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Legislators question price of leukemia drug
Photo from Business Wire
A pair of US legislators are questioning why ARIAD Pharmaceuticals, Inc. has increased the price of its leukemia drug Iclusig (ponatinib) by more than $80,000 over the last several years.
ARIAD raised the price of Iclusig 4 times in 2016. The drug now costs nearly $199,000 a year.
Senator Bernie Sanders (Vermont) and Congressman Elijah Cummings (Maryland) sent a letter to ARIAD last week requesting information about these price increases.
Cummings and Sanders are also investigating whether ARIAD took additional steps to boost profits by discontinuing sales of certain dosages and quantities of Iclusig in order to charge patients and insurers more in exchange for less medicine.
“These outrageous sales tactics indicate that ARIAD is more concerned with its profit than with its patients,” Sanders and Cummings wrote in the letter.
The US Food and Drug Administration (FDA) approved Iclusig in December 2012 to treat chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).
In late 2013, the FDA suspended sales and clinical trials of the drug due to reports of serious adverse events.
The FDA allowed ARIAD to resume selling Iclusig in December 2013, but only to CML/ALL patients who cannot tolerate, or whose disease is resistant to, other tyrosine kinase inhibitors.
“Despite this new evidence showing the drug posed a far greater safety risk to patients than was known when the drug came on the market, ARIAD nonetheless raised the price of Iclusig several times over the subsequent 4 years,” Sanders and Cummings wrote.
“In the interest of patients and taxpayers, we are interested in learning more about the impact that the escalating price and restrictions on product availability have had.”
ARIAD has released a statement acknowledging Cummings’ and Sanders’ letter and defending its decisions to increase the price of Iclusig.
The company said it “makes significant investments in research and development (R&D) to advance breakthrough treatments” for patients with rare cancers.
In fact, ARIAD has invested more than $1.3 billion in R&D and accumulated losses of approximately $1.4 billion, which have not been recovered. In 2015, ARIAD generated $119 million in total revenue and invested $171 million in R&D.
The company said it intends to respond to Cummings’ and Sanders’ request for information. 
Photo from Business Wire
A pair of US legislators are questioning why ARIAD Pharmaceuticals, Inc. has increased the price of its leukemia drug Iclusig (ponatinib) by more than $80,000 over the last several years.
ARIAD raised the price of Iclusig 4 times in 2016. The drug now costs nearly $199,000 a year.
Senator Bernie Sanders (Vermont) and Congressman Elijah Cummings (Maryland) sent a letter to ARIAD last week requesting information about these price increases.
Cummings and Sanders are also investigating whether ARIAD took additional steps to boost profits by discontinuing sales of certain dosages and quantities of Iclusig in order to charge patients and insurers more in exchange for less medicine.
“These outrageous sales tactics indicate that ARIAD is more concerned with its profit than with its patients,” Sanders and Cummings wrote in the letter.
The US Food and Drug Administration (FDA) approved Iclusig in December 2012 to treat chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).
In late 2013, the FDA suspended sales and clinical trials of the drug due to reports of serious adverse events.
The FDA allowed ARIAD to resume selling Iclusig in December 2013, but only to CML/ALL patients who cannot tolerate, or whose disease is resistant to, other tyrosine kinase inhibitors.
“Despite this new evidence showing the drug posed a far greater safety risk to patients than was known when the drug came on the market, ARIAD nonetheless raised the price of Iclusig several times over the subsequent 4 years,” Sanders and Cummings wrote.
“In the interest of patients and taxpayers, we are interested in learning more about the impact that the escalating price and restrictions on product availability have had.”
ARIAD has released a statement acknowledging Cummings’ and Sanders’ letter and defending its decisions to increase the price of Iclusig.
The company said it “makes significant investments in research and development (R&D) to advance breakthrough treatments” for patients with rare cancers.
In fact, ARIAD has invested more than $1.3 billion in R&D and accumulated losses of approximately $1.4 billion, which have not been recovered. In 2015, ARIAD generated $119 million in total revenue and invested $171 million in R&D.
The company said it intends to respond to Cummings’ and Sanders’ request for information.
Photo from Business Wire
A pair of US legislators are questioning why ARIAD Pharmaceuticals, Inc. has increased the price of its leukemia drug Iclusig (ponatinib) by more than $80,000 over the last several years.
ARIAD raised the price of Iclusig 4 times in 2016. The drug now costs nearly $199,000 a year.
Senator Bernie Sanders (Vermont) and Congressman Elijah Cummings (Maryland) sent a letter to ARIAD last week requesting information about these price increases.
Cummings and Sanders are also investigating whether ARIAD took additional steps to boost profits by discontinuing sales of certain dosages and quantities of Iclusig in order to charge patients and insurers more in exchange for less medicine.
“These outrageous sales tactics indicate that ARIAD is more concerned with its profit than with its patients,” Sanders and Cummings wrote in the letter.
The US Food and Drug Administration (FDA) approved Iclusig in December 2012 to treat chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).
In late 2013, the FDA suspended sales and clinical trials of the drug due to reports of serious adverse events.
The FDA allowed ARIAD to resume selling Iclusig in December 2013, but only to CML/ALL patients who cannot tolerate, or whose disease is resistant to, other tyrosine kinase inhibitors.
“Despite this new evidence showing the drug posed a far greater safety risk to patients than was known when the drug came on the market, ARIAD nonetheless raised the price of Iclusig several times over the subsequent 4 years,” Sanders and Cummings wrote.
“In the interest of patients and taxpayers, we are interested in learning more about the impact that the escalating price and restrictions on product availability have had.”
ARIAD has released a statement acknowledging Cummings’ and Sanders’ letter and defending its decisions to increase the price of Iclusig.
The company said it “makes significant investments in research and development (R&D) to advance breakthrough treatments” for patients with rare cancers.
In fact, ARIAD has invested more than $1.3 billion in R&D and accumulated losses of approximately $1.4 billion, which have not been recovered. In 2015, ARIAD generated $119 million in total revenue and invested $171 million in R&D.
The company said it intends to respond to Cummings’ and Sanders’ request for information.
FDA issues warning about radiation therapy devices
to receive radiation
Photo by Rhoda Baer
The US Food and Drug Administration (FDA) has warned healthcare providers to stop using radiation therapy devices manufactured and sold by Multidata Systems International Corporation.
The FDA said the company has distributed at least 2 devices in the US that were never reviewed by or registered with the FDA—(1) accessories to radiation therapy devices including the Real Time Dosimetry Waterphantom System and (2) the Dual Channel Electrometer.
Since 2003, Multidata has been under a decree that prohibits the company from designing, manufacturing, processing, and distributing medical devices, among other restrictions.
However, the FDA learned that Multidata manufactured and distributed medical devices in violation of the decree, including repairing and exchanging Waterphantom devices for newer design models.
As a result, on March 3, 2016, the FDA sent a letter to Multidata ordering the firm to stop designing, manufacturing, processing, packing, repacking, labeling, installing, holding for sale, and distributing any medical device. The company has permanently ceased operations and will be dissolving.
The FDA said it doesn’t know how many devices manufactured by Multidata are in use throughout the US or if any of these devices have caused adverse events since the decree was issued.
The agency has urged healthcare providers to stop using and dispose of any devices manufactured by Multidata.
Instead, providers should use accessories to radiation therapy devices and radiation treatment planning software that have been cleared by the FDA. Registered manufacturers of such products are listed under the IYE product code in the FDA’s Registration and Listing Database.
The FDA has also recommended that providers report any adverse events related to Multidata devices. Reports can be submitted through MedWatch, the FDA’s Safety Information and Adverse Event Reporting Program.
to receive radiation
Photo by Rhoda Baer
The US Food and Drug Administration (FDA) has warned healthcare providers to stop using radiation therapy devices manufactured and sold by Multidata Systems International Corporation.
The FDA said the company has distributed at least 2 devices in the US that were never reviewed by or registered with the FDA—(1) accessories to radiation therapy devices including the Real Time Dosimetry Waterphantom System and (2) the Dual Channel Electrometer.
Since 2003, Multidata has been under a decree that prohibits the company from designing, manufacturing, processing, and distributing medical devices, among other restrictions.
However, the FDA learned that Multidata manufactured and distributed medical devices in violation of the decree, including repairing and exchanging Waterphantom devices for newer design models.
As a result, on March 3, 2016, the FDA sent a letter to Multidata ordering the firm to stop designing, manufacturing, processing, packing, repacking, labeling, installing, holding for sale, and distributing any medical device. The company has permanently ceased operations and will be dissolving.
The FDA said it doesn’t know how many devices manufactured by Multidata are in use throughout the US or if any of these devices have caused adverse events since the decree was issued.
The agency has urged healthcare providers to stop using and dispose of any devices manufactured by Multidata.
Instead, providers should use accessories to radiation therapy devices and radiation treatment planning software that have been cleared by the FDA. Registered manufacturers of such products are listed under the IYE product code in the FDA’s Registration and Listing Database.
The FDA has also recommended that providers report any adverse events related to Multidata devices. Reports can be submitted through MedWatch, the FDA’s Safety Information and Adverse Event Reporting Program.
to receive radiation
Photo by Rhoda Baer
The US Food and Drug Administration (FDA) has warned healthcare providers to stop using radiation therapy devices manufactured and sold by Multidata Systems International Corporation.
The FDA said the company has distributed at least 2 devices in the US that were never reviewed by or registered with the FDA—(1) accessories to radiation therapy devices including the Real Time Dosimetry Waterphantom System and (2) the Dual Channel Electrometer.
Since 2003, Multidata has been under a decree that prohibits the company from designing, manufacturing, processing, and distributing medical devices, among other restrictions.
However, the FDA learned that Multidata manufactured and distributed medical devices in violation of the decree, including repairing and exchanging Waterphantom devices for newer design models.
As a result, on March 3, 2016, the FDA sent a letter to Multidata ordering the firm to stop designing, manufacturing, processing, packing, repacking, labeling, installing, holding for sale, and distributing any medical device. The company has permanently ceased operations and will be dissolving.
The FDA said it doesn’t know how many devices manufactured by Multidata are in use throughout the US or if any of these devices have caused adverse events since the decree was issued.
The agency has urged healthcare providers to stop using and dispose of any devices manufactured by Multidata.
