until disease progression or unacceptable toxicity.
The overall response rate was 53% in the EPd arm and 26% in the Pd arm (odds ratio=3.25; P=0.0029).
There were two stringent complete responses (CRs) and three CRs in the EPd arm, and there was one CR in the Pd arm.
The median duration of response was 8.3 months in the Pd arm and was not reached in the EPd arm.
The median PFS was 10.3 months with EPd and 4.7 months with Pd (hazard ratio=0.54, P=0.008).
Overall survival data were not mature at the time of analysis, but there was a trend favoring EPd over Pd (hazard ratio=0.62). There were 13 deaths in the EPd arm and 18 in the Pd arm.
The most common treatment-related adverse events (in the EPd and Pd arms, respectively) were neutropenia (18% and 20%), hyperglycemia (18% and 11%), and anemia (10% and 15%).
This trial was supported by Bristol-Myers Squibb and AbbVie Biotherapeutics, and researchers reported relationships with several other companies.
Adding elotuzumab to pomalidomide and low-dose dexamethasone can improve progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM), according to the ELOQUENT-3 trial.
These results support the recent U.S. approval of elotuzumab, pomalidomide, and dexamethasone in adults with MM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.
Results from ELOQUENT-3 were recently published in The New England Journal of Medicine and previously presented at the 23rd Congress of the European Hematology Association in June.
The phase 2 trial included patients with refractory or relapsed and refractory MM who had received lenalidomide and a proteasome inhibitor.
The patients were randomized to receive elotuzumab plus pomalidomide and low-dose dexamethasone (EPd, n=60) or pomalidomide and low-dose dexamethasone (Pd, n=57) in 28-day cycles until disease progression or unacceptable toxicity.
The overall response rate was 53% in the EPd arm and 26% in the Pd arm (odds ratio=3.25; P=0.0029).
There were two stringent complete responses (CRs) and three CRs in the EPd arm, and there was one CR in the Pd arm.
The median duration of response was 8.3 months in the Pd arm and was not reached in the EPd arm.
The median PFS was 10.3 months with EPd and 4.7 months with Pd (hazard ratio=0.54, P=0.008).
Overall survival data were not mature at the time of analysis, but there was a trend favoring EPd over Pd (hazard ratio=0.62). There were 13 deaths in the EPd arm and 18 in the Pd arm.
The most common treatment-related adverse events (in the EPd and Pd arms, respectively) were neutropenia (18% and 20%), hyperglycemia (18% and 11%), and anemia (10% and 15%).
This trial was supported by Bristol-Myers Squibb and AbbVie Biotherapeutics, and researchers reported relationships with several other companies.
Adding elotuzumab to pomalidomide and low-dose dexamethasone can improve progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM), according to the ELOQUENT-3 trial.
These results support the recent U.S. approval of elotuzumab, pomalidomide, and dexamethasone in adults with MM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.
Results from ELOQUENT-3 were recently published in The New England Journal of Medicine and previously presented at the 23rd Congress of the European Hematology Association in June.
The phase 2 trial included patients with refractory or relapsed and refractory MM who had received lenalidomide and a proteasome inhibitor.
The patients were randomized to receive elotuzumab plus pomalidomide and low-dose dexamethasone (EPd, n=60) or pomalidomide and low-dose dexamethasone (Pd, n=57) in 28-day cycles until disease progression or unacceptable toxicity.
The overall response rate was 53% in the EPd arm and 26% in the Pd arm (odds ratio=3.25; P=0.0029).
There were two stringent complete responses (CRs) and three CRs in the EPd arm, and there was one CR in the Pd arm.
The median duration of response was 8.3 months in the Pd arm and was not reached in the EPd arm.
The median PFS was 10.3 months with EPd and 4.7 months with Pd (hazard ratio=0.54, P=0.008).
Overall survival data were not mature at the time of analysis, but there was a trend favoring EPd over Pd (hazard ratio=0.62). There were 13 deaths in the EPd arm and 18 in the Pd arm.
The most common treatment-related adverse events (in the EPd and Pd arms, respectively) were neutropenia (18% and 20%), hyperglycemia (18% and 11%), and anemia (10% and 15%).
This trial was supported by Bristol-Myers Squibb and AbbVie Biotherapeutics, and researchers reported relationships with several other companies.
P-BCMA-101 gains FDA regenerative medicine designation
(MM), has received the regenerative medicine advanced therapy (RMAT) designation from the Food and Drug Administration.
P-BCMA-101 modifies patients’ T cells using a nonviral DNA modification system known as piggyBac. The modified T cells target cells expressing B-cell maturation antigen (BCMA), which is expressed on essentially all MM cells.
Early results from the phase 1 clinical trial of P-BCMA-101 were recently reported at the 2018 CAR-TCR Summit by Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, the company developing P-BCMA-101.
Initial results of the trial (NCT03288493) included data on 11 patients with heavily pretreated MM. Patients were a median age of 60, and 73% were high risk. They had a median of six prior therapies.
Patients received conditioning treatment with fludarabine and cyclophosphamide for 3 days prior to receiving P-BCMA-101. They then received one of three doses of CAR T cells – 51×106 (n=3), 152×106 (n=7), or 430×106 (n=1).
The investigators observed no dose-limiting toxicities. Adverse events included neutropenia in eight patients and thrombocytopenia in five.
One patient may have had cytokine release syndrome, but the condition resolved without drug intervention. And investigators observed no neurotoxicity.
Seven of ten patients evaluable for response by International Myeloma Working Group criteria achieved at least a partial response, including very good partial responses and stringent complete response.
The eleventh patient has oligosecretory disease and was only evaluable by PET, which indicated a near-complete response.
Poseida expects to have additional data to report by the end of the year, according to Dr. Ostertag. The study is funded by the California Institute for Regenerative Medicine and Poseida Therapeutics.RMAT designation is intended to expedite development and review of regenerative medicines that are intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition.
Preliminary evidence must indicate that the therapy has the potential to address unmet medical needs for the disease or condition. RMAT designation includes all the benefits of fast track and breakthrough therapy designations, including early interactions with the FDA.
(MM), has received the regenerative medicine advanced therapy (RMAT) designation from the Food and Drug Administration.
P-BCMA-101 modifies patients’ T cells using a nonviral DNA modification system known as piggyBac. The modified T cells target cells expressing B-cell maturation antigen (BCMA), which is expressed on essentially all MM cells.
Early results from the phase 1 clinical trial of P-BCMA-101 were recently reported at the 2018 CAR-TCR Summit by Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, the company developing P-BCMA-101.
Initial results of the trial (NCT03288493) included data on 11 patients with heavily pretreated MM. Patients were a median age of 60, and 73% were high risk. They had a median of six prior therapies.
Patients received conditioning treatment with fludarabine and cyclophosphamide for 3 days prior to receiving P-BCMA-101. They then received one of three doses of CAR T cells – 51×106 (n=3), 152×106 (n=7), or 430×106 (n=1).
The investigators observed no dose-limiting toxicities. Adverse events included neutropenia in eight patients and thrombocytopenia in five.