Instead, providers should use accessories to radiation therapy devices and radiation treatment planning software that have been cleared by the FDA. Registered manufacturers of such products are listed under the IYE product code in the FDA’s Registration and Listing Database.
The FDA has also recommended that providers report any adverse events related to Multidata devices. Reports can be submitted through MedWatch, the FDA’s Safety Information and Adverse Event Reporting Program.
Burden of cancer varies by cancer type, race
Photo by Rhoda Baer
A new study suggests that leukemia and non-Hodgkin lymphoma (NHL) are among the top 10 cancers with the greatest burden (most years of healthy life lost) in the US.
The research also showed that the burden of different cancer types varied between patients belonging to different racial/ethnic groups.
For example, the contribution of leukemia to the overall cancer burden was twice as high in Hispanics as it was in non-Hispanic blacks. The same was true for NHL.
Joannie Lortet-Tieulent, of the American Cancer Society in Atlanta, Georgia, and her colleagues conducted this study and reported the results in the American Journal of Preventive Medicine.
The researchers calculated the burden of cancer in the US in 2011 for 24 cancer types. They calculated burden using disability-adjusted life years (DALYs), which combine cancer incidence, mortality, survival, and quality of life into a summary indicator.
The results suggested the burden of cancer in 2011 was over 9.8 million DALYs, which was equally shared between men and women—4.9 million DALYs for each sex.
DALYs lost to cancer were mostly related to premature death due to cancer (91%). The remaining 9% were related to impaired quality of life because of the disease or its treatment, or other disease-related issues.
Top 10 contributors
The researchers calculated the proportion of DALYs lost for each of the cancer types. And they found that lung cancer was the largest contributor to the loss of healthy years, accounting for 24% of the burden (2.4 million DALYs).
The second biggest contributor to the loss of healthy years was breast cancer (10%), followed by colorectal cancer (9%), pancreatic cancer (6%), prostate cancer (5%), leukemia (4%), liver cancer (4%), brain cancer (3%), NHL (3%), and ovarian cancer (3%).
The researchers also calculated the proportion of DALYs lost from the top 10 cancer types according to race/ethnicity.
They found the contribution of leukemia to the loss of healthy years was greatest for Hispanics (6%), followed by non-Hispanic Asians (5%), non-Hispanic whites (4%), and non-Hispanic blacks (3%).
The contribution of NHL to the loss of healthy years was greatest for Hispanics (4%), followed by non-Hispanic Asians/non-Hispanic whites (3% for both), and non-Hispanic blacks (2%).
DALYs by race/ethnicity
The researchers found that, overall, the cancer burden was highest in non-Hispanic blacks, followed by non-Hispanic whites, Hispanics, and non-Hispanic Asians. However, this pattern was not consistent across the different cancer types.
Age-standardized DALYs lost (per 100,000 individuals) were as follows:
All cancers combined
3588 for non-Hispanic blacks
2898 for non-Hispanic whites
1978 for Hispanics
1798 for non-Hispanic Asians.
Leukemia
115 for non-Hispanic blacks and non-Hispanic whites
98 for Hispanics
82 for non-Hispanic Asians.
NHL
93 for non-Hispanic whites
86 for non-Hispanic blacks
78 for Hispanics
60 for non-Hispanic Asians.
Hodgkin lymphoma
11 for non-Hispanic blacks
10 for non-Hispanic whites and Hispanics
3 for non-Hispanic Asians.
Myeloma
93 for non-Hispanic blacks
43 for non-Hispanic whites
42 for Hispanics
26 for non-Hispanic Asians.
The researchers noted that, despite these differences, the cancer burden in all races/ethnicities was driven by years of life lost. They said this highlights the need to prevent deaths by improving prevention, early detection, and treatment of cancers.
Photo by Rhoda Baer
A new study suggests that leukemia and non-Hodgkin lymphoma (NHL) are among the top 10 cancers with the greatest burden (most years of healthy life lost) in the US.
The research also showed that the burden of different cancer types varied between patients belonging to different racial/ethnic groups.
For example, the contribution of leukemia to the overall cancer burden was twice as high in Hispanics as it was in non-Hispanic blacks. The same was true for NHL.
Joannie Lortet-Tieulent, of the American Cancer Society in Atlanta, Georgia, and her colleagues conducted this study and reported the results in the American Journal of Preventive Medicine.
The researchers calculated the burden of cancer in the US in 2011 for 24 cancer types. They calculated burden using disability-adjusted life years (DALYs), which combine cancer incidence, mortality, survival, and quality of life into a summary indicator.
The results suggested the burden of cancer in 2011 was over 9.8 million DALYs, which was equally shared between men and women—4.9 million DALYs for each sex.
DALYs lost to cancer were mostly related to premature death due to cancer (91%). The remaining 9% were related to impaired quality of life because of the disease or its treatment, or other disease-related issues.
Top 10 contributors
The researchers calculated the proportion of DALYs lost for each of the cancer types. And they found that lung cancer was the largest contributor to the loss of healthy years, accounting for 24% of the burden (2.4 million DALYs).
The second biggest contributor to the loss of healthy years was breast cancer (10%), followed by colorectal cancer (9%), pancreatic cancer (6%), prostate cancer (5%), leukemia (4%), liver cancer (4%), brain cancer (3%), NHL (3%), and ovarian cancer (3%).
The researchers also calculated the proportion of DALYs lost from the top 10 cancer types according to race/ethnicity.
They found the contribution of leukemia to the loss of healthy years was greatest for Hispanics (6%), followed by non-Hispanic Asians (5%), non-Hispanic whites (4%), and non-Hispanic blacks (3%).
The contribution of NHL to the loss of healthy years was greatest for Hispanics (4%), followed by non-Hispanic Asians/non-Hispanic whites (3% for both), and non-Hispanic blacks (2%).
DALYs by race/ethnicity
The researchers found that, overall, the cancer burden was highest in non-Hispanic blacks, followed by non-Hispanic whites, Hispanics, and non-Hispanic Asians. However, this pattern was not consistent across the different cancer types.
Age-standardized DALYs lost (per 100,000 individuals) were as follows:
All cancers combined
3588 for non-Hispanic blacks
2898 for non-Hispanic whites
1978 for Hispanics
1798 for non-Hispanic Asians.
Leukemia
115 for non-Hispanic blacks and non-Hispanic whites
98 for Hispanics
82 for non-Hispanic Asians.
NHL
93 for non-Hispanic whites
86 for non-Hispanic blacks
78 for Hispanics
60 for non-Hispanic Asians.
Hodgkin lymphoma
11 for non-Hispanic blacks
10 for non-Hispanic whites and Hispanics
3 for non-Hispanic Asians.
Myeloma
93 for non-Hispanic blacks
43 for non-Hispanic whites
42 for Hispanics
26 for non-Hispanic Asians.
The researchers noted that, despite these differences, the cancer burden in all races/ethnicities was driven by years of life lost. They said this highlights the need to prevent deaths by improving prevention, early detection, and treatment of cancers.
Photo by Rhoda Baer
A new study suggests that leukemia and non-Hodgkin lymphoma (NHL) are among the top 10 cancers with the greatest burden (most years of healthy life lost) in the US.
The research also showed that the burden of different cancer types varied between patients belonging to different racial/ethnic groups.
For example, the contribution of leukemia to the overall cancer burden was twice as high in Hispanics as it was in non-Hispanic blacks. The same was true for NHL.
Joannie Lortet-Tieulent, of the American Cancer Society in Atlanta, Georgia, and her colleagues conducted this study and reported the results in the American Journal of Preventive Medicine.
The researchers calculated the burden of cancer in the US in 2011 for 24 cancer types. They calculated burden using disability-adjusted life years (DALYs), which combine cancer incidence, mortality, survival, and quality of life into a summary indicator.
The results suggested the burden of cancer in 2011 was over 9.8 million DALYs, which was equally shared between men and women—4.9 million DALYs for each sex.
DALYs lost to cancer were mostly related to premature death due to cancer (91%). The remaining 9% were related to impaired quality of life because of the disease or its treatment, or other disease-related issues.
Top 10 contributors
The researchers calculated the proportion of DALYs lost for each of the cancer types. And they found that lung cancer was the largest contributor to the loss of healthy years, accounting for 24% of the burden (2.4 million DALYs).
The second biggest contributor to the loss of healthy years was breast cancer (10%), followed by colorectal cancer (9%), pancreatic cancer (6%), prostate cancer (5%), leukemia (4%), liver cancer (4%), brain cancer (3%), NHL (3%), and ovarian cancer (3%).
The researchers also calculated the proportion of DALYs lost from the top 10 cancer types according to race/ethnicity.
They found the contribution of leukemia to the loss of healthy years was greatest for Hispanics (6%), followed by non-Hispanic Asians (5%), non-Hispanic whites (4%), and non-Hispanic blacks (3%).
The contribution of NHL to the loss of healthy years was greatest for Hispanics (4%), followed by non-Hispanic Asians/non-Hispanic whites (3% for both), and non-Hispanic blacks (2%).
DALYs by race/ethnicity
The researchers found that, overall, the cancer burden was highest in non-Hispanic blacks, followed by non-Hispanic whites, Hispanics, and non-Hispanic Asians. However, this pattern was not consistent across the different cancer types.
Age-standardized DALYs lost (per 100,000 individuals) were as follows:
All cancers combined
3588 for non-Hispanic blacks
2898 for non-Hispanic whites
1978 for Hispanics
1798 for non-Hispanic Asians.
Leukemia
115 for non-Hispanic blacks and non-Hispanic whites
98 for Hispanics
82 for non-Hispanic Asians.
NHL
93 for non-Hispanic whites
86 for non-Hispanic blacks
78 for Hispanics
60 for non-Hispanic Asians.
Hodgkin lymphoma
11 for non-Hispanic blacks
10 for non-Hispanic whites and Hispanics
3 for non-Hispanic Asians.
Myeloma
93 for non-Hispanic blacks
43 for non-Hispanic whites
42 for Hispanics
26 for non-Hispanic Asians.
The researchers noted that, despite these differences, the cancer burden in all races/ethnicities was driven by years of life lost. They said this highlights the need to prevent deaths by improving prevention, early detection, and treatment of cancers.
Single-cell findings could inform CLL treatment
Researchers say they have found a better way to examine individual cells, and this tool provided insight that could inform the treatment of leukemia.