One patient may have had cytokine release syndrome, but the condition resolved without drug intervention. And investigators observed no neurotoxicity.
Seven of ten patients evaluable for response by International Myeloma Working Group criteria achieved at least a partial response, including very good partial responses and stringent complete response.
The eleventh patient has oligosecretory disease and was only evaluable by PET, which indicated a near-complete response.
Poseida expects to have additional data to report by the end of the year, according to Dr. Ostertag. The study is funded by the California Institute for Regenerative Medicine and Poseida Therapeutics.RMAT designation is intended to expedite development and review of regenerative medicines that are intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition.
Preliminary evidence must indicate that the therapy has the potential to address unmet medical needs for the disease or condition. RMAT designation includes all the benefits of fast track and breakthrough therapy designations, including early interactions with the FDA.
(MM), has received the regenerative medicine advanced therapy (RMAT) designation from the Food and Drug Administration.
P-BCMA-101 modifies patients’ T cells using a nonviral DNA modification system known as piggyBac. The modified T cells target cells expressing B-cell maturation antigen (BCMA), which is expressed on essentially all MM cells.
Early results from the phase 1 clinical trial of P-BCMA-101 were recently reported at the 2018 CAR-TCR Summit by Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, the company developing P-BCMA-101.
Initial results of the trial (NCT03288493) included data on 11 patients with heavily pretreated MM. Patients were a median age of 60, and 73% were high risk. They had a median of six prior therapies.
Patients received conditioning treatment with fludarabine and cyclophosphamide for 3 days prior to receiving P-BCMA-101. They then received one of three doses of CAR T cells – 51×106 (n=3), 152×106 (n=7), or 430×106 (n=1).
The investigators observed no dose-limiting toxicities. Adverse events included neutropenia in eight patients and thrombocytopenia in five.
One patient may have had cytokine release syndrome, but the condition resolved without drug intervention. And investigators observed no neurotoxicity.
Seven of ten patients evaluable for response by International Myeloma Working Group criteria achieved at least a partial response, including very good partial responses and stringent complete response.
The eleventh patient has oligosecretory disease and was only evaluable by PET, which indicated a near-complete response.
Poseida expects to have additional data to report by the end of the year, according to Dr. Ostertag. The study is funded by the California Institute for Regenerative Medicine and Poseida Therapeutics.RMAT designation is intended to expedite development and review of regenerative medicines that are intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition.
Preliminary evidence must indicate that the therapy has the potential to address unmet medical needs for the disease or condition. RMAT designation includes all the benefits of fast track and breakthrough therapy designations, including early interactions with the FDA.
CAR T therapy for MM receives RMAT designation
P-BCMA-101, an autologous chimeric antigen receptor (CAR) T-cell therapy being developed to treat patients with relapsed/refractory multiple myeloma (MM), has received regenerative medicine advanced therapy (RMAT) designation from the U.S. Food and Drug Administration (FDA).
RMAT designation is intended to expedite the development and review of regenerative medicines that are intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition.
For a therapy to receive RMAT designation, preliminary evidence must indicate the therapy has the potential to address unmet medical needs for the disease or condition.
RMAT designation provides all the benefits of fast track and breakthrough therapy designations, including early interactions with the FDA.
About P-BCMA-101
To create P-BCMA-101, patients’ T cells are modified using a non-viral DNA modification system known as piggyBac™. The modified T cells target cells expressing B-cell maturation antigen (BCMA), which is expressed on essentially all MM cells.
Early results from the phase 1 trial (NCT03288493) of P-BCMA-101 were recently reported at the 2018 CAR-TCR Summit by Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics Inc., the company developing P-BCMA-101.
The presentation included data on 11 patients with heavily pretreated MM. Patients were a median age of 60, and 73% were high risk. They had a median of six prior therapies.
Patients received conditioning with fludarabine and cyclophosphamide for 3 days prior to receiving P-BCMA-101. They then received one of three doses of CAR T cells—51×106 (n=3), 152×106 (n=7), or 430×106 (n=1).
The investigators observed no dose-limiting toxicities. Adverse events included neutropenia in eight patients and thrombocytopenia in five.
One patient may have had cytokine release syndrome, but the condition resolved without drug intervention. And investigators observed no neurotoxicity.
Seven of ten patients evaluable for response by International Myeloma Working Group criteria achieved at least a partial response, including very good partial responses and stringent complete response.
The eleventh patient has oligosecretory disease and was only evaluable by PET, which indicated a near complete response.
Additional results from this trial are scheduled to be presented at the 2018 ASH Annual Meeting (abstract 1012).
The study is funded by the California Institute for Regenerative Medicine and Poseida Therapeutics.
P-BCMA-101, an autologous chimeric antigen receptor (CAR) T-cell therapy being developed to treat patients with relapsed/refractory multiple myeloma (MM), has received regenerative medicine advanced therapy (RMAT) designation from the U.S. Food and Drug Administration (FDA).
RMAT designation is intended to expedite the development and review of regenerative medicines that are intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition.
For a therapy to receive RMAT designation, preliminary evidence must indicate the therapy has the potential to address unmet medical needs for the disease or condition.
RMAT designation provides all the benefits of fast track and breakthrough therapy designations, including early interactions with the FDA.
About P-BCMA-101
To create P-BCMA-101, patients’ T cells are modified using a non-viral DNA modification system known as piggyBac™. The modified T cells target cells expressing B-cell maturation antigen (BCMA), which is expressed on essentially all MM cells.
Early results from the phase 1 trial (NCT03288493) of P-BCMA-101 were recently reported at the 2018 CAR-TCR Summit by Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics Inc., the company developing P-BCMA-101.
The presentation included data on 11 patients with heavily pretreated MM. Patients were a median age of 60, and 73% were high risk. They had a median of six prior therapies.
Patients received conditioning with fludarabine and cyclophosphamide for 3 days prior to receiving P-BCMA-101. They then received one of three doses of CAR T cells—51×106 (n=3), 152×106 (n=7), or 430×106 (n=1).
The investigators observed no dose-limiting toxicities. Adverse events included neutropenia in eight patients and thrombocytopenia in five.
One patient may have had cytokine release syndrome, but the condition resolved without drug intervention. And investigators observed no neurotoxicity.
Seven of ten patients evaluable for response by International Myeloma Working Group criteria achieved at least a partial response, including very good partial responses and stringent complete response.
The eleventh patient has oligosecretory disease and was only evaluable by PET, which indicated a near complete response.
Additional results from this trial are scheduled to be presented at the 2018 ASH Annual Meeting (abstract 1012).
The study is funded by the California Institute for Regenerative Medicine and Poseida Therapeutics.
P-BCMA-101, an autologous chimeric antigen receptor (CAR) T-cell therapy being developed to treat patients with relapsed/refractory multiple myeloma (MM), has received regenerative medicine advanced therapy (RMAT) designation from the U.S. Food and Drug Administration (FDA).
RMAT designation is intended to expedite the development and review of regenerative medicines that are intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition.
For a therapy to receive RMAT designation, preliminary evidence must indicate the therapy has the potential to address unmet medical needs for the disease or condition.
RMAT designation provides all the benefits of fast track and breakthrough therapy designations, including early interactions with the FDA.
About P-BCMA-101
To create P-BCMA-101, patients’ T cells are modified using a non-viral DNA modification system known as piggyBac™. The modified T cells target cells expressing B-cell maturation antigen (BCMA), which is expressed on essentially all MM cells.
Early results from the phase 1 trial (NCT03288493) of P-BCMA-101 were recently reported at the 2018 CAR-TCR Summit by Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics Inc., the company developing P-BCMA-101.
The presentation included data on 11 patients with heavily pretreated MM. Patients were a median age of 60, and 73% were high risk. They had a median of six prior therapies.
Patients received conditioning with fludarabine and cyclophosphamide for 3 days prior to receiving P-BCMA-101. They then received one of three doses of CAR T cells—51×106 (n=3), 152×106 (n=7), or 430×106 (n=1).
The investigators observed no dose-limiting toxicities. Adverse events included neutropenia in eight patients and thrombocytopenia in five.
One patient may have had cytokine release syndrome, but the condition resolved without drug intervention. And investigators observed no neurotoxicity.
Seven of ten patients evaluable for response by International Myeloma Working Group criteria achieved at least a partial response, including very good partial responses and stringent complete response.
The eleventh patient has oligosecretory disease and was only evaluable by PET, which indicated a near complete response.
Additional results from this trial are scheduled to be presented at the 2018 ASH Annual Meeting (abstract 1012).
The study is funded by the California Institute for Regenerative Medicine and Poseida Therapeutics.
Aberrant RNA editing linked to aggressive myeloma
Overly zealous editing of messenger RNA in multiple myeloma cells appears to contribute to myeloma pathogenesis, and is prognostic of poor outcomes, investigators contend.
Over-expression of RNA editing enzymes in the adenosine deaminases acting on RNA (ADAR) family, specifically ADAR1, lead to hyperediting of the multiple myeloma (MM) transcriptome that in turn appears related to a drug-resistant disease phenotype and worse prognosis, reported Phaik Ju Teoh, PhD, of the Cancer Science Institute of Singapore, and colleagues.
The investigators implicate aberrant editing of adenosine to inosine (A-to-I) in malignant plasma cells, and its effects on NEIL1, a gene that encodes proteins involved in base excision repair of DNA, as important mechanisms in multiple myeloma pathogenesis.
“To the best of our knowledge, this is the first report of ADAR1-mediated hypereditome being an independent prognostic factor. The compromised integrity of MM transcriptome drives oncogenic phenotypes, likely contributing to the disease pathogenesis. Our current work, therefore, recognizes the clear biological and clinical importance of A-to-I editing at both the whole-transcriptome and gene-specific level (NEIL1) in MM,” they wrote in Blood.
A-to-I editing is the most prevalent form of RNA editing in humans, and aberrant editing mediated by ADAR1 has recently been linked to the development of several different cancer types, the investigators noted.
To see whether this process may also be involved in multiple myeloma, the investigators examined whole blood or bone marrow samples from healthy volunteers and patients with multiple myeloma.
They first looked at gene-expression profiling in the control and multiple myeloma samples and found that ADAR1 was overexpressed in the multiple myeloma cells, compared with nonmalignant plasma cells. Additionally, they saw that, at the protein level, ADAR1 was expressed at higher levels in patients with newly diagnosed or relapsed disease, compared with patients with smoldering myeloma or monoclonal gammopathy of undetermined significance.
They next determined that ADAR1 directly regulates hyperediting of the MM transcriptome, evidenced by the observation of a significant increase in A-to-G editing in the newly diagnosed and relapsed myeloma samples, compared with normal plasma cells. They confirmed this finding by observing the effects of ADAR1 levels on editing events across the transcriptome.
The authors followed this observation with experiments to see whether RNA editing by ADAR1 contributes to oncogenesis in myeloma cells. They silenced its expression and found that growth rate slowed and that ADAR1 wild-type protein introduced into cells promoted growth and proliferation.
“As the rescue with mutant ADAR1 is incomplete, we do not discount potential nonediting effects in ADAR1-induced oncogenesis in vivo. Nevertheless, taking into consideration the collective results from both the in vitro and in vivo studies, the RNA editing function of ADAR1 is important for its oncogenic effects in myeloma,” they wrote.
In the final steps, they identified NEIL1 as an important target for editing in multiple myeloma and observed that the editing compromised the ability of the proteins produced by the gene to accurately repair DNA damage.
“Further demonstrating its vital contribution to disease aggressiveness, patients with high ADAR1 expression showed less responsiveness toward standard and novel therapies. Therefore, our findings implied that a disturbed editome mediated by ADAR1 overexpression is both clinically and functionally crucial in our disease setting, and that ADAR1 confers oncogenic properties in myeloma in an editing-dependent manner,” they wrote.
The study was supported by the National Research Foundation Singapore, the Singapore Ministry of Education, and the National University of Singapore. The authors reported having no competing financial interests.
SOURCE: Teoh PJ et al. Blood. 2018;132(12):1304-17.
Overly zealous editing of messenger RNA in multiple myeloma cells appears to contribute to myeloma pathogenesis, and is prognostic of poor outcomes, investigators contend.
Over-expression of RNA editing enzymes in the adenosine deaminases acting on RNA (ADAR) family, specifically ADAR1, lead to hyperediting of the multiple myeloma (MM) transcriptome that in turn appears related to a drug-resistant disease phenotype and worse prognosis, reported Phaik Ju Teoh, PhD, of the Cancer Science Institute of Singapore, and colleagues.
The investigators implicate aberrant editing of adenosine to inosine (A-to-I) in malignant plasma cells, and its effects on NEIL1, a gene that encodes proteins involved in base excision repair of DNA, as important mechanisms in multiple myeloma pathogenesis.
“To the best of our knowledge, this is the first report of ADAR1-mediated hypereditome being an independent prognostic factor. The compromised integrity of MM transcriptome drives oncogenic phenotypes, likely contributing to the disease pathogenesis. Our current work, therefore, recognizes the clear biological and clinical importance of A-to-I editing at both the whole-transcriptome and gene-specific level (NEIL1) in MM,” they wrote in Blood.
A-to-I editing is the most prevalent form of RNA editing in humans, and aberrant editing mediated by ADAR1 has recently been linked to the development of several different cancer types, the investigators noted.
To see whether this process may also be involved in multiple myeloma, the investigators examined whole blood or bone marrow samples from healthy volunteers and patients with multiple myeloma.
They first looked at gene-expression profiling in the control and multiple myeloma samples and found that ADAR1 was overexpressed in the multiple myeloma cells, compared with nonmalignant plasma cells. Additionally, they saw that, at the protein level, ADAR1 was expressed at higher levels in patients with newly diagnosed or relapsed disease, compared with patients with smoldering myeloma or monoclonal gammopathy of undetermined significance.