The team used a technique called microarrayed single-cell sequencing (MASC-seq) to examine individual cells in samples from patients with chronic lymphocytic leukemia (CLL).
This revealed a number of CLL subclones within each sample that exhibited different gene expression.
“With this new, highly cost-effective technology, we can now get a whole new view of this complexity within the blood cancer sample,” said study author Joakim Lundeberg, PhD, of KTH Royal Institute of Technology in Stockholm, Sweden.
“Molecular resolution of single cells is likely to become a more widely used therapy option.”
Dr Lundeberg and his colleagues described this work in Nature Communications.
The researchers said current methods of single-cell analysis don’t allow for the combination of cell imaging and transcriptome profiling, exhibit low-throughput by analyzing a single cell at a time, or require expensive droplet instrumentation for high-throughput analysis.
MASC-seq, on the other hand, can image cells to provide information on morphology and profile the expression of thousands of single cells per day at a cost of $0.13 USD per cell.
Dr Lundeberg and his colleagues tested MASC-seq by analyzing samples from 3 patients with different subtypes of CLL.
The team found clear differences in the average gene expression levels of cells from the different CLL subtypes, but they also found subtle differences between single cells within each of the subtypes.
The researchers therefore concluded that MASC-seq has the potential to accelerate the study of subtle clonal dynamics and help provide insight into the development of CLL and other diseases.
Researchers say they have found a better way to examine individual cells, and this tool provided insight that could inform the treatment of leukemia.
The team used a technique called microarrayed single-cell sequencing (MASC-seq) to examine individual cells in samples from patients with chronic lymphocytic leukemia (CLL).
This revealed a number of CLL subclones within each sample that exhibited different gene expression.
“With this new, highly cost-effective technology, we can now get a whole new view of this complexity within the blood cancer sample,” said study author Joakim Lundeberg, PhD, of KTH Royal Institute of Technology in Stockholm, Sweden.
“Molecular resolution of single cells is likely to become a more widely used therapy option.”
Dr Lundeberg and his colleagues described this work in Nature Communications.
The researchers said current methods of single-cell analysis don’t allow for the combination of cell imaging and transcriptome profiling, exhibit low-throughput by analyzing a single cell at a time, or require expensive droplet instrumentation for high-throughput analysis.
MASC-seq, on the other hand, can image cells to provide information on morphology and profile the expression of thousands of single cells per day at a cost of $0.13 USD per cell.
Dr Lundeberg and his colleagues tested MASC-seq by analyzing samples from 3 patients with different subtypes of CLL.
The team found clear differences in the average gene expression levels of cells from the different CLL subtypes, but they also found subtle differences between single cells within each of the subtypes.
The researchers therefore concluded that MASC-seq has the potential to accelerate the study of subtle clonal dynamics and help provide insight into the development of CLL and other diseases.
Researchers say they have found a better way to examine individual cells, and this tool provided insight that could inform the treatment of leukemia.
The team used a technique called microarrayed single-cell sequencing (MASC-seq) to examine individual cells in samples from patients with chronic lymphocytic leukemia (CLL).
This revealed a number of CLL subclones within each sample that exhibited different gene expression.
“With this new, highly cost-effective technology, we can now get a whole new view of this complexity within the blood cancer sample,” said study author Joakim Lundeberg, PhD, of KTH Royal Institute of Technology in Stockholm, Sweden.
“Molecular resolution of single cells is likely to become a more widely used therapy option.”
Dr Lundeberg and his colleagues described this work in Nature Communications.
The researchers said current methods of single-cell analysis don’t allow for the combination of cell imaging and transcriptome profiling, exhibit low-throughput by analyzing a single cell at a time, or require expensive droplet instrumentation for high-throughput analysis.
MASC-seq, on the other hand, can image cells to provide information on morphology and profile the expression of thousands of single cells per day at a cost of $0.13 USD per cell.
Dr Lundeberg and his colleagues tested MASC-seq by analyzing samples from 3 patients with different subtypes of CLL.
The team found clear differences in the average gene expression levels of cells from the different CLL subtypes, but they also found subtle differences between single cells within each of the subtypes.
The researchers therefore concluded that MASC-seq has the potential to accelerate the study of subtle clonal dynamics and help provide insight into the development of CLL and other diseases.
Combo produces CR/CRis in FLT3-ITD AML
Photo by Bill Branson
A 2-drug combination has shown promise for treating patients with FLT3-ITD acute myeloid leukemia (AML), according to research published in Science Translational Medicine.
Researchers found that omacetaxine mepesuccinate (formerly known as homoharringtonine) exhibits preferential antileukemic activity against FLT3-ITD AML.
Subsequent preclinical experiments revealed that omacetaxine synergizes with sorafenib and other FLT3 inhibitors.
So researchers tested omacetaxine in combination with sorafenib in a phase 2 trial of patients with FLT3-ITD AML.
The combination produced complete responses (CRs) or CRs with incomplete hematologic recovery (CRis) in a majority of patients, and researchers said the treatment was well-tolerated.
Anskar Y. H. Leung, MD, PhD, of The University of Hong Kong, and his colleagues conducted this research.
The team first performed an in vitro screen on AML patient samples to determine their responses to various drugs.
One of the compounds tested, the protein translation inhibitor omacetaxine mepesuccinate, showed strong antileukemic effects against FLT3-ITD AML. In fact, omacetaxine preferentially inhibited the growth of FLT3-ITD cell lines.
The researchers then found that omacetaxine synergizes with sorafenib and other FLT3 inhibitors to suppress leukemia growth in FLT3-ITD AML cell lines.
Omacetaxine and sorafenib in combination also prolonged survival in mouse models of FLT3-ITD AML (mice transplanted with MV4-11 or MOLM-13 cells).
Phase 2 trial
The researchers went on to test omacetaxine and sorafenib in a phase 2 trial. The trial enrolled 24 patients with FLT3-ITD AML and a median age of 50 (range, 21-76).
Most of the patients had relapsed or refractory disease, but 2 were unsuitable for induction chemotherapy because of advanced age and comorbidities.
The patients received omacetaxine and sorafenib continuously until intolerance, disease progression, or allogeneic hematopoietic stem cell transplant (HSCT).
Twenty patients (83.3%) achieved a CR or CRi at a median of 22 days (range, 18-55). Three patients did not respond, and 1 patient experienced a near-CRi—a reduction of blasts without complete clearance.
Fifteen of the responders relapsed, but 3 of these patients received omacetaxine and sorafenib again and achieved a CRi. One patient received re-treatment and failed to achieve a response.
Seven patients proceeded to HSCT after receiving omacetaxine and sorafenib.
At a median follow-up of 7.1 months (range, 2.2 to 20.5), 4 patients were still in CR/CRi (3 patients after HSCT), and 1 patient who had relapsed was still alive.
The remaining 19 patients had died—14 due to relapse, 4 due to non-response (1 after re-treatment), and 1 due to HSCT.
The median leukemia-free survival was 88 days (range, 9-510), and the median overall survival was 228 days (range, 53 to 615).
Adverse events occurring after treatment with omacetaxine and sorafenib included fever (n=14), rash (n=8), hand-foot-skin reactions (n=6), pneumonia (n=2), neutropenic fever (n=1), and bacteremia (n=1).
The researchers said this study validated the principle and clinical relevance of in vitro drug testing and identified a drug combination that might improve the treatment of FLT3-ITD AML.
Photo by Bill Branson
A 2-drug combination has shown promise for treating patients with FLT3-ITD acute myeloid leukemia (AML), according to research published in Science Translational Medicine.
Researchers found that omacetaxine mepesuccinate (formerly known as homoharringtonine) exhibits preferential antileukemic activity against FLT3-ITD AML.
Subsequent preclinical experiments revealed that omacetaxine synergizes with sorafenib and other FLT3 inhibitors.
So researchers tested omacetaxine in combination with sorafenib in a phase 2 trial of patients with FLT3-ITD AML.
The combination produced complete responses (CRs) or CRs with incomplete hematologic recovery (CRis) in a majority of patients, and researchers said the treatment was well-tolerated.
Anskar Y. H. Leung, MD, PhD, of The University of Hong Kong, and his colleagues conducted this research.
The team first performed an in vitro screen on AML patient samples to determine their responses to various drugs.
One of the compounds tested, the protein translation inhibitor omacetaxine mepesuccinate, showed strong antileukemic effects against FLT3-ITD AML. In fact, omacetaxine preferentially inhibited the growth of FLT3-ITD cell lines.
The researchers then found that omacetaxine synergizes with sorafenib and other FLT3 inhibitors to suppress leukemia growth in FLT3-ITD AML cell lines.
Omacetaxine and sorafenib in combination also prolonged survival in mouse models of FLT3-ITD AML (mice transplanted with MV4-11 or MOLM-13 cells).
Phase 2 trial
The researchers went on to test omacetaxine and sorafenib in a phase 2 trial. The trial enrolled 24 patients with FLT3-ITD AML and a median age of 50 (range, 21-76).
Most of the patients had relapsed or refractory disease, but 2 were unsuitable for induction chemotherapy because of advanced age and comorbidities.
The patients received omacetaxine and sorafenib continuously until intolerance, disease progression, or allogeneic hematopoietic stem cell transplant (HSCT).
Twenty patients (83.3%) achieved a CR or CRi at a median of 22 days (range, 18-55). Three patients did not respond, and 1 patient experienced a near-CRi—a reduction of blasts without complete clearance.
Fifteen of the responders relapsed, but 3 of these patients received omacetaxine and sorafenib again and achieved a CRi. One patient received re-treatment and failed to achieve a response.
Seven patients proceeded to HSCT after receiving omacetaxine and sorafenib.
At a median follow-up of 7.1 months (range, 2.2 to 20.5), 4 patients were still in CR/CRi (3 patients after HSCT), and 1 patient who had relapsed was still alive.
The remaining 19 patients had died—14 due to relapse, 4 due to non-response (1 after re-treatment), and 1 due to HSCT.
The median leukemia-free survival was 88 days (range, 9-510), and the median overall survival was 228 days (range, 53 to 615).
Adverse events occurring after treatment with omacetaxine and sorafenib included fever (n=14), rash (n=8), hand-foot-skin reactions (n=6), pneumonia (n=2), neutropenic fever (n=1), and bacteremia (n=1).