They next determined that ADAR1 directly regulates hyperediting of the MM transcriptome, evidenced by the observation of a significant increase in A-to-G editing in the newly diagnosed and relapsed myeloma samples, compared with normal plasma cells. They confirmed this finding by observing the effects of ADAR1 levels on editing events across the transcriptome.
The authors followed this observation with experiments to see whether RNA editing by ADAR1 contributes to oncogenesis in myeloma cells. They silenced its expression and found that growth rate slowed and that ADAR1 wild-type protein introduced into cells promoted growth and proliferation.
“As the rescue with mutant ADAR1 is incomplete, we do not discount potential nonediting effects in ADAR1-induced oncogenesis in vivo. Nevertheless, taking into consideration the collective results from both the in vitro and in vivo studies, the RNA editing function of ADAR1 is important for its oncogenic effects in myeloma,” they wrote.
In the final steps, they identified NEIL1 as an important target for editing in multiple myeloma and observed that the editing compromised the ability of the proteins produced by the gene to accurately repair DNA damage.
“Further demonstrating its vital contribution to disease aggressiveness, patients with high ADAR1 expression showed less responsiveness toward standard and novel therapies. Therefore, our findings implied that a disturbed editome mediated by ADAR1 overexpression is both clinically and functionally crucial in our disease setting, and that ADAR1 confers oncogenic properties in myeloma in an editing-dependent manner,” they wrote.
The study was supported by the National Research Foundation Singapore, the Singapore Ministry of Education, and the National University of Singapore. The authors reported having no competing financial interests.
SOURCE: Teoh PJ et al. Blood. 2018;132(12):1304-17.
Overly zealous editing of messenger RNA in multiple myeloma cells appears to contribute to myeloma pathogenesis, and is prognostic of poor outcomes, investigators contend.
Over-expression of RNA editing enzymes in the adenosine deaminases acting on RNA (ADAR) family, specifically ADAR1, lead to hyperediting of the multiple myeloma (MM) transcriptome that in turn appears related to a drug-resistant disease phenotype and worse prognosis, reported Phaik Ju Teoh, PhD, of the Cancer Science Institute of Singapore, and colleagues.
The investigators implicate aberrant editing of adenosine to inosine (A-to-I) in malignant plasma cells, and its effects on NEIL1, a gene that encodes proteins involved in base excision repair of DNA, as important mechanisms in multiple myeloma pathogenesis.
“To the best of our knowledge, this is the first report of ADAR1-mediated hypereditome being an independent prognostic factor. The compromised integrity of MM transcriptome drives oncogenic phenotypes, likely contributing to the disease pathogenesis. Our current work, therefore, recognizes the clear biological and clinical importance of A-to-I editing at both the whole-transcriptome and gene-specific level (NEIL1) in MM,” they wrote in Blood.
A-to-I editing is the most prevalent form of RNA editing in humans, and aberrant editing mediated by ADAR1 has recently been linked to the development of several different cancer types, the investigators noted.
To see whether this process may also be involved in multiple myeloma, the investigators examined whole blood or bone marrow samples from healthy volunteers and patients with multiple myeloma.
They first looked at gene-expression profiling in the control and multiple myeloma samples and found that ADAR1 was overexpressed in the multiple myeloma cells, compared with nonmalignant plasma cells. Additionally, they saw that, at the protein level, ADAR1 was expressed at higher levels in patients with newly diagnosed or relapsed disease, compared with patients with smoldering myeloma or monoclonal gammopathy of undetermined significance.
They next determined that ADAR1 directly regulates hyperediting of the MM transcriptome, evidenced by the observation of a significant increase in A-to-G editing in the newly diagnosed and relapsed myeloma samples, compared with normal plasma cells. They confirmed this finding by observing the effects of ADAR1 levels on editing events across the transcriptome.
The authors followed this observation with experiments to see whether RNA editing by ADAR1 contributes to oncogenesis in myeloma cells. They silenced its expression and found that growth rate slowed and that ADAR1 wild-type protein introduced into cells promoted growth and proliferation.
“As the rescue with mutant ADAR1 is incomplete, we do not discount potential nonediting effects in ADAR1-induced oncogenesis in vivo. Nevertheless, taking into consideration the collective results from both the in vitro and in vivo studies, the RNA editing function of ADAR1 is important for its oncogenic effects in myeloma,” they wrote.
In the final steps, they identified NEIL1 as an important target for editing in multiple myeloma and observed that the editing compromised the ability of the proteins produced by the gene to accurately repair DNA damage.
“Further demonstrating its vital contribution to disease aggressiveness, patients with high ADAR1 expression showed less responsiveness toward standard and novel therapies. Therefore, our findings implied that a disturbed editome mediated by ADAR1 overexpression is both clinically and functionally crucial in our disease setting, and that ADAR1 confers oncogenic properties in myeloma in an editing-dependent manner,” they wrote.
The study was supported by the National Research Foundation Singapore, the Singapore Ministry of Education, and the National University of Singapore. The authors reported having no competing financial interests.
SOURCE: Teoh PJ et al. Blood. 2018;132(12):1304-17.
FROM BLOOD
Key clinical point:
Major finding: ADAR1-mediated editing of NEIL1 leads to a weakened DNA base excision repair mechanism.
Study details: Experimental series using plasma samples from healthy volunteers and patients with multiple myeloma.
Disclosures: The study was supported by the National Research Foundation Singapore, the Singapore Ministry of Education, and the National University of Singapore. The authors reported having no competing financial interests.
Source: Teoh PJ et al. Blood. 2018;132(12):1304-17.
What’s the Impact of Osteoporosis in Multiple Myeloma?
Osteoporosis is common among patients with multiple myeloma (MM), in part because both largely affect older adults. And more than half of MM patients will have MM skeletal-related events, which are painful, and can lead to complications (such as spinal cord compression) and death.
But how does pre-existing bone disease contribute to clinical outcomes in MM? Osteoporosis is a “silent condition” and very little is known about its role in MM, say researchers from The Ohio State University in Columbus and University of Massachusetts in Worcester. The standard diagnostic evaluation for MM does not include dual-energy x-ray absorptiometry, therefore assessments of underlying osteoporosis are not routine. Moreover, it is a challenge to distinguish osteoporotic fragility fractures from pathologic MM-induced fractures. Skeletal surveys underestimate bone involvement by about 40%, the researchers note, and are even less specific for distinguishing myeloma-related secondary osteoporosis from primary osteoporosis.
The researchers examined the relationship between the Fracture Risk Assessment Tool (FRAX) and the risk of death in women who developed MM. They analyzed data from 161,808 women in the Women’s Health Initiative (WHI). Of those, 409 developed MM; 362 had no history of cancer.
At baseline, 98 (27%) women had high FRAX scores, and 264 (73%) had low scores. The median follow-up period was 10.5 years from enrollment and 7.2 years from the time of MM diagnosis. Of the patients with MM, 226 died during the follow-up period, including 71 with high FRAX scores and 155 with low scores. MM mortality was higher among women with high FRAX scores: 72%, vs 59% of those with low scores. Poor bone health was associated with greater MM mortality but was not related to delay in time to diagnosis.
During the evaluation, 57 fractures were reported, 65% before MM diagnosis. Fewer than half of the women had a first fracture after diagnosis. The probability of fracture was similar among the women, regardless of FRAX score. Not surprisingly, older women with lower BMI were most at risk.
The WHI does not include information on staging, chemotherapy, or use of bisphosphonates. Therefore, the impact of bisphosphonates could not be determined in this study. The researchers also did not know how many patients might have had pre-existing monoclonal gammopathy of undetermined significance, a disorder in about 3% of the aging population that progresses to MM in 1% per year.
Source:
Rosko AE, Hade EM, Li W, et al. Clin Lymphoma Myeloma Leuk. 2018;18(9):597-602.
Osteoporosis is common among patients with multiple myeloma (MM), in part because both largely affect older adults. And more than half of MM patients will have MM skeletal-related events, which are painful, and can lead to complications (such as spinal cord compression) and death.
But how does pre-existing bone disease contribute to clinical outcomes in MM? Osteoporosis is a “silent condition” and very little is known about its role in MM, say researchers from The Ohio State University in Columbus and University of Massachusetts in Worcester. The standard diagnostic evaluation for MM does not include dual-energy x-ray absorptiometry, therefore assessments of underlying osteoporosis are not routine. Moreover, it is a challenge to distinguish osteoporotic fragility fractures from pathologic MM-induced fractures. Skeletal surveys underestimate bone involvement by about 40%, the researchers note, and are even less specific for distinguishing myeloma-related secondary osteoporosis from primary osteoporosis.
The researchers examined the relationship between the Fracture Risk Assessment Tool (FRAX) and the risk of death in women who developed MM. They analyzed data from 161,808 women in the Women’s Health Initiative (WHI). Of those, 409 developed MM; 362 had no history of cancer.
At baseline, 98 (27%) women had high FRAX scores, and 264 (73%) had low scores. The median follow-up period was 10.5 years from enrollment and 7.2 years from the time of MM diagnosis. Of the patients with MM, 226 died during the follow-up period, including 71 with high FRAX scores and 155 with low scores. MM mortality was higher among women with high FRAX scores: 72%, vs 59% of those with low scores. Poor bone health was associated with greater MM mortality but was not related to delay in time to diagnosis.
During the evaluation, 57 fractures were reported, 65% before MM diagnosis. Fewer than half of the women had a first fracture after diagnosis. The probability of fracture was similar among the women, regardless of FRAX score. Not surprisingly, older women with lower BMI were most at risk.
The WHI does not include information on staging, chemotherapy, or use of bisphosphonates. Therefore, the impact of bisphosphonates could not be determined in this study. The researchers also did not know how many patients might have had pre-existing monoclonal gammopathy of undetermined significance, a disorder in about 3% of the aging population that progresses to MM in 1% per year.
Source:
Rosko AE, Hade EM, Li W, et al. Clin Lymphoma Myeloma Leuk. 2018;18(9):597-602.
Osteoporosis is common among patients with multiple myeloma (MM), in part because both largely affect older adults. And more than half of MM patients will have MM skeletal-related events, which are painful, and can lead to complications (such as spinal cord compression) and death.
But how does pre-existing bone disease contribute to clinical outcomes in MM? Osteoporosis is a “silent condition” and very little is known about its role in MM, say researchers from The Ohio State University in Columbus and University of Massachusetts in Worcester. The standard diagnostic evaluation for MM does not include dual-energy x-ray absorptiometry, therefore assessments of underlying osteoporosis are not routine. Moreover, it is a challenge to distinguish osteoporotic fragility fractures from pathologic MM-induced fractures. Skeletal surveys underestimate bone involvement by about 40%, the researchers note, and are even less specific for distinguishing myeloma-related secondary osteoporosis from primary osteoporosis.
The researchers examined the relationship between the Fracture Risk Assessment Tool (FRAX) and the risk of death in women who developed MM. They analyzed data from 161,808 women in the Women’s Health Initiative (WHI). Of those, 409 developed MM; 362 had no history of cancer.
At baseline, 98 (27%) women had high FRAX scores, and 264 (73%) had low scores. The median follow-up period was 10.5 years from enrollment and 7.2 years from the time of MM diagnosis. Of the patients with MM, 226 died during the follow-up period, including 71 with high FRAX scores and 155 with low scores. MM mortality was higher among women with high FRAX scores: 72%, vs 59% of those with low scores. Poor bone health was associated with greater MM mortality but was not related to delay in time to diagnosis.
During the evaluation, 57 fractures were reported, 65% before MM diagnosis. Fewer than half of the women had a first fracture after diagnosis. The probability of fracture was similar among the women, regardless of FRAX score. Not surprisingly, older women with lower BMI were most at risk.
The WHI does not include information on staging, chemotherapy, or use of bisphosphonates. Therefore, the impact of bisphosphonates could not be determined in this study. The researchers also did not know how many patients might have had pre-existing monoclonal gammopathy of undetermined significance, a disorder in about 3% of the aging population that progresses to MM in 1% per year.
Source:
Rosko AE, Hade EM, Li W, et al. Clin Lymphoma Myeloma Leuk. 2018;18(9):597-602.
Report details financial burden of blood cancers
with costs for acute leukemia almost tripling that amount, according to a new report from the Leukemia & Lymphoma Society (LLS).
Total allowed cost – the average amount paid by the insurer and patient combined – for acute leukemia was more than $463,000 for the 12 months after initial diagnosis. Averages for the other four cancers included in the analysis came in at $214,000 for multiple myeloma, $134,000 for bone marrow disorders, $131,000 for lymphoma, and $89,000 for chronic leukemia, the LLS said.
The cost figures are drawn from claims data for 2,332 patients diagnosed in 2014.
Differences in out-of-pocket (OOP) costs were smaller, with the average for all patients at almost $3,900 in the year after diagnosis and acute leukemia coming in the highest at $5,100. Over time, however, OOP costs for multiple myeloma patients became the highest, totaling $9,100 for the 3 years after diagnosis, compared with $8,800 for acute leukemia and an average of less than $7,800 for the other blood cancers, the LLS said in the report, which was prepared by the actuarial firm Milliman.
OOP costs also varied by the type of plan. Patients in high-deductible plans averaged nearly $5,400 for the first year after diagnosis, compared with $3,300 for those with traditional insurance, the LLS noted. For acute leukemia, the OOP costs of high-deductible plans were more than twice as high as those of traditional plans.
The study was based on data for adults aged 18-64 years from the Truven Health MarketScan commercial claims databases for the years from 2013 to 2016. The LLS received support for the study from Pfizer, Genentech, and Amgen.
with costs for acute leukemia almost tripling that amount, according to a new report from the Leukemia & Lymphoma Society (LLS).
Total allowed cost – the average amount paid by the insurer and patient combined – for acute leukemia was more than $463,000 for the 12 months after initial diagnosis. Averages for the other four cancers included in the analysis came in at $214,000 for multiple myeloma, $134,000 for bone marrow disorders, $131,000 for lymphoma, and $89,000 for chronic leukemia, the LLS said.