The researchers said this study validated the principle and clinical relevance of in vitro drug testing and identified a drug combination that might improve the treatment of FLT3-ITD AML.
Photo by Bill Branson
A 2-drug combination has shown promise for treating patients with FLT3-ITD acute myeloid leukemia (AML), according to research published in Science Translational Medicine.
Researchers found that omacetaxine mepesuccinate (formerly known as homoharringtonine) exhibits preferential antileukemic activity against FLT3-ITD AML.
Subsequent preclinical experiments revealed that omacetaxine synergizes with sorafenib and other FLT3 inhibitors.
So researchers tested omacetaxine in combination with sorafenib in a phase 2 trial of patients with FLT3-ITD AML.
The combination produced complete responses (CRs) or CRs with incomplete hematologic recovery (CRis) in a majority of patients, and researchers said the treatment was well-tolerated.
Anskar Y. H. Leung, MD, PhD, of The University of Hong Kong, and his colleagues conducted this research.
The team first performed an in vitro screen on AML patient samples to determine their responses to various drugs.
One of the compounds tested, the protein translation inhibitor omacetaxine mepesuccinate, showed strong antileukemic effects against FLT3-ITD AML. In fact, omacetaxine preferentially inhibited the growth of FLT3-ITD cell lines.
The researchers then found that omacetaxine synergizes with sorafenib and other FLT3 inhibitors to suppress leukemia growth in FLT3-ITD AML cell lines.
Omacetaxine and sorafenib in combination also prolonged survival in mouse models of FLT3-ITD AML (mice transplanted with MV4-11 or MOLM-13 cells).
Phase 2 trial
The researchers went on to test omacetaxine and sorafenib in a phase 2 trial. The trial enrolled 24 patients with FLT3-ITD AML and a median age of 50 (range, 21-76).
Most of the patients had relapsed or refractory disease, but 2 were unsuitable for induction chemotherapy because of advanced age and comorbidities.
The patients received omacetaxine and sorafenib continuously until intolerance, disease progression, or allogeneic hematopoietic stem cell transplant (HSCT).
Twenty patients (83.3%) achieved a CR or CRi at a median of 22 days (range, 18-55). Three patients did not respond, and 1 patient experienced a near-CRi—a reduction of blasts without complete clearance.
Fifteen of the responders relapsed, but 3 of these patients received omacetaxine and sorafenib again and achieved a CRi. One patient received re-treatment and failed to achieve a response.
Seven patients proceeded to HSCT after receiving omacetaxine and sorafenib.
At a median follow-up of 7.1 months (range, 2.2 to 20.5), 4 patients were still in CR/CRi (3 patients after HSCT), and 1 patient who had relapsed was still alive.
The remaining 19 patients had died—14 due to relapse, 4 due to non-response (1 after re-treatment), and 1 due to HSCT.
The median leukemia-free survival was 88 days (range, 9-510), and the median overall survival was 228 days (range, 53 to 615).
Adverse events occurring after treatment with omacetaxine and sorafenib included fever (n=14), rash (n=8), hand-foot-skin reactions (n=6), pneumonia (n=2), neutropenic fever (n=1), and bacteremia (n=1).
The researchers said this study validated the principle and clinical relevance of in vitro drug testing and identified a drug combination that might improve the treatment of FLT3-ITD AML.
Doc provides perspective on CAR T-cell therapy in CLL
Photo from Penn Medicine
NEW YORK—Trial data on the use of chimeric antigen receptor (CAR) T cells in chronic lymphocytic leukemia (CLL) are maturing, and a speaker at Lymphoma & Myeloma 2016 provided some perspective on the therapy as it now stands.
Stephen J. Schuster, MD, of the University of Pennsylvania in Philadelphia, noted that some CLL patients treated with CAR T cells remain in complete remission (CR) for more than 5 years.
Therefore, CAR T cells may be a consideration for patients who are resistant to chemotherapy.
“[I]mportantly, this immunologic approach, like other immunologic approaches . . ., tends to be non-cross-resistant to chemotherapy,” Dr Schuster said.
He made these and other observations while discussing trials of CAR T-cell therapy (particularly CTL019) in CLL.
Pilot study of CTL019 in CLL
CTL019, which is the CAR T-cell therapy used by investigators at the University of Pennsylvania, is licensed to Novartis.
The pilot study of CTL019, begun in 2009, enrolled 14 patients who had failed at least 2 prior therapies and progressed within 2 years of their last treatment.
Four patients (29%) achieved a CR, and 4 (29%) achieved a partial response (PR), for an overall response rate of 57%. Detailed results from this trial were reported earlier in HematologyTimes.
Two patients in this trial are still in CR beyond 5 years.
When investigators analyzed the different variables that might affect response—including age, number of prior therapies, p53 status, CAR T-cell dose, and the presence of cytokine release syndrome (CRS)—2 things became apparent.
First, patients who responded tended to have greater in vivo expansion of the CAR T cells than non-responders. And second, the responders had a greater incidence of CRS than non-responders.
Additionally, complete responders were negative for minimal residual disease (MRD) and had durable responses.
“This actually is different from the data you see in lymphoma with CAR cells,” Dr Schuster said. “[However,] it’s what we see in ALL [acute lymphoblastic leukemia] as well.”
Investigators also discovered that persistence of CAR T cells correlates with B-cell aplasia. In this trial, persistence of CAR T cells and B-cell aplasia were apparent at 12 and 18 months, and, in some cases, even longer.
“This is in distinction to what we are observing in trials with the lymphomas,” Dr Schuster said. “So what’s going to emerge is that the different diseases will have different response rates, different degrees of persistence of CAR cells and different toxicities.”
“When we compare B-cell ALL, B-cell non-Hodgkin lymphomas, you’ll get different responses across the subtypes of lymphomas, some unique toxicities, and differences in CLL. So these are all different diseases.”
Dose-finding trial of CTL019 in CLL
The second trial of CTL019 in relapsed/refractory CLL patients was a dose-finding study. Updated results from this study were presented at ASCO 2016.
The high-dose arm (5x108 CTL019) had a 10 times higher dose of CAR T cells than the low-dose arm (5x107 CTL019).
Investigators treated 12 patients in each arm in the first phase of the study, and then expanded the trial to include another 8 patients at the recommended dose. The phase 2 trial was powered for response rates but not duration of response.
Twenty-eight patients were enrolled, with 24 evaluable, 11 in the high-dose arm and 13 in the low-dose arm.
Their median age was 62 (range, 51-75), the median number of prior therapies was 4 (range, 2–7), 38% had p53 deletion, and 12% had received prior ibrutinib therapy.
With the 2 arms pooled together, 25% of patients achieved a CR, and 17% achieved a PR, for an overall response rate of 42%.
“Toxicities were identical in each group,” Dr Schuster said.
He noted that the CRS rate was “fairly high.” The incidence was 55% in the high-dose arm and 54% in the low-dose arm.
There was a tendency, although not statistically significant, for the higher-dose patients to have a greater response rate than the lower-dose group—54% and 31%, respectively.
So the investigators decided the expansion cohort should be conducted with the higher dose, “even though we weren’t sure there really was a difference,” Dr Schuster said.
Seventeen evaluable patients received the higher dose in the expansion cohort. Six (35%) achieved a CR, and 3 (18%) achieved a PR, for an overall response rate of 53%.
“Most [adverse] events happen in the first 3 months,” after infusion, Dr Schuster said. “And then nothing much happens. That’s because the patients that are responsive to this therapy have durable responses.”
Of all the patients who achieved a CR, only 2 have relapsed, he said, “and now many of these patients have passed the 5-year mark for complete remissions.”
Toxicity of CTL019 in CLL
“When you give the cells, there’s not much toxicity,” Dr Schuster said. “These are the patients’ own cells; they’re not reacting adversely to that. It’s what happens afterwards that you have to be on the lookout for as the cells begin to expand in vivo.”
Patients experience some reversible renal toxicity, mostly hypertension-related, and some tumor lysis syndrome (TLS). No deaths occurred from TLS in CLL.
B-cell aplasia and hypogammaglobulinema occur in responding patients. They receive gamma globulin replacement as supportive therapy and generally experience no excessive or unusual infections.
“Cytokine release syndrome is the real thing to look at,” Dr Schuster said, “and that’s where early recognition and management will be life-saving.”
In both CLL and ALL, almost all responding patients develop CRS, which can be rapidly reversed with tocilizumab, the IL-6 receptor blocker.
Other CAR T-cell trials in CLL
Institutions other than the University of Pennsylvania have conducted trials of CAR T-cell therapies other than CTL019, and response rates in CLL patients have ranged from 25% (MSKCC) to 46% (Seattle), as reported at ASCO this year.
“But what’s really important to keep in mind is almost all patients who achieve complete response to date have stayed in complete response,” Dr Schuster said.
Combination trials with ibrutinib
Dr Schuster noted that patients in CAR T-cell trials who had been on ibrutinib for more than 5 months “had really robust T-cell expansion.”
So investigators believe treatment with ibrutinib may be a way of enhancing T-cell function.
A combination trial of ibrutinib and CTL019 is underway (NCT02640209). Six patients have been treated thus far, and although the follow-up is short, all 6 achieved CR at the 3-month assessment.
“So the hope is that this is going to be a partner [therapy],” Dr Schuster said. “And maybe these complete responses will be very durable, like the responses in earlier trials of CAR therapy in patients with CLL.”
Photo from Penn Medicine
NEW YORK—Trial data on the use of chimeric antigen receptor (CAR) T cells in chronic lymphocytic leukemia (CLL) are maturing, and a speaker at Lymphoma & Myeloma 2016 provided some perspective on the therapy as it now stands.
Stephen J. Schuster, MD, of the University of Pennsylvania in Philadelphia, noted that some CLL patients treated with CAR T cells remain in complete remission (CR) for more than 5 years.
Therefore, CAR T cells may be a consideration for patients who are resistant to chemotherapy.
“[I]mportantly, this immunologic approach, like other immunologic approaches . . ., tends to be non-cross-resistant to chemotherapy,” Dr Schuster said.
He made these and other observations while discussing trials of CAR T-cell therapy (particularly CTL019) in CLL.
Pilot study of CTL019 in CLL
CTL019, which is the CAR T-cell therapy used by investigators at the University of Pennsylvania, is licensed to Novartis.
The pilot study of CTL019, begun in 2009, enrolled 14 patients who had failed at least 2 prior therapies and progressed within 2 years of their last treatment.
Four patients (29%) achieved a CR, and 4 (29%) achieved a partial response (PR), for an overall response rate of 57%. Detailed results from this trial were reported earlier in HematologyTimes.
Two patients in this trial are still in CR beyond 5 years.
When investigators analyzed the different variables that might affect response—including age, number of prior therapies, p53 status, CAR T-cell dose, and the presence of cytokine release syndrome (CRS)—2 things became apparent.
First, patients who responded tended to have greater in vivo expansion of the CAR T cells than non-responders. And second, the responders had a greater incidence of CRS than non-responders.
Additionally, complete responders were negative for minimal residual disease (MRD) and had durable responses.
“This actually is different from the data you see in lymphoma with CAR cells,” Dr Schuster said. “[However,] it’s what we see in ALL [acute lymphoblastic leukemia] as well.”
Investigators also discovered that persistence of CAR T cells correlates with B-cell aplasia. In this trial, persistence of CAR T cells and B-cell aplasia were apparent at 12 and 18 months, and, in some cases, even longer.
“This is in distinction to what we are observing in trials with the lymphomas,” Dr Schuster said. “So what’s going to emerge is that the different diseases will have different response rates, different degrees of persistence of CAR cells and different toxicities.”
“When we compare B-cell ALL, B-cell non-Hodgkin lymphomas, you’ll get different responses across the subtypes of lymphomas, some unique toxicities, and differences in CLL. So these are all different diseases.”
Dose-finding trial of CTL019 in CLL
The second trial of CTL019 in relapsed/refractory CLL patients was a dose-finding study. Updated results from this study were presented at ASCO 2016.
The high-dose arm (5x108 CTL019) had a 10 times higher dose of CAR T cells than the low-dose arm (5x107 CTL019).
Investigators treated 12 patients in each arm in the first phase of the study, and then expanded the trial to include another 8 patients at the recommended dose. The phase 2 trial was powered for response rates but not duration of response.
Twenty-eight patients were enrolled, with 24 evaluable, 11 in the high-dose arm and 13 in the low-dose arm.
Their median age was 62 (range, 51-75), the median number of prior therapies was 4 (range, 2–7), 38% had p53 deletion, and 12% had received prior ibrutinib therapy.
With the 2 arms pooled together, 25% of patients achieved a CR, and 17% achieved a PR, for an overall response rate of 42%.
“Toxicities were identical in each group,” Dr Schuster said.
He noted that the CRS rate was “fairly high.” The incidence was 55% in the high-dose arm and 54% in the low-dose arm.
There was a tendency, although not statistically significant, for the higher-dose patients to have a greater response rate than the lower-dose group—54% and 31%, respectively.
So the investigators decided the expansion cohort should be conducted with the higher dose, “even though we weren’t sure there really was a difference,” Dr Schuster said.
Seventeen evaluable patients received the higher dose in the expansion cohort. Six (35%) achieved a CR, and 3 (18%) achieved a PR, for an overall response rate of 53%.
“Most [adverse] events happen in the first 3 months,” after infusion, Dr Schuster said. “And then nothing much happens. That’s because the patients that are responsive to this therapy have durable responses.”
Of all the patients who achieved a CR, only 2 have relapsed, he said, “and now many of these patients have passed the 5-year mark for complete remissions.”
Toxicity of CTL019 in CLL
“When you give the cells, there’s not much toxicity,” Dr Schuster said. “These are the patients’ own cells; they’re not reacting adversely to that. It’s what happens afterwards that you have to be on the lookout for as the cells begin to expand in vivo.”
Patients experience some reversible renal toxicity, mostly hypertension-related, and some tumor lysis syndrome (TLS). No deaths occurred from TLS in CLL.
B-cell aplasia and hypogammaglobulinema occur in responding patients. They receive gamma globulin replacement as supportive therapy and generally experience no excessive or unusual infections.
“Cytokine release syndrome is the real thing to look at,” Dr Schuster said, “and that’s where early recognition and management will be life-saving.”
In both CLL and ALL, almost all responding patients develop CRS, which can be rapidly reversed with tocilizumab, the IL-6 receptor blocker.
Other CAR T-cell trials in CLL
Institutions other than the University of Pennsylvania have conducted trials of CAR T-cell therapies other than CTL019, and response rates in CLL patients have ranged from 25% (MSKCC) to 46% (Seattle), as reported at ASCO this year.
“But what’s really important to keep in mind is almost all patients who achieve complete response to date have stayed in complete response,” Dr Schuster said.
Combination trials with ibrutinib
Dr Schuster noted that patients in CAR T-cell trials who had been on ibrutinib for more than 5 months “had really robust T-cell expansion.”
So investigators believe treatment with ibrutinib may be a way of enhancing T-cell function.
A combination trial of ibrutinib and CTL019 is underway (NCT02640209). Six patients have been treated thus far, and although the follow-up is short, all 6 achieved CR at the 3-month assessment.
“So the hope is that this is going to be a partner [therapy],” Dr Schuster said. “And maybe these complete responses will be very durable, like the responses in earlier trials of CAR therapy in patients with CLL.”
Photo from Penn Medicine
NEW YORK—Trial data on the use of chimeric antigen receptor (CAR) T cells in chronic lymphocytic leukemia (CLL) are maturing, and a speaker at Lymphoma & Myeloma 2016 provided some perspective on the therapy as it now stands.
Stephen J. Schuster, MD, of the University of Pennsylvania in Philadelphia, noted that some CLL patients treated with CAR T cells remain in complete remission (CR) for more than 5 years.
Therefore, CAR T cells may be a consideration for patients who are resistant to chemotherapy.
“[I]mportantly, this immunologic approach, like other immunologic approaches . . ., tends to be non-cross-resistant to chemotherapy,” Dr Schuster said.
He made these and other observations while discussing trials of CAR T-cell therapy (particularly CTL019) in CLL.
Pilot study of CTL019 in CLL
CTL019, which is the CAR T-cell therapy used by investigators at the University of Pennsylvania, is licensed to Novartis.
The pilot study of CTL019, begun in 2009, enrolled 14 patients who had failed at least 2 prior therapies and progressed within 2 years of their last treatment.
Four patients (29%) achieved a CR, and 4 (29%) achieved a partial response (PR), for an overall response rate of 57%. Detailed results from this trial were reported earlier in HematologyTimes.
Two patients in this trial are still in CR beyond 5 years.
When investigators analyzed the different variables that might affect response—including age, number of prior therapies, p53 status, CAR T-cell dose, and the presence of cytokine release syndrome (CRS)—2 things became apparent.
First, patients who responded tended to have greater in vivo expansion of the CAR T cells than non-responders. And second, the responders had a greater incidence of CRS than non-responders.
Additionally, complete responders were negative for minimal residual disease (MRD) and had durable responses.
“This actually is different from the data you see in lymphoma with CAR cells,” Dr Schuster said. “[However,] it’s what we see in ALL [acute lymphoblastic leukemia] as well.”
Investigators also discovered that persistence of CAR T cells correlates with B-cell aplasia. In this trial, persistence of CAR T cells and B-cell aplasia were apparent at 12 and 18 months, and, in some cases, even longer.
“This is in distinction to what we are observing in trials with the lymphomas,” Dr Schuster said. “So what’s going to emerge is that the different diseases will have different response rates, different degrees of persistence of CAR cells and different toxicities.”
“When we compare B-cell ALL, B-cell non-Hodgkin lymphomas, you’ll get different responses across the subtypes of lymphomas, some unique toxicities, and differences in CLL. So these are all different diseases.”
Dose-finding trial of CTL019 in CLL
The second trial of CTL019 in relapsed/refractory CLL patients was a dose-finding study. Updated results from this study were presented at ASCO 2016.
The high-dose arm (5x108 CTL019) had a 10 times higher dose of CAR T cells than the low-dose arm (5x107 CTL019).
Investigators treated 12 patients in each arm in the first phase of the study, and then expanded the trial to include another 8 patients at the recommended dose. The phase 2 trial was powered for response rates but not duration of response.
Twenty-eight patients were enrolled, with 24 evaluable, 11 in the high-dose arm and 13 in the low-dose arm.
Their median age was 62 (range, 51-75), the median number of prior therapies was 4 (range, 2–7), 38% had p53 deletion, and 12% had received prior ibrutinib therapy.
With the 2 arms pooled together, 25% of patients achieved a CR, and 17% achieved a PR, for an overall response rate of 42%.
“Toxicities were identical in each group,” Dr Schuster said.
He noted that the CRS rate was “fairly high.” The incidence was 55% in the high-dose arm and 54% in the low-dose arm.
There was a tendency, although not statistically significant, for the higher-dose patients to have a greater response rate than the lower-dose group—54% and 31%, respectively.
So the investigators decided the expansion cohort should be conducted with the higher dose, “even though we weren’t sure there really was a difference,” Dr Schuster said.
Seventeen evaluable patients received the higher dose in the expansion cohort. Six (35%) achieved a CR, and 3 (18%) achieved a PR, for an overall response rate of 53%.
“Most [adverse] events happen in the first 3 months,” after infusion, Dr Schuster said. “And then nothing much happens. That’s because the patients that are responsive to this therapy have durable responses.”
Of all the patients who achieved a CR, only 2 have relapsed, he said, “and now many of these patients have passed the 5-year mark for complete remissions.”
Toxicity of CTL019 in CLL
“When you give the cells, there’s not much toxicity,” Dr Schuster said. “These are the patients’ own cells; they’re not reacting adversely to that. It’s what happens afterwards that you have to be on the lookout for as the cells begin to expand in vivo.”
Patients experience some reversible renal toxicity, mostly hypertension-related, and some tumor lysis syndrome (TLS). No deaths occurred from TLS in CLL.
B-cell aplasia and hypogammaglobulinema occur in responding patients. They receive gamma globulin replacement as supportive therapy and generally experience no excessive or unusual infections.
“Cytokine release syndrome is the real thing to look at,” Dr Schuster said, “and that’s where early recognition and management will be life-saving.”
In both CLL and ALL, almost all responding patients develop CRS, which can be rapidly reversed with tocilizumab, the IL-6 receptor blocker.
Other CAR T-cell trials in CLL
Institutions other than the University of Pennsylvania have conducted trials of CAR T-cell therapies other than CTL019, and response rates in CLL patients have ranged from 25% (MSKCC) to 46% (Seattle), as reported at ASCO this year.