The cost figures are drawn from claims data for 2,332 patients diagnosed in 2014.
Differences in out-of-pocket (OOP) costs were smaller, with the average for all patients at almost $3,900 in the year after diagnosis and acute leukemia coming in the highest at $5,100. Over time, however, OOP costs for multiple myeloma patients became the highest, totaling $9,100 for the 3 years after diagnosis, compared with $8,800 for acute leukemia and an average of less than $7,800 for the other blood cancers, the LLS said in the report, which was prepared by the actuarial firm Milliman.
OOP costs also varied by the type of plan. Patients in high-deductible plans averaged nearly $5,400 for the first year after diagnosis, compared with $3,300 for those with traditional insurance, the LLS noted. For acute leukemia, the OOP costs of high-deductible plans were more than twice as high as those of traditional plans.
The study was based on data for adults aged 18-64 years from the Truven Health MarketScan commercial claims databases for the years from 2013 to 2016. The LLS received support for the study from Pfizer, Genentech, and Amgen.
with costs for acute leukemia almost tripling that amount, according to a new report from the Leukemia & Lymphoma Society (LLS).
Total allowed cost – the average amount paid by the insurer and patient combined – for acute leukemia was more than $463,000 for the 12 months after initial diagnosis. Averages for the other four cancers included in the analysis came in at $214,000 for multiple myeloma, $134,000 for bone marrow disorders, $131,000 for lymphoma, and $89,000 for chronic leukemia, the LLS said.
The cost figures are drawn from claims data for 2,332 patients diagnosed in 2014.
Differences in out-of-pocket (OOP) costs were smaller, with the average for all patients at almost $3,900 in the year after diagnosis and acute leukemia coming in the highest at $5,100. Over time, however, OOP costs for multiple myeloma patients became the highest, totaling $9,100 for the 3 years after diagnosis, compared with $8,800 for acute leukemia and an average of less than $7,800 for the other blood cancers, the LLS said in the report, which was prepared by the actuarial firm Milliman.
OOP costs also varied by the type of plan. Patients in high-deductible plans averaged nearly $5,400 for the first year after diagnosis, compared with $3,300 for those with traditional insurance, the LLS noted. For acute leukemia, the OOP costs of high-deductible plans were more than twice as high as those of traditional plans.
The study was based on data for adults aged 18-64 years from the Truven Health MarketScan commercial claims databases for the years from 2013 to 2016. The LLS received support for the study from Pfizer, Genentech, and Amgen.
Molecule enhances PI activity in multiple myeloma
Researchers say they have identified a new class of protein disulfide isomerase (PDI) inhibitors that sensitize multiple myeloma (MM) cells to proteasome inhibitors (PIs).
The investigators screened approximately 20,000 compounds spanning multiple chemical libraries and found the compound E61 to be a “striking hit,” with a six-fold increase in bortezomib cytotoxicity and the ability to re-sensitize PI activity at low micromolar concentrations.
The researchers then synthesized and evaluated 150 E61 derivatives and discovered the lead candidate, E64FC26, which was highly synergistic with PIs at concentrations as low as 200 nM.
They reported that E64FC26 has “several advantages over previously reported PDI inhibitors, including superior potency and a pan-style mode of inhibition.”
“PDI is an attractive target in oncology, but good PDI inhibitors have been hard to find,” said Nathan G. Dolloff, PhD, of the Medical University of South Carolina (MUSC) in Charleston.
“The compounds we discovered have a lot of advantages, including high potency and good drug-like properties. We hope that those strengths translate into an effective new drug that can ultimately help patients.”
Dr. Dolloff and his colleagues reported their discovery in Leukemia.
The investigators detected the synergistic effects of E61 in combination with next-generation PIs, including carfilzomib, ixazomib, and oprozomib in both PI-sensitive and -resistant MM cell lines.
On the other hand, E61 had no effect on dexamethasone activity in dexamethasone-resistant cells. And E61 did not affect lenalidomide or doxorubicin cytotoxicity in PI-resistant cells.
The researchers also determined that E61 was only active in MM cells. E61 did not enhance the cytotoxic effects of PIs in normal cells.
This selective toxicity suggests that E61 may have “a wide therapeutic index in vivo,” the investigators wrote.
In vivo activity
To investigate the anti-MM activity and tolerability of E61 in vivo, the researchers treated a NOD-SCID IL2Rγ−/− mouse model with E61 at a continuous dose of 50 mg/kg/day.
E61 prolonged survival by 11 days in the treated mice (P=0.0007), and four of the 11 treated mice survived to the experiment’s end.
In another experiment, two of eight mice achieved a complete response.
After continuous dosing for 40 or more days, E61 was well tolerated, the investigators reported. The mice showed no overt signs of distress and did not lose weight.
Molecular target of E61
Using click (Cu(I)-catalyzed azide-alkyne cycloaddition) chemistry and a proteomics approach, the researchers then confirmed that PDI family members are the molecular target of E61.
Functional studies indicated that E61 inhibited PDI reductase activity in vitro. E61 also enhanced the accumulation of ubiquitinylated proteins and produced strong endoplasmic reticulum (ER) and oxidative stress responses when combined with PIs.
Anti-MM activity of E64FC26
The investigators used a structure activity relationship program to narrow the candidate molecules down to E64FC26.
E64FC26 demonstrated pan-inhibition in that it inhibited all members of the PDI family tested, including PDIA3, PDIA4, TXNDC5, and PDIA6.
E64FC26 also had greater in vitro potency against PDIA1 and the other PDI isoforms. It was the only compound to sensitize MM cells to PIs, with an average increase in PI sensitivity ranging from six- to seven-fold.
The researchers also noted that E64FC26 was superior to other PDI inhibitors they tested in activating ER stress.
The investigators tested the activity of E64FC26 in vivo using Vk*MYC transgenic mice, a model that closely resembles human MM.
Mice treated with E64FC26 had an immediate anti-MM response. Serum M-protein decreased in all mice by an average of 33 ± 7.9% (P=0.0135).
The investigators observed similar effects in a human xenotransplant MM model.
These mice were randomized to receive treatment with vehicle, E64FC26 (2 mg/kg for 3 days/week), bortezomib (0.25 mg/kg for 2 days/week), or a combination of the two agents.
E64FC26 increased median survival by 2 weeks compared with vehicle-treated mice (P<0.0001). By day 36, no vehicle-treated mouse survived, compared with 100% of the E64FC26-treated mice.
Single-agent bortezomib increased survival by 6 days (P=0.0007).
And the combination produced the greatest improvement in median survival, increasing it by 20 days (P<0.0001).
The investigators reported no overt toxicity or body weight fluctuation for mice treated with E64FC26 or the combination.
“These results provide preclinical proof of concept for the strategy of targeting PDI with this new class of compound for the treatment of MM,” the researchers concluded.