“But what’s really important to keep in mind is almost all patients who achieve complete response to date have stayed in complete response,” Dr Schuster said.
Combination trials with ibrutinib
Dr Schuster noted that patients in CAR T-cell trials who had been on ibrutinib for more than 5 months “had really robust T-cell expansion.”
So investigators believe treatment with ibrutinib may be a way of enhancing T-cell function.
A combination trial of ibrutinib and CTL019 is underway (NCT02640209). Six patients have been treated thus far, and although the follow-up is short, all 6 achieved CR at the 3-month assessment.
“So the hope is that this is going to be a partner [therapy],” Dr Schuster said. “And maybe these complete responses will be very durable, like the responses in earlier trials of CAR therapy in patients with CLL.”
Work reveals potential therapeutic targets in AML
By adapting CRISPR-Cas9 technology and using it to screen the leukemia genome, researchers have identified hundreds of potential therapeutic targets for acute myeloid leukemia (AML).
The group’s work revealed nearly 500 genes, many of which had not been identified previously, that might serve as targets for AML treatment.
Subsequent experiments showed that targeting one of the genes, KAT2A, can destroy AML cells without harming normal blood cells.
This research was published in Cell Reports.
For this study, the researchers used CRISPR-Cas9 gene-editing technology to screen leukemia cells for vulnerable points. The team said they refined the technology so they could disrupt all genes in the leukemia cell genome individually.
This allowed the researchers to identify those genes whose disruption was detrimental to the growth and survival of AML cells, particularly the AML cell lines MOLM-13, HL-60, OCI-AML2, OCI-AML3, and MV4-11.
“Previous studies showed proof of principle, but this is one of the first systematic attempts to identify the genetic vulnerabilities of AML,” said study author Kosuke Yusa, PhD, of Wellcome Trust Sanger Institute in Hinxton, Cambridge, UK.
“We have improved and applied CRISPR-Cas9 technology to look at what actually kills cells.”
In this way, the researchers identified 492 genes that are essential for AML cell survival, including 227 genes that are druggable.
The team noted that a handful of the genes they identified—including DOT1L, BCL2, and MEN1—are already established therapeutic targets, but most of them are not.
The researchers chose to perform additional experiments with one of the genes they identified, KAT2A, to demonstrate the validity of their findings.
KAT2A was one of 66 genes that were essential to 3 or more of the AML cell lines studied. KAT2A was essential for survival in MOLM-13, OCI-AML2, and OCI-AML3.
The team inhibited KAT2A in vitro using genetic and drug-based techniques. Results showed that disrupting KAT2A inhibited the growth and survival of AML cells but did not affect normal blood cells.
“This is an exciting finding, as KAT2A inhibition worked on a number of primary AML cells with diverse genotypes,” said study author Konstantinos Tzelepis, a PhD student at Wellcome Trust Sanger Institute.
“Whilst the gene needs to be studied in greater depth to understand its potential for use in the clinic, we show that targeting KAT2A destroyed AML cells in the laboratory while sparing healthy blood cells.”
The researchers also targeted KAT2A in transgenic mice. The team observed a significant reduction in AML cell expansion and a significant improvement in survival when KAT2A was disrupted.
“This research has led to the identification of many potential gene targets for future AML therapy, which we are making available to other researchers to explore,” said study author George Vassiliou, PhD, of Wellcome Trust Sanger Institute.
“Whilst KAT2A inhibition now needs to be investigated as a treatment strategy for acute myeloid leukemia, there are many more candidates to pursue by the leukemia research community. Our hope is that this work will lead to more effective treatments against AML that will improve both the survival and the quality of life of patients.”
By adapting CRISPR-Cas9 technology and using it to screen the leukemia genome, researchers have identified hundreds of potential therapeutic targets for acute myeloid leukemia (AML).
The group’s work revealed nearly 500 genes, many of which had not been identified previously, that might serve as targets for AML treatment.
Subsequent experiments showed that targeting one of the genes, KAT2A, can destroy AML cells without harming normal blood cells.
This research was published in Cell Reports.
For this study, the researchers used CRISPR-Cas9 gene-editing technology to screen leukemia cells for vulnerable points. The team said they refined the technology so they could disrupt all genes in the leukemia cell genome individually.
This allowed the researchers to identify those genes whose disruption was detrimental to the growth and survival of AML cells, particularly the AML cell lines MOLM-13, HL-60, OCI-AML2, OCI-AML3, and MV4-11.
“Previous studies showed proof of principle, but this is one of the first systematic attempts to identify the genetic vulnerabilities of AML,” said study author Kosuke Yusa, PhD, of Wellcome Trust Sanger Institute in Hinxton, Cambridge, UK.
“We have improved and applied CRISPR-Cas9 technology to look at what actually kills cells.”
In this way, the researchers identified 492 genes that are essential for AML cell survival, including 227 genes that are druggable.
The team noted that a handful of the genes they identified—including DOT1L, BCL2, and MEN1—are already established therapeutic targets, but most of them are not.
The researchers chose to perform additional experiments with one of the genes they identified, KAT2A, to demonstrate the validity of their findings.
KAT2A was one of 66 genes that were essential to 3 or more of the AML cell lines studied. KAT2A was essential for survival in MOLM-13, OCI-AML2, and OCI-AML3.
The team inhibited KAT2A in vitro using genetic and drug-based techniques. Results showed that disrupting KAT2A inhibited the growth and survival of AML cells but did not affect normal blood cells.
“This is an exciting finding, as KAT2A inhibition worked on a number of primary AML cells with diverse genotypes,” said study author Konstantinos Tzelepis, a PhD student at Wellcome Trust Sanger Institute.
“Whilst the gene needs to be studied in greater depth to understand its potential for use in the clinic, we show that targeting KAT2A destroyed AML cells in the laboratory while sparing healthy blood cells.”
The researchers also targeted KAT2A in transgenic mice. The team observed a significant reduction in AML cell expansion and a significant improvement in survival when KAT2A was disrupted.
“This research has led to the identification of many potential gene targets for future AML therapy, which we are making available to other researchers to explore,” said study author George Vassiliou, PhD, of Wellcome Trust Sanger Institute.
“Whilst KAT2A inhibition now needs to be investigated as a treatment strategy for acute myeloid leukemia, there are many more candidates to pursue by the leukemia research community. Our hope is that this work will lead to more effective treatments against AML that will improve both the survival and the quality of life of patients.”
By adapting CRISPR-Cas9 technology and using it to screen the leukemia genome, researchers have identified hundreds of potential therapeutic targets for acute myeloid leukemia (AML).
The group’s work revealed nearly 500 genes, many of which had not been identified previously, that might serve as targets for AML treatment.
Subsequent experiments showed that targeting one of the genes, KAT2A, can destroy AML cells without harming normal blood cells.
This research was published in Cell Reports.
For this study, the researchers used CRISPR-Cas9 gene-editing technology to screen leukemia cells for vulnerable points. The team said they refined the technology so they could disrupt all genes in the leukemia cell genome individually.
This allowed the researchers to identify those genes whose disruption was detrimental to the growth and survival of AML cells, particularly the AML cell lines MOLM-13, HL-60, OCI-AML2, OCI-AML3, and MV4-11.
“Previous studies showed proof of principle, but this is one of the first systematic attempts to identify the genetic vulnerabilities of AML,” said study author Kosuke Yusa, PhD, of Wellcome Trust Sanger Institute in Hinxton, Cambridge, UK.
“We have improved and applied CRISPR-Cas9 technology to look at what actually kills cells.”
In this way, the researchers identified 492 genes that are essential for AML cell survival, including 227 genes that are druggable.
The team noted that a handful of the genes they identified—including DOT1L, BCL2, and MEN1—are already established therapeutic targets, but most of them are not.
The researchers chose to perform additional experiments with one of the genes they identified, KAT2A, to demonstrate the validity of their findings.
KAT2A was one of 66 genes that were essential to 3 or more of the AML cell lines studied. KAT2A was essential for survival in MOLM-13, OCI-AML2, and OCI-AML3.
The team inhibited KAT2A in vitro using genetic and drug-based techniques. Results showed that disrupting KAT2A inhibited the growth and survival of AML cells but did not affect normal blood cells.
“This is an exciting finding, as KAT2A inhibition worked on a number of primary AML cells with diverse genotypes,” said study author Konstantinos Tzelepis, a PhD student at Wellcome Trust Sanger Institute.
“Whilst the gene needs to be studied in greater depth to understand its potential for use in the clinic, we show that targeting KAT2A destroyed AML cells in the laboratory while sparing healthy blood cells.”
The researchers also targeted KAT2A in transgenic mice. The team observed a significant reduction in AML cell expansion and a significant improvement in survival when KAT2A was disrupted.
“This research has led to the identification of many potential gene targets for future AML therapy, which we are making available to other researchers to explore,” said study author George Vassiliou, PhD, of Wellcome Trust Sanger Institute.
“Whilst KAT2A inhibition now needs to be investigated as a treatment strategy for acute myeloid leukemia, there are many more candidates to pursue by the leukemia research community. Our hope is that this work will lead to more effective treatments against AML that will improve both the survival and the quality of life of patients.”
Findings could aid treatment of resistant T-ALL
(blue and purple) invaded
by leukemia cells (yellow).
Image courtesy of Edwin
Hawkins, Delfim Duarte,
and Imperial College London
Preclinical research has shed light on how certain leukemia cells survive treatment and could pave the way for better therapeutic targeting of these resistant cells.
Researchers have speculated that some leukemia cells survive treatment by hiding out in specific niches in the bone marrow.
Results of the new research, conducted in mouse models and human samples of T-cell acute lymphoblastic leukemia (T-ALL), contradict that theory.
The experiments showed that resistant T-ALL cells move rapidly through the bone marrow before, during, and after treatment, interacting with—and sometimes killing—healthy cells.
“We expected the cells that survived treatment to be sat in particular niches, but, instead, they are very active throughout the bone marrow,” said Cristina Lo Celso, PhD, of Imperial College London in the UK.
“We now know that it would be ineffective to target particular niches in the bone marrow to tackle treatment-resistant leukemia. Now that we know that the cells don’t hide, we can explore why that is and how their movement helps them to survive. Ultimately, we want to find out whether we can stop the movement and whether this could kill the treatment-resistant cells.”