“One of the strengths of this study is that we spanned almost the entire drug discovery process,” Dr. Dolloff said. “We screened thousands of compounds, found an exciting molecule, deconvoluted what its binding target was, synthesized hundreds of derivatives to make it better, and then conducted animal studies.”
“The study has everything from biochemistry and cell biology to medicinal chemistry and animal pharmacology in it. There is still a lot of work to be done before this drug is ready for clinical trials in humans, but it has been a rewarding project, and I’m looking forward to the next steps.”
Dr. Dolloff is founder of Leukogene Therapeutics, Inc., which has licensed patents from MUSC, and a second study author is an inventor on patents. The other authors declared no conflicts of interest.
The research was supported by the National Institutes of Health/National Cancer Institute, the South Carolina Clinical & Translational Research Institute, the MUSC Hollings Cancer Center, and by the Hollings Cancer Center T32 Ruth L. Kirschstein National Research Service Award Training Program.
Researchers say they have identified a new class of protein disulfide isomerase (PDI) inhibitors that sensitize multiple myeloma (MM) cells to proteasome inhibitors (PIs).
The investigators screened approximately 20,000 compounds spanning multiple chemical libraries and found the compound E61 to be a “striking hit,” with a six-fold increase in bortezomib cytotoxicity and the ability to re-sensitize PI activity at low micromolar concentrations.
The researchers then synthesized and evaluated 150 E61 derivatives and discovered the lead candidate, E64FC26, which was highly synergistic with PIs at concentrations as low as 200 nM.
They reported that E64FC26 has “several advantages over previously reported PDI inhibitors, including superior potency and a pan-style mode of inhibition.”
“PDI is an attractive target in oncology, but good PDI inhibitors have been hard to find,” said Nathan G. Dolloff, PhD, of the Medical University of South Carolina (MUSC) in Charleston.
“The compounds we discovered have a lot of advantages, including high potency and good drug-like properties. We hope that those strengths translate into an effective new drug that can ultimately help patients.”
Dr. Dolloff and his colleagues reported their discovery in Leukemia.
The investigators detected the synergistic effects of E61 in combination with next-generation PIs, including carfilzomib, ixazomib, and oprozomib in both PI-sensitive and -resistant MM cell lines.
On the other hand, E61 had no effect on dexamethasone activity in dexamethasone-resistant cells. And E61 did not affect lenalidomide or doxorubicin cytotoxicity in PI-resistant cells.
The researchers also determined that E61 was only active in MM cells. E61 did not enhance the cytotoxic effects of PIs in normal cells.
This selective toxicity suggests that E61 may have “a wide therapeutic index in vivo,” the investigators wrote.
In vivo activity
To investigate the anti-MM activity and tolerability of E61 in vivo, the researchers treated a NOD-SCID IL2Rγ−/− mouse model with E61 at a continuous dose of 50 mg/kg/day.
E61 prolonged survival by 11 days in the treated mice (P=0.0007), and four of the 11 treated mice survived to the experiment’s end.
In another experiment, two of eight mice achieved a complete response.
After continuous dosing for 40 or more days, E61 was well tolerated, the investigators reported. The mice showed no overt signs of distress and did not lose weight.
Molecular target of E61
Using click (Cu(I)-catalyzed azide-alkyne cycloaddition) chemistry and a proteomics approach, the researchers then confirmed that PDI family members are the molecular target of E61.
Functional studies indicated that E61 inhibited PDI reductase activity in vitro. E61 also enhanced the accumulation of ubiquitinylated proteins and produced strong endoplasmic reticulum (ER) and oxidative stress responses when combined with PIs.
Anti-MM activity of E64FC26
The investigators used a structure activity relationship program to narrow the candidate molecules down to E64FC26.
E64FC26 demonstrated pan-inhibition in that it inhibited all members of the PDI family tested, including PDIA3, PDIA4, TXNDC5, and PDIA6.
E64FC26 also had greater in vitro potency against PDIA1 and the other PDI isoforms. It was the only compound to sensitize MM cells to PIs, with an average increase in PI sensitivity ranging from six- to seven-fold.
The researchers also noted that E64FC26 was superior to other PDI inhibitors they tested in activating ER stress.
The investigators tested the activity of E64FC26 in vivo using Vk*MYC transgenic mice, a model that closely resembles human MM.
Mice treated with E64FC26 had an immediate anti-MM response. Serum M-protein decreased in all mice by an average of 33 ± 7.9% (P=0.0135).
The investigators observed similar effects in a human xenotransplant MM model.
These mice were randomized to receive treatment with vehicle, E64FC26 (2 mg/kg for 3 days/week), bortezomib (0.25 mg/kg for 2 days/week), or a combination of the two agents.
E64FC26 increased median survival by 2 weeks compared with vehicle-treated mice (P<0.0001). By day 36, no vehicle-treated mouse survived, compared with 100% of the E64FC26-treated mice.
Single-agent bortezomib increased survival by 6 days (P=0.0007).
And the combination produced the greatest improvement in median survival, increasing it by 20 days (P<0.0001).
The investigators reported no overt toxicity or body weight fluctuation for mice treated with E64FC26 or the combination.
“These results provide preclinical proof of concept for the strategy of targeting PDI with this new class of compound for the treatment of MM,” the researchers concluded.
“One of the strengths of this study is that we spanned almost the entire drug discovery process,” Dr. Dolloff said. “We screened thousands of compounds, found an exciting molecule, deconvoluted what its binding target was, synthesized hundreds of derivatives to make it better, and then conducted animal studies.”
“The study has everything from biochemistry and cell biology to medicinal chemistry and animal pharmacology in it. There is still a lot of work to be done before this drug is ready for clinical trials in humans, but it has been a rewarding project, and I’m looking forward to the next steps.”
Dr. Dolloff is founder of Leukogene Therapeutics, Inc., which has licensed patents from MUSC, and a second study author is an inventor on patents. The other authors declared no conflicts of interest.
The research was supported by the National Institutes of Health/National Cancer Institute, the South Carolina Clinical & Translational Research Institute, the MUSC Hollings Cancer Center, and by the Hollings Cancer Center T32 Ruth L. Kirschstein National Research Service Award Training Program.
Researchers say they have identified a new class of protein disulfide isomerase (PDI) inhibitors that sensitize multiple myeloma (MM) cells to proteasome inhibitors (PIs).
The investigators screened approximately 20,000 compounds spanning multiple chemical libraries and found the compound E61 to be a “striking hit,” with a six-fold increase in bortezomib cytotoxicity and the ability to re-sensitize PI activity at low micromolar concentrations.
The researchers then synthesized and evaluated 150 E61 derivatives and discovered the lead candidate, E64FC26, which was highly synergistic with PIs at concentrations as low as 200 nM.
They reported that E64FC26 has “several advantages over previously reported PDI inhibitors, including superior potency and a pan-style mode of inhibition.”
“PDI is an attractive target in oncology, but good PDI inhibitors have been hard to find,” said Nathan G. Dolloff, PhD, of the Medical University of South Carolina (MUSC) in Charleston.
“The compounds we discovered have a lot of advantages, including high potency and good drug-like properties. We hope that those strengths translate into an effective new drug that can ultimately help patients.”