Dr Lo Celso and her colleagues described these findings in a letter to Nature.
The researchers used intravital microscopy to track the movement of T-ALL cells in mice—before, during, and after treatment. Treatment consisted of dexamethasone alone, vincristine alone, or combination dexamethasone, vincristine, and L-asparaginase.
The team found that T-ALL cells moved around rapidly, not showing any preference for bone marrow subcompartments. The cells’ behavior was consistent over time—from the earliest bone marrow seeding through to treatment response and resistance.
However, the researchers noted that surviving T-ALL cells were “highly migratory” and travelled at significantly faster speeds than early infiltrating cells. In addition, resistant T-ALL cells were still capable of undergoing division at times when other T-ALL cells were dying.
The team suggested that the act of moving may help T-ALL cells to survive, possibly through short-lived interactions with other cells.
This theory was supported by the discovery that T-ALL cells actively attack osteoblasts. The researchers noted that osteoblasts are associated with hematopoietic fitness. So the loss of osteoblasts may contribute to the loss of healthy hematopoiesis observed in leukemia patients.
The team believes this insight could aid the development of treatments to safeguard the production of healthy blood cells in T-ALL patients.
“Our study supports the idea that, at least in this leukemia, new therapies should target the cancer cells themselves instead of the surrounding normal stromal cells to better eradicate the disease,” said study author Delfim Duarte, MD, a PhD student at Imperial College London.
“Our work also suggests that protecting normal stromal bone cells from the attack of leukemia cells can have wide implications in the support of healthy blood cell production,” said Edwin Hawkins, PhD, of the Walter and Eliza Hall Institute of Medical Research in Melbourne, Victoria, Australia.
“Keeping blood cell levels up would prevent anemia, infection, and bleeding.”
(blue and purple) invaded
by leukemia cells (yellow).
Image courtesy of Edwin
Hawkins, Delfim Duarte,
and Imperial College London
Preclinical research has shed light on how certain leukemia cells survive treatment and could pave the way for better therapeutic targeting of these resistant cells.
Researchers have speculated that some leukemia cells survive treatment by hiding out in specific niches in the bone marrow.
Results of the new research, conducted in mouse models and human samples of T-cell acute lymphoblastic leukemia (T-ALL), contradict that theory.
The experiments showed that resistant T-ALL cells move rapidly through the bone marrow before, during, and after treatment, interacting with—and sometimes killing—healthy cells.
“We expected the cells that survived treatment to be sat in particular niches, but, instead, they are very active throughout the bone marrow,” said Cristina Lo Celso, PhD, of Imperial College London in the UK.
“We now know that it would be ineffective to target particular niches in the bone marrow to tackle treatment-resistant leukemia. Now that we know that the cells don’t hide, we can explore why that is and how their movement helps them to survive. Ultimately, we want to find out whether we can stop the movement and whether this could kill the treatment-resistant cells.”
Dr Lo Celso and her colleagues described these findings in a letter to Nature.
The researchers used intravital microscopy to track the movement of T-ALL cells in mice—before, during, and after treatment. Treatment consisted of dexamethasone alone, vincristine alone, or combination dexamethasone, vincristine, and L-asparaginase.
The team found that T-ALL cells moved around rapidly, not showing any preference for bone marrow subcompartments. The cells’ behavior was consistent over time—from the earliest bone marrow seeding through to treatment response and resistance.
However, the researchers noted that surviving T-ALL cells were “highly migratory” and travelled at significantly faster speeds than early infiltrating cells. In addition, resistant T-ALL cells were still capable of undergoing division at times when other T-ALL cells were dying.
The team suggested that the act of moving may help T-ALL cells to survive, possibly through short-lived interactions with other cells.
This theory was supported by the discovery that T-ALL cells actively attack osteoblasts. The researchers noted that osteoblasts are associated with hematopoietic fitness. So the loss of osteoblasts may contribute to the loss of healthy hematopoiesis observed in leukemia patients.
The team believes this insight could aid the development of treatments to safeguard the production of healthy blood cells in T-ALL patients.
“Our study supports the idea that, at least in this leukemia, new therapies should target the cancer cells themselves instead of the surrounding normal stromal cells to better eradicate the disease,” said study author Delfim Duarte, MD, a PhD student at Imperial College London.
“Our work also suggests that protecting normal stromal bone cells from the attack of leukemia cells can have wide implications in the support of healthy blood cell production,” said Edwin Hawkins, PhD, of the Walter and Eliza Hall Institute of Medical Research in Melbourne, Victoria, Australia.
“Keeping blood cell levels up would prevent anemia, infection, and bleeding.”
(blue and purple) invaded
by leukemia cells (yellow).
Image courtesy of Edwin
Hawkins, Delfim Duarte,
and Imperial College London
Preclinical research has shed light on how certain leukemia cells survive treatment and could pave the way for better therapeutic targeting of these resistant cells.
Researchers have speculated that some leukemia cells survive treatment by hiding out in specific niches in the bone marrow.
Results of the new research, conducted in mouse models and human samples of T-cell acute lymphoblastic leukemia (T-ALL), contradict that theory.
The experiments showed that resistant T-ALL cells move rapidly through the bone marrow before, during, and after treatment, interacting with—and sometimes killing—healthy cells.
“We expected the cells that survived treatment to be sat in particular niches, but, instead, they are very active throughout the bone marrow,” said Cristina Lo Celso, PhD, of Imperial College London in the UK.
“We now know that it would be ineffective to target particular niches in the bone marrow to tackle treatment-resistant leukemia. Now that we know that the cells don’t hide, we can explore why that is and how their movement helps them to survive. Ultimately, we want to find out whether we can stop the movement and whether this could kill the treatment-resistant cells.”
Dr Lo Celso and her colleagues described these findings in a letter to Nature.
The researchers used intravital microscopy to track the movement of T-ALL cells in mice—before, during, and after treatment. Treatment consisted of dexamethasone alone, vincristine alone, or combination dexamethasone, vincristine, and L-asparaginase.
The team found that T-ALL cells moved around rapidly, not showing any preference for bone marrow subcompartments. The cells’ behavior was consistent over time—from the earliest bone marrow seeding through to treatment response and resistance.
However, the researchers noted that surviving T-ALL cells were “highly migratory” and travelled at significantly faster speeds than early infiltrating cells. In addition, resistant T-ALL cells were still capable of undergoing division at times when other T-ALL cells were dying.
The team suggested that the act of moving may help T-ALL cells to survive, possibly through short-lived interactions with other cells.
This theory was supported by the discovery that T-ALL cells actively attack osteoblasts. The researchers noted that osteoblasts are associated with hematopoietic fitness. So the loss of osteoblasts may contribute to the loss of healthy hematopoiesis observed in leukemia patients.
The team believes this insight could aid the development of treatments to safeguard the production of healthy blood cells in T-ALL patients.
“Our study supports the idea that, at least in this leukemia, new therapies should target the cancer cells themselves instead of the surrounding normal stromal cells to better eradicate the disease,” said study author Delfim Duarte, MD, a PhD student at Imperial College London.
“Our work also suggests that protecting normal stromal bone cells from the attack of leukemia cells can have wide implications in the support of healthy blood cell production,” said Edwin Hawkins, PhD, of the Walter and Eliza Hall Institute of Medical Research in Melbourne, Victoria, Australia.
“Keeping blood cell levels up would prevent anemia, infection, and bleeding.”
Proteins may be therapeutic targets for AML subtype
Image by Eric Smith
Preclinical research suggests a pair of histone-modifying proteins may be promising therapeutic targets for NPM1-mutated acute myeloid leukemia (AML).
Investigators found that these proteins—MLL and DOT1L—play key roles in NPM1-mutated AML.
Pharmacologic inhibition of either protein alone produced anti-leukemic activity in vitro and in vivo, but inhibiting both proteins together had a more profound effect.
Michael Kühn, MD, of the Mainz University Medical Center in Mainz, Germany, and his colleagues reported these findings in Cancer Discovery.
The investigators noted that nearly all NPM1-mutated AMLs are characterized by aberrant HOX expression, and FLT3 is concomitantly mutated in roughly 60% of these cases. However, it hasn’t been clear how mutant NPM1 cells maintain aberrant gene expression.
With this study, Dr Kühn and his colleagues showed that MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1-mutated AML.
The investigators were able to demonstrate that survival of NPM1-mutated AML cells depends on these 2 proteins. And NPM1-mutated AML is “exceptionally dependent” on the menin binding site in MLL1.
The team tested MI-503, a menin–MLL1 inhibitor, and the DOT1L inhibitor EPZ4777 in human and murine models of NPM1-mutated AML.
Each of the drugs reduced the activity of HOX genes in NPM1-mutated AML cells, but combining the drugs resulted in near-complete inactivation of HOX genes.
When given alone, EPZ4777 and MI-503 each reduced the proliferation and colony-forming potential of NPM1-mutated AML cells in vitro. And each of the drugs prolonged survival in mouse models of NPM1-mutated AML.
However, EPZ4777 and MI-503 given in combination significantly delayed the onset of leukemia and significantly prolonged survival when compared to either drug given alone.
The investigators said this suggests that inhibiting both DOT1L and menin–MLL1 affects leukemia-initiating cells, and this approach represents the first molecularly targeted treatment of NPM1-mutated AML that works by reversing a key mechanism of leukemogenesis.
They added that this research paves the way for trials assessing EPZ4777 and MI-503 in patients with NPM1-mutated AML.
Image by Eric Smith
Preclinical research suggests a pair of histone-modifying proteins may be promising therapeutic targets for NPM1-mutated acute myeloid leukemia (AML).
Investigators found that these proteins—MLL and DOT1L—play key roles in NPM1-mutated AML.
Pharmacologic inhibition of either protein alone produced anti-leukemic activity in vitro and in vivo, but inhibiting both proteins together had a more profound effect.
Michael Kühn, MD, of the Mainz University Medical Center in Mainz, Germany, and his colleagues reported these findings in Cancer Discovery.
The investigators noted that nearly all NPM1-mutated AMLs are characterized by aberrant HOX expression, and FLT3 is concomitantly mutated in roughly 60% of these cases. However, it hasn’t been clear how mutant NPM1 cells maintain aberrant gene expression.