Dr. Dolloff and his colleagues reported their discovery in Leukemia.
The investigators detected the synergistic effects of E61 in combination with next-generation PIs, including carfilzomib, ixazomib, and oprozomib in both PI-sensitive and -resistant MM cell lines.
On the other hand, E61 had no effect on dexamethasone activity in dexamethasone-resistant cells. And E61 did not affect lenalidomide or doxorubicin cytotoxicity in PI-resistant cells.
The researchers also determined that E61 was only active in MM cells. E61 did not enhance the cytotoxic effects of PIs in normal cells.
This selective toxicity suggests that E61 may have “a wide therapeutic index in vivo,” the investigators wrote.
In vivo activity
To investigate the anti-MM activity and tolerability of E61 in vivo, the researchers treated a NOD-SCID IL2Rγ−/− mouse model with E61 at a continuous dose of 50 mg/kg/day.
E61 prolonged survival by 11 days in the treated mice (P=0.0007), and four of the 11 treated mice survived to the experiment’s end.
In another experiment, two of eight mice achieved a complete response.
After continuous dosing for 40 or more days, E61 was well tolerated, the investigators reported. The mice showed no overt signs of distress and did not lose weight.
Molecular target of E61
Using click (Cu(I)-catalyzed azide-alkyne cycloaddition) chemistry and a proteomics approach, the researchers then confirmed that PDI family members are the molecular target of E61.
Functional studies indicated that E61 inhibited PDI reductase activity in vitro. E61 also enhanced the accumulation of ubiquitinylated proteins and produced strong endoplasmic reticulum (ER) and oxidative stress responses when combined with PIs.
Anti-MM activity of E64FC26
The investigators used a structure activity relationship program to narrow the candidate molecules down to E64FC26.
E64FC26 demonstrated pan-inhibition in that it inhibited all members of the PDI family tested, including PDIA3, PDIA4, TXNDC5, and PDIA6.
E64FC26 also had greater in vitro potency against PDIA1 and the other PDI isoforms. It was the only compound to sensitize MM cells to PIs, with an average increase in PI sensitivity ranging from six- to seven-fold.
The researchers also noted that E64FC26 was superior to other PDI inhibitors they tested in activating ER stress.
The investigators tested the activity of E64FC26 in vivo using Vk*MYC transgenic mice, a model that closely resembles human MM.
Mice treated with E64FC26 had an immediate anti-MM response. Serum M-protein decreased in all mice by an average of 33 ± 7.9% (P=0.0135).
The investigators observed similar effects in a human xenotransplant MM model.
These mice were randomized to receive treatment with vehicle, E64FC26 (2 mg/kg for 3 days/week), bortezomib (0.25 mg/kg for 2 days/week), or a combination of the two agents.
E64FC26 increased median survival by 2 weeks compared with vehicle-treated mice (P<0.0001). By day 36, no vehicle-treated mouse survived, compared with 100% of the E64FC26-treated mice.
Single-agent bortezomib increased survival by 6 days (P=0.0007).
And the combination produced the greatest improvement in median survival, increasing it by 20 days (P<0.0001).
The investigators reported no overt toxicity or body weight fluctuation for mice treated with E64FC26 or the combination.
“These results provide preclinical proof of concept for the strategy of targeting PDI with this new class of compound for the treatment of MM,” the researchers concluded.
“One of the strengths of this study is that we spanned almost the entire drug discovery process,” Dr. Dolloff said. “We screened thousands of compounds, found an exciting molecule, deconvoluted what its binding target was, synthesized hundreds of derivatives to make it better, and then conducted animal studies.”
“The study has everything from biochemistry and cell biology to medicinal chemistry and animal pharmacology in it. There is still a lot of work to be done before this drug is ready for clinical trials in humans, but it has been a rewarding project, and I’m looking forward to the next steps.”
Dr. Dolloff is founder of Leukogene Therapeutics, Inc., which has licensed patents from MUSC, and a second study author is an inventor on patents. The other authors declared no conflicts of interest.
The research was supported by the National Institutes of Health/National Cancer Institute, the South Carolina Clinical & Translational Research Institute, the MUSC Hollings Cancer Center, and by the Hollings Cancer Center T32 Ruth L. Kirschstein National Research Service Award Training Program.
FDA clears portable hematology analyzer
The U.S. Food and Drug Administration (FDA) has granted 510(k) clearance for PixCell Medical’s HemoScreen™.
This portable hematology analyzer is used to perform a complete blood count at the point of care.
HemoScreen requires a single drop of blood and uses disposable cartridges that provide automatic sample preparation.
HemoScreen can analyze 20 standard complete blood count parameters and produces results within 5 minutes.
Study results suggested that HemoScreen provides results comparable to those of another hematology analyzer, Sysmex XE-2100. This study was published in the Journal of Clinical Pathology in 2016.
“The HemoScreen delivers lab-accurate results,” said Avishay Bransky, PhD, chief executive officer of PixCell Medical.
He added that HemoScreen “would be especially useful” in physicians’ offices, emergency rooms, intensive care units, oncology clinics, and remote locations.
HemoScreen makes use of a technology called viscoelastic focusing, which employs microfluidics and machine vision algorithms to analyze cells.
The U.S. Food and Drug Administration (FDA) has granted 510(k) clearance for PixCell Medical’s HemoScreen™.
This portable hematology analyzer is used to perform a complete blood count at the point of care.
HemoScreen requires a single drop of blood and uses disposable cartridges that provide automatic sample preparation.
HemoScreen can analyze 20 standard complete blood count parameters and produces results within 5 minutes.
Study results suggested that HemoScreen provides results comparable to those of another hematology analyzer, Sysmex XE-2100. This study was published in the Journal of Clinical Pathology in 2016.
“The HemoScreen delivers lab-accurate results,” said Avishay Bransky, PhD, chief executive officer of PixCell Medical.
He added that HemoScreen “would be especially useful” in physicians’ offices, emergency rooms, intensive care units, oncology clinics, and remote locations.
HemoScreen makes use of a technology called viscoelastic focusing, which employs microfluidics and machine vision algorithms to analyze cells.
The U.S. Food and Drug Administration (FDA) has granted 510(k) clearance for PixCell Medical’s HemoScreen™.
This portable hematology analyzer is used to perform a complete blood count at the point of care.
HemoScreen requires a single drop of blood and uses disposable cartridges that provide automatic sample preparation.
HemoScreen can analyze 20 standard complete blood count parameters and produces results within 5 minutes.
Study results suggested that HemoScreen provides results comparable to those of another hematology analyzer, Sysmex XE-2100. This study was published in the Journal of Clinical Pathology in 2016.
“The HemoScreen delivers lab-accurate results,” said Avishay Bransky, PhD, chief executive officer of PixCell Medical.
He added that HemoScreen “would be especially useful” in physicians’ offices, emergency rooms, intensive care units, oncology clinics, and remote locations.
HemoScreen makes use of a technology called viscoelastic focusing, which employs microfluidics and machine vision algorithms to analyze cells.