With this study, Dr Kühn and his colleagues showed that MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1-mutated AML.
The investigators were able to demonstrate that survival of NPM1-mutated AML cells depends on these 2 proteins. And NPM1-mutated AML is “exceptionally dependent” on the menin binding site in MLL1.
The team tested MI-503, a menin–MLL1 inhibitor, and the DOT1L inhibitor EPZ4777 in human and murine models of NPM1-mutated AML.
Each of the drugs reduced the activity of HOX genes in NPM1-mutated AML cells, but combining the drugs resulted in near-complete inactivation of HOX genes.
When given alone, EPZ4777 and MI-503 each reduced the proliferation and colony-forming potential of NPM1-mutated AML cells in vitro. And each of the drugs prolonged survival in mouse models of NPM1-mutated AML.
However, EPZ4777 and MI-503 given in combination significantly delayed the onset of leukemia and significantly prolonged survival when compared to either drug given alone.
The investigators said this suggests that inhibiting both DOT1L and menin–MLL1 affects leukemia-initiating cells, and this approach represents the first molecularly targeted treatment of NPM1-mutated AML that works by reversing a key mechanism of leukemogenesis.
They added that this research paves the way for trials assessing EPZ4777 and MI-503 in patients with NPM1-mutated AML.
Image by Eric Smith
Preclinical research suggests a pair of histone-modifying proteins may be promising therapeutic targets for NPM1-mutated acute myeloid leukemia (AML).
Investigators found that these proteins—MLL and DOT1L—play key roles in NPM1-mutated AML.
Pharmacologic inhibition of either protein alone produced anti-leukemic activity in vitro and in vivo, but inhibiting both proteins together had a more profound effect.
Michael Kühn, MD, of the Mainz University Medical Center in Mainz, Germany, and his colleagues reported these findings in Cancer Discovery.
The investigators noted that nearly all NPM1-mutated AMLs are characterized by aberrant HOX expression, and FLT3 is concomitantly mutated in roughly 60% of these cases. However, it hasn’t been clear how mutant NPM1 cells maintain aberrant gene expression.
With this study, Dr Kühn and his colleagues showed that MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1-mutated AML.
The investigators were able to demonstrate that survival of NPM1-mutated AML cells depends on these 2 proteins. And NPM1-mutated AML is “exceptionally dependent” on the menin binding site in MLL1.
The team tested MI-503, a menin–MLL1 inhibitor, and the DOT1L inhibitor EPZ4777 in human and murine models of NPM1-mutated AML.
Each of the drugs reduced the activity of HOX genes in NPM1-mutated AML cells, but combining the drugs resulted in near-complete inactivation of HOX genes.
When given alone, EPZ4777 and MI-503 each reduced the proliferation and colony-forming potential of NPM1-mutated AML cells in vitro. And each of the drugs prolonged survival in mouse models of NPM1-mutated AML.
However, EPZ4777 and MI-503 given in combination significantly delayed the onset of leukemia and significantly prolonged survival when compared to either drug given alone.
The investigators said this suggests that inhibiting both DOT1L and menin–MLL1 affects leukemia-initiating cells, and this approach represents the first molecularly targeted treatment of NPM1-mutated AML that works by reversing a key mechanism of leukemogenesis.
They added that this research paves the way for trials assessing EPZ4777 and MI-503 in patients with NPM1-mutated AML.
CHMP recommends conditional approval of drug for CLL
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion of venetoclax (Venclyxto™).
The CHMP is recommending that venetoclax receive conditional marketing authorization to treat adults with chronic lymphocytic leukemia (CLL) who have 17p deletion or TP53 mutation and are unsuitable for or have failed treatment with an inhibitor of the B-cell receptor pathway.
The CHMP is also recommending the conditional authorization of venetoclax as a treatment for adults with CLL who do not have 17p deletion or TP53 mutation but have failed both chemo immunotherapy and treatment with an inhibitor of the B-cell receptor pathway.
The European Commission (EC) will review the CHMP’s opinion and is expected to make a final decision about venetoclax in late 2016.
If the EC follows the CHMP’s recommendations, venetoclax will become the first BCL-2 inhibitor approved for use in Europe. The authorization will be valid in all member states of the European Union, as well as Iceland, Liechtenstein, and Norway.
Conditional marketing authorization represents an expedited path for approval. The EC grants conditional marketing authorization to products whose benefits are thought to outweigh their risks, products that address unmet needs, and products that are expected to provide a significant public health benefit.
Conditional marketing authorization is granted before pivotal registration studies of a product are completed, but the company developing the product is required to complete post-marketing studies showing that the product provides a clinical benefit.
Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.
Venetoclax is currently approved for use in Argentina, Canada, Puerto Rico, and the US. The drug is being evaluated in phase 3 trials for the treatment of relapsed, refractory, and previously untreated CLL.
Phase 2 trial
Results from a phase 2 trial of venetoclax in CLL (M13-982, NCT01889186) were published in The Lancet Oncology in June. The trial enrolled 107 patients with relapsed or refractory CLL and 17p deletion.
Patients received venetoclax at 400 mg once daily following a weekly ramp-up schedule for the first 5 weeks. The primary endpoint was overall response rate, as determined by an independent review committee.
At a median follow-up of 12.1 months, 85 patients had responded to treatment, for an overall response rate of 79%.
Eight patients (8%) achieved a complete response or complete response with incomplete count recovery, 3 (3%) had a near-partial response, and 74 (69%) had a partial response. Twenty-two patients (21%) did not respond.
At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival. The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.
The incidence of treatment-emergent adverse events was 96%. The most frequent grade 3/4 adverse events were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%).
The incidence of serious adverse events was 55%. The most common of these were pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%).
Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients during the ramp-up period only. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.
In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.
However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion of venetoclax (Venclyxto™).
The CHMP is recommending that venetoclax receive conditional marketing authorization to treat adults with chronic lymphocytic leukemia (CLL) who have 17p deletion or TP53 mutation and are unsuitable for or have failed treatment with an inhibitor of the B-cell receptor pathway.
The CHMP is also recommending the conditional authorization of venetoclax as a treatment for adults with CLL who do not have 17p deletion or TP53 mutation but have failed both chemo immunotherapy and treatment with an inhibitor of the B-cell receptor pathway.
The European Commission (EC) will review the CHMP’s opinion and is expected to make a final decision about venetoclax in late 2016.
If the EC follows the CHMP’s recommendations, venetoclax will become the first BCL-2 inhibitor approved for use in Europe. The authorization will be valid in all member states of the European Union, as well as Iceland, Liechtenstein, and Norway.
Conditional marketing authorization represents an expedited path for approval. The EC grants conditional marketing authorization to products whose benefits are thought to outweigh their risks, products that address unmet needs, and products that are expected to provide a significant public health benefit.
Conditional marketing authorization is granted before pivotal registration studies of a product are completed, but the company developing the product is required to complete post-marketing studies showing that the product provides a clinical benefit.
Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.
Venetoclax is currently approved for use in Argentina, Canada, Puerto Rico, and the US. The drug is being evaluated in phase 3 trials for the treatment of relapsed, refractory, and previously untreated CLL.
Phase 2 trial
Results from a phase 2 trial of venetoclax in CLL (M13-982, NCT01889186) were published in The Lancet Oncology in June. The trial enrolled 107 patients with relapsed or refractory CLL and 17p deletion.
Patients received venetoclax at 400 mg once daily following a weekly ramp-up schedule for the first 5 weeks. The primary endpoint was overall response rate, as determined by an independent review committee.
At a median follow-up of 12.1 months, 85 patients had responded to treatment, for an overall response rate of 79%.
Eight patients (8%) achieved a complete response or complete response with incomplete count recovery, 3 (3%) had a near-partial response, and 74 (69%) had a partial response. Twenty-two patients (21%) did not respond.
At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival. The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.
The incidence of treatment-emergent adverse events was 96%. The most frequent grade 3/4 adverse events were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%).
The incidence of serious adverse events was 55%. The most common of these were pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%).
Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients during the ramp-up period only. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.
In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.
However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion of venetoclax (Venclyxto™).
The CHMP is recommending that venetoclax receive conditional marketing authorization to treat adults with chronic lymphocytic leukemia (CLL) who have 17p deletion or TP53 mutation and are unsuitable for or have failed treatment with an inhibitor of the B-cell receptor pathway.
The CHMP is also recommending the conditional authorization of venetoclax as a treatment for adults with CLL who do not have 17p deletion or TP53 mutation but have failed both chemo immunotherapy and treatment with an inhibitor of the B-cell receptor pathway.
The European Commission (EC) will review the CHMP’s opinion and is expected to make a final decision about venetoclax in late 2016.
If the EC follows the CHMP’s recommendations, venetoclax will become the first BCL-2 inhibitor approved for use in Europe. The authorization will be valid in all member states of the European Union, as well as Iceland, Liechtenstein, and Norway.
Conditional marketing authorization represents an expedited path for approval. The EC grants conditional marketing authorization to products whose benefits are thought to outweigh their risks, products that address unmet needs, and products that are expected to provide a significant public health benefit.
Conditional marketing authorization is granted before pivotal registration studies of a product are completed, but the company developing the product is required to complete post-marketing studies showing that the product provides a clinical benefit.
Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.
Venetoclax is currently approved for use in Argentina, Canada, Puerto Rico, and the US. The drug is being evaluated in phase 3 trials for the treatment of relapsed, refractory, and previously untreated CLL.
Phase 2 trial
Results from a phase 2 trial of venetoclax in CLL (M13-982, NCT01889186) were published in The Lancet Oncology in June. The trial enrolled 107 patients with relapsed or refractory CLL and 17p deletion.
Patients received venetoclax at 400 mg once daily following a weekly ramp-up schedule for the first 5 weeks. The primary endpoint was overall response rate, as determined by an independent review committee.
At a median follow-up of 12.1 months, 85 patients had responded to treatment, for an overall response rate of 79%.
Eight patients (8%) achieved a complete response or complete response with incomplete count recovery, 3 (3%) had a near-partial response, and 74 (69%) had a partial response. Twenty-two patients (21%) did not respond.
At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival. The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.
The incidence of treatment-emergent adverse events was 96%. The most frequent grade 3/4 adverse events were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%).
The incidence of serious adverse events was 55%. The most common of these were pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%).
Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients during the ramp-up period only. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.
In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.
However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